THE 2002 OFFICIAL PATIENT’S SOURCEBOOK
on
EMOPHILIA
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
ii
ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright Ó2002 by ICON Group International, Inc. Copyright Ó2002 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Tiffany LaRochelle Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher’s note: The ideas, procedures, and suggestions contained in this book are not intended as a substitute for consultation with your physician. All matters regarding your health require medical supervision. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation, in close consultation with a qualified physician. The reader is advised to always check product information (package inserts) for changes and new information regarding dose and contraindications before taking any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960The 2002 Official Patient’s Sourcebook on Hemophilia: A Revised and Updated Directory for the Internet Age/James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary and index. ISBN: 0-597-83181-5 1. Hemophilia-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem or as a substitute for consultation with licensed medical professionals. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors or authors. ICON Group International, Inc., the editors, or the authors are not responsible for the content of any Web pages nor publications referenced in this publication.
Copyright Notice If a physician wishes to copy limited passages from this sourcebook for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications are copyrighted. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs or other materials, please contact us to request permission (e-mail:
[email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this sourcebook.
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Dedication To the healthcare professionals dedicating their time and efforts to the study of hemophilia.
Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this sourcebook which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which directly or indirectly are dedicated to hemophilia. All of the Official Patient’s Sourcebooks draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this sourcebook. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany LaRochelle for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for the Official Patient’s Sourcebook series published by ICON Health Publications.
Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for the Official Patient’s Sourcebook series published by ICON Health Publications.
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About ICON Health Publications In addition to hemophilia, Official Patient’s Sourcebooks are available for the following related topics: ·
The Official Patient's Sourcebook on Immune Thrombocytopenic Purpura
·
The Official Patient's Sourcebook on Raynaud
·
The Official Patient's Sourcebook on Sickle Cell Anemia
To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
Contents vii
Table of Contents INTRODUCTION ................................................................................................................................. 1 Overview ....................................................................................................................................... 1 Organization ................................................................................................................................. 3 Scope.............................................................................................................................................. 3 Moving Forward............................................................................................................................ 4 PART I: THE ESSENTIALS ............................................................................................................. 7 CHAPTER 1. THE ESSENTIALS ON HEMOPHILIA: GUIDELINES ........................................................ 9 Overview ....................................................................................................................................... 9 What Is Hemophilia?................................................................................................................... 11 Challenges.................................................................................................................................... 12 Safety of Products Used for Treatment........................................................................................ 12 Management of the Disease ......................................................................................................... 13 Progress Toward a Cure .............................................................................................................. 14 Prospects...................................................................................................................................... 14 More Guideline Sources .............................................................................................................. 15 Vocabulary Builder...................................................................................................................... 21 CHAPTER 2. SEEKING GUIDANCE ................................................................................................... 23 Overview ..................................................................................................................................... 23 Associations and Hemophilia ...................................................................................................... 23 Finding More Associations ......................................................................................................... 34 Finding Doctors........................................................................................................................... 36 Selecting Your Doctor ................................................................................................................. 37 Working with Your Doctor ......................................................................................................... 38 Broader Health-Related Resources .............................................................................................. 39 Vocabulary Builder...................................................................................................................... 39 CHAPTER 3. CLINICAL TRIALS AND HEMOPHILIA ......................................................................... 43 Overview ..................................................................................................................................... 43 Recent Trials on Hemophilia ....................................................................................................... 46 Benefits and Risks........................................................................................................................ 51 Keeping Current on Clinical Trials ............................................................................................. 54 General References....................................................................................................................... 55 Vocabulary Builder...................................................................................................................... 56 PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL ........................... 57 CHAPTER 4. STUDIES ON HEMOPHILIA .......................................................................................... 59 Overview ..................................................................................................................................... 59 The Combined Health Information Database .............................................................................. 59 Federally-Funded Research on Hemophilia ................................................................................. 64 E-Journals: PubMed Central ....................................................................................................... 79 The National Library of Medicine: PubMed................................................................................ 79 Vocabulary Builder...................................................................................................................... 80 CHAPTER 5. PATENTS ON HEMOPHILIA ......................................................................................... 83 Overview ..................................................................................................................................... 83 Patents on Hemophilia ................................................................................................................ 84 Patent Applications on Hemophilia............................................................................................. 91 Keeping Current .......................................................................................................................... 91 Vocabulary Builder...................................................................................................................... 92 CHAPTER 6. BOOKS ON HEMOPHILIA ............................................................................................ 93 Overview ..................................................................................................................................... 93 Book Summaries: Federal Agencies ............................................................................................. 93
viii Contents
Book Summaries: Online Booksellers .......................................................................................... 96 The National Library of Medicine Book Index............................................................................. 97 Chapters on Hemophilia ............................................................................................................ 100 Directories ................................................................................................................................. 101 General Home References .......................................................................................................... 103 Vocabulary Builder.................................................................................................................... 104 CHAPTER 7. MULTIMEDIA ON HEMOPHILIA ................................................................................ 105 Overview ................................................................................................................................... 105 Video Recordings....................................................................................................................... 105 Audio Recordings ...................................................................................................................... 108 Bibliography: Multimedia on Hemophilia ................................................................................. 110 Vocabulary Builder.................................................................................................................... 112 CHAPTER 8. PERIODICALS AND NEWS ON HEMOPHILIA ............................................................. 115 Overview ................................................................................................................................... 115 News Services & Press Releases ................................................................................................ 115 Newsletters on Hemophilia........................................................................................................ 117 Newsletter Articles .................................................................................................................... 118 Academic Periodicals covering Hemophilia............................................................................... 119 CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES .............................................................. 121 Overview ................................................................................................................................... 121 NIH Guidelines ......................................................................................................................... 121 NIH Databases .......................................................................................................................... 123 Other Commercial Databases .................................................................................................... 130 The Genome Project and Hemophilia ........................................................................................ 131 Specialized References ............................................................................................................... 135 Vocabulary Builder.................................................................................................................... 136 PART III. APPENDICES .............................................................................................................. 137 APPENDIX A. RESEARCHING YOUR MEDICATIONS ..................................................................... 139 Overview ................................................................................................................................... 139 Your Medications: The Basics ................................................................................................... 140 Learning More about Your Medications ................................................................................... 141 Commercial Databases............................................................................................................... 142 Researching Orphan Drugs....................................................................................................... 143 Contraindications and Interactions (Hidden Dangers)............................................................. 145 A Final Warning ....................................................................................................................... 146 General References..................................................................................................................... 147 APPENDIX B. RESEARCHING NUTRITION ..................................................................................... 149 Overview ................................................................................................................................... 149 Food and Nutrition: General Principles .................................................................................... 150 Finding Studies on Hemophilia................................................................................................. 154 Federal Resources on Nutrition................................................................................................. 155 Additional Web Resources......................................................................................................... 156 Vocabulary Builder.................................................................................................................... 157 APPENDIX C. FINDING MEDICAL LIBRARIES ............................................................................... 159 Overview ................................................................................................................................... 159 Preparation ................................................................................................................................ 159 Finding a Local Medical Library ............................................................................................... 160 Medical Libraries Open to the Public ........................................................................................ 160 APPENDIX D. NIH CONSENSUS STATEMENT ON FRESH FROZEN PLASMA ................................ 167 Overview ................................................................................................................................... 167 Fresh Frozen Plasma: Indications and Risks ............................................................................. 168 Panel’s Conclusions................................................................................................................... 169 What Are the Currently Recommended Clinical Indications for FFP?..................................... 169
Contents
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Risks of FFP............................................................................................................................... 171 What Alternative Therapies Exist? ........................................................................................... 171 Current Scientific Knowledge Regarding the Effectiveness of FFP........................................... 172 Directions for Future Research.................................................................................................. 173 Vocabulary Builder.................................................................................................................... 174 APPENDIX E. NIH CONSENSUS STATEMENT ON INFECTIOUS DISEASE TESTING FOR BLOOD TRANSFUSIONS .............................................................................................................................. 175 Overview ................................................................................................................................... 175 Abstract ..................................................................................................................................... 176 What Is Infectious Disease Testing for Blood Transfusions? .................................................... 177 Background for the Role of ALT and Anti-HBc Testing ........................................................... 179 Do Tests for Hepatitis B Core Antibody and for Syphilis Contribute to Transfusion Safety? . 182 Transfusion Safety..................................................................................................................... 185 What Are the Highest Priorities for Research? ......................................................................... 188 Conclusions ............................................................................................................................... 189 ONLINE GLOSSARIES ............................................................................................................... 191 Online Dictionary Directories................................................................................................... 192 HEMOPHILIA GLOSSARY ........................................................................................................ 193 General Dictionaries and Glossaries ......................................................................................... 204 INDEX.............................................................................................................................................. 206
Introduction
1
INTRODUCTION Overview Dr. C. Everett Koop, former U.S. Surgeon General, once said, “The best prescription is knowledge.”1 The Agency for Healthcare Research and Quality (AHRQ) of the National Institutes of Health (NIH) echoes this view and recommends that every patient incorporate education into the treatment process. According to the AHRQ: Finding out more about your condition is a good place to start. By contacting groups that support your condition, visiting your local library, and searching on the Internet, you can find good information to help guide your treatment decisions. Some information may be hard to find—especially if you don’t know where to look.2 As the AHRQ mentions, finding the right information is not an obvious task. Though many physicians and public officials had thought that the emergence of the Internet would do much to assist patients in obtaining reliable information, in March 2001 the National Institutes of Health issued the following warning: The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.3
Quotation from http://www.drkoop.com. The Agency for Healthcare Research and Quality (AHRQ): http://www.ahcpr.gov/consumer/diaginfo.htm. 3 From the NIH, National Cancer Institute (NCI): http://cancertrials.nci.nih.gov/beyond/evaluating.html. 1 2
2
Hemophilia
Since the late 1990s, physicians have seen a general increase in patient Internet usage rates. Patients frequently enter their doctor’s offices with printed Web pages of home remedies in the guise of latest medical research. This scenario is so common that doctors often spend more time dispelling misleading information than guiding patients through sound therapies. The Official Patient’s Sourcebook on Hemophilia has been created for patients who have decided to make education and research an integral part of the treatment process. The pages that follow will tell you where and how to look for information covering virtually all topics related to hemophilia, from the essentials to the most advanced areas of research. The title of this book includes the word “official.” This reflects the fact that the sourcebook draws from public, academic, government, and peerreviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on hemophilia. Given patients’ increasing sophistication in using the Internet, abundant references to reliable Internet-based resources are provided throughout this sourcebook. Where possible, guidance is provided on how to obtain free-ofcharge, primary research results as well as more detailed information via the Internet. E-book and electronic versions of this sourcebook are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). Hard copy users of this sourcebook can type cited Web addresses directly into their browsers to obtain access to the corresponding sites. Since we are working with ICON Health Publications, hard copy Sourcebooks are frequently updated and printed on demand to ensure that the information provided is current. In addition to extensive references accessible via the Internet, every chapter presents a “Vocabulary Builder.” Many health guides offer glossaries of technical or uncommon terms in an appendix. In editing this sourcebook, we have decided to place a smaller glossary within each chapter that covers terms used in that chapter. Given the technical nature of some chapters, you may need to revisit many sections. Building one’s vocabulary of medical terms in such a gradual manner has been shown to improve the learning process. We must emphasize that no sourcebook on hemophilia should affirm that a specific diagnostic procedure or treatment discussed in a research study, patent, or doctoral dissertation is “correct” or your best option. This sourcebook is no exception. Each patient is unique. Deciding on appropriate
Introduction
3
options is always up to the patient in consultation with their physician and healthcare providers.
Organization This sourcebook is organized into three parts. Part I explores basic techniques to researching hemophilia (e.g. finding guidelines on diagnosis, treatments, and prognosis), followed by a number of topics, including information on how to get in touch with organizations, associations, or other patient networks dedicated to hemophilia. It also gives you sources of information that can help you find a doctor in your local area specializing in treating hemophilia. Collectively, the material presented in Part I is a complete primer on basic research topics for patients with hemophilia. Part II moves on to advanced research dedicated to hemophilia. Part II is intended for those willing to invest many hours of hard work and study. It is here that we direct you to the latest scientific and applied research on hemophilia. When possible, contact names, links via the Internet, and summaries are provided. It is in Part II where the vocabulary process becomes important as authors publishing advanced research frequently use highly specialized language. In general, every attempt is made to recommend “free-to-use” options. Part III provides appendices of useful background reading for all patients with hemophilia or related disorders. The appendices are dedicated to more pragmatic issues faced by many patients with hemophilia. Accessing materials via medical libraries may be the only option for some readers, so a guide is provided for finding local medical libraries which are open to the public. Part III, therefore, focuses on advice that goes beyond the biological and scientific issues facing patients with hemophilia.
Scope While this sourcebook covers hemophilia, your doctor, research publications, and specialists may refer to your condition using a variety of terms. Therefore, you should understand that hemophilia is often considered a synonym or a condition closely related to the following: ·
AHF Deficiency
·
AHG Deficiency
·
Antihemophilic Factor Deficiency
4
Hemophilia
·
Antihemophilic Globulin Deficiency
·
Christmas Disease
·
Classic Hemophilia
·
Classical Hemophilia
·
Factor Ix Deficiency
·
Factor Ix Hemophilia
·
Factor Viii Deficiency
·
Factor Viii Deficiency Hemophilia
·
Hemophilia A
·
Hemophilia A: Classic Hemophilia
·
Hemophilia B
·
Hemophilia B: Christmas Disease
In addition to synonyms and related conditions, physicians may refer to hemophilia using certain coding systems. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) is the most commonly used system of classification for the world’s illnesses. Your physician may use this coding system as an administrative or tracking tool. The following classification is commonly used for hemophilia:4 ·
286.0 hemophilia a
·
286.1 hemophilia b
For the purposes of this sourcebook, we have attempted to be as inclusive as possible, looking for official information for all of the synonyms relevant to hemophilia. You may find it useful to refer to synonyms when accessing databases or interacting with healthcare professionals and medical librarians.
Moving Forward Since the 1980s, the world has seen a proliferation of healthcare guides covering most illnesses. Some are written by patients or their family members. These generally take a layperson’s approach to understanding and 4 This list is based on the official version of the World Health Organization’s 9th Revision, International Classification of Diseases (ICD-9). According to the National Technical Information Service, “ICD-9CM extensions, interpretations, modifications, addenda, or errata other than those approved by the U.S. Public Health Service and the Health Care Financing Administration are not to be considered official and should not be utilized. Continuous maintenance of the ICD-9-CM is the responsibility of the federal government.”
Introduction
5
coping with an illness or disorder. They can be uplifting, encouraging, and highly supportive. Other guides are authored by physicians or other healthcare providers who have a more clinical outlook. Each of these two styles of guide has its purpose and can be quite useful. As editors, we have chosen a third route. We have chosen to expose you to as many sources of official and peer-reviewed information as practical, for the purpose of educating you about basic and advanced knowledge as recognized by medical science today. You can think of this sourcebook as your personal Internet age reference librarian. Why “Internet age”? All too often, patients diagnosed with hemophilia will log on to the Internet, type words into a search engine, and receive several Web site listings which are mostly irrelevant or redundant. These patients are left to wonder where the relevant information is, and how to obtain it. Since only the smallest fraction of information dealing with hemophilia is even indexed in search engines, a non-systematic approach often leads to frustration and disappointment. With this sourcebook, we hope to direct you to the information you need that you would not likely find using popular Web directories. Beyond Web listings, in many cases we will reproduce brief summaries or abstracts of available reference materials. These abstracts often contain distilled information on topics of discussion. While we focus on the more scientific aspects of hemophilia, there is, of course, the emotional side to consider. Later in the sourcebook, we provide a chapter dedicated to helping you find peer groups and associations that can provide additional support beyond research produced by medical science. We hope that the choices we have made give you the most options available in moving forward. In this way, we wish you the best in your efforts to incorporate this educational approach into your treatment plan. The Editors
7
PART I: THE ESSENTIALS
ABOUT PART I Part I has been edited to give you access to what we feel are “the essentials” on hemophilia. The essentials of a disease typically include the definition or description of the disease, a discussion of who it affects, the signs or symptoms associated with the disease, tests or diagnostic procedures that might be specific to the disease, and treatments for the disease. Your doctor or healthcare provider may have already explained the essentials of hemophilia to you or even given you a pamphlet or brochure describing hemophilia. Now you are searching for more in-depth information. As editors, we have decided, nevertheless, to include a discussion on where to find essential information that can complement what your doctor has already told you. In this section we recommend a process, not a particular Web site or reference book. The process ensures that, as you search the Web, you gain background information in such a way as to maximize your understanding.
Guidelines
CHAPTER 1. GUIDELINES
THE
ESSENTIALS
ON
9
HEMOPHILIA:
Overview Official agencies, as well as federally-funded institutions supported by national grants, frequently publish a variety of guidelines on hemophilia. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. The great advantage of guidelines over other sources is that they are often written with the patient in mind. Since new guidelines on hemophilia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
The National Institutes of Health (NIH)5 The National Institutes of Health (NIH) is the first place to search for relatively current patient guidelines and fact sheets on hemophilia. Originally founded in 1887, the NIH is one of the world’s foremost medical research centers and the federal focal point for medical research in the United States. At any given time, the NIH supports some 35,000 research grants at universities, medical schools, and other research and training institutions, both nationally and internationally. The rosters of those who have conducted research or who have received NIH support over the years include the world’s most illustrious scientists and physicians. Among them are 97 scientists who have won the Nobel Prize for achievement in medicine.
5
Adapted from the NIH: http://www.nih.gov/about/NIHoverview.html.
10 Hemophilia
There is no guarantee that any one Institute will have a guideline on a specific disease, though the National Institutes of Health collectively publish over 600 guidelines for both common and rare diseases. The best way to access NIH guidelines is via the Internet. Although the NIH is organized into many different Institutes and Offices, the following is a list of key Web sites where you are most likely to find NIH clinical guidelines and publications dealing with hemophilia and associated conditions: ·
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
·
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines available at http://www.nlm.nih.gov/medlineplus/healthtopics.html
·
National Heart, Lung, and Blood Institute (NHLBI); guidelines at http://www.nhlbi.nih.gov/guidelines/index.htm
Among these, the National Heart, Lung, and Blood Institute (NHLBI) is particularly noteworthy. The NHLBI provides leadership for a national program in diseases of the heart, blood vessels, lung, and blood; blood resources; and sleep disorders.6 Since October 1997, the NHLBI has also had administrative responsibility for the NIH Woman’s Health Initiative. The Institute plans, conducts, fosters, and supports an integrated and coordinated program of basic research, clinical investigations and trials, observational studies, and demonstration and education projects. Research is related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The NHLBI plans and directs research in development and evaluation of interventions and devices related to prevention, treatment, and rehabilitation of patients suffering from such diseases and disorders. It also supports research on clinical use of blood and all aspects of the management of blood resources. Research is conducted in the Institute’s own laboratories and by scientific institutions and individuals supported by research grants and contracts. For health professionals and the public, the NHLBI conducts educational activities, including development and dissemination of materials in the above areas, with an emphasis on prevention. Within the NHLBI, the Division of Blood Diseases and Resources (DBDR) plans, directs, and evaluates the Institute’s programs in hematology, hematologic diseases (except malignancies of the blood), and immunologic and other disorders of white blood cells, transfusion medicine, blood This paragraph has been adapted from the NHLBI: http://www.nhlbi.nih.gov/about/org/mission.htm. “Adapted” signifies that a passage is reproduced exactly or slightly edited for this book. 6
Guidelines 11
resources, and marrow and stem cell transplantation.7 These programs include basic research, prevention, applied research and development, clinical trials, education, demonstration, and control activities. The Division monitors current activities and national needs and seeks to develop and support research into the causes, prevention, diagnosis, and treatment of diseases of the blood. Research on the use of blood and blood components in the treatment and prevention of diseases and the management of the nation’s blood resources and transplantable tissue are also supported. A variety of support mechanisms are utilized, including research grants, contracts, cooperative agreements, centers, grants, career development awards, fellowships, and research training grants. Two programs comprise the DBDR: the Blood Diseases Program and the Blood Resources Program. The following patient guideline was recently published by the NHLBI and the DBDR on hemophilia.
What Is Hemophilia?8 Hemophilia is the oldest known hereditary bleeding disorder. There are two types of hemophilia, A and B (Christmas Disease). Both are caused by low levels or complete absence of a blood protein essential for clotting. Patients with hemophilia A lack the blood clotting protein, factor VIII, and those with hemophilia B lack factor IX. There are about 20,000 hemophilia patients in the United States. Each year, about 400 babies are born with this disorder. Approximately 85% have hemophilia A and the remainder have hemophilia B. The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia A patients have less than one percent of the normal amount and, thus, have severe hemophilia. A small increase in the blood level of the clotting factor, up to five percent of normal, results in mild hemophilia with rare bleeding except after injuries or surgery. Enormous strides made in assuring the safety of the blood supply and in the genetic aspects of hemophilia research allow us now to focus on issues which will improve the quality of life of the hemophilia patient and, ultimately, develop a cure.
7 This paragraph has been adapted from the DBDR: http://www.nhlbi.nih.gov/about/dbdr/index.htm. For more information, contact: Division of Blood Diseases and Resources; The National Heart, Lung and Blood Institute; ATTN: Web Site Inquiries; Two Rockledge Center, Suite 10138; 6701 Rockledge Dr., MSC 7950; Bethesda, Maryland 20892-7950. 8 Adapted from the National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/health/public/blood/other/hemophel.htm.
12 Hemophilia
Challenges The most important challenges facing the hemophilia patient, health care provider, and research community today are: ·
Safety of products used for treatment
·
Management of the disease including inhibitor formation, irreversible joint damage, and life-threatening hemorrhage
·
Progress toward a cure
Safety of Products Used for Treatment In the past 10 to 15 years, advances in screening of blood donors, laboratory testing of donated blood, and techniques to inactivate viruses in blood and blood products have remarkably increased the safety of blood products used to treat hemophilia. Although treatment-related infection with the AIDS virus or most of the hepatitis viruses is a thing of the past, these measures do not completely avoid viruses such as hepatitis A and parvo virus. These infections are rare; nevertheless, they can pose a threat. Researchers are working to improve procedures to destroy these viruses. There is a great deal of concern about Creutzfeldt-Jakob disease (CJD), a rare transmissible nervous system disease that is inevitably fatal, being transmitted through transfusion. The infection of many hemophilia patients with the AIDS virus before the virus was discovered has elicited a great deal of concern in the hemophilia community about CJD and its potential transmission through blood-derived treatment products. A disorder related to CJD, bovine spongiforme encephalopathy or “mad cow disease”, and its suspected relationship to an especially severe form of CJD, has generated considerable interest recently in Britain. No one has ever detected the transmission of CJD disease through blood or blood products, although a number of CJD victims have been blood donors, even within weeks of coming down with the disease. Collaborative studies are underway by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to determine, in experimental animals, if the CJD agent(s) can be transmitted by blood. To ensure absolute safety from transfusion-transmitted viruses and other agents, hemophiliacs may now be treated with factor VIII which has been produced through biotechnology. This product, recombinant factor VIII, is manufactured by a process entirely free of blood products. It, thus, contains
Guidelines 13
only the factor VIII necessary to treat the disease and none of the other components of blood or attendant unwanted agents. Although the cost of this product exceeds that of the blood-derived product, it is clearly the treatment of choice for those, such as newborns, who have not yet been exposed to blood products. A factor IX product has also been produced by such a process and is currently in clinical trials. Once this product is shown to be safe and effective, all hemophiliacs will have available a treatment for bleeding which is totally free of any contaminating agents.
Management of the Disease While current treatment has greatly improved the outlook for most hemophiliacs, the development of antibodies (inhibitors) that block the activity of the clotting factors has complicated treatment for some patients. Approximately 15 percent of severe hemophilia A patients and 2.5 percent of hemophilia B patients develop such antibodies after exposure to transfused factors. When inhibitors are present in large amounts, the patient may require very high and expensive quantities of transfused clotting factors to stem bleeding, and, in some instances, even that may not be effective. The factor VIII products produced through biotechnology have been found to cause inhibitors in only about 5 percent of patients and are, thus, safer in this respect. Nevertheless, these inhibiting antibodies will remain a concern for hemophilia patients unless our ability to understand and control the immune system is improved. A number of NHLBI-supported scientists are directing research at this problem. The major cause of disability in hemophilia patients is chronic joint disease “arthropathy” - caused by uncontrolled bleeding into the joints. Lifethreatening hemorrhage is a constant risk. Traditional treatment of hemophilia in the United States has involved “on-demand” treatment, meaning that patients are treated with factor replacement only after bleeding symptoms are recognized. These bleeds ultimately result in severely impaired joints. Several European countries are treating hemophiliacs by periodic infusion (prophylaxis) regardless of bleeding status. This approach maintains the factor level high enough that bleeding, joint destruction, and life-threatening hemorrhage are almost entirely avoided. There are, nevertheless, serious disadvantages such as the need for frequent infusions, the requirement for almost continuous access to veins by catheters, and the considerable cost of factor. In the United States, it is estimated that most patients on prophylaxis which is begun in the first few years of life will easily exceed the common life-time insurance cap of $1,000,000 by the second decade of life. The treatment decisions are not easy ones.
14 Hemophilia
Progress Toward a Cure Although treatment for hemophilia has become safer, therapeutic products are still not risk free. The ultimate goal is to offer a cure for the disease. Hemophilia is known to be caused by defects in the genes for factor VIII and factor IX. The challenge is to transfer normal genes into a patient so that they will produce the normal clotting protein. A small amount of active factor produced by the patient’s own body will correct the disease. Although much remains to be studied before such treatment can be offered to patients, there have been a number of studies done in animals such as mice and dogs in which a factor VIII or IX gene has been inserted and has produced the proper blood product for periods that exceed one year. Major issues that remain to be resolved include the low level of production of the clotting factor, reduction of immune reactions that stop the production after a period, and development of ways to insert the gene directly into the body without manipulating cells outside the body. Until recently, dogs with naturally occurring hemophilia were used for testing of gene therapy techniques; however, the number of such animals is very limited. Recently, a mouse model of hemophilia produced through genetic technology was announced. The availability of this small animal will accelerate the development of technologies for ultimate use in humans.
Prospects It is clear that tremendous progress has been made to reduce the exposure of hemophilia patients to transfusion-transmitted disease through making the blood supply safer and by providing replacement products from sources not involving blood. However, concern remains for hemophiliacs still dependent on blood products and the threat of agents which may contaminate the blood supply and are not avoided or inactivated with currently available techniques. It is also known from international studies that crippling joint involvement can be avoided through periodic and regular transfusion. The expense, danger of indwelling catheters, and inconvenience of the treatment regimen are all negative factors. All of these issues will become less important, even irrelevant, if the disease can be cured. At the present time, there are sufficient indications that gene therapy will ultimately be this cure. The technology for gene therapy is not as simple as was first thought. Yet because of its special characteristics, hemophilia will likely be among the first genetic diseases to be successfully treated.
Guidelines 15
More Guideline Sources The guideline above on hemophilia is only one example of the kind of material that you can find online and free of charge. The remainder of this chapter will direct you to other sources which either publish or can help you find additional guidelines on topics related to hemophilia. Many of the guidelines listed below address topics that may be of particular relevance to your specific situation or of special interest to only some patients with hemophilia. Due to space limitations these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly.
Topic Pages: MEDLINEplus For patients wishing to go beyond guidelines published by specific Institutes of the NIH, the National Library of Medicine has created a vast and patientoriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages.” You can think of a health topic page as a guide to patient guides. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. If you do not find topics of interest when browsing health topic pages, then you can choose to use the advanced search utility of MEDLINEplus at http://www.nlm.nih.gov/medlineplus/advancedsearch.html. This utility is similar to the NIH Search Utility, with the exception that it only includes material linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.
The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on hemophilia and related conditions. One of the advantages of CHID over other sources is that it offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. Go to http://chid.nih.gov/detail/detail.html to search
16 Hemophilia
this database,. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: ·
National Hemophilia Foundation: The Tex Cen Chapter Source: (n.d.). Contact: National Hemophilia Foundation Texas Central Chapter, 2995 LBJ Fwy, Ste. 128, Dallas, TX 75234. (214) 484-8860. Summary: This brochure describes hemophilia, which is a genetic disease; treatment programs for hemophiliacs; activities of the National Hemophilia Foundation; and suggestions for community support. Hemophiliacs who received blood clotting factor before 1985 are at high risk of exposure to Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS).
·
AIDS and Hemophilia: What Everyone Needs to Know. Source: 1989. Contact: National Hemophilia Foundation Northern California Chapter, 7700 Edgewater Dr., Ste. 710, Oakland, CA 94621-3017. (510) 568-NCHF. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure is directed to the hemophiliacs who were infected with the Human immunodeficiency (HIV) virus on receiving blood or blood products before 1985, when the blood supply was not protected. A history of the symptomology of HIV infection is given and how it can develop into Acquired immunodeficiency syndrome (AIDS). A checklist of HIV-infection symptoms is given against which health status can be measured.
·
Questions and Answers About HIV and AIDS for Young People With Hemophilia Source: 1987. Contact: Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53213-0127. (414) 257-0200. Approximate price range per copy: Under $5. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure provides young hemophiliacs with information on Acquired immunodeficiency syndrome (AIDS) and Human
Guidelines 17
immunodeficiency virus (HIV), including forms of transmission and preventive measures. It explains the meaning of positive results on the HIV-antibody test. ·
Encounters with AIDS: Women, hemophilia, and HIV Source: Princeton, NJ: CSG Enterprises. 1990. 6 v. Contact: Available from Librarian, National Center for Education in Maternal and Child Health, 2000 15th Street, North, Suite 701, Arlington, VA 22201-2617. Telephone: (703) 524-7802 / fax: (703) 524- 9335 / e-mail:
[email protected] / Web site: http://www.ncemch.org. Available for loan. Summary: This set of six booklets is a structured role play simulation designed to increase participants' ability to communicate about difficult topics. It presents 20 situations that are frequently described in counseling sessions, and guides Speaker A and Speaker B through a simulated discussion of the problem. Other participants are a group leader, an advisor to Speaker A and an advisor to Speaker B. A separate booklet is provided for each participant. The sixth booklet is an operator's manual. The operator's manual provides an overview of the program, practical considerations, running the simulation, and leading the discussion. The program was sponsored by the U.S. Office of Maternal and Child Health Hemophilia Program. [Funded by the Maternal and Child Health Bureau].
·
Health Insurance Options for Persons With Hemophilia and HIV / ARC / AIDS Source: 1991. Contact: Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53213-0127. (414) 257-0200. 40 cents, plus postage, in 4/92. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure provides insurance information to hemophiliacs, particularly those infected with HIV/AIDS. Healthinsurance options and assistance programs that may provide health benefits are listed and briefly described.
·
Questions and Answers About HIV and AIDS for the Parents of Young People With Hemophilia. Preguntas y Respuestas Acerca del HIV y el SIDA Para los Padres de Ninos Hemofilicos Source: 1991.
18 Hemophilia
Contact: Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53213-0127. (414) 257-0200. Price: 40 cents, plus postage, in 4/92. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure asks and answers questions about AIDS and hemophilia. It explains how HIV contaminated the blood supply and infected persons with hemophilia, and outlines the relationship between HIV infection and AIDS. The brochure studies the emotional factors that affect adolescents or young adults with hemophilia and HIV infection, in particular addressing their fear of the diagnosis. Young persons who may have been exposed to HIV should take the HIV-antibody test and should be warned about the possibility of passing on the infection through sexual intercourse. However, the myth of casual contact transmission is dispelled. ·
Living With HIV: For Adolescents With Hemophilia Source: 1990. Contact: Hemophilia and AIDS Network for the Dissemination of Information National Hemophilia Foundation, 116 W. 32nd St., Fl. 11, New York, NY 10001-3212. (212) 328-3700. www.hemophilia.org. Summary: This brochure answers questions about HIV that might be asked by adolescents with hemophilia. The brochure discusses symptoms of AIDS, modes of HIV transmission, the HIV-antibody test, studies regarding casual contact transmission, and the need for sexually active adolescents to engage in safer sexual conduct. Other issues that are explored include AIDS-related discrimination, the benefits and drawbacks of informing schools of seropositive results, infection-control procedures, health practices for HIV-positive persons, and available treatment programs.
·
Provider Packet on Adolescent HIV / AIDS Medical Management Source: 1995. Contact: A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This information package provides information about the medical management of adolescents with HIV infection. The articles cover the epidemiology of adolescent infection, HIV-antibody testing, medical treatment, clinical trials, psychosocial issues, sexually
Guidelines 19
transmitted diseases (STDs), and risk assessment and reduction. Specific issues addressed include condom use, males who have sex with males, lesbian youth, heterosexual females, runaway and homeless youth, and sexual abuse. Substance use, hemophilia and blood transfusions, and congenitally-infected adolescents are also discussed. A health risk questionnaire is detailed, which provides information on sexual history, sexual behaviors, and drug use behaviors. An order form for a book aimed at the adolescent reader, which candidly discusses these issues, is included. ·
What You Should Know About Hemophilia Source: 1988. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure gives detailed information about hemophilia. It mentions that many persons with hemophilia became infected with the Human immunodeficiency virus (HIV) through blood transfusions.
The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search their site located at http://www.guideline.gov by using the keyword “hemophilia” or synonyms.
Healthfinder™ Healthfinder™ is an additional source sponsored by the U.S. Department of Health and Human Services which offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines.
20 Hemophilia
The NIH Search Utility After browsing the references listed at the beginning of this chapter, you may want to explore the NIH Search Utility. This allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEBSPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to hemophilia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.
NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing, for a nominal fee, short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is www.rarediseases.org. To see if a recent fact sheet has been published on hemophilia, simply go to http://www.rarediseases.org/cgi-bin/nord/alphalist. A complete guide on hemophilia can be purchased from NORD for a nominal fee. Additional Web Sources A number of Web sites that often link to government sites are available to the public. These can also point you in the direction of essential information. The following is a representative sample: ·
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
·
drkoop.comÒ: http://www.drkoop.com/conditions/ency/index.html
·
Family Village: http://www.familyvillage.wisc.edu/specific.htm
·
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
·
Med Help International: http://www.medhelp.org/HealthTopics/A.html
·
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
Guidelines 21
·
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
·
WebMDÒHealth: http://my.webmd.com/health_topics
Vocabulary Builder The material in this chapter may have contained a number of unfamiliar words. The following Vocabulary Builder introduces you to terms used in this chapter that have not been covered in the previous chapter: Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]
Anthropology: The science devoted to the comparative study of man. [NIH] Antibodies: Specific proteins produced by the body's immune system that bind with foreign proteins (antigens). [NIH] Antibody: An immunoglobulin molecule that has a specific amino acid sequence by virtue of which it interacts only with the antigen that induced its synthesis in cells of the lymphoid series (especially plasma cells), or with antigen closely related to it. Antibodies are classified according to their ode of action as agglutinins, bacteriolysins, haemolysins, opsonins, precipitins, etc. [EU] Arthropathy: Any joint disease. [EU] Catheter: Thin, flexible medical tube; one use is to insert it into a blood vessel to measure blood pressure. [NIH] Cell: Basic subunit of every living organism; the simplest unit that can exist as an independent living system. [NIH] Chronic: Of long duration; frequently recurring. [NIH] Encephalopathy: Any degenerative disease of the brain. [EU] Fatal: Causing death, deadly; mortal; lethal. [EU] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatitis: Inflammation of the liver. [EU] Infusion: The therapeutic introduction of a fluid other than blood, as saline solution, solution, into a vein. [EU] Neonatology:
A subspecialty of Pediatrics concerned with the newborn
22 Hemophilia
infant. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Prophylaxis: The prevention of disease; preventive treatment. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]
Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Transfusion: The introduction of whole blood or blood component directly into the blood stream. [EU] Transplantation: The grafting of tissues taken from the patient's own body or from another. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viruses: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. [NIH]
Seeking Guidance 23
CHAPTER 2. SEEKING GUIDANCE Overview Some patients are comforted by the knowledge that a number of organizations dedicate their resources to helping people with hemophilia. These associations can become invaluable sources of information and advice. Many associations offer aftercare support, financial assistance, and other important services. Furthermore, healthcare research has shown that support groups often help people to better cope with their conditions.9 In addition to support groups, your physician can be a valuable source of guidance and support. Therefore, finding a physician that can work with your unique situation is a very important aspect of your care. In this chapter, we direct you to resources that can help you find patient organizations and medical specialists. We begin by describing how to find associations and peer groups that can help you better understand and cope with hemophilia. The chapter ends with a discussion on how to find a doctor that is right for you.
Associations and Hemophilia As mentioned by the Agency for Healthcare Research and Quality, sometimes the emotional side of an illness can be as taxing as the physical side.10 You may have fears or feel overwhelmed by your situation. Everyone has different ways of dealing with disease or physical injury. Your attitude, your expectations, and how well you cope with your condition can all Churches, synagogues, and other houses of worship might also have groups that can offer you the social support you need. 10 This section has been adapted from http://www.ahcpr.gov/consumer/diaginf5.htm. 9
24 Hemophilia
influence your well-being. This is true for both minor conditions and serious illnesses. For example, a study on female breast cancer survivors revealed that women who participated in support groups lived longer and experienced better quality of life when compared with women who did not participate. In the support group, women learned coping skills and had the opportunity to share their feelings with other women in the same situation. In addition to associations or groups that your doctor might recommend, we suggest that you consider the following list (if there is a fee for an association, you may want to check with your insurance provider to find out if the cost will be covered): ·
AIDS Project National Institute of Child Health and Human Development National Institutes of Health Public Health Service U.S. Department of Health and Human Services Address: 9000 Rockville Pike, Bldg. 31, Rm. 2A18 Bethesda, MD 20892 Telephone: (301) 496-1877 Fax: (301) 496-0588 Web Site: http://www.nichd.nih.gov/default.htm Background: The National Institute of Child Health And Human Development (NICHD) supports 70 research projects that primarily address maternal, pediatric, childhood, and adolescent AIDS issues. Highlights of current NICHD AIDS research activities include: 1) A multicenter contract to research therapeutic agents to treat HIV infection and its sequelae; 2) a study of the natural history of vertically transmitted HIV infection; 3) a collaborative agency project to study the impact of HIV infection on children with hemophilia; 4) new techniques for early diagnosis of HIV infection in infants and children; 5) a study of the seroprevalence of HIV infection in childbearing women; 6) investigation of the reproductive tract cells involved in the infectivity process; 7) a project to determine the relationship among diarrhea, poor growth, the occurrence of enteric infection, immunologic dysfunction, diminished caloric intake, and nutrient malabsorption in children infected with HIV; 8) a study of human milk to assess the risk factors associated with perinatal infection; 9) funding to develop an archive of data sets that contain social and behavioral science data relevant to the study of STDs and HIV/AIDS; 10) cooperative agreements to address interventions and evaluations aimed at decreasing STDs and HIV infection among minority youth; 11) assessment of condoms for prevention of heterosexual transmission of HIV; 12) continuing projects and an RFA supporting social and behavioral research on AIDS prevention in developing countries and in the US; 13) an RFA to address questions relating to the
Seeking Guidance 25
relationship between STDs, including AIDS, and fertility-related behavior. Relevant area(s) of interest: Child health; Healthcare; HIV/AIDS; STDs ·
American Blood Resources Association Address: 147 Old Solomon's Island Rd. Annapolis, MD 21401 Telephone: (410) 263-8296 Fax: (410) 263-2298 Web Site: http://www.plasmainfo.org/abra Background: The American Blood Resources Association (ABRA) represents companies worldwide that are involved in the collection, manufacture, or distribution of blood or plasma for further manufacture. ABRA's membership consists of nearly every company in the world who collects or purchases plasma for further manufacture purposes. ABRA members collect nearly 100% of the commercial supply of Source Plasma. Source Plasma is used to manufacture human plasma based therapies for immune disorders, shock and surgery patients, hemophilia, hepatitis, measles, rabies, rubella, tetanus, burn victims, and many more. Relevant area(s) of interest: Blood and lymphatic diseases; Blood banks
·
American Society of Hematology Address: 1900 M St. NW, Suite 200 Washington, DC 20036 Telephone: (202) 776-0544 Fax: (202) 857-1164 Email:
[email protected] Web Site: http://www.hematology.org Background: The American Society of Hematology represents over 9,500 clinicians and scientists committed to promoting the exchange of information and ideas relating to blood, blood-forming tissues, and blood diseases. ASH was founded in April 1958 by 150 hematologists who met in Boston in response to the need for a forum to discuss clinical and research matters related to blood and blood diseases and has served as a forum for bringing together those involved in the broad array of sciences that impinge upon blood. The Society has played an active role in the development of hematology as a discipline through bringing together clinicians and scientists and establishing standards for certification. Publication(s): ASH News (Newsletter); Blood (Journal of ASH).
26 Hemophilia
Relevant area(s) of interest: Anemia; Blood disease; Hematology; Hemophilia; HIV/AIDS; Leukemia; Lymphoma; Oncology ·
Canadian Hemophilia Society Address: Canadian Hemophilia Society 625 President Kennedy, Suite 1210, Montreal, Quebec, H3A 1K2, Canada Telephone: (514) 848-0503 Toll-free: (800) 668-2686 Fax: (514) 848-9661 Email:
[email protected] Background: The Canadian Hemophilia Society (CHS) is a registered charity dedicated to improving the quality of life for all persons with hemophilia and other inherited bleeding disorders. Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enable the blood to clot. Hemophilia may be classified as mild, moderate, or severe. The level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. CHS was established in 1953 and its goals and objectives are to assure that all persons with hemophilia have ready access to the highest possible level of care; assure that the hemophilia community is made aware of issues that affect every aspect of hemophilia and that the general public be informed on matters deemed appropriate; initiate and promote research that will continue to improve care and result in a cure for hemophilia; encourage peer support and social interaction among the hemophilia community; assist persons with hemophilia in being aware of their rights and ensure that no discrimination occurs; and assist persons with hemophilia living in third world countries to improve their quality of care. CHS publishes a quarterly newsletter entitled 'Hemophilia Today' in both English and French. An extensive list of educational material includes 'Helping Others Is In Our Blood - Canadian Hemophilia Society,' 'We're All Related By Blood,' 'What You Should Know About Blood Transfusion,' 'Hemophilia In Perspective,' and 'A Vision of Comprehensive Care for Persons with Inherited Bleeding Disorders.' All materials are available in both English and French. Relevant area(s) of interest: AHF Deficiency, AHG Deficiency, Antihemophilic Factor Deficiency, Antihemophilic Globulin Deficiency, Classical Hemophilia, Factor VIII Deficiency, Hemophilia, Hemophilia A
Seeking Guidance 27
·
Children's Blood Foundation Address: Children's Blood Foundation 333 East 38th Street, Room 830, New York, NY 10016-2745 Telephone: (212) 297-433 Fax: (212) 297-4340 Email:
[email protected] Background: The Children's Blood Foundation (CBF) is a nonprofit organization dedicated to promoting and/or supporting research, medical training of physicians, and care of children with leukemia, thalassemia, hemophilia, anemia, cancer, immune disorders, and AIDS. Established in 1952, the CBF has the largest hemophilia center in the New York area and the largest thalassemia center in North America, receiving more than 5,000 patient visits every year. All affected children are served, regardless of the family's ability to pay. Educational materials include a self-titled brochure, a regular newsletter entitled 'The Key to Life for a Child,' and a booklet entitled 'What's It Called Again? - Answers to the Most Commonly Asked Questions About Idiopathic Thrombocytopenic Purpura (ITP) In Children.' CBF has support groups, offers networking services, and engages in educational activities. Relevant area(s) of interest: Hemophilia
·
Committee of Ten Thousand Address: 918 Pennslyvania Avenue SE Washington, DC 20003 Telephone: (800) 488-COTT(2688) Fax: (202) 543-6720 Email:
[email protected] Web Site: http://www.cott.org Background: The Committee of Ten Thousand (COTT) is a peer-led organization seeking to help overcome the social stigma, inadequate health care, and isolation experienced by persons living with HIV/AIDS (PLWAs), primarily persons living with hemophilia. Its services include advocacy, support groups, and social activities. COTT also makes policy recommendations, offers information, and networks with other organizations. COTT services are available for health professionals; community service professionals; persons with AIDS; persons with hemophilia with HIV/AIDS; HIV positive persons; and government agencies.
28 Hemophilia
·
Department of Hematology Norris Comprehensive Cancer Center and Hospital School of Medicine University of Southern California Address: 1441 Eastlake Ave. Los Angeles, CA 90033 Telephone: (323) 865-3914 Web Site: http://ccnt.hsc.usc.edu/departments/hematology/f1.html Background: The primary areas of research of the Division of Hematology at the USC Norris Cancer Center are lymphoma, leukemia, bone marrow transplantation, AIDS-related neoplasms, blood coagulation research, folate and vitamin B12 metabolism, sickle cell disease, hematologic malignancies, and hemophilia. The Division answers inquiries, provides consulting services, and conducts seminars and workshops. Relevant area(s) of interest: Blood coagulation; Blood diseases; Blood neoplasms; Hematology; Hemophilia; Leukemia; Lymphomas; Megaloblastic anemias; Sickle cell anemia; Vitamin B12 metabolism
·
Haemophilia Society Address: 385 Euston Road Chesterfield House London NW1 3AU, UK Telephone: 44 (0)20 7380 0600 Fax: 44 (0)20 7387 8220 Email:
[email protected] Web Site: http://www.haemophilia.org.uk/ Background: The Haemophilia Society was established in 1950 and is the national charity in the UK that represents people with haemophilia, von Willebrand's disease and related bleeding disorders. The Society is partially supported by the British government. Interests of the Society include hemophilia, acquired immune deficiency syndrome (AIDS), and hepatitis. The Society has a collection of international publications on hemophilia and AIDS related to the use of antihemophilic factors (AHF); answers inquiries; provides advisory, reference, and current-awareness services; evaluates data; provides information on research in progress; distribute publications; and makes referrals to other sources of information. Publication(s): The Bulletin (quarterly); books; standards; state-of-the-art reviews. Relevant area(s) of interest: AIDS; Hemophilia; Hepatitis
Seeking Guidance 29
·
Institute for Behavioral Research University of Georgia Address: 111 Barrow Hall Athens, GA 30602 Telephone: (706) 542-1806 Fax: (706) 542-6064 Email:
[email protected] Web Site: http://www.ibr.uga.edu/ Background: The Institute for Behavioral Research includes the Center for Family Research, the Center for Research on Deviance and Behavioral Health, the Cognitive Studies Group, and the Survey Research Center. Interests of the Institute include family interaction; divorce and adolescent adjustment; cognitive studies, including cognitive development, reading, memory, and mathematical schemas; research on deviance, including problem children, alcoholism, criminal justice; and methodological and statistical issues in social sciences. The Institute has data on adolescents from married and divorced families; data on families with hemophilia and HIV; and the Georgia Poll. The Survey Research Center provides consultation on survey research and conducts survey research. Relevant area(s) of interest: Adolescent psychology; Adult development; Alcoholism; Behavioral-science research; Child development; Cognitive development; Cognitive processes; Family relations; Juvenile delinquents; Self-esteem; Social cognition; Social surveys; Socially deviant behavior; Socially-deviant behavior
·
Louisiana Department of Health and Hospitals Address: 1201 Capitol Access Road, P.O. Box 629 Baton Rouge, LA, 70821-0629 Telephone: (225) 342-9500 Voice Fax: (225) 342-5568 Web Site: http://www.dhh.state.la.us/ Background: The Louisiana Department of Health and Hospitals (DHH) provides preventive care, community support, and residential care services to the poor, the physically disabled, people with mental disabilities, and alcohol and drug abusers. DHH services include health promotion, a geriatric hospital, mental hospitals, rehabilitation centers, mental health centers, group homes, alcoholism and drug abuse treatment, rehabilitation for children and adults with physical disabilities, day care, day developmental training, food and medical assistance, health screening, maternal and child health programs, home care,
30 Hemophilia
immunizations, family planning, venereal disease control, hypertension control, lead poisoning prevention, hemophilia care, health care for female prisoners, family counseling, child protection, youth guidance, and information and referrals. Relevant area(s) of interest: Consumer resources; Louisiana; Public health ·
March of Dimes Birth Defects Foundation Address: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue, White Plains, NY 10605 Telephone: (914) 428-710 Toll-free: (888) 663-4637 TTY: (914) 997-476 Fax: (914) 997-4763 Email:
[email protected] Web Site: http://www.modimes.org Background: The March of Dimes Birth Defects Foundation is a national not-for- profit organization that was established in 1938. The mission of the Foundation is to improve the health of babies by preventing birth defects and infant mortality. Through the Campaign for Healthier Babies, the March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the Foundation and to that end it produces a wide variety of printed informational materials and videos. The March of Dimes public health educational materials provide information encouraging health- enhancing behaviors that lead to a healthy pregnancy and a healthy baby. Relevant area(s) of interest: Factor IX Deficiency, Hemophilia
·
Maryland Advisory Council on Hereditary Disorders Maryland Department of Health and Mental Hygiene Office of the Secretary Address: 201 West Preston Street Baltimore, MD 21201 Telephone: (410) 767-6566 Fax: (410) 767-6489 Web Site: http://www.dhmh.state.md.us/ Background: The Maryland Advisory Council on Heredity Disorders was created by the State legislature to advise the Department of Health and Mental Hygiene about policy decisions for programs for the detection and management of hereditary disorders. Interests of the Council include sickle cell anemia, cystic fibrosis, hemophilia, Tay-Sachs disease, retinitis pigmentosa, muscular dystrophy, Cooley's anemia, Huntington's disease, and phenylketonuria. The Council answers inquiries, provides reference
Seeking Guidance 31
service and information on research in progress, distributes publications, and makes referrals to other sources of information. Services are free, except for bulk copies of publications, and available to anyone. Publication(s): Understanding Heredity Disorders; annual report; technical reports; data compilations. Relevant area(s) of interest: Cooley's anemia; Cystic fibrosis; Hemophilia; Hereditary diseases; Huntington's disease; Muscular dystrophy; Phenylketonuria; Retinitis pigmentosa; Sickle cell anemia; Tay-Sachs disease ·
National Hemophilia Foundation Address: Telephone: (212) 219-8180 Toll-free: (800) 424-2634 Fax: (212) 431-0906. Background: The National Hemophilia Foundation is a national not-forprofit organization that was founded in 1948. The mission of the Foundation includes supporting people with Hemophilia, their families, and physicians; increasing public awareness of Hemophilia; advocating on behalf of people with Hemophilia; providing up-to-date information on Hemophilia and other clotting disorders; raising funds for medical research; and achieving its legislative goals. Educational materials produced by the Foundation include brochures, newsletters, and audiovisual aids. Relevant area(s) of interest: Hemophilia
·
Ohio Department of Health Address: 246 North High Street Columbus, OH, 43216-0118 Telephone: (614) 462-8562 Voice Web Site: http://www.odh.state.oh.us Background: The Ohio Department of Health coordinates and plans health services, offers consultation and technical assistance to service providers, directly provides a variety of health services, and conducts public and professional education programs. Consultation is available to local agencies and providers on program development in the areas of maternal and child health, disabled children, environmental health, preventive medicine, radiation protection, sanitation, school health education, and emergency medical services. Directly provided health care services include maternal and child nutrition, outreach and team management for children with disabilities, demonstration dental health
32 Hemophilia
prevention projects, and primary health care for migrant workers. The Department operates special programs involving hemophilia, venereal disease, immunizations, veterinary health, lead poisoning, and sudden infant death syndrome. Public education programs are conducted on a variety of topics, including maternal and child health. An information clearinghouse on Department services, a health film library, and public service announcements are available. Health professional services include training and placement for health educators and education and inservice training for nursing, nutrition, preventive medicine, and maternal and child health care personnel. Relevant area(s) departments ·
of
interest:
Consumer
resources;
State
health
Swedish Hemophilia Society Address: Swedish Hemophilia Society Box 555 07, Stockholm, SE-102 04, Sweden Telephone: 46 08 661 9455 Fax: 46 08 661 9465 Email:
[email protected] Web Site: http://www.xpress.se/fbis/ Background: The Swedish Hemophilia Society (FBIS) is a nonprofit organization for individuals affected by hemophilia in Sweden. Hemophilia is a group of hereditary bleeding disorders characterized by deficiency of one of the blood factors necessary for blood clotting (coagulation). Affected individuals may experience bleeding episodes that occur for no apparent reason or due to surgery, dental extractions, or injuries. Recurrent bleeding into the joints and muscles may cause painful inflammation of the joints (arthritis) and associated deformities. The Swedish Hemophilia Society, which was established in 1964, currently serves as an umbrella organization consisting of eight local societies. The FBIS disseminates information and provides assistance to these local societies. On the national level, the Society establishes contacts with authorities and other government-supported organizations for disabled individuals. The Swedish Hemophilia Society has several primary objectives, including informing the general public, the community, and governmental institutions about hemophilia disease and improving the quality of life of affected individuals by arranging conferences and meetings where current issues are discussed. The Society offers several programs and services, including providing summer and winter camps for affected children and youths and recreation trips that provide
Seeking Guidance 33
physical training opportunities. The Swedish Hemophilia Society also maintains a web site on the Internet. Relevant area(s) of interest: Hemophilia ·
World Federation of Hemophilia Address: Telephone: 514-875-7944 Fax: 514-875-8916 Email:
[email protected] Web Site: http://www.wfh.org Background: The World Federation of Hemophilia is an international notfor-profit organization in Canada that was founded in 1963 to promote the care of individuals with hemophilia throughout the world. Hemophilia is a group of hereditary bleeding disorders characterized by deficiency of one of the blood factors necessary for blood clotting (coagulation). Affected individuals may experience bleeding episodes that occur for no apparent reason or due to surgery, dental extractions, or injuries. Recurring bleeding into the joints and muscles may cause painful inflammation of the joints (arthritis) and associated deformities. The primary objective of the World Federation of Hemophilia is to help bring treatment to individuals with hemophilia throughout the world. To help fulfill its objective, the Federation conducts international symposia, offers educational materials for affected individuals and family members, and maintains a web site on the Internet. The Federation's web site discusses the organization's mission, goals, and services; offers information concerning hemophilia product notifications, withdrawals, and medical advisories; provides access to educational materials on hemophilia; and offers an FAQ ('frequently asked questions') area entitled 'Ask the Expert' with answers to questions submitted by individuals with hemophilia, family members, health care professionals, and other organizational members. The FAQ includes sections on general guidelines, information for parents, specific hemophilia topics, bloodrelated topics, hemophilia carriers, musculoskeletal and surgical issues, von Willebrand's disease, gene therapy, hepatitis, HIV/AIDS and hemophilia, inhibitors, product information/queries, and issues/reports from developing countries. Relevant area(s) of interest: Factor IX Deficiency, Hemophilia
34 Hemophilia
Finding More Associations There are a number of directories that list additional medical associations that you may find useful. While not all of these directories will provide different information than what is listed above, by consulting all of them, you will have nearly exhausted all sources for patient associations.
The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about hemophilia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.
DIRLINE A comprehensive source of information on associations is the DIRLINE database maintained by the National Library of Medicine. The database comprises some 10,000 records of organizations, research centers, and government institutes and associations which primarily focus on health and biomedicine. DIRLINE is available via the Internet at the following Web site: http://dirline.nlm.nih.gov/. Simply type in “hemophilia” (or a synonym) or the name of a topic, and the site will list information contained in the database on all relevant organizations.
The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “hemophilia”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” By making these selections and typing in “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on organizations dealing with hemophilia. You should check back periodically with this database since it is updated every 3 months.
Seeking Guidance 35
The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by specific diseases. You can access this database at the following Web site: http://www.rarediseases.org/cgi-bin/nord/searchpage. Select the option called “Organizational Database (ODB)” and type “hemophilia” (or a synonym) in the search box.
Online Support Groups In addition to support groups, commercial Internet service providers offer forums and chat rooms for people with different illnesses and conditions. WebMDÒ, for example, offers such a service at their Web site: http://boards.webmd.com/roundtable. These online self-help communities can help you connect with a network of people whose concerns are similar to yours. Online support groups are places where people can talk informally. If you read about a novel approach, consult with your doctor or other healthcare providers, as the treatments or discoveries you hear about may not be scientifically proven to be safe and effective. The following Internet sites may be of particular interest: ·
Childrens Hospital Medical Center of Cincinnati www.cincinnatichildrens.org/Your_Visit/Patient_Family_Activities/ Support+groups/Hemophilia
·
Haemostasis Research Group Database Resource Site www.shemophilia.org/community/support.html
·
Hemophilia Society of Canada www.hemophilia.ca/fr/8.4.html
36 Hemophilia
Finding Doctors One of the most important aspects of your treatment will be the relationship between you and your doctor or specialist. All patients with hemophilia must go through the process of selecting a physician. While this process will vary from person to person, the Agency for Healthcare Research and Quality makes a number of suggestions, including the following:11 ·
If you are in a managed care plan, check the plan’s list of doctors first.
·
Ask doctors or other health professionals who work with doctors, such as hospital nurses, for referrals.
·
Call a hospital’s doctor referral service, but keep in mind that these services usually refer you to doctors on staff at that particular hospital. The services do not have information on the quality of care that these doctors provide.
·
Some local medical societies offer lists of member doctors. Again, these lists do not have information on the quality of care that these doctors provide.
Additional steps you can take to locate doctors include the following: ·
Check with the associations listed earlier in this chapter.
·
Information on doctors in some states is available on the Internet at http://www.docboard.org. This Web site is run by “Administrators in Medicine,” a group of state medical board directors.
·
The American Board of Medical Specialties can tell you if your doctor is board certified. “Certified” means that the doctor has completed a training program in a specialty and has passed an exam, or “board,” to assess his or her knowledge, skills, and experience to provide quality patient care in that specialty. Primary care doctors may also be certified as specialists. The AMBS Web site is located at http://www.abms.org/newsearch.asp.12 You can also contact the ABMS by phone at 1-866-ASK-ABMS.
·
You can call the American Medical Association (AMA) at 800-665-2882 for information on training, specialties, and board certification for many licensed doctors in the United States. This information also can be found in “Physician Select” at the AMA’s Web site: http://www.amaassn.org/aps/amahg.htm.
This section is adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. While board certification is a good measure of a doctor’s knowledge, it is possible to receive quality care from doctors who are not board certified. 11 12
Seeking Guidance 37
If the previous sources did not meet your needs, you may want to log on to the Web site of the National Organization for Rare Disorders (NORD) at http://www.rarediseases.org/. NORD maintains a database of doctors with expertise in various rare diseases. The Metabolic Information Network (MIN), 800-945-2188, also maintains a database of physicians with expertise in various metabolic diseases.
Selecting Your Doctor13 When you have compiled a list of prospective doctors, call each of their offices. First, ask if the doctor accepts your health insurance plan and if he or she is taking new patients. If the doctor is not covered by your plan, ask yourself if you are prepared to pay the extra costs. The next step is to schedule a visit with your chosen physician. During the first visit you will have the opportunity to evaluate your doctor and to find out if you feel comfortable with him or her. Ask yourself, did the doctor: ·
Give me a chance to ask questions about hemophilia?
·
Really listen to my questions?
·
Answer in terms I understood?
·
Show respect for me?
·
Ask me questions?
·
Make me feel comfortable?
·
Address the health problem(s) I came with?
·
Ask me my preferences about different kinds of treatments for hemophilia?
·
Spend enough time with me?
Trust your instincts when deciding if the doctor is right for you. But remember, it might take time for the relationship to develop. It takes more than one visit for you and your doctor to get to know each other.
13 This
section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.
38 Hemophilia
Working with Your Doctor14 Research has shown that patients who have good relationships with their doctors tend to be more satisfied with their care and have better results. Here are some tips to help you and your doctor become partners: ·
You know important things about your symptoms and your health history. Tell your doctor what you think he or she needs to know.
·
It is important to tell your doctor personal information, even if it makes you feel embarrassed or uncomfortable.
·
Bring a “health history” list with you (and keep it up to date).
·
Always bring any medications you are currently taking with you to the appointment, or you can bring a list of your medications including dosage and frequency information. Talk about any allergies or reactions you have had to your medications.
·
Tell your doctor about any natural or alternative medicines you are taking.
·
Bring other medical information, such as x-ray films, test results, and medical records.
·
Ask questions. If you don’t, your doctor will assume that you understood everything that was said.
·
Write down your questions before your visit. List the most important ones first to make sure that they are addressed.
·
Consider bringing a friend with you to the appointment to help you ask questions. This person can also help you understand and/or remember the answers.
·
Ask your doctor to draw pictures if you think that this would help you understand.
·
Take notes. Some doctors do not mind if you bring a tape recorder to help you remember things, but always ask first.
·
Let your doctor know if you need more time. If there is not time that day, perhaps you can speak to a nurse or physician assistant on staff or schedule a telephone appointment.
·
Take information home. Ask for written instructions. Your doctor may also have brochures and audio and videotapes that can help you.
This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.
14
Seeking Guidance 39
·
After leaving the doctor’s office, take responsibility for your care. If you have questions, call. If your symptoms get worse or if you have problems with your medication, call. If you had tests and do not hear from your doctor, call for your test results. If your doctor recommended that you have certain tests, schedule an appointment to get them done. If your doctor said you should see an additional specialist, make an appointment.
By following these steps, you will enhance the relationship you will have with your physician.
Broader Health-Related Resources In addition to the references above, the NIH has set up guidance Web sites that can help patients find healthcare professionals. These include:15 ·
Caregivers: http://www.nlm.nih.gov/medlineplus/caregivers.html
·
Choosing a Doctor or Healthcare Service: http://www.nlm.nih.gov/medlineplus/choosingadoctororhealthcareserv ice.html
·
Hospitals and Health Facilities: http://www.nlm.nih.gov/medlineplus/healthfacilities.html
Vocabulary Builder The following vocabulary builder provides definitions of words used in this chapter that have not been defined in previous chapters: Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Coagulation: 1. the process of clot formation. 2. in colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html.
15
40 Hemophilia
irreversible. 3. in surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colorectal: Pertaining to or affecting the colon and rectum. [EU] Condoms: A sheath that is worn over the penis during sexual behavior in order to prevent pregnancy or spread of sexually transmitted disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Fibrosis: Process by which inflamed tissue becomes scarred. [NIH] Haemophilia: A haemorrhagic diathesis occurring in two main forms : (1) haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; (2) haemophilia B (factor IX deficiency, Christmas disease), also X-linked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [EU] Heredity: 1. the genetic transmission of a particular quality or trait from parent to offspring. 2. the genetic constitution of an individual. [EU] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH]
Hypertension: High blood pressure (i.e., abnormally high blood pressure tension involving systolic and/or diastolic levels). The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines hypertension as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or taking hypertensive medication. The cause may be adrenal, benign, essential, Goldblatt's, idiopathic, malignant PATE, portal, postpartum, primary, pulmonary, renal or renovascular. [NIH] Idiopathic: Results from an unknown cause. [NIH] Immunization: Protection from disease by administering vaccines that induce the body to form antibodies against infectious agents. [NIH] Immunogenetics: A branch of genetics which deals with the genetic basis of the immune response. [NIH] Inflammation: Response of the body tissues to injury; typical signs are swelling, redness, and pain. [NIH]
Seeking Guidance 41
Lymphoma: Cancer of the lymph nodes. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Melanoma: A tumour arising from the melanocytic system of the skin and other organs. When used alone the term refers to malignant melanoma. [EU] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]
Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Sanitation: The development and establishment of environmental conditions favorable to the health of the public. [NIH] Surgical: Of, pertaining to, or correctable by surgery. [EU] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely
42 Hemophilia
detectable hematologic abnormality to severe and fatal anemia. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Withdrawal: 1. a pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) a substancespecific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU]
Clinical Trials 43
CHAPTER 3. CLINICAL TRIALS AND HEMOPHILIA Overview Very few medical conditions have a single treatment. The basic treatment guidelines that your physician has discussed with you, or those that you have found using the techniques discussed in Chapter 1, may provide you with all that you will require. For some patients, current treatments can be enhanced with new or innovative techniques currently under investigation. In this chapter, we will describe how clinical trials work and show you how to keep informed of trials concerning hemophilia.
What Is a Clinical Trial?16 Clinical trials involve the participation of people in medical research. Most medical research begins with studies in test tubes and on animals. Treatments that show promise in these early studies may then be tried with people. The only sure way to find out whether a new treatment is safe, effective, and better than other treatments for hemophilia is to try it on patients in a clinical trial.
The discussion in this chapter has been adapted from the NIH and the NEI: www.nei.nih.gov/netrials/ctivr.htm.
16
44 Hemophilia
What Kinds of Clinical Trials Are There? Clinical trials are carried out in three phases: ·
Phase I. Researchers first conduct Phase I trials with small numbers of patients and healthy volunteers. If the new treatment is a medication, researchers also try to determine how much of it can be given safely.
·
Phase II. Researchers conduct Phase II trials in small numbers of patients to find out the effect of a new treatment on hemophilia.
·
Phase III. Finally, researchers conduct Phase III trials to find out how new treatments for hemophilia compare with standard treatments already being used. Phase III trials also help to determine if new treatments have any side effects. These trials--which may involve hundreds, perhaps thousands, of people--can also compare new treatments with no treatment. How Is a Clinical Trial Conducted?
Various organizations support clinical trials at medical centers, hospitals, universities, and doctors’ offices across the United States. The “principal investigator” is the researcher in charge of the study at each facility participating in the clinical trial. Most clinical trial researchers are medical doctors, academic researchers, and specialists. The “clinic coordinator” knows all about how the study works and makes all the arrangements for your visits. All doctors and researchers who take part in the study on hemophilia carefully follow a detailed treatment plan called a protocol. This plan fully explains how the doctors will treat you in the study. The “protocol” ensures that all patients are treated in the same way, no matter where they receive care. Clinical trials are controlled. This means that researchers compare the effects of the new treatment with those of the standard treatment. In some cases, when no standard treatment exists, the new treatment is compared with no treatment. Patients who receive the new treatment are in the treatment group. Patients who receive a standard treatment or no treatment are in the “control” group. In some clinical trials, patients in the treatment group get a new medication while those in the control group get a placebo. A placebo is a harmless substance, a “dummy” pill, that has no effect on hemophilia. In other clinical trials, where a new surgery or device (not a medicine) is being tested, patients in the control group may receive a “sham treatment.” This
Clinical Trials 45
treatment, like a placebo, has no effect on hemophilia and does not harm patients. Researchers assign patients “randomly” to the treatment or control group. This is like flipping a coin to decide which patients are in each group. If you choose to participate in a clinical trial, you will not know which group you will be appointed to. The chance of any patient getting the new treatment is about 50 percent. You cannot request to receive the new treatment instead of the placebo or sham treatment. Often, you will not know until the study is over whether you have been in the treatment group or the control group. This is called a “masked” study. In some trials, neither doctors nor patients know who is getting which treatment. This is called a “double masked” study. These types of trials help to ensure that the perceptions of the patients or doctors will not affect the study results. Natural History Studies Unlike clinical trials in which patient volunteers may receive new treatments, natural history studies provide important information to researchers on how hemophilia develops over time. A natural history study follows patient volunteers to see how factors such as age, sex, race, or family history might make some people more or less at risk for hemophilia. A natural history study may also tell researchers if diet, lifestyle, or occupation affects how a disease or disorder develops and progresses. Results from these studies provide information that helps answer questions such as: How fast will a disease or disorder usually progress? How bad will the condition become? Will treatment be needed? What Is Expected of Patients in a Clinical Trial? Not everyone can take part in a clinical trial for a specific disease or disorder. Each study enrolls patients with certain features or eligibility criteria. These criteria may include the type and stage of disease or disorder, as well as, the age and previous treatment history of the patient. You or your doctor can contact the sponsoring organization to find out more about specific clinical trials and their eligibility criteria. If you are interested in joining a clinical trial, your doctor must contact one of the trial’s investigators and provide details about your diagnosis and medical history. If you participate in a clinical trial, you may be required to have a number of medical tests. You may also need to take medications and/or undergo
46 Hemophilia
surgery. Depending upon the treatment and the examination procedure, you may be required to receive inpatient hospital care. Or, you may have to return to the medical facility for follow-up examinations. These exams help find out how well the treatment is working. Follow-up studies can take months or years. However, the success of the clinical trial often depends on learning what happens to patients over a long period of time. Only patients who continue to return for follow-up examinations can provide this important long-term information.
Recent Trials on Hemophilia The National Institutes of Health and other organizations sponsor trials on various diseases and disorders. Because funding for research goes to the medical areas that show promising research opportunities, it is not possible for the NIH or others to sponsor clinical trials for every disease and disorder at all times. The following lists recent trials dedicated to hemophilia.17 If the trial listed by the NIH is still recruiting, you may be eligible. If it is no longer recruiting or has been completed, then you can contact the sponsors to learn more about the study and, if published, the results. Further information on the trial is available at the Web site indicated. Please note that some trials may no longer be recruiting patients or are otherwise closed. Before contacting sponsors of a clinical trial, consult with your physician who can help you determine if you might benefit from participation. ·
Effect of Indinavir Plus Two Other Anti-HIV Drugs on Blood Clotting in HIV-Positive Males with Hemophilia Condition(s): HIV Infections; Hemophilia A Study Status: This study is no longer recruiting patients. Sponsor(s): Merck Research Laboratories Purpose - Excerpt: The purpose of this study is to see if indinavir plus two other anti-HIV drugs affect blood clotting in HIV-positive patients with hemophilia. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00002386
17
These are listed at www.ClinicalTrials.gov.
Clinical Trials 47
·
Epidemiology and Immunology of Hemophilia A Inhibitors Condition(s): Blood Disease; Hemophilia A Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the risk factors associated with inhibitor formation in hemophilia A and to study the mechanism of tolerance in the murine hemophilia A model. Study Type: Epidemiology Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00005518
·
Hepatitis C in Clinically Discordant Hemophilic Siblings Condition(s): Blood Disease; Hemophilia A; Hepatitis, Viral, Human Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To define the natural history, immunologic, and genetic factors that influence the clinical outcome of hepatitis C in a cohort of hemophilic siblings. Study Type: Epidemiology Contact(s): Fried, Michael W. Chapel Hill, North Carolina, United States . Study chairs or principal investigators: Fried, Michael W., Study Chair; University of North Carolina Chapel Hill, North Carolina, United States Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00007371
·
The Effects of AZT and Ibuprofen on HIV-Infected Patients with Hemophilia Condition(s): HIV Infections; Hemophilia A Study Status: This study is no longer recruiting patients. Sponsor(s): University of Pittsburgh Purpose - Excerpt: To determine if platelet dysfunction and/or pharmacologic drug interaction occurs in patients taking both AZT and ibuprofen, which might account for enhanced bleeding tendency. Study Type: Interventional Contact(s): Pennsylvania; Hemophilia Ctr of Western PA / Univ of Pittsburgh, Pittsburgh, Pennsylvania, 15219, United States Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00002276
48 Hemophilia
·
A Study of Zidovudine in HIV-Infected Patients Who Have Hemophilia Condition(s): HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Study A: To determine whether treatment with zidovudine (ZDV) will delay or change the disease process in hemophilic patients who have HIV infection with no symptoms. The major clinical question is whether patients who receive chronic ZDV therapy will have a delay in the development of AIDS or AIDS-related complex (ARC). The pharmacokinetics (blood levels) of ZDV in hemophilic patients will also be studied. Study B: To determine if ZDV therapy changes the risk of a hemophiliac transmitting HIV to his wife or other female sexual partner. To determine the effectiveness of counseling and education on the behaviors of the wives that place them at risk for HIV infection. To determine if antibodies to HIV either appear or disappear from the blood of any of the wives during the study. Study A: Individuals who are infected with HIV can benefit from therapy with an effective anti-AIDS virus agent. ZDV is a potent inhibitor of HIV in vitro (test tube) and is safe in humans at the dose planned. It may be effective in preventing the development of AIDS or ARC in hemophiliacs who have the HIV antibody in their blood. The pharmacokinetic studies are especially important because the high prevalence of hepatic disease in this population may affect the metabolism and blood levels of ZDV. Study B: HIV is transmitted by sexual contact, and wives of infected hemophilic patients have become infected during long-term sexual relationships. Transmission of the virus does not occur during casual family contact. This study will aid in determining if therapy influences the transmission of HIV, because the wives of hemophiliacs generally have no risk for HIV infection other than sexual contact with their spouse. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00001104
·
Cooperative Study of Factor VIII Inhibitors Condition(s): Blood Coagulation Disorders; Hematologic Diseases; Hemophilia A; Hemorrhagic Disorders Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)
Clinical Trials 49
Purpose - Excerpt: To test the efficacy of prothrombin complex concentrates (Factor IX) in the treatment of hemophiliac patients who had inhibitors to Factor VIII. Phase(s): Phase III Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00000582 ·
Delta Hepatitis and Liver Disease in Hemophiliacs Condition(s): Blood Disease; Hepatitis, Viral, Human; Hemophilia A; Liver Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the prevalence of hepatitis delta virus (HDV) in a large cohort of hemophiliacs and to elucidate the role of HDV in the development and progression of liver disease in this population. Study Type: Epidemiology Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00005304
·
Hepatitis Delta Infections in Hemophiliacs Condition(s): Blood Disease; Hepatitis, Viral, Human; Liver Diseases; Hemophilia A Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To elucidate the role of hepatitis delta virus (HDV) in the development of chronic liver disease in patients with hemophilia. Study Type: Epidemiology Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00005305
·
Phase I/II Study of Monoclonal Factor IX Concentrate for Factor IX Deficiency Condition(s): Hemophilia B; Factor IX Deficiency Study Status: This study is completed.
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Sponsor(s): National Center for Research Resources (NCRR); University of North Carolina Purpose - Excerpt: Objectives: Assess the safety and long-term efficacy of monoclonal factor IX concentrate in patients with factor IX deficiency. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s):. Study chairs or principal investigators: Gilbert C. White, Study Chair; University of North Carolina Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00004801 ·
Prospective Study of HIV Infection in Hemophiliacs Condition(s): Acquired Immunodeficiency Syndrome; HIV Infections; Blood Disease; Hemophilia A; Hepatitis, Viral, Human; Blood Transfusion; Cytomegalovirus Infections Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine mechanisms of individual differences in the progression of HIV infection in hemophiliacs. Study Type: Epidemiology Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00005309
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Safety and Effectiveness of Azidothymidine (AZT) in HIV-Positive Patients with Hemophilia Condition(s): HIV Infections; Hemophilia A Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to see if giving azidothymidine (AZT) to HIV-positive patients with hemophilia is safe and if it is effective in lowering HIV levels and boosting the immune system. HIV infects and inactivates certain blood cells that are part of the body's immune system. The damage to the body's immune system can result in unusual infections and/or unusual forms of cancer. A large percentage of hemophiliacs are HIV-positive and there is a clear risk for the development of AIDS in these patients. AZT may be effective in lowering HIV levels and boosting the immune system but its side effects are not understood in these patients.
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Phase(s): Phase I Study Type: Interventional Contact(s): New York; Univ of Rochester Medical Center, Rochester, New York, 14642, United States; New York; SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York, 14215, United States. Study chairs or principal investigators: Richard C. Reichman, Study Chair Web Site: http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00000705
Benefits and Risks18 What Are the Benefits of Participating in a Clinical Trial? If you are interested in a clinical trial, it is important to realize that your participation can bring many benefits to you and society at large: ·
A new treatment could be more effective than the current treatment for hemophilia. Although only half of the participants in a clinical trial receive the experimental treatment, if the new treatment is proved to be more effective and safer than the current treatment, then those patients who did not receive the new treatment during the clinical trial may be among the first to benefit from it when the study is over.
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If the treatment is effective, then it may improve health or prevent diseases or disorders.
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Clinical trial patients receive the highest quality of medical care. Experts watch them closely during the study and may continue to follow them after the study is over.
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People who take part in trials contribute to scientific discoveries that may help other people with hemophilia. In cases where certain diseases or disorders run in families, your participation may lead to better care or prevention for your family members.
This section has been adapted from ClinicalTrials.gov, a service of the National Institutes of Health: http://www.clinicaltrials.gov/ct/gui/c/a1r/info/whatis?JServSessionIdzone_ct=9jmun6f2 91. 18
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The Informed Consent Once you agree to take part in a clinical trial, you will be asked to sign an “informed consent.” This document explains a clinical trial’s risks and benefits, the researcher’s expectations of you, and your rights as a patient. What Are the Risks? Clinical trials may involve risks as well as benefits. Whether or not a new treatment will work cannot be known ahead of time. There is always a chance that a new treatment may not work better than a standard treatment. There is also the possibility that it may be harmful. The treatment you receive may cause side effects that are serious enough to require medical attention. How Is Patient Safety Protected? Clinical trials can raise fears of the unknown. Understanding the safeguards that protect patients can ease some of these fears. Before a clinical trial begins, researchers must get approval from their hospital’s Institutional Review Board (IRB), an advisory group that makes sure a clinical trial is designed to protect patient safety. During a clinical trial, doctors will closely watch you to see if the treatment is working and if you are experiencing any side effects. All the results are carefully recorded and reviewed. In many cases, experts from the Data and Safety Monitoring Committee carefully monitor each clinical trial and can recommend that a study be stopped at any time. You will only be asked to take part in a clinical trial as a volunteer giving informed consent. What Are a Patient’s Rights in a Clinical Trial? If you are eligible for a clinical trial, you will be given information to help you decide whether or not you want to participate. As a patient, you have the right to: ·
Information on all known risks and benefits of the treatments in the study.
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Know how the researchers plan to carry out the study, for how long, and where.
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Know what is expected of you.
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Know any costs involved for you or your insurance provider.
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Know before any of your medical or personal information is shared with other researchers involved in the clinical trial.
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Talk openly with doctors and ask any questions.
After you join a clinical trial, you have the right to: ·
Leave the study at any time. Participation is strictly voluntary. However, you should not enroll if you do not plan to complete the study.
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Receive any new information about the new treatment.
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Continue to ask questions and get answers.
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Maintain your privacy. Your name will not appear in any reports based on the study.
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Know whether you participated in the treatment group or the control group (once the study has been completed).
What about Costs? In some clinical trials, the research facility pays for treatment costs and other associated expenses. You or your insurance provider may have to pay for costs that are considered standard care. These things may include inpatient hospital care, laboratory and other tests, and medical procedures. You also may need to pay for travel between your home and the clinic. You should find out about costs before committing to participation in the trial. If you have health insurance, find out exactly what it will cover. If you don’t have health insurance, or if your insurance company will not cover your costs, talk to the clinic staff about other options for covering the cost of your care. What Should You Ask before Deciding to Join a Clinical Trial? Questions you should ask when thinking about joining a clinical trial include the following: ·
What is the purpose of the clinical trial?
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What are the standard treatments for hemophilia? Why do researchers think the new treatment may be better? What is likely to happen to me with or without the new treatment?
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What tests and treatments will I need? Will I need surgery? Medication? Hospitalization?
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How long will the treatment last? How often will I have to come back for follow-up exams?
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What are the treatment’s possible benefits to my condition? What are the short- and long-term risks? What are the possible side effects?
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Will the treatment be uncomfortable? Will it make me feel sick? If so, for how long?
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How will my health be monitored?
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Where will I need to go for the clinical trial? How will I get there?
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How much will it cost to be in the study? What costs are covered by the study? How much will my health insurance cover?
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Will I be able to see my own doctor? Who will be in charge of my care?
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Will taking part in the study affect my daily life? Do I have time to participate?
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How do I feel about taking part in a clinical trial? Are there family members or friends who may benefit from my contributions to new medical knowledge?
Keeping Current on Clinical Trials Various government agencies maintain databases on trials. The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide patients, family members, and physicians with current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to their Web site (www.clinicaltrials.gov) and search by “hemophilia” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The
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following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: ·
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
General References The following references describe clinical trials and experimental medical research. They have been selected to ensure that they are likely to be available from your local or online bookseller or university medical library. These references are usually written for healthcare professionals, so you may consider consulting with a librarian or bookseller who might recommend a particular reference. The following includes some of the most readily available references (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·
A Guide to Patient Recruitment : Today’s Best Practices & Proven Strategies by Diana L. Anderson; Paperback - 350 pages (2001), CenterWatch, Inc.; ISBN: 1930624115; http://www.amazon.com/exec/obidos/ASIN/1930624115/icongroupinterna
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A Step-By-Step Guide to Clinical Trials by Marilyn Mulay, R.N., M.S., OCN; Spiral-bound - 143 pages Spiral edition (2001), Jones & Bartlett Pub; ISBN: 0763715697; http://www.amazon.com/exec/obidos/ASIN/0763715697/icongroupinterna
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The CenterWatch Directory of Drugs in Clinical Trials by CenterWatch; Paperback - 656 pages (2000), CenterWatch, Inc.; ISBN: 0967302935; http://www.amazon.com/exec/obidos/ASIN/0967302935/icongroupinterna
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The Complete Guide to Informed Consent in Clinical Trials by Terry Hartnett (Editor); Paperback - 164 pages (2000), PharmSource Information Services, Inc.; ISBN: 0970153309; http://www.amazon.com/exec/obidos/ASIN/0970153309/icongroupinterna
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Dictionary for Clinical Trials by Simon Day; Paperback - 228 pages (1999), John Wiley & Sons; ISBN: 0471985961; http://www.amazon.com/exec/obidos/ASIN/0471985961/icongroupinterna
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Extending Medicare Reimbursement in Clinical Trials by Institute of Medicine Staff (Editor), et al; Paperback 1st edition (2000), National Academy Press; ISBN: 0309068886; http://www.amazon.com/exec/obidos/ASIN/0309068886/icongroupinterna
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Handbook of Clinical Trials by Marcus Flather (Editor); Paperback (2001), Remedica Pub Ltd; ISBN: 1901346293; http://www.amazon.com/exec/obidos/ASIN/1901346293/icongroupinterna
Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Cytomegalovirus: A genus of the family herpesviridae, subfamily betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] Pharmacokinetics: The action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Prothrombin: Factor II. [EU]
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PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL
ABOUT PART II In Part II, we introduce you to additional resources and advanced research on hemophilia. All too often, patients who conduct their own research are overwhelmed by the difficulty in finding and organizing information. The purpose of the following chapters is to provide you an organized and structured format to help you find additional information resources on hemophilia. In Part II, as in Part I, our objective is not to interpret the latest advances on hemophilia or render an opinion. Rather, our goal is to give you access to original research and to increase your awareness of sources you may not have already considered. In this way, you will come across the advanced materials often referred to in pamphlets, books, or other general works. Once again, some of this material is technical in nature, so consultation with a professional familiar with hemophilia is suggested.
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CHAPTER 4. STUDIES ON HEMOPHILIA Overview Every year, academic studies are published on hemophilia or related conditions. Broadly speaking, there are two types of studies. The first are peer reviewed. Generally, the content of these studies has been reviewed by scientists or physicians. Peer-reviewed studies are typically published in scientific journals and are usually available at medical libraries. The second type of studies is non-peer reviewed. These works include summary articles that do not use or report scientific results. These often appear in the popular press, newsletters, or similar periodicals. In this chapter, we will show you how to locate peer-reviewed references and studies on hemophilia. We will begin by discussing research that has been summarized and is free to view by the public via the Internet. We then show you how to generate a bibliography on hemophilia and teach you how to keep current on new studies as they are published or undertaken by the scientific community.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hemophilia, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the
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format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type in “hemophilia” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is a sample of what you can expect from this type of search: ·
Bad Blood Source: in Florida; Vol. 40, No. 51, Dec. 1993. 1993. p. 11-25. Contact: A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This magazine article chronicles the events that led to a class action suit filed against drug companies and the National Hemophilia Foundation (NHF) by hemophiliacs and their families. There are more than 10,000 hemophiliacs in the U.S. who contracted AIDS in the early 1980s from a blood-based clotting agent approved by the NHF and sold by pharmaceutical companies. The suit cites the fact that the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) had already warned the pharmaceutical companies and the NHF that the clotting agent was dangerous. The suit also asserts that because of the NHF's close ties to the drug industry, the nonprofit consumer group played down the danger of the medicine. The drug companies are accused of continuing to sell HIV-infected medication even after top scientists, government officials, and company officials knew that it was contaminated. The plasma that was used in the clotting concentrate came from blood that was bought and sold from thousands of different donors. Two of the companies that made the clotting factor drew plasma from prison inmates. The clotting factor that hemophiliacs were receiving was equated to having unprotected sex with 20,000 strangers every week. This magazine article looks at the cases of several hemophiliacs who died of AIDS, or are living with AIDS, as a direct result of the clotting factor.
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Placebo - Controlled Trial to Evaluate Zidovudine in Treatment of Human Immunodeficiency Virus Infection in Asymptomatic Patients With Hemophilia Source: Aug. 1991. Aidsline Citation: Med/91329838.
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Contact: Stanford University School of Medicine Division of Infectious Disease AIDS Clinical Trials Unit, SUMC Rm. S-156, Stanford, CA 94305. (415) 723-6231. Summary: One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients. ·
Multiple - Dose Pharmacokinetics of Oral Zidovudine in Hemophilia Patients With Human Immunodeficiency Virus Infection Source: March 1990. Aidsline Citation: Med/90240693.
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Contact: State University of New York Buffalo Erie County Medical Center, 462 Grider St., Buffalo, NY 14215. (716) 898-4119. Summary: The disposition of zidovudine (ZDV) was examined during chronic oral dosing (300 mg every 4 h while awake) for 12 weeks in eight asymptomatic patients with hemophilia who were infected with the human immunodeficiency virus. Pharmacokinetic studies were conducted at the initiation of drug administration and after 6 and 12 weeks. Baseline liver function tests indicated normal values for bilirubin, albumin, and prothrombin time, while hepatic enzyme levels ranged from one to three times the normal levels. Initially, the mean peak ZDV concentration in plasma was 2,052 ng/ml with a range of 1,033 to 3,907 ng/ml, while during chronic dosing the peaks were 1,619 +/- 1,062 ng/ml and 1,711 +/- 786 ng/ml at weeks 6 and 12, respectively. ZDV concentrations at 4 h declined to 77 +/- 53 ng/ml, 110 +/- 43 ng/ml, and 101 +/- 49 ng/ml at weeks 1, 6, and 12, respectively. Initially, the plasma concentration-versus-time decay in three patients was linear, with a mean half-life (t1/2) of 1.3 +/- 0.5 h, while five patients had detectable concentrations in plasma after 4 h with an apparent delayed terminalphase t1/2 of 4.8 +/- 2.8 h. At week 6 the prolonged elimination pattern was noted in all patients (terminal t1/2 = 4.1 +/- 2.0 h). No correlation between hepatic enzyme levels and t1/2 was noted. These findings suggest that ZDV may display a prolonged elimination phase during multiple dosing. Further studies utilizing a more sensitive assay may help to further define this later phase of ZDV elimination. ·
Psychosocial Aspects of Hemophilia in Families: 2. Intervention Strategies and Procedures Source: Clinical Psychology Review. 2(2):171-181, 1982. Summary: A brief review is presented of the available literature concerning the effect of psychotherapeutic and patient education for hemophilia patients and their families. A session-by-session outline of a family-group educational strategy is presented, along with a rationale for the content of each session. This strategy utilizes a family systems perspective, is research-oriented and rigorous; maintains an educational focus, and is time-limited. An evaluation plan is recommended to assess the effectiveness of the intervention strategy. Suggestions are offered for using this modular design with other chronic disease groups. In addition, the potential for developing a patient education monograph from the material presented in the intervention sessions is described. 18 references.
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When the Bleeding Won't Stop: A Case Report on a Patient with Hemophilia Source: JADA. Journal of the American Dental Association. 124(12): 64-67. December 1993. Summary: This article presents a case report of a 39-year-old male who developed severe prolonged bleeding after periodontal surgery because of a previously undetected clotting Factor XI deficiency (Hemophilia C). The author also discusses the diagnosis and treatment of this bleeding disorder. The author reminds readers that unexplained prolonged postsurgical bleeding should alert the practitioner to possible previously undiagnosed bleeding or a clotting disorder. 3 figures. 22 references.
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Pharmacokinetics of Orally Administered Zidovudine Among Patients With Hemophilia and Asymptomatic Human Immunodeficiency Virus (HIV) Infection Source: March 1989. Aidsline Citation: Med/89271836. Contact: State University of New York Buffalo Erie County Medical Center, 462 Grider St., Buffalo, NY 14215. (716) 898-4119. Summary: Zidovudine (formerly azidothymidine, AZT) is used to treat certain patients infected with the human immunodeficiency virus (HIV). However, the clinical use of zidovudine (ZDV) in hemophilia patients may be complicated by the high incidence of chronic hepatitis in this patient population. To examine the pharmacokinetics of ZDV eight asymptomatic HIV-infected hemophilia patients received a single oral dose (300 mg). ZDV and its glucuronide metabolite (GZDV) were measured in serum by PLC. ZDV was rapidly absorbed with a wide range of peak serum concentrations (2052 +/- 970 ng/ml) at 0.5 h. Peak GZDV serum concentrations were 4751 +/- 2269 ng/ml at 1 h. Both ZDV and GZDV declined in a biexponential manner over 4 h. After 4 h, the ZDV serum concentration decay in three patients continued a log-linear decline, while five patients demonstrated a tri-exponential curve which had a mean terminal elimination half-life of 4.8 +/- 2.8 h. No relationship between ZDV or GZDV kinetics and the degree of hepatic enzyme elevation was observed. Although a therapeutic window for ZDV has yet to be described, the wide range of serum concentrations that result from a standard dose suggests that clinical monitoring of ZDV levels may be of value in certain patients. In addition, the prolonged elimination half-life of ZDV in the present study may provide a rationale for less frequent dosing in certain patients.
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AIDS, Hemophilia, and Prevention Efforts Within A Comprehensive Care Program Source: in American Psychologist; Vol. 43, No. 11. 1988. 6 p. (p. 971-976): b&w, refs. Contact: University of Oklahoma Health Sciences Center Mental Health Clinic, P.O. Box 26901, Oklahoma City, OK 73190-3048. (405) 271-4219. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: Approximately 92 percent of the persons with severe hemophilia A in the United States have been exposed to HIV from contaminated blood products. This article describes HIV prevention efforts initiated by the federally funded comprehensive hemophilia program. The authors point out that comprehensive care centers are useful for the delivery and evaluation of educational and preventive efforts. Since the majority of people with hemophilia receive health services from the centers, it is possible to use these existing structures to facilitate multicenter studies of AIDS prevention programs. The article discusses treatment center prevention and education services targeted to the spouses and sexual partners of persons with hemophilia, and adolescents and children with hemophilia and HIV/AIDs.
Federally-Funded Research on Hemophilia The U.S. Government supports a variety of research studies relating to hemophilia and associated conditions. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.19 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally-funded biomedical research projects conducted at universities, hospitals, and other institutions. Visit the CRISP Web site at http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket. You can perform targeted searches by various criteria including geography, date, as well as topics related to hemophilia and related conditions. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, 19 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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many federally-funded studies use animals or simulated models to explore hemophilia and related conditions. In some cases, therefore, it may be difficult to understand how some basic or fundamental research could eventually translate into medical practice. The following sample is typical of the type of information found when searching the CRISP database for hemophilia: ·
Project Title: CD4+ T Cell Response to Porcine Factor VIII Principal Investigator & Institution: Conti-Fine, Bianca M.; Distinguished Mcnight University Profess; University of Minnesota Twin Cities Twin Cities Minneapolis, Mn 55455 Timing: Fiscal Year 2000; Project Start 5-SEP-2000; Project End 1-JUL-2005 Summary: Patients with severe hemophilia A, after therapeutic exposure to factor VIII (fVIII), may develop inhibitory antibodies (Ab) to fVIII, that make their treatment difficult and costly. Antigen (Ag)-specific tolerance can be induced by administering the Ag through routes [e.g. nasal subcutaneous (s.c.)] that stimulate an immune response, than to abrogate an established response. In hemophilia patients with inhibitors, prevention of their further inhibitory response to forms of fVIII antigenically different from human fVIII may be easier to obtain that abrogation of their existing response to human fVIII. Porcine fVIII (pfVIII) is a possible such alternative to human fVIII. Mice genetically deficient in fVIII are a good model of hemophilia A, including appearance of inhibitors after intravenous (i.v.) Exposure to fVIII. To determine whether tolerization procedures using synthetic epitopes recognized by pfVIII-specific CD4+ cells prevent an immune response to pfVIII, in hemophilia A mice which already had inhibitors to human fVIII, will help development of similar treatments for hemophilia patients. The specific aims will be: 1) To determine the epitopes recognized and the cytokines secreted by anti- fVIII CD4+ cells in hemophilia A mice immunized with pfVIII, using overlapping peptides spanning the pfVIII sequence. To know the epitope repertoire of antipfVIII CD4+ cells, and whether they are of the Th1, Th2 or other subsets will help selecting the best tolerization procedures. 2) To determine whether prior i.v. exposure of hemophilia A mice to human fVIII affects the epitopes recognized by anti-pfVIII CD4+ cells after i.v. administrations of pfVIII. 3) To use synthetic pfVIII peptides forming CD4+ epitope sequences, for tolerization procedures in hemophilia A mice. Nasal tolerization procedures will be attempted first, using synthetic pfVIII CD4+ epitopes. If nasal tolerization will not prevent development of CD4+ and Ab responses to pfVIII, s.c. OR I.V. tolerization procedures will be attempted, using the same pfVIII epitope
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peptides. 4) To investigate the epitope repertoire of anti-pfVIII CD4+ cells in hemophilia patients treated sequentially with human and porcine fVIII to assess whether the characteristics of the anti-fVIII CD4+ cells in the mice are representative of those of CD4+ cells in hemophilia patients treated with human and porcine fVIII. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Chimeraplasty for Factor IX and VII Gene Expression Principal Investigator & Institution: Steer, Clifford J.; Professor; University of Minnesota Twin Cities Twin Cities Minneapolis, Mn 55455 Timing: Fiscal Year 2001 Summary: Site-specific correction of defective genes by homologous recombination has been achieved at only very low frequencies in the treatment of inherited metabolic diseases by gene therapy. Recently, a synthetic RNA/DNA hybrid duplex, oligonucleotide designed to align in perfect register with the homologous genomic sequence except for a single base mismatch was show to promote targeted single nucleotide (nt) conversion in genomic DNA in rat hepatocytes The process exploits the cell's efficient endogenous DNA mismatch repair pathways, thereby, making it a novel approach to gene therapy. The main objective of t his research project is to evaluate the utility of these molecules in correcting the single nt mutations associated with hemophilia. This objective tests our hypothesis that gene correction in effected hepatocytes will improve the phenotype associated with the disease. The first specific aim is to optimize (1) in vitro our non-viral asialoglycoprotein receptor hepatocyte- specific delivery systems, and (ii) chimeric RNA/DNA oligo oligonucleotide design for maximal conversion of the G to A transition at nt 1477 in the hemophilia B factor IX gene expressed in the Chapel Hill strain of dogs. The second specific aim is to evaluate the capacity of these molecules/delivery systems to promote targeted single nt conversion to correct the G to A transition in the canine factor IX in vivo. The non-viral delivery systems and chimeric oligonucleotides identified in Specific Aim 1 will be utilized. The relevant metabolic parameters will be monitored to quantitate the therapeutic effect of in situ genomic correction. Optimization of the dosing regimen, as well as the delivery vehicle and route of administration will be established. The third specific aim is to evaluate the potential of this technology in altering the genomic factor VII gene to produce the optimized factor VIIa mutations devised in Project 2. The initial work will be performed in vitro using cultured hepatocytes to optimize the delivery and design of the chimeric oligonucleotides. The selected factor VIIa mutation will then be generated in vivo and evaluated in collected hemophilia A phenotype in a factor
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VIII deficient mouse model. The relevant metabolic parameters will be monitored to quantitate the therapeutic effect of in situ genomic correction. Optimization of the dosing regimen, as well as the delivery vehicle and route of administration will be established. The long term goal of this research proposal is to: (i) to optimize non-viral delivery systems and oligonucleotide design that will promote the utility of RNA/DNA oligonucleotides for correcting single nt mutations associated with hemophilia; (ii) elucidate the optimal parameters for in vivo therapeutic correction of single nt mutations using this technology in the Chapel Hill strain of hemophilia B dogs, and (iii) evaluate the use of this technology for creating factor VIIa variants in vivo and there therapeutic benefit. The comparison of the in vitro and in vivo correction results will establish the feasibility for in vivo gene therapy approach using this technology for treatment of hemophilia. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Developing Gene Correcting Technology for Hemophilia Principal Investigator & Institution: Kurihara, Takao; ; Kimeragen, Inc. 300 Pheasant Run Newtown, Pa 18940 Timing: Fiscal Year 2000; Project Start 9-SEP-2000; Project End 8-MAR2001 Summary: A novel oligonucleotide-mediated gene targeting technology (Chimeraplasty in concert with a delivery technology are proposed to demonstrate the feasibility of permanently correcting point mutations that cause hemophilia in animal models of the disease. Current treatments for hemophilia, which is caused by a deficiency in blood clotting factors, involve injections of factor concentrates. This treatment must be repeated periodically, since the genetic mutations that cause the disease have not been corrected. Preliminary results demonstrated that Chimeraplasty can effect specific sequence changes in several chromosomal genes at high frequency, a requirement for a technology that could revolutionize therapy by correcting mutations that cause disease. We propose to demonstrate that Chimeraplasty can be used to target the factor VIII and factor IX genes, which are frequently mutated in hemophilia patients. We also propose to develop and optimize the hepatocyte delivery system for use in mice and dogs. These developments will enable testing the effectiveness of Chimeraplasty to correct factor VIII and factor IX gene mutations that cause hemophilia in mice and dogs. Testing Chimeraplasty in these animal models will provide critical information about the potential of gene correction therapies. PROPOSED COMMERCIAL APPLICATIONS: Hemophilia represents a significant health care market with 20,000 cases of
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hemophilia A and B in the US and over 80,000 cases in Europe. Since the majority of mutations that cause hemophilia are point mutations, they would be potential targets for gene correction using Chimeraplasty. Gene correction therapy would be a novel alternative to current treatments that require repeated injections of clotting factor concentrates, which can cost $65,000 or more per year. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Effects of Combined Antiretroviral Therapy on Coagulation Factors Principal Investigator & Institution: Eyster, M E.; ; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002 Summary: Effects of Combination Antiretroviral Therapy including Indinavir Sulfate on Coagulation Factors, on Platelet Aggregation and on Factor VIII/IX in HIV-1 Seropositive patients with Hemophilia A or B. The objectives of this protocol are to assess whether, in the specific population being studied, a combined therapy of indinavir sulfate NRTIs induces changes in prospectively identified elements of the coagulation system. It is recognized apriori, that due to the nonfeasibility of having a group in which indinivar sulfate is not added to combination NRTI therapy, it will be impossible to determine what changes in the coagulation system, if any, would have been observed in the absence of indinivar sulfate. However, to help assess changes in the pharmacokinetic half-life and recovery of infused factor VIII, protease inhibitor-experienced HIV-1 seropositive hemophilia A patients will serve as a laboratory control group. We hypothesize that after 12 weeks of treatment, coadministration of indinavir sulfate and NRTIs to protease inhibitor-naive HIV-1 seropositive hemophilia A patients will decrease the pharmacokinetic half-life of infused factor VIII compared to preindinavir sulfate therapy baseline relative to changes observed in the laboratory control group. Secondarily, during a 52 week coadministration of indinavir sulfate and combination NTRI therapy to protease inhibitornaive HIV-1 seropositive hemophilia patients after 12 weeks of treatment: the pharmacokinetic recovery of infused factor VIII in hemophilia A patients will be reduced, relative to changes observed in the laboratory control group; the pharmacokinetic half-life of infused factor IX in hemophilia B patients will be reduced and the pharmacokinetic recovery of infused factor IX in hemophilia B patients will be reduced. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket
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Project Title: Epidemiology and Immunology of Hemophilia A Inhibitors Principal Investigator & Institution: Ragni, Margaret V.; Medicine; University of Pittsburgh at Pittsburgh 4200 5Th Ave Pittsburgh, Pa 15260 Timing: Fiscal Year 2000; Project Start 0-SEP-1998; Project End 1-AUG2002 Summary: (Adapted from the Applicant's Abstract) The purpose of this study is to determine the risk factors associated with inhibitor formation in hemophilia A and to study the mechanism of tolerance in the murine hemophilia A model. Clinical data on 364 individuals with hemophilia and inhibitors, and stored frozen plasma and white cells on 189 of these, identified in the Hemophilia Malignancy Study (HMS), and the hemophilia A murine model are available for study. Inhibitor formation in individuals with hemophilia is a difficult therapeutic challenge, refractory to standard treatment, potentially life-threatening, costly, and a potential complication of new treatment, such as gene therapy. The major hypothesis of this study is that suppression of immunoregulatory cytokines will prevent factor VIII inhibitor formation in the hemophilia A murine model: if successful, a treatment protocol could be developed for individuals identified to be at highest risk for inhibitor formation. Through this approach to the epidemiology and immunology of inhibitor formation, the investigators may improve the health care of individuals with hemophilia. The specific aims include: (1) A case-control study comparing prevalent hemophilia patients with inhibitors identified in the HMS Study with three age-matched controls without inhibitors to determine clinical and laboratory characteristics associated with inhibitor development. (2) a histocompatibility study identifying patterns of HLA Class II antigens by molecular typing in hemophilic subjects identified in HMS, with and without inhibitors, which may be linked to inhibitor formation. (3) An animal tolerance study in the hemophilia A murine model, evaluating blockade of T cell costimulatory pathways by CTLA4Ig and anti-CD40L mAb, to prevent inhibitor formation. (End of Abstract) Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket
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Project Title: Factor VIII Vector for Treatment of Severe Hemophilia A Principal Investigator & Institution: White, Gilbert C.; Professor; University of North Carolina Chapel Hill Chapel Hill, Nc 27514 Timing: Fiscal Year 2000; Project Start 1-OCT-1974; Project End 0-NOV2002 Summary: The purpose of this study is to use an experimental form of gene therapy treatment for hemophilia, using a human Factor VIII
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retrovirus vector [hFVIII(V)]. In gene therapy, a gene is put into cells to provide different instructions from those provided by the genes a person already has. Genes are like "blueprints" which provide detailed instructions to a cell about how to function. People with severe hemophilia are born without a gene, which makes normal FVIII. The goal of gene therapy for hemophilia is to provide a FVIII-producing gene to the body cells so that a person with hemophilia will be able to make his own FVIII. There are two primary goals of this study: 1) to find out how safe and effective human factor VIII vector treatment is for individuals with severe hemophilia A and 2) to measure the amount of Factor VIII which is produced in the body after a given dose of human factor VIII vector in order to determine the best dose for treatment. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Gene Therapy for Blood Protein Deficiencies Principal Investigator & Institution: Ponder, Katherine P.; Associate Professor; Barnes-Jewish Hospital 216 S Kingshighway Blvd St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 5-SEP-1996; Project End 1-DEC2005 Summary: Hemophilia B occurs in 1:30,000 males and is associated with a life-long bleeding diathesis. Although IV injection of Factor IX can prevent or stop bleeding, this treatment is inconvenient, expensive, and can transmit infections. Hepatic gene therapy could permanently correct the clinical manifestations of hemophilia. Retroviral vectors (RV) can result in long-term and therapeutic levels of expression of coagulation factors from the liver in rodents, and are currently being used in a clinical trial for Hemophilia A in humans. However, there are two major problems that must be solved before RV-mediated hepatic gene therapy will be used routinely: 1) identify ways to achieve a higher efficiency of stable gene transfer without major toxicity; and 2) identify methods for blocking an immune response to the therapeutic gene in the context of RV-mediated hepatic gene therapy. This project will address both of these issues. The first aim is to determine if delivery of an RV expressing the canine Factor IX (cFIX) cDNA into the liver can reduce the bleeding manifestations of Hemophilia B dogs obtained from a colony that rarely makes antibodies to the canine protein. This should allow us to quantify gene expression without the confounding issue of an immune response. Initial studies will use neonatal dogs, as their high baseline level of hepatocyte replication allows transduction of 9 percent of liver cells. Subsequent studies will use hepatocyte growth factor to induce replication in young adult dogs. Animals will be evaluated for cFIX
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levels, development of antibodies, bleeding, and for other adverse effects. The second aim will address the second major problem of RV-mediated hepatic gene therapy, that of immune responses to the therapeutic gene product. In this aim, we will try to block immune responses to the de novo expression of a transgene from an RV in mice by either performing neonatal gene transfer, or by injecting immunoinhibitory agents at the time of gene therapy in young adults. Although mice are optimal for initial studies due to cost considerations, approaches that function in inbred mice sometimes fail in outbred larger animals. We will therefore test any immunomodulatory approaches that function in mice for their efficacy in normal and Hemophilia B dogs in Aim III. Success in this project might lead to a safe, effective, and permanent therapy for Hemophilia B. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Genetics of Inhibitor Formation in Hemophilia Principal Investigator & Institution: Gill, Joan C.; Pediatrics; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 53226 Timing: Fiscal Year 2000; Project Start 0-SEP-1998; Project End 1-AUG2002 Summary: Hemophilia A is a severe hemorrhagic disorder due to deficiency of coagulation factor VIII. Approximately 15 to 20 percent of severely affected patients develop antibodies to factor VIII with replacement therapy. These antibodies, termed inhibitors, neutralize factor VIII therapy causing significant morbidity and mortality. Recent studies in animal models suggest that inhibitors are also likely to hinder the success of gene therapy approaches. Several lines of evidence, including analyses of hemophilic brother pairs and animal models, indicate that the propensity to develop inhibitors is strongly influenced by genetic factors other than the specific factor VIII mutation or histocompatibility (MHC) locus type. This proposal aims to employ newly developed techniques for genetic linkage analysis and genome scanning to identify the inhibitor susceptibility genes. At least 200 well characterized severe hemophilia A brother pairs, both concordant and discordant for inhibitor formation, and other informative family members will be identified through a collaborative network of investigators in over 70 hemophilia treatment centers. Samples will be collected, and a repository of genomic DNA accompanied by a clinical and epidemiologic data base characterizing the hemophilic inhibitor phenotype including screening for the intron 22 inversion mutation, will be created. A panel of candidate genes that are likely to play a positive or negative role in inhibitor development will then be examined through
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fine mapping of polymorphic markers in the regions of interest, including the MHC, immunoglobulin genes, the T-cell receptor genes, and selected cytokine and cytokine receptor genes. If candidate genes fail to account for the genetic susceptibility to inhibitor development, a total 10 cM genome scan utilizing approximately 350 highly polymorphic microsatellite repeat markers will be performed. Linkage analysis will include both non-parametric testing of brother pairs for multiple susceptibility genes and more powerful parametric methods for one and two gene models in extended pedigrees. Identification of new genomic regions linked to inhibitor development will then be explored with fine mapping of the chromosomal areas and gene cloning techniques. The DNA bank and database will also be a uniquely valuable resource for future studies of patients with hemophilia. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Human Application of AAV Mediated Muscle Directed Factor IX Gene Transfer Principal Investigator & Institution: Cohen, Alan R.; Professor and Chairman; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001 Summary: Project #4. Hemophilia B is an X-linked bleeding disorder resulting from a deficiency of coagulation factor IX. Studies of patients treated with prophylactic factor IX protein infusions to maintain plasma levels >1% show that the chronic arthropathy and life-threatening hemorrhages associated with the disease may be prevented. This experience and the ongoing concern about blood-borne diseases transmitted by the use of factor concentrates forms the rationale for a gene transfer approach to treating hemophilia. Our group has developed a solid preclinical experience with gene transfer using an adenoassociated viral (AAV) vector to mediate transfer of the gene for factor IX to muscle. We have shown an absence of local or systemic toxicity due to AAV injection in rodents and dogs, and demonstrated proof of principle that ultrasound- guided intramuscular administration of AAV containing a species-specific transgene in dogs with hemophilia B results in expression of factor IX in muscle and therapeutically meaningful levels of factor IX (1-2%) in the plasma. Persistent of high-titer antibodies to factor IX or the presence of vector sequences in the semen have been demonstrated in this large animal model. Herein, we propose to carry out studies in humans with severe hemophilia B. Aim #1 details 2 studies using AAV to direct expression of human factor IX in muscle in patients with hemophilia B after ultrasound guided injection of vector into
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muscle. In the first a dose-escalation study 3 groups of 3 patients will be evaluated for toxicity. The second is a dose finding and efficacy study to determine the dose of AAV-hFIX that results in 5-7% plasma factor IX levels (0.25- 0.35 mug/mL), and to show efficacy of this dose in a group of approximately 25 patients by assessing number of bleeds, factor concentrate use and clinical effect using a hemophilia-specific health assessment tool that we will design. In Aim #2 we will measure levels of circulating reporter gene in rabbits following ultrasound guided administration of AAV in order to determine the optimal volume of injectate, concentration of vector, and the number of injection sites. In Aim #3, we will characterize the human immune response to vector proteins and the expressed factor IX transgene, including surveillance for the formation of anti-factor IX. Experiments in ultrasound guided injection of vector. Given the preclinical experience using this strategy, the proposed studies are likely to result in the first long-lived meaningfully correction of a human genetic disorder. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Inhibitor Formation in Gene Therapy for Hemophilia Principal Investigator & Institution: High, Katherine A.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 0-SEP-1998; Project End 1-AUG2002 Summary: Our laboratory has had a longstanding interest in gene therapy as an approach to treating hemophilia B. Recently we have developed promising data in animal models of hemophilia using AAVmediated gene transfer into muscle and liver. AAV is particularly attractive as a gene transfer vehicle because it is not associated with a strong immune response to the vector itself. In an engineered mouse model of hemophilia B in which the F.IX gene is deleted, however, successful gene transfer and expression have been accompanied by development of antibodies to the transgene product. In dogs with hemophilia B resulting from a missense mutation in the F.IX gene, antibody formation following AAV-mediated muscle-directed gene transfer has been either absent or transient and low-level. Based on our studies thus far, we hypothesize that the antibody response to the transgene product in AAV- mediated gene transfer will be influenced by the underlying mutation, and that this effect is based on whether or not the mutation allows the development of T cell tolerance. In the proposed studies we will use murine and canine models of hemophilia B to 1) define the role of T helper cells in the immune response to a transgene
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administered via intramuscular injection of an AAV vector; 2) characterize more fully the immune response to the transgene product in dogs with hemophilia B; and 3) determine whether any of several straightforward clinically feasible maneuvers can be used to modulate the immune response to the transgene product. These studies will involve a collaboration between the P.I.'s lab and the laboratory of Dr. Hildegund Ertl, an immunologist with experience in characterizing immune responses in the setting of viral vectors. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Low Antigenicity Factor VIII Principal Investigator & Institution: Bergman, Garrett E.; ; Octagen Corporation 1 Bala Ave, Ste 300 Bala Cynwyd, Pa 19004 Timing: Fiscal Year 2001; Project Start 1-JUL-2000; Project End 0-JUN2003 Summary: (Applicant's Description Verbatim): Our goal is to obtain registration of a low antigenicity recombinant fVIII product for the treatment of patients with neutralizing antibodies against human fVIII. Such inhibitor patients include those with hemophilia A who develop alloantibodies when treated with replacement human fVIII, as well as patients with "acquired hemophilia" who develop autoantibodies against endogenous fVIII. The development of an inhibitor to Will is a serious, potentially life threatening condition. Current treatment options are limited to so-called "bypassing" agents" and plasma derived porcine fVIII (Hyate:C). Bypassing agents are nonphysiologic and occasionally cause overdrive of the coagulation cascade. This may result in severe complications, such as disseminated intravascular thrombosis or myocardial infarction. Use of Hyate:C is currently limited by regulatory, treater and patient concerns arising from the plasma source of the product and side effects attributable to the relative impurity of the product. Applicant has exclusive access to recombinant porcine fVIII. Applicant has obtained substantial in vitro and in vivo data that supports the suitability of recombinant porcine Will for development as a low antigenicity fVIII product. Phase II of applicant's SBIR project shall include: completion of the preclinical development of the product, submission of an IND to the FDA, and initial safety and efficacy studies of the product in hemophilia A patients. In the preclinical stage, the safety and immunogenicity of the product will be studied in mice and cynomolgus monkeys. Pharmacokinetic data will be obtained in a highly predictive dog model of hemophilia A. After an ND is filed, the safety and pharmacokinetics of the product will be studied in a clinical trial in which approximately twelve inhibitor patients shall receive the product.
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Proposed Commercial Application: Approximately 26% of all hemophilia A patients develop antibodies. A significant portion cannot successfully be treated with human fVIII. A recombinant, low antigenicity fVIII product would compete well in the fVIII inhibitor patient market and be a first line therapy for "acquired hemophilia." Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: New Therapies for Hemophilia Principal Investigator & Institution: Key, Nigel S.; Associate Professor; Medicine; University of Minnesota Twin Cities Twin Cities Minneapolis, Mn 55455 Timing: Fiscal Year 2000; Project Start 5-SEP-2000; Project End 1-JUL-2005 Summary: The theme of this Program Project proposal is to develop novel therapies for hemophilia. In particular, the focus will be on the most significant complication of the disease, namely the occurrence of inhibitory antibodies to the clotting factors that are normally used to treat bleeding episodes. The development of an inhibitory is a devastating event, which leads inevitably to increased morbidity, and cost of therapy (which is already exceptionally high for patients without this complication). Furthermore, development of inhibitors remains one of the principal concerns surrounding gene therapy for hemophilia. We will adopt a multi- disciplinary approach to this problem, concentrating on bio-engineered clotting factors (mutants of factor VIIa with enhanced pro-coagulant activity, and human-porcine factor VIII hybrid molecules with reduced immunogenicity and antigenicity. Although not part of this proposal, clinical trials involving these proteins can be realistically anticipated as a longer term goal. In Project 1 ("The Role of Tissue trials involving these proteins can be realistically anticipated as a longer term goal. In Project 1 ("The Role of Tissue Factor in Hemophilia"), we will examine the biochemical basis for tissue factor encryption in vitro, and develop methods to measure expression of both the encrypted and procoagulant forms of tissue factor in vivo. In Project ("Enhanced Vitamin Kdependent Proteins in Hemophilia"), recombinant factor VII molecules that have been mutated at specific residues in the membrane contact region will be characterized with respect to their pro-coagulant activity. The anti-hemorrhagic efficacy (and potential undesirable thrombogenicity) of selected mutants will be tested in animal models of hemophilia. In Project 3 ("CD4+ T Cell Response to Porcine Factor VIII"), CD4+ T cell responses to human-porcine hybrid FVIII molecules will be examined, primarily in the murine model of hemophilia A with a FVIII inhibitor. It is our hypotheses that these hybrid molecules may be less immunogenic than human FVIII. Finally, in Project 4 ("Chimeraplasty for
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Factor IX and Factor VII Gene Expression"), we will use chimeric RNA/DNA constructs to "repair" the point mutation in the factor IX gene in canine hemophilia, and deliberately induce a selected point mutation in the factor VII gene to promote expression of high activity FVII(a) in vivo that will "by-pass" the need for factor VIII (or IX) in patients with inhibitors. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Targeted Gene Therapy for Hemophilia A Principal Investigator & Institution: Bahou, Wadie F.; Professor; Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2000; Project Start 0-SEP-1994; Project End 0-JUN2004 Summary: Hemophilia A (congenital deficiency of coagulation factor VIII) is the most common (serious) congenital bleeding disorder worldwide. Hemophilia A is a model system for definitive genetic therapy for the following reasons: (I) it is caused by a single- gene defect, (ii) its biological processing and synthesis have been extensively studied, (iii) therapeutic levels of plasmatic clotting factors ameliorate hemorrhagic episodes, and (iv) physiologic levels in human are low (100 200 ng/mL), with clinical manifestations closely paralleling circulating fVIII levels such that therapeutic benefit can be reached with 5 percent fVIII activity (5 - 10 ng/mL). As a definitive means of genetic treatment, this laboratory has focused on adeno- associated virus (AAV) for fVIII gene therapy strategies, as AAV infection is not associated with human diseases, and cells carrying proviruses fail to express novel cell-surface antigens, thereby failing to serve as immunological targets. If a helper virus is not present during an AAV infection, the AAV genome integrates in a site-specific region (AAVS1) on human chromosome 19q, a property that is dependent on AAV rep68/78 and inverted terminal repeats (TR's). By virtue of being produced primarily in the liver, the hepatocyte is the logical site for gene replacement strategies for hemophilia A, although vascular endothelial cells remain an attractive target as a means of regulated delivery by co-expression with Von Willebrand factor. In this proposal, we will continue to develop novel viral vectors for hemophilia A gene therapy, viruses which collectively share the unique integrating properties of the AAV terminal repeats, as a means of definitive treatment for hemophilia A. To date, we have been the only laboratory that has successfully generated a fVIII/rAAV virus, serving as proof-ofprinciple for further research in this direction. Three viruses will be characterized for their ability to deliver B-domain-deleted factor VIII recombinant AAV, adeno/adeno-associated hybrid (Ad/AAV) virus,
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and mini-adenovirus (mAD) containing the AAV TR's, generated as a unique transcriptional byproduct of parental Ad/AAV hybrid viruses. Additional aims will be directed at establishing the utility of vascular endothelial cells as targets for fVIII delivery, using both in vitro and in vivo models for targeted delivery into these cellular types. Optimal viral vectors will be studied in murine and canine models of hemophilia A. The proposed work is designed to lay the foundation for anticipated trials in humans. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Third Workshop on Gene Therapies for Hemophilia Principal Investigator & Institution: Verma, Inder M.; Professor; National Hemophilia Foundation 116 W 32Nd St, 11Th Fl New York, Ny 10001 Timing: Fiscal Year 2000; Project Start 5-APR-2000; Project End 4-APR2001 Summary: Hemophilia is a genetic disorder of blood coagulation affecting approximately 17,000 individuals in the United States. The two most commons forms of hemophilia are hemophilia A and hemophilia B, caused by defects or deficiencies in clotting factors VIII and IX, respectively. While treatment is effective for many people with hemophilia, it consists of life-long, intravenous infusions with clotting factor administered during or after a bleeding event. This therapy has many drawbacks, and thus gene therapy has been investigated as a means of curing hemophilia. Hemophilia is among those genetic disorders most likely to be amenable to gene therapy because it results from defects within single genes. Gene therapy for hemophilia would transfer functioning clotting factor genes into cells in a person with hemophilia, enabling that individual's body to manufacture clotting factor proteins. There has been considerable success in pre-clinical studies in using various viral vectors to obtain sustained expression of clotting factor in animals. Also, the first human trial for an ex vivo, nonviral gene therapy began in December 1998. However, a number of research questions remain unanswered, and progress in the field is facilitated by holding regularly convened workshops where investigators can discuss the current state of their work. The National Hemophilia Foundation proposes to hold the third in a series of gene therapy workshops in March 2000. The last workshop in November of 1998 raised troubling questions about toxicity and inhibitory response in animal trials, and a major portion of the workshop will be devoted to the immune response to gene therapy. Other concerns to be addressed include translation of pre-clinical findings to human trials; ethical concerns in the use of human subjects; the effect of hepatitis C and HIV
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infection and treatment on gene therapy; regulatory issues involved in approval of gene therapy trials; and intellectual property issues that may impede the marketing of gene therapy products. The workshop affords a critically important opportunity for open communication and debate among basic researchers, clinicians, federal regulators, representatives of biotechnology companies, and members of the bleeding disorders community as human clinical trials proceed. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·
Project Title: Universal Data and Serum Specimen Collection System for Hemophilia Principal Investigator & Institution: Bona, Robert D.; ; University of Connecticut Sch of Med/Dnt of Medicine and Dentistry Farmington, Ct 06032 Timing: Fiscal Year 2000; Project Start 5-DEC-1993; Project End 0-NOV2003 Summary: The primary congenital bleeding disorders are hemophilia A and B, which affect approximately 1 in 5,000 males and von Willebrand's Disease which affects 1 in 100 men and women. Several plasma proteins called factors are necessary for normal blood clotting. Persons with hemophilia are either missing a particular factor in their blood that is essential to the clotting process or the protein is present but does not work. Without this factor, bleeding into muscles, joints, and internal organs often occurs without any noticeable trauma. The treatment of a bleeding episode involves the replacement of the missing protein through intravenous administration of factor concentrate which is derived from, or contains components of human blood. The frequent bleeding and the necessary intravenous administration of blood products to control the bleeding are responsible for the two most severe complications of hemophilia: 1) development of chronic joint disease from repeated bleeding into major joints; and 2) infection with viral, blood-borne disease such as hepatitis and HIV. About three-fourths of all persons with hemophilia in the US receive some of their treatment from federally-sponsored, specialized hemophilia treatment centers (HTCs). The Center for Disease Control and Prevention (CDC) provides support to these treatment centers for programs designed to prevent complications of hemophilia. The Universal Data and Serum Specimen Collection System will extend CDC's collaboration with the HTCs by assisting with the analysis of a uniform set of clinical data which are used to monitor the extent of complications in congenital bleeding disorders in the US. Specific measurements will be used to evaluate the degree of joint disease. In addition, serum will be tested for the presence of blood borne
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pathogens. The remainder of each serum specimen will be used by the CDC to establish a serum bank for possible future use in evaluating the safety of blood products. Information from this system will be used to assess the safety of the blood supply and to develop and monitor the effectiveness of interventions designed to address the mandate from congress which is to reduce or prevent the complications of hemophilia. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket
E-Journals: PubMed Central20 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).21 Access to this growing archive of e-journals is free and unrestricted.22 To search, go to http://www.pubmedcentral.nih.gov/index.html#search, and type “hemophilia” (or synonyms) into the search box. This search gives you access to full-text articles.
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine. The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to the public.23 If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html. 21 With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 22 The value of PubMed Central, in addition to its role as an archive, lies the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 23 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication. 20
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some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with hemophilia, simply go to the PubMed Web site at www.ncbi.nlm.nih.gov/pubmed. Type “hemophilia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for “hemophilia” (hyperlinks lead to article summaries):
Vocabulary Builder Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized Tlymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Lack or loss of strength and energy, weakness. [EU] Asymptomatic: Showing or causing no symptoms. [EU] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Chromosomal: Pertaining to chromosomes. [EU] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Cytokines: Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. [NIH] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU]
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Endogenous: Developing or originating within the organisms or arising from causes within the organism. [EU] Enzyme: Substance, made by living cells, that causes specific chemical changes. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Granulocytopenia: Agranulocytosis. [EU] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Infarction: 1. the formation of an infarct. 2. an infarct. [EU] Intramuscular: Within the substance of a muscle. [EU] Intravascular: Within a vessel or vessels. [EU] Intravenous: Within a vein or veins. [EU] Malaise: A vague feeling of bodily discomfort. [EU] Membrane: Thin, flexible film of proteins and lipids that encloses the contents of a cell; it controls the substances that go into and come out of the cell. Also, a thin layer of tissue that covers the surface or lines the cavity of an organ. [NIH] Metabolite: process. [EU]
Any substance produced by metabolism or by a metabolic
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Nasal: Pertaining to the nose. [EU] Nausea: An unpleasant sensation, vaguely referred to the epigastrium and abdomen, and often culminating in vomiting. [EU] Neonatal: Pertaining to the first four weeks after birth. [EU] Pathogen: Any disease-producing microorganism. [EU] Phenotype: The entire physical, biochemical, and physiological makeup of an individual as determined by his or her genes and by the environment in the broad sense. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU]
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Preclinical: Before a disease becomes clinically recognizable. [EU] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Proviruses: Duplex DNA sequences in eukaryotic chromosomes, corresponding to the genome of a virus, that are transmitted from one cell generation to the next without causing lysis of the host. Proviruses are often associated with neoplastic cell transformation and are key features of retrovirus biology. [NIH] Receptor: 1. a molecular structure within a cell or on the surface characterized by (1) selective binding of a specific substance and (2) a specific physiologic effect that accompanies the binding, e.g., cell-surface receptors for peptide hormones, neurotransmitters, antigens, complement fragments, and immunoglobulins and cytoplasmic receptors for steroid hormones. 2. a sensory nerve terminal that responds to stimuli of various kinds. [EU] Refractory: Not readily yielding to treatment. [EU] Serum: The clear portion of any body fluid; the clear fluid moistening serous membranes. 2. blood serum; the clear liquid that separates from blood on clotting. 3. immune serum; blood serum from an immunized animal used for passive immunization; an antiserum; antitoxin, or antivenin. [EU] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Systemic: Relating to a process that affects the body generally; in this instance, the way in which blood is supplied through the aorta to all body organs except the lungs. [NIH] Thrombosis: The formation, development, or presence of a thrombus. [EU] Toxic: Pertaining to, due to, or of the nature of a poison or toxin; manifesting the symptoms of severe infection. [EU] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]
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CHAPTER 5. PATENTS ON HEMOPHILIA Overview You can learn about innovations relating to hemophilia by reading recent patents and patent applications. Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.24 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available to patients with hemophilia within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available to patients with hemophilia. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information.
24Adapted
from The U. S. Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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Patents on Hemophilia By performing a patent search focusing on hemophilia, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on hemophilia: ·
Adenoviral vectors for treatment of hemophilia Inventor(s): Connelly; Sheila (Gaithersburg, MD), Kaleko; Michael (Rockville, MD), Smith; Theodore (Germantown, MD) Assignee(s): Genetic Therapy, Inc. (Gaithersburg, MD) Patent Number: 5,935,935 Date filed: June 7, 1995 Abstract: An adenoviral vector including at least one DNA sequence encoding a clotting factor, such as, for example, Factor VIII, or Factor IX. Such vectors may be administered to a host in an amount effective to treat hemophilia in the host. The vectors infect hepatocytes very efficiently, whereby the hepatocytes express the DNA sequence encoding the clotting factor. Excerpt(s): This invention relates to adenoviral vectors. More particularly, this invention relates to adenoviral vectors which may be employed in the treatment of hemophilia. ... Hemophilias A and B are X-linked, recessive bleeding disorders caused by deficiencies of clotting Factors VIII and IX, respectively. In the United States there are approximately 17,000 patients with hemophilia A and 2,800 with hemophilia B. The clinical presentations for both hemophilias are characterized by episodes of spontaneous and prolonged bleeding. Patients frequently suffer joint bleeds which lead to a disabling arthropathy. Current treatment is directed at stopping the bleeding episodes with intravenous infusions of plasma-derived clotting factors or, for hemophilia A, recombinant Factor VIII. However, therapy is limited by the availability of clotting factors, their short half-lives in vivo, and the high cost of treatment, which can approach 100,000 dollars per year. ... Gene therapy offers the promise of a new method of treating hemophilia. Several groups of researchers have
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conducted research with retroviral vectors containing RNA encoding Factor VIII and Factor IX. Prior to Applicants' invention, virtually every attempt to produce therapeutic levels of these factors in vivo with such vectors, however, has been unsuccessful. The cDNA and the RNA for Factor VIII has been particularly difficult to work with. Web site: http://www.delphion.com/details?pn=US05935935__ ·
Methods for treating hemophilia A and B and AIDS and devices used therein Inventor(s): Pollard; Harvey B. (11008 Lamplighter La., Potomac, MD 20854) Assignee(s): none reported Patent Number: 5,908,399 Date filed: September 26, 1996 Abstract: The present invention provides a method for treating Hemophilia A or B which comprises implanting in fluid communication with the bloodstream of a mammal in need of such treatment a permeable membrane having one or more walls, a hollow chamber therewithin, a plurality of holes extending through the walls of the membrane and permitting fluid to enter and exit the chamber of the membrane, each of the holes being sized so that it is large enough to permit inactive Factor VII to enter the chamber of the membrane and activated Factor VIIa to exit the chamber of the membrane but small enough to prevent fibrinogen from entering the chamber of the membrane, a plurality of supports being disposed within the chamber, and an effective amount of a Factor VII activator or a source of the activator being bound to the supports, wherein inactive Factor VII in blood passing through the membrane becomes activated into Factor VIIa upon contact with the activator within the chamber.The present invention also provides a method for treating Hemophilia A or B extracorporeally. The present invention further provides methods for treating AIDS as well as permeable membranes for use in the methods above. Excerpt(s): The extrinsic pathway in hemophilia patients is normal, but since all of Factor VII is in the inactivated state, little or no activation of the extrinsic pathway occurs when needed. Apparently, the intrinsic pathway is needed for tonic activation of Xa and generation of VIIa. The relative rate of conversion of X to Xa by VIIa alone is 15 million-fold less than the rate observed when VIIa is complexed with Tissue Factor (Bom, VJJ and Bertina, RM (1990) Biochem. J. 265:327-336). Nonetheless, the
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small amount of Xa generated by the administration of r-Factor VIIa is sufficient to reduce bleeding in afflicted patients. ... The present invention provides a method for treating Hemophilia A or B which comprises implanting in fluid communication with the bloodstream of a mammal in need of such treatment a permeable membrane having one or more walls, a hollow chamber therewithin, a plurality of holes extending through the walls of the membrane and permitting fluid to enter and exit the chamber of the membrane, each of the holes being sized so that it is large enough to permit inactive Factor VII to enter the chamber of the membrane and activated Factor VIIa to exit the chamber of the membrane but small enough to prevent fibrinogen from entering the chamber of the membrane, a plurality of supports being disposed within the chamber, and an effective amount of a Factor VII activator or a source of the activator being bound to the supports, wherein inactive Factor VII in blood passing through the membrane becomes activated into Factor VIIa upon contact with the activator within the chamber. ... The present invention also provides a method for treating Hemophilia A or B which comprises circulating extracorporeally blood from a mammal in need of such treatment through a permeable membrane having one or more walls, a hollow chamber therewithin, a plurality of holes extending through the walls of the membrane and permitting fluid to enter and exit the chamber of the membrane, each of the holes being sized so that it is large enough to permit inactive Factor VII to enter the chamber of the membrane and activated Factor VIIa to exit the chamber of the membrane but small enough to prevent fibrinogen from entering the chamber of the membrane, a plurality of supports being disposed within the chamber, and an effective amount of a Factor VII activator or a source of the activator being bound to the supports, wherein inactive Factor VII in blood passing through the membrane becomes activated into Factor VIIa upon contact with the activator within the chamber. Web site: http://www.delphion.com/details?pn=US05908399__ ·
Agent for the therapy of factor VIII-resistant hemophilia A, and a process for the preparation thereof Inventor(s): Heimburger; Norbert (Marburg, DE), Wenz; Karlheinz (Weimar, DE), Wormsbacher; Wilfried (Kirchhain, DE) Assignee(s): Behringwerke Aktiengesellschaft (Marburg/Lahn, DE) Patent Number: 5,091,363 Date filed: August 10, 1988
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Abstract: An agent for the therapy of hemophilia A which is resistant to treatment with factor VIII is described, and is obtainable by maintaining a mixture of factor VIII, antithrombin III, a phospholipid and calcium ions in an aqueous solution at a temperature of from 1.degree. to 45.degree. C. for at least one minute, adding factor IX, and maintaining the solution at a temperature offrom 1.degree. to 45.degree. C. until addition of a sample of this solution to an inhibitor plasma results in a partial thromboplastin time (PTT) of 15 to 30 seconds, where appropriate adding a polyol and, where appropriate, an amino acid, and, where appropriate, drying the solution. Excerpt(s): The invention relates to an agent for the treatment of patients who have hemophilia A and do not respond to the conventional treatment with factor VIII, and to a process for the preparation thereof. ... Up to about one quarter of patients who have hemophilia A and are treated with factor VIII concentrates develop what are called inhibitor hemophilias. It is characteristic of these that non-precipitating isoantibodies against the subunit of the factor VIII molecule which harbors the clotting activity (F VIII:C) circulate in the blood of the patient. These antibodies, which are found in titers which may reach very high levels, namely from 100 up to a few 1000 U/ml, in the plasma of hemophiliacs, neutralize corresponding activities of F VIII when they are infused for replacement in patients who do not synthesize factor VIII or synthesize it in inadequate amounts. The amount of inhibiting antibodies is often so high that even administration of large amounts of factor VIII do not result in successful therapy. ... A number of measures have been tried for the treatment of the serious hemorrhages which often occur in patients who have hemophilia A and have developed antibodies, but these measures have been only partially successful. These measures include infusion of prothrombin complex concentrates (PCC) which contain factors II, VII, IX and X. In emergency situations there has even been use of factor VIII from animal plasma, predominantly from bovine or porcine plasma, with acceptance of the risk of administration of foreign protein. In recent times, activated coagulation factors have also been used with a certain success. Web site: http://www.delphion.com/details?pn=US05091363__
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·
Preparation for the treatment of hemophilia A inhibitor patients and a process for producing such a preparation Inventor(s): Nordfang; Ole (Selskovvej 6, DK-3400 Hillerod, DK), Rasmussen; Mirella E. (Abildgaardsgade 24, DK-2100 Copenhagen 0, DK) Assignee(s): none reported Patent Number: 4,831,119 Date filed: June 20, 1986 Abstract: A preparation for the treatment of hemophilia A inhibitor patients contains a protein or peptide having a specific Factor VIII:CAg activity of at least 0.5, preferably at least 1 VIII:CAg unit per mg protein, the ratio between the VIII:CAg activity and the VIII:C procoagulant activity being greater than 5:1, preferably greater than 10:1. A fragment of Factor VI-II:C, which displays a doublet of a molecular weight of 80/77 kD in electrophoresis, is reactive hemophilia A inhibitor antibodies and has VIII:CAg activity. This fragment and more low-molecular fragments of Factor VIII:C are capable of neutralizing the coagulation inhibiting effect of all tested antibodies. Such fragments can therefore be used as active component in preparations for providing immunotolerance towards Factor VIII:C in high-dose treatment of inhibitor patients. The peptides are moreover useful as an immunosorbent in specific extracorporeal adsorption treatment of inhibitor patients. The inhibitor reactive peptides can e.g. be recovered from plasma fractions by affinity chromatography, hydrophobic interaction chromatography or cation exchange or they may be biosynthetically and recovered in a similar manner. Excerpt(s): The present invention relates to a preparation for the treatment of hemophilia A inhibitor patients and processes for producing such a preparation. ... Hemophilia A is a congenital disease which is due to lack of coagulation Factor VIII:C. This factor is present in blood plasma and can be partially purified from blood. Preparations containing this factor (AHF) can be administered to hemophilia A patients so that the patients' blood will be able to coagulate. Production of this type of preparation is described e.g. in the U.S. Pat. No. 3,652,530 and International Application WO No. 84/03628. In these preparations the Factor VIII:C protein typically amounts to 0.1% of the total protein amount. Factor VIII:C of greater purity can be obtained by affinity chromatography (Zimmerman et al., U.S. Pat. No. 4,361,509, Fass et al. Blood 59, 394, 1982). ... It is known that 10 to 20% of hemophilia A patients do not only lack Factor VIII:C, but also develop antibodies against Factor VIII:C. Such patients are called inhibitor patients, and the antibodies in these patients are called inhibitor antibodies because they
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inhibit the procoagulant activity of Factor VIII:C (H. R. Roberts & R. Cromartie, Progress in Clinical and Biological Research 150, 1, 1984). The presence of these antibodies causes administration of AHF preparation to have no effect since Factor VIII:C is neutralized, and AHF administration induces increased antibody level. Web site: http://www.delphion.com/details?pn=US04831119__ ·
Composition for controlling hemophilia in mammals Inventor(s): Giles; Alan R. (Kingston, CA), Mann; Kenneth G. (Rochester, MN) Assignee(s): Queen's University at Kingston (Kingston, CA) Patent Number: 4,610,880 Date filed: February 6, 1985 Abstract: A composition of matter for controlling Hemophilia A (Antihemophilic Factor (F. VIII:C) deficiency) in mammals is described. Factor VIII:C deficiency in the mammal is bypassed by infusion of a synergistic mixture of a phospholipid and Factor Xa so that the cascade process of blood clotting may continue. The proportions of phospholipid and Factor Xa in the mixture are critical as too little Xa has no effect while too much is toxic (thrombogenic). Excerpt(s): Classic Hemophilia A is a sex-linked recessive inherited disorder of the blood where the activity of a specific coagulation factor (protein), required for the cascade or chain process for blood coagulation, is either reduced or absent. Hemophilia afflicts about 1 in 10,000 of the male population. This produces a severe bleeding disorder and constitutes the most frequently clinically encountered congenital coagulation disorder. Since about 1965 the prognosis of affected individuals has considerably improved due to the availability of specific clotting factor replacement products derived from the blood of normal donors which can be transfused. These products contain the most usually absent factor, Factor VIII in a concentrated form. Unfortunately, however, approximately 10% of all treated hemophiliacs develop antibodies to the transfused Factor VIII:C and become untreatable by this means. It is an aim of the present invention to provide a method for the treatment and management of such antibody sensitized hemophiliacs. ... Heretofore hemophiliacs with antibodies to F. VIII:C have been managed by various therapies none of which are satisfactory. The use of immunosuppressive therapy is not entirely satisfactory and is associated with increased morbidity. The use of Factor VIII:C derived from other species, i.e. porcine or bovine, has been shown to be an effective replacement but
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may be associated with major side effects due to the development of heterologous antibodies. Recently considerable interest has been shown in using prothrombin complex concentrates (PCC). As explained in more detail hereinafter, blood coagulation proceeds by a series or cascade of activation steps where circulating inactive clotting factors (zymogens) are converted to proteolytic enzymes. The final product of the cascade is thrombin (IIa) which converts the sol protein, fibrinogen, to its gel form, fibrin. Recent work has demonstrated that Factor VIII:C is not a proteolytic enzyme but a potent co-factor of the activation step whereby Factor IXa activates Factor X to Xa. In classic Hemophilia A, this co-factor activity is reduced or missing so that insignificant activation of Factor X takes place despite all other clotting factors being present at normal levels. As noted above, transfusion of Factor VIII:C concentrates can correct this abnormality and similar concentrates have been developed for the congenital deficiency of Factor IX. These concentrates differ from those of Factor VIII:C in containing significant quantities of other clotting factors namely X, VII and II (prothrombin). Moreover, it is the rule that all concentrates contain trace contaminents of the activated products of these clotting factors, namely IXa, Xa, VIIa and IIa (thrombin). It will be noted that, with the exception of Factor IX, the remaining three clotting factors are placed in the cascade below the critically important Factor VIII:C-dependent step. It has been postulated, that these concentrates, by providing pre-formed activated products, may achieve Factor VIII:C bypassing activity (FEBA) in hemophiliacs where Factor VIII:C replacement is precluded by the development of antibodies to this clotting factor. Initial anecdotal clinical reports were promising but by no means unanimous. This lack of unanimity related to the uncertainty as to which, if any, of the component clotting factors were the most critical. The products used are of two types. The first are known as "unactivated" PCC and are products that have been developed specifically to replace deficiencies of the clotting factors that they contain. In such patients, it is considered undesirable to infuse preactivated clotting factors because of concern for thromboembolic side effects. Therefore, attempts are made, in the fractionation process, to minimize the activated clotting factor content although all products contain some. As it was the activated clotting factor content that was considered to be the putative agent(s) in the treatment of hemophiliacs with inhibitors, some manufacturers have deliberately activated the PCC preparations for this purpose. These are known as "activated" PCC. Recent clinical trials have confirmed the benefit of the use of non-activated PCC as compared with placebo but the response was less than optimal in comparison to that which would be expected from conventional Factor VIII:C replacement in hemophiliacs without inhibitors. A similar study compared treatment with an unactivated PCC
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with an activated PCC prepared by the same manufacturer. There appeared to be a marginal benefit in favour of the activated preparation. Despite this, the response remained suboptimal and the absence of any clear indication as to the specific constituent of the preparation responsible for the effect seen, it is impossible to ensure inter-batch reproducibility of individual production lots of apparently the same product. As a result, there is still not universal agreement as to the validity of this approach. ... Thus, by one aspect of this invention there is provided a method for controlling hemophilia in mammals comprising administering intravenously to said mammal a synergistic mixture of phospholipid vesicles and mammalian blood Factor Xa in relative proportions and in an amount just sufficient to arrest bleeding. Web site: http://www.delphion.com/details?pn=US04610880__
Patent Applications on Hemophilia As of December 2000, U.S. patent applications are open to public viewing.25 Applications are patent requests which have yet to be granted (the process to achieve a patent can take several years).
Keeping Current In order to stay informed about patents and patent applications dealing with hemophilia, you can access the U.S. Patent Office archive via the Internet at no cost to you. This archive is available at the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” You will see two broad options: (1) Patent Grants, and (2) Patent Applications. To see a list of granted patents, perform the following steps: Under “Patent Grants,” click “Quick Search.” Then, type “hemophilia” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on hemophilia. You can also use this procedure to view pending patent applications concerning hemophilia. Simply go back to the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” Select “Quick Search” under “Patent Applications.” Then proceed with the steps listed above.
25
This has been a common practice outside the United States prior to December 2000.
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Vocabulary Builder Adsorption: The attachment of one substance to the surface of another; the concentration of a gas or a substance in solution in a liquid on a surface in contact with the gas or liquid, resulting in a relatively high concentration of the gas or solution at the surface. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH] Fibrinogen: A plasma protein that is converted into fibrin by thrombin in the presence of calcium ions. Fibrin is responsible for the semisolid character of a blood clot. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Membranes: Thin layers of tissue which cover parts of the body, separate adjacent cavities, or connect adjacent structures. [NIH] Proteolytic: 1. pertaining to, characterized by, or promoting proteolysis. 2. an enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Tonic: 1. producing and restoring the normal tone. 2. characterized by continuous tension. 3. a term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU]
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CHAPTER 6. BOOKS ON HEMOPHILIA Overview This chapter provides bibliographic book references relating to hemophilia. You have many options to locate books on hemophilia. The simplest method is to go to your local bookseller and inquire about titles that they have in stock or can special order for you. Some patients, however, feel uncomfortable approaching their local booksellers and prefer online sources (e.g. www.amazon.com and www.bn.com). In addition to online booksellers, excellent sources for book titles on hemophilia include the Combined Health Information Database and the National Library of Medicine. Once you have found a title that interests you, visit your local public or medical library to see if it is available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go to: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “hemophilia” (or synonyms) into the “For these words:” box. You will only receive results on books. You should check back periodically with this database which is updated every 3 months. The following is a typical result when searching for books on hemophilia:
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·
Financial Considerations for Reimbursement of New Technology Hemophilia Products Source: 1990. Contact: Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53213-0127. (414) 257-0200. Approximate price range per copy: Under $5. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This monograph is addressed to hemophilia professionals and others who are interested in the management of hemophilia medical service costs and related insurance concerns. It helps professionals develop a financial plan to manage associated costs for hemophiliacs receiving new technology products. Factors that are considered in such a plan include product costs, insurance coverage and reimbursement, provider charges and billing, and insurance options. New technology products are used to counteract the threat of viruses, including hepatitis and HIV.
·
HIV, AIDS and Hemophilia: Perspectives on Chronic Illness Source: 1989. Contact: Canadian Hemophilia Society Calgary Region AIDS and Hemophilia Support and Education Program, Alberta Children' Hospital, 1820 Richmond Rd., SW., Calgary, T2T 5C7, Canada. (604) 229-7211. Summary: This monograph examines the psychosocial issues of Acquired immunodeficiency syndrome (AIDS) and Human immunodeficiency virus (HIV) infection in the hemophiliac community in Canada. It provides basic information about AIDS and its transmission, antibody testing, and, particularly, the meaning of seropositive test results. In discussing the implications of seropositivity regarding sexual practice, pregnancy, and personal health status, it focuses on personal choice issues and a wellness approach. The monograph also lists financial and community resources.
·
HIV Disease in People With Hemophilia: Your Questions Answered Source: 1991. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network
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Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This monograph uses a question-and-answer format to discuss the connection between hemophilia and AIDS. Divided into five sections, it starts with general information on AIDS. This section discusses the HIV-antibody test, why and how often people with hemophilia should be tested, and the meaning of positive and negative results. The safety of clotting factor today is compared to its safety prior to 1985. Section B, on the management of HIV disease, looks at symptoms, diagnosis, treatment programs, and when to seek medical attention. The benefits of early intervention with azidothymidine (AZT) are explained. Risks to sexual partners are discussed in the third section, which explains safer sexual conduct and the risks involved in pregnancy. Myths of casual contact transmission are dispelled. The fourth section analyzes the effects of HIV on children with hemophilia. This chapter includes a listing of universal precautions to prevent HIV transmission while giving personal care. The final two sections look at what individuals should do when confronted with HIV, and what the National Hemophilia Foundation is doing. ·
Your Child and Hemophilia Source: 1990. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This monograph provides information to new parents of babies with hemophilia about comprehensive care issues, symptoms and treatment of bleeding episodes, and well baby care. A potential complication of hemophilia is AIDS.
·
Current Information About AIDS: The National Hemophilia Foundation; HIV Infection and Hemophilia, Answers to Your Questions. (translated title) Actualizacion Sobre el SIDA: The National Hemophilia Foundation. La Source: 1989. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network
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Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This monograph uses a question-and-answer format to provide persons with hemophilia with information about Human immunodeficiency virus (HIV) and Acquired immunodeficiency syndrome (AIDS). It gives background information on AIDS and the HIV-antibody test, pointing out that all U.S. blood products have been screened for antibodies since 1985. It recommends that persons with hemophilia and their families take the antibody test, which indicates exposure to the virus. The causes of AIDS, its symptoms, and the risk factors associated with it are discussed. The monograph places special emphasis on the risks of perinatal transmission, suggesting antibody testing for children born to these persons before 1984. Parents are assured that their children can live normal lives, and that they will not transmit HIV through casual contact at school or at play. Readers are assured that members of the blood industry are working to make the blood supply as safe as possible.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes & Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in PrintÒ). The following have been recently listed with online booksellers as relating to hemophilia (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): ·
Hemophilia (Diseases and People) by Edward Willett (2001); ISBN: 0766016846 http://www.amazon.com/exec/obidos/ASIN/0766016846/icongroupin terna
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Vox Sanguinis (Viral Safety of Plasma-Derived Replacement Factors for Hemophilia , Vol 67, Suppl 4) by P. M. Mannucci, S.M. Lemon (Editor) (1994); ISBN: 3805560664 http://www.amazon.com/exec/obidos/ASIN/3805560664/icongroupin terna
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New Aspects of Hemophilia Treatment : 3rd Symposium, September 21-23, 1995 Copenhagen, Denmark (Haemostasis, Vol 26, Suppl 1) by Harold R. Roberts (Editor) (1996); ISBN: 3805562799 http://www.amazon.com/exec/obidos/ASIN/3805562799/icongroupin terna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “hemophilia” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:26 ·
30th hemophilia symposium: Hamburg, 1999. Author: editors, I. Scharrer, W. Schramm; Year: 2001; Berlin; New York: Springer, c2001; ISBN: 3540676775 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/3540676775/icongroupin terna
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Acquired hemophilia: continuing medical education monograph. Author: written by David Green, Carol K. Kasper, Jeanne M. Lusher; sponsored by Orthopaedic Hospital; Year: 1990; Los Angeles: Orthopaedic Hospital, [199?]
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Acquired hemophilia. Author: Craig Kessler, editor; Year: 1995; Princeton: Excerpta Medica, c1995; ISBN: 0444019081 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0444019081/icongroupin terna
In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a “Books” button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
26
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Blood saga: hemophilia, AIDS, and the survival of a community. Author: Susan Resnik; Year: 1999; Berkeley: University of California Press, c1999; ISBN: 0520211952 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0520211952/icongroupin terna
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Control of hemophilia: hemophilia care in developing countries: report of a Joint WHO. Author: World Federation of Hemophilia Meeting; Year: 1998; [Geneva]: World Health Organization, c1998
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Desmopressin in bleeding disorders. Author: edited by G. Mariani, P.M. Mannucci, and M. Cattaneo; Year: 1993; New York: Plenum Press, c1993; ISBN: 0306444143 http://www.amazon.com/exec/obidos/ASIN/0306444143/icongroupin terna
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Factor VIII: purity and prophylaxis. Author: edited by Clive Wood; Year: 1991; [Oxford?]: Royal Society of Medicine Services, c1991
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Final report. Author: Commission of Inquiry on the Blood System in Canada; Year: 1997; [Ottawa]: The Commission, c1997; ISBN: 0660172305 http://www.amazon.com/exec/obidos/ASIN/0660172305/icongroupin terna
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Hemophilia care, a way of thinking: the treatment of hemophilia in Australia, 1991. Author: written by John Singleton in liaison with the HFA; Year: 1992; Hartwell, Vic.: Hemophilia Foundation of Australia, [1992?]; ISBN: 0646092855
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Hemophilia and von Willebrand's disease in the 1990s: a new decade of hopes and challenges: proceedings of the XIX Congress of the World Federation of Hemophilia, Washington, D.C., 14-19 August 1990. Author: editors, Jeanne M. Lusher, Craig M.Kessler; Year: 1991; Amsterdam; New York: Excerpta Medica; New York, NY, USA: Sole distributors for the USA and Canada, Elsevier Science Pub. Co., 1991; ISBN: 0444814329 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0444814329/icongroupin terna
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Hemophilia nursing handbook. Author: written by the Nursing Executive Committee of the National Hemophilia Foundation; Year: 1995; New York, N.Y.: The Committee, c1995
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Hemophilia. Author: edited by C.D. Forbes, L.M. Aledort, and R. Madhok; Year: 1997; London; New York: Chapman & Hall Medical, 1997; ISBN: 0412638207 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0412638207/icongroupin terna
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Life and achievements of Professor Robert Gwyn Macfarlane FRS: pioneer in the care of hemophiliacs. Author: Alastair Robb-Smith; foreword by David Weatherall; Year: 1993; London; New York: Royal Society of Medicine Services, c1993; ISBN: 1853151963 http://www.amazon.com/exec/obidos/ASIN/1853151963/icongroupin terna
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Living with hemophilia. Author: Peter Jones; Year: 1995; Oxford; New York: Oxford University Press, 1995; ISBN: 019263030X http://www.amazon.com/exec/obidos/ASIN/019263030X/icongroupi nterna
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Management of musculoskeletal problems in the hemophilia. Author: Robert B. Duthie ... [et al.]; with special contributions by Louis M. Aledort ... [et al.]; Year: 1994; Oxford; New York: Oxford University Press, 1994; ISBN: 0192623176 (hbk.) http://www.amazon.com/exec/obidos/ASIN/0192623176/icongroupin terna
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Measuring patient preferences in hemophilia: development and pilot testing of instrumentation: prepared for Miles, Inc. Author: by Dennis Revicki ... [et al.]; Year: 1992; Washington, DC: Battelle Medical Technology Assessment and Policy Research Center, [1992]
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Molecular biology and immunology in hemophilia A: satellite symposion, XXIII. International Congress of the World Federation of Hemophilia. Author: editor, H.-H. Brackmann; Year: 1998; Frankfurt: Medizinische Verlagsgesellschaft Umwelt & Medizin, [1998]; ISBN: 3921320402
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Musculoskeletal aspects of hemophilia. Author: [edited by] E.C. Rodriguez-Merchan, N.J. Goddard, C.A. Lee; Year: 2000; Oxford: Malden, MA; Blackwell Science, 2000; ISBN: 0632056711 http://www.amazon.com/exec/obidos/ASIN/0632056711/icongroupin terna
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Physiotherapy management of hemophilia. Author: edited by Brenda Buzzard and Karen Beeton; Year: 2000; Oxford; Malden, MA: Blackwell Science, 2000; ISBN: 0632057645 http://www.amazon.com/exec/obidos/ASIN/0632057645/icongroupin terna
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Procedure coding for hemophilia treatment: an educational guide. Author: Forbes, Lynn M; Year: 1990; Kankakee, Ill.: Armour Pharmaceutical Co., c1990
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Queen Victoria's gene. Author: D.M. Potts and W.T.W. Potts; Year: 1995; Stroud, Gloucestershire: Alan Sutton Pub., 1995; ISBN: 0750908688
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http://www.amazon.com/exec/obidos/ASIN/0750908688/icongroupin terna ·
Report of a joint WHO. Author: WFH meeting on the control of haemophilia: modern treatment of haemophilia: Geneva, 21-23 March 1994; Year: 1994; [Geneva]: World Health Organization, Hereditary Diseases Programme, Division of Noncommunicable Diseases, [1994]
Chapters on Hemophilia Frequently, hemophilia will be discussed within a book, perhaps within a specific chapter. In order to find chapters that are specifically dealing with hemophilia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and hemophilia using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” By making these selections and typing in “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on chapters in books. The following is a typical result when searching for book chapters on hemophilia: ·
Hemophilia and AIDS: AIDS in the Hemophilia Community Source: 1987. p. 185-197. Contact: University of California San Francisco AIDS Health Project, P.O. Box 0884, San Francisco, CA 94143-0884. (415) 476-6430. Summary: Written for mental health professionals, this paper focuses on the impact of AIDS on the hemophiliac community, the psychosocial issues involved, and treatment issues. The incidence of AIDS is higher in persons with hemophilia A, although a few individuals with hemophilia B have also developed AIDS. Clients may continue to fear using the clowning factors needed for hemophilia treatment. Some have discontinued their self treatments, risking the pain and disability that may result from uncontrolled bleeding episodes. Hemophiliacs diagnosed with AIDS experience the same complex set of emotions that confront others with AIDS. In addition, they may fear further misunderstanding and isolation by the public and are angry about their exposure to AIDS. A discussion of general treatment issues, two case examples, counseling plans for each case, a counseling plan checklist, and cross-references to related information in other book chapters are included.
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Disorders of the Blood Source: in Grundy, M.C.; Shaw, L.; and Hamilton, D.V. Illustrated Guide to Dental Care for the Medically Compromised Patient. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 27-36. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 432-1380; E-mail:
[email protected]; http://www.mosby.com. PRICE: $24.95 plus shipping and handling. ISBN: 0815140223. Summary: This chapter, from an illustrated guide to dental care for medically compromised patients, discusses disorders of the blood. Topics covered include hemophilia; Christmas disease (hemophilia B); Von Willebrand's disease (vascular hemophilia); thrombocytopenia; anemia, including sickle cell anemia and thalassemia; and leukemia. For each condition, the authors provide a brief description, the components of medical management, and suggestions for dental care. Illustrations, including photographs, are included. 7 figures.
Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to hemophilia have been published that consolidate information across various sources. These too might be useful in gaining access to additional guidance on hemophilia. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:27 ·
Directory of Hemophilia Treatment Centers and Facilities Source: 1993. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network
You will need to limit your search to “Directories” and hemophilia using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by”. For publication date, select “All Years”, select language and the format option “Directory”. By making these selections and typing in “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on directories dealing with hemophilia. You should check back periodically with this database as it is updated every three months. 27
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Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This directory provides access to hemophilia treatment centers in the United States. It also includes the National Hemophilia Foundation (NHF) Mission statement, a message from the president of the NHF, a message from the chair of the Treatment Center Standards and Criteria Committee, Ten Tips for the Traveler with Hemophilia, and 1990 NHF Standards and Criteria for Hemophilia Treatment Facilities. Broken down by states, the entries for the treatment centers include name of the organization, address, telephone number, and contact persons. The mission statement includes Human immunodeficiency virus (HIV) infection as one of the complications of hemophilia. ·
HANDI Resource Listing: NHF Regionally Produced Educational Materials Source: 1990. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This resources lists educational materials designed for preventing the spread of Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS), that are targeted specifically toward hemophiliacs. The general section lists brochures, flyers, instructional programs, manuals, newsletters, pamphlets, posters, reports, videotapes, and resource guides. HIV-risk reduction materials for culturally diverse communities focus on general HIV-prevention guidelines, as well as those developed for the Black, Asian and Pacific Islander, Haitian, Hispanic, and Native American communities. A list of other organizations working with various ethnic groups is provided. Pamphlets, booklets, and books are listed in the section of HIV-educational materials targeted toward women, and the section on materials for adolescents is comprised of resource lists, reports, brochures, comic books, and pamphlets.
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The National Hemophilia Foundation Chapter Roster Source: 1988. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303,
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New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This directory lists the names, addresses, and telephone numbers of the chapter offices and chapter officers of the National Hemophilia Foundation. A map showing chapter locations and lists of Federal government regions for hemophilia treatment and the regions of the National Hemophilia Foundation are also included.
General Home References In addition to references for hemophilia, you may want a general home medical guide that spans all aspects of home healthcare. The following list is a recent sample of such guides (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · American College of Physicians Complete Home Medical Guide (with Interactive Human Anatomy CD-ROM) by David R. Goldmann (Editor), American College of Physicians; Hardcover - 1104 pages, Book & CD-Rom edition (1999), DK Publishing; ISBN: 0789444127; http://www.amazon.com/exec/obidos/ASIN/0789444127/icongroupinterna · The American Medical Association Guide to Home Caregiving by the American Medical Association (Editor); Paperback - 256 pages, 1st edition (2001), John Wiley & Sons; ISBN: 0471414093; http://www.amazon.com/exec/obidos/ASIN/0471414093/icongroupinterna · Anatomica : The Complete Home Medical Reference by Peter Forrestal (Editor); Hardcover (2000), Book Sales; ISBN: 1740480309; http://www.amazon.com/exec/obidos/ASIN/1740480309/icongroupinterna · The HarperCollins Illustrated Medical Dictionary : The Complete Home Medical Dictionary by Ida G. Dox, et al; Paperback - 656 pages, 4th edition (2001), Harper Resource; ISBN: 0062736469; http://www.amazon.com/exec/obidos/ASIN/0062736469/icongroupinterna · Mayo Clinic Guide to Self-Care: Answers for Everyday Health Problems by Philip Hagen, M.D. (Editor), et al; Paperback - 279 pages, 2nd edition (December 15, 1999), Kensington Publishing Corp.; ISBN: 0962786578; http://www.amazon.com/exec/obidos/ASIN/0962786578/icongroupinterna · The Merck Manual of Medical Information: Home Edition (Merck Manual of Medical Information Home Edition (Trade Paper) by Robert Berkow (Editor), Mark H. Beers, M.D. (Editor); Paperback - 1536 pages
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(2000), Pocket Books; ISBN: 0671027263; http://www.amazon.com/exec/obidos/ASIN/0671027263/icongroupinterna · What Do You Know About Hematology (Test Your Knowledge Series (Q - 68)) by Jack Rudman; (Paperback - February 1997), National Learning Corporation; ISBN: 083737068X; http://www.amazon.com/exec/obidos/ASIN/083737068X/icongroupinterna
Vocabulary Builder Blindness: The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. [NIH] Orthopaedic: Pertaining to the correction of deformities of the musculoskeletal system; pertaining to orthopaedics. [EU] Thrombocytopenia: Decrease in the number of blood platelets. [EU]
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CHAPTER 7. MULTIMEDIA ON HEMOPHILIA Overview Information on hemophilia can come in a variety of formats. Among multimedia sources, video productions, slides, audiotapes, and computer databases are often available. In this chapter, we show you how to keep current on multimedia sources of information on hemophilia. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine. If you see an interesting item, visit your local medical library to check on the availability of the title.
Video Recordings Most diseases do not have a video dedicated to them. If they do, they are often rather technical in nature. An excellent source of multimedia information on hemophilia is the Combined Health Information Database. You will need to limit your search to “video recording” and “hemophilia” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” By making these selections and typing “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on video productions. The following is a typical result when searching for video recordings on hemophilia: ·
Eagle Scout: The Story of Henry Nicols Source: New York, NY: Select Media Incorporated. 1995.
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Contact: Select Media Incorporated, 60 Warren St., New York, NY 10007. (212) 732-4437. Summary: This video is a documentary on the life on a teenage boy with AIDS. In order to fulfill the prerequisite of Eagle Scout status, Henry Nicols began an HIV/AIDS health education and public awareness project. The documentary combines still photographs from Henry's childhood through the present, interviews with family and friends and live footage. Henry who has hemophilia, was infected through donated blood. When the family first learned of Henry's HIV status, they were shocked. Until Henry's HIV developed into symptomatic AIDS, the family agreed to keep his condition a secret. At the age of 17, Henry and his family held a press conference to reveal his HIV status, and the school and community rallied to their side. The video portrays Henry working with community groups as an HIV/AIDS educator. He asks his audiences not to isolate, pity, or judge those with HIV/AIDS, and to allow PWAs to lead a normal active life as long as possible. The video ends with Henry embarking on the ascent of Mount Ranier with fellow Eagle Scouts. ·
Inside Edition in L.A.: AIDS, Profits Before Protection Source: Aug. 1991. Contact: King World Distributors, 402 E. 76th St., New York, NY 10021. (212) 737-3399. Summary: This video production analyzes the blood distribution system in the early 1980's, when blood suppliers were aware that blood products were contaminated with HIV, but did nothing to stop their distribution. It asserts that blood suppliers and the Food and Drug Administration knew about this from 1982, but no action was taken until after 1984. In the interim, many children had been infected with HIV through the blood products they received to combat their hemophilia. Interviews with Dr. Don Francis of the Centers for Disease Control and Prevention (CDC) indicates that the bloodborne nature of HIV was evident early on. Nevertheless, blood suppliers did not screen their supply of potential donors, of whom many were gay, drug abusers, or prostitutes. Even after heat treatments were found to destroy HIV, some suppliers did not fully comply with the acceptable procedure. The theme of the entire segment is that the blood suppliers engaged in this highly unethical practice concerned only about maintaining their profits, and without any consideration for the persons with hemophilia who were receiving the blood.
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The Preparation of Cryoprecipitate Source: 1990. Contact: World Health Organization Health Laboratory Technology and Blood Safety Unit, 20 Avenue Appia, 1211 Geneva 27, Switzerland. 01 92 21 11. Summary: This videorecording explains the preparation of Factor VIII as a cryoprecipitate for hemophilia treatment. This method offers advantages over complex fractionation procedures that require specialized technology and financial resources because it can be utilized in any blood transfusion center with minimum basic equipment. To dispel fears about HIV in the blood, safety measures are described. Additionally, plasmapheresis is a method where the blood of an individual may be returned to the donor after the removal of the Factor VIII, thereby reducing the number of potential donors in any single sample. Advances in the production of the cryoprecipitate also include lyophilization of the samples which allows the samples to be stored without refrigeration.
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Double Whammy Source: 1995. Contact: LIFEJACKETS Productions, 332 19th St., Manhattan Beach, CA 90266. (310) 545-0067. Summary: This video presents issues for adolescents living with hemophilia and HIV/AIDS. Katie and Jake have been dating for a number of months. When Jake says he wants to wait to have sex, Katie assumes that Jake doesn't like her. He explains that he has hemophilia, and as a result of getting a blood transfusion with HIV-infected blood, he is HIV-positive. Although Katie is angry at first, she begins to realize that she needs to be supportive and understanding. The couple decides to wait to have sex. Individual question-and-answer sessions with Katie and Jake are provided.
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Song of Superman Source: 1992. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY 10001-3212. (212) 328-3700. www.hemophilia.org. Summary: This video discusses sexuality for adolescents with hemophilia and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). The video uses the story of Superman and
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Lois Lane to illustrate the difficulties an adolescent with hemophilia may have communicating that he is HIV positive to his partner. It discusses how sex can lead to health and transmission risks for individuals with hemophilia and HIV/AIDS and their partners. It provides an overview of ways to prevent the transmission of HIV during intercourse. It covers topics related to self-esteem, ways to increase self-esteem, and sexual identity.
Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” By making these selections and typing “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on sound recordings (again, most diseases do not have results, so do not expect to find many). The following is a typical result when searching for sound recordings on hemophilia: ·
Panel: Special Community Programs; Alternative Schools, Minneapolis Urban League, University of Minnesota Comprehensive Hemophilia Clinic, University of Minnesota Youth and AIDS Project Source: Oct. 1990. Contact: University of Minnesota Continuing Medical Education, 420 Delaware St., SE, Box 202 UMHC, Minneapolis, MN 55455. (612) 6265525. Summary: This sound recording of proceedings from the 12th Annual Adolescent Health Care Conference, held October 12-13, 1990, in Minneapolis, MN, features four speakers who discuss peer education programs. Sandy Naughton, the first speaker, talks about recruiting students to act as peer educators in special community programs through alternative schools. She says it has improved students' sexual and drugusing behaviors in a dramatic fashion. Next, Grace Moore talks about peer education for African American adolescents through the Minneapolis Urban League. She says the program is called PREP, Planned Responsibility Equals Prevention, and that they train youth to become peer educators and to present information on AIDS, sexuality, sexually transmitted diseases (STDs), and drug abuse. Next, Roxanna Boelson, a nurse, tells about her work at the University of Minnesota
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Comprehensive Hemophilia Center. She explains that the center began in the mid-1970s to teach persons with hemophilia to become more independent in living with a chronic illness, but that HIV has added a whole new dimension to their work. She began working with the center in 1988, counseling adolescent hemophiliacs and their sex partners. Boelson started a program of handing out condoms and evaluating adolescents for inclusion in clinical trials. All information is kept confidential from their parents. The final speaker, Dr. Gary Remafedi, details his work with homosexual youth at the University of Minnesota Youth and AIDS Project. The goal of the program, he says, is to prevent transmission of HIV to and from homosexual youth. Remafedi says that aside from transfusion-related AIDS, 70 percent of all adolescent AIDS cases are among homosexuals. He says some adolescents come to the project through self-referral, some through peer referral, and some through professional referral. At the project, they are counseled on sexuality and HIV prevention. He says that according to their behaviors, 75 percent are at extreme risk. A question-and-answer period follows the panel discussion. ·
Blood & Blood Products -- Transfusion Associated AIDS & Hemophilia. III International Conference on Acquired Immunodeficiency Syndrome (AIDS); Washington, D.C., June 1-5, 1987 Source: Garden Grove, CA: InfoMedix. June 1987. Contact: InfoMedix, 12800 Garden Grove Blvd.,, Ste. F, Garden Grove, CA 92643. (714) 530-3454. Summary: This sound recording of proceedings from the III International Conference on AIDS, held June 1-5, 1987, in Washington, D.C., deals with transmission of the Human immunodeficiency virus (HIV) in blood transfusions, especially to hemophiliacs. Although screening and antibody tests have led to the elimination of nearly all such transmission, there are still a few such cases of Acquired immunodeficiency syndrome (AIDS) every year. Speakers address questions about risk of disease when a person receives one large injection of HIV in a transfusion as compared to many smaller doses from IV-needle sharing, and whether HIVincubation rates vary between adults and children. One transfusion safety study found that not all recipients of HIV-infected blood become infected, but most do. Transmission rates for various blood products also vary. Paid donors are at higher risk of being infected with HIV or Hepatitis B. Antibodies as diagnostic and prognostic indicators were also studied.
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Bibliography: Multimedia on Hemophilia The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in hemophilia (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on hemophilia. For more information, follow the hyperlink indicated: ·
50. Source: 50 chance / developed by the Pennsylvania State University, in association with the Hastings Center, Institute of Society, Ethics, and the Life Sciences; Year: 1982; Format: Videorecording; Washington, D.C.: PBS Video, c1982
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Are you a bleeder. Source: David J. Gerrick; Year: 1979; Format: Slide; [Lorain, OH]: Dayton Lab, 1979
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Biopharmaceutical research ; Treating cardiac r[h]ythm; Immunodiagnostic testing; Earth-friendly food packing; Hemophilia medication; Alternative trading systems. Year: 2001; Format: Videorecording; [Boca Raton, Fla.]: Multi-Media Productions, c2001
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Blood component therapy in surgery. Source: American College of Surgeons; Year: 1974; Format: Motion picture; Morton Grove, Ill.: Fenwall Laboratories; [Los Angeles: for sale by Wexler Films], c1974
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Genetic discoveries, disorders, and mutations. Source: a presentation of Films for the Humanities and Sciences; [presented by] Animated Biomedical Productions; Year: 2000; Format: Videorecording; Princeton, N.J.: Films for the Humanities and Sciences, c2000
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Hemophilia. Source: F. Josso, J. P. Soulier and D. Alagille; Year: 1960; Format: Motion picture; East Hanover, N. J.: Sandoz: [for loan by Sandoz Pharmaceuticals Medical Film Library, 196-]
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Hemophilia : orthopaedic manifestations and treatment. Source: American Academy of Orthop[a]edic Surgeons; Year: 1985; Format: Slide; [Park Ridge, Ill.]: AAOS, [1985]
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Hemophilia . Year: 1987; Format: Slide; [Columbus, Ohio]: Center for Continuing Medical Education, the Ohio State University College of Medicine, [1987]
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Hemophilia and von Willebrand's disease. Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1982; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1982
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Hemophilia in infants and children. Source: [presented by] the Medical University of South Carolina, Departments of Pathology and Laboratory Medicine and Pediatrics; produced by the Health Communications Network, Division of Television Services; Year: 1993; Format: Videorecording; Charleston, S.C.: The University, c1993
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Hemophilia in the 1990's. Source: produced by UT-TV Houston; Year: 1991; Format: Videorecording; [Houston, Tex.]: UT-TV Houston, c1991
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Hemophilia update. Source: College of Medicine, Division of Hemophilia, the Pennsylvania State University; produced by Penn-State Television; Year: 1975; Format: Videorecording; University Park, Pa.: The University: [for loan or sale by its Audio-Visual Services], c1975
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Hemophilia. Source: Children's Hospital, Boston; Year: 1994; Format: Videorecording; Boynton Beach, FL: Universal Health Communications, [1994]
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Hemophilia. Source: [Stanley P.] Balcerzak; produced by Ohio State University, Medical Audiovisual and Television Center; Year: 1971; Format: Videorecording; [Columbus, Ohio]: The Center, c1971
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Hemophilia. Source: American Society of Hematology; Year: 1974; Format: Slide; [Seattle: The Society: for sale by American Society of Hematology National Slide Bank, 1974]
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Inherited coagulation disorders. Source: Health Sciences McMaster University; produced by Audio Visual Services, McMaster University; Year: 1970; Format: Slide; [Hamilton, Ont.]: Health Sciences McMaster Univ., [1970]
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Medical aspects of disabilities. HIV. Source: AIDS, hemophelia , sicklecell anemia [videorecording]; Year: 1996; Format: Sic; [Logan, Utah]: Vocational Rehabilitation Distance Learning Project, Utah State University; [Stillwater, Okla.]: National Clearinghouse of Rehabilitation Training Materials [distributor], c1996
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Mild analgesic therapy for problem patients. Source: produced by Aegis Productions, Inc.; presented by McNeil Laboratories, Inc; Year: 1973; Format: Motion picture; United States: McNeil Laboratories, c1973
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Neurologic disorders in hematologic patients. Source: Anthony P. Tartaglia ... [et al.]; Year: 1975; Format: Slide; New York: Medcom, c1975
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New directions in blood transfusions. Source: a presentation of Films for the Humanities & Sciences; Year: 1996; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1996
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Oral manifestations of blood diseases. Source: produced by American Dental Association, Council on Dental Therapeutics; Year: 1968; Format: Slide; Chicago, Ill.: The Association, 1968
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Orthopaedic surgery : AIDS--trauma and hemophilia. Source: American College of Surgeons; Year: 1989; Format: Sound recording; Chicago, IL: The College, [1989]
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Pathogenesis & treatment of hemophilic arthropathy & deep muscle bleed. Source: [authored by John E. Handlesman, Robert A. Glasser]; Year: 1985; Format: Slide; [Park Ridge, Ill.]: AAOS, [1985]
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Practical aspects of genetic counseling. Source: Academy of Health Sciences, United States Army Medical Department; Year: 1973; Format: Videorecording; Fort Sam Houston, Tex.: The Academy: [for loan by its Health Sciences Media Division], 1973
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Recombinant DNA technology and prenatal diagnosis of genetic disease. Source: with Haig Kazazian, Corinne D. Boehm, and Virginia Corson; Year: 1987; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, 1987
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Systemic conditions affecting non-specific gingivitis. Source: College of Dentistry, University of Florida; produced by Ron Baughman; Year: 1973; Format: Slide; [Gainesville, Fla.]: The College, [1973]
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Ultrasound in prenatal diagnosis. Source: produced and distributed by DG, Davis & Geck; Year: 1981; Format: Videorecording; Danbury, Conn.: American Cyanamid, c1981
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X-ray findings related to erythrocytosis. Source: M.I. Goldstein; produced by Ohio State University Medical Audiovisual and Television Center; Year: 1972; Format: Videorecording; [Columbus, Ohio]: The Center, c1972
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X-ray findings related to hemophilia. Source: M.I. Goldstein; produced by Ohio State University Medical Audiovisual and Television Center; Year: 1972; Format: Videorecording; [Columbus, Ohio]: The Center, c1972
Vocabulary Builder Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Cardiac: Pertaining to the heart. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other health-related event occurring in such outbreaks. [EU]
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Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Homosexuality: Sexual attraction or relationship between members of the same sex. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Inertia: Inactivity, inability to move spontaneously. [EU] Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of Pneumocystis carinii pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects. [NIH]
Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Prenatal: Occurring before birth. [NIH] Vaccine: A suspension of attenuated or killed microorganisms (bacteria, viruses, or rickettsiae), administered for the prevention, amelioration or treatment of infectious diseases. [EU]
Periodicals and News 115
CHAPTER 8. PERIODICALS AND NEWS ON HEMOPHILIA Overview Keeping up on the news relating to hemophilia can be challenging. Subscribing to targeted periodicals can be an effective way to stay abreast of recent developments on hemophilia. Periodicals include newsletters, magazines, and academic journals. In this chapter, we suggest a number of news sources and present various periodicals that cover hemophilia beyond and including those which are published by patient associations mentioned earlier. We will first focus on news services, and then on periodicals. News services, press releases, and newsletters generally use more accessible language, so if you do chose to subscribe to one of the more technical periodicals, make sure that it uses language you can easily follow.
News Services & Press Releases Well before articles show up in newsletters or the popular press, they may appear in the form of a press release or a public relations announcement. One of the simplest ways of tracking press releases on hemophilia is to search the news wires. News wires are used by professional journalists, and have existed since the invention of the telegraph. Today, there are several major “wires” that are used by companies, universities, and other organizations to announce new medical breakthroughs. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing.
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PR Newswire Perhaps the broadest of the wires is PR Newswire Association, Inc. To access this archive, simply go to http://www.prnewswire.com. Below the search box, select the option “The last 30 days.” In the search box, type “hemophilia” or synonyms. The search results are shown by order of relevance. When reading these press releases, do not forget that the sponsor of the release may be a company or organization that is trying to sell a particular product or therapy. Their views, therefore, may be biased.
Reuters The Reuters’ Medical News database can be very useful in exploring news archives relating to hemophilia. While some of the listed articles are free to view, others can be purchased for a nominal fee. To access this archive, go to http://www.reutershealth.com/frame2/arch.html and search by “hemophilia” (or synonyms).
The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within their search engine.
Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com. You can scan the news by industry category or company name. Internet Wire Internet Wire is more focused on technology than the other wires. To access this site, go to http://www.internetwire.com and use the “Search Archive” option. Type in “hemophilia” (or synonyms). As this service is oriented to
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technology, you may wish to search for press releases covering diagnostic procedures or tests that you may have read about.
Search Engines Free-to-view news can also be found in the news section of your favorite search engines (see the health news page at Yahoo: http://dir.yahoo.com/Health/News_and_Media/, or use this Web site’s general news search page http://news.yahoo.com/. Type in “hemophilia” (or synonyms). If you know the name of a company that is relevant to hemophilia, you can go to any stock trading Web site (such as www.etrade.com) and search for the company name there. News items across various news sources are reported on indicated hyperlinks.
BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “hemophilia” (or synonyms).
Newsletters on Hemophilia Given their focus on current and relevant developments, newsletters are often more useful to patients than academic articles. You can find newsletters using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Your investigation must limit the search to “Newsletter” and “hemophilia.” Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter.” By making these selections and typing in “hemophilia” or synonyms into the “For these words:” box, you will only receive results on newsletters. The following list was generated using the options described above: ·
HANDI quarterly Source: New York, NY: National Hemophilia Foundation. 1992-. quarterly.
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Contact: Available from Hemophilia and AIDS/HIV Network for the Dissemination of Information, 116 West 32nd Street, 11th Floor, New York, NY 10001. Telephone: (212) 328-3700 or (800) 42-HANDI / fax: (212) 328-3799 / e-mail:
[email protected] / Web site: http://WWW.INFONHF.ORG. Available at no charge. Summary: This newsletter is the official publication of the Hemophilia and AIDS-HIV Network for the Dissemination of Information (HANDI). It provides information for people with hemophilia and those with hemophilia and HIV. Each issue focuses on a single topic, such as nutrition, financing care, or information needs, and includes a listing of resources most of which are available through HANDI.
Newsletter Articles If you choose not to subscribe to a newsletter, you can nevertheless find references to newsletter articles. We recommend that you use the Combined Health Information Database, while limiting your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” By making these selections, and typing in “hemophilia” (or synonyms) into the “For these words:” box, you will only receive results on newsletter articles. You should check back periodically with this database as it is updated every 3 months. The following is a typical result when searching for newsletter articles on hemophilia: ·
Warning Signs in the Mouth Source: Closing the Gap. p. 13. July 1999. Contact: Available from Office of Minority Health Resource Center. P.O. Box 37337, Washington, DC 20013-7337. (800) 444-6472. Summary: This brief newsletter article describes the warning signs and symptoms that may show up in the mouth with systemic diseases such as kidney disease, anemia, hemophilia and other bleeding disorders, adrenal gland disorders, and inflammatory bowel diseases. Chronic renal (kidney) disease has several early oral signs, including a metallic taste in the mouth, dry mouth, swelling glands, and frequent infection of the soft tissues. In the early stages of anemia, patients often complain about their
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tongue becoming smooth and glistening and feeling like it is burning. Unprovoked bleeding of the gums is a warning sign of bleeding disorders such as hemophilia, von Willebrand's disease, leukemia, and lymphomas. Brown or black splotches on the inner lining of the cheeks and lips are seen in the early stages of Addison's disease and other adrenal gland disorders. A cobblestone appearance of the soft tissue of the mouth and a generalized swelling of the linings of the cheeks and lips are early signs of inflamed bowels and Crohn's disease. Patients with ulcers often have a history of oral cold sores because mouth and intestinal tissues are closely related.
Academic Periodicals covering Hemophilia Academic periodicals can be a highly technical yet valuable source of information on hemophilia. We have compiled the following list of periodicals known to publish articles relating to hemophilia and which are currently indexed within the National Library of Medicine’s PubMed database (follow hyperlinks to view more information, summaries, etc., for each). In addition to these sources, to keep current on articles written on hemophilia published by any of the periodicals listed below, you can simply follow the hyperlink indicated or go to the following Web site: www.ncbi.nlm.nih.gov/pubmed. Type the periodical’s name into the search box to find the latest studies published. If you want complete details about the historical contents of a periodical, you can also visit http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/ you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.” The following is a sample of periodicals which publish articles on hemophilia:
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CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES Overview Doctors and medical researchers rely on a number of information sources to help patients with their conditions. Many will subscribe to journals or newsletters published by their professional associations or refer to specialized textbooks or clinical guides published for the medical profession. In this chapter, we focus on databases and Internet-based guidelines created or written for this professional audience.
NIH Guidelines For the more common diseases, The National Institutes of Health publish guidelines that are frequently consulted by physicians. Publications are typically written by one or more of the various NIH Institutes. For physician guidelines, commonly referred to as “clinical” or “professional” guidelines, you can visit the following Institutes: ·
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
·
National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
·
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
·
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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The NHLBI recently recommended the following guidelines and references to physicians treating patients with blood-related conditions:
Sickle Cell Disease Information ·
Management and Therapy of Sickle Cell Disease: http://www.nhlbi.nih.gov/health/prof/blood/sickle/sick-mt.htm
·
Sickle Cell Disease Advisory Committee: http://www.nhlbi.nih.gov/meetings/scd/index.htm Blood Transfusion Safety Information
·
Transfusion Alert: Use of Autologous Blood: http://www.nhlbi.nih.gov/health/prof/blood/transfusion/logo.htm
·
Transfusion Alert: Indications for the Use of Red Blood Cells, Platelets, and Fresh Frozen Plasma: http://www.nhlbi.nih.gov/health/prof/blood/transfusion/transfin.htm Other Blood Information
·
Research Agenda on Complications of Hemophilia and Other Bleeding Disorders: http://www.nhlbi.nih.gov/health/prof/blood/other/hemophilia/index.htm
·
Cooley’s Anemia: Progress in Biology and Medicine-1995: http://www.nhlbi.nih.gov/health/prof/blood/other/cooleys.htm
·
Blood Information for Patients and the General Public: http://www.nhlbi.nih.gov/health/public/blood/index.htm
·
List of Publications: http://www.nhlbi.nih.gov/health/pubs/index.htm
·
Information Center: http://www.nhlbi.nih.gov/health/infoctr/index.htm
·
National Cancer Institute (for cancers of the blood): http://www.nci.nih.gov/
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.28 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:29 ·
Bioethics: Access to published literature on the ethical, legal and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
·
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
·
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
·
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
·
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
·
Cancer Information: Access to caner-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 29 See http://www.nlm.nih.gov/databases/databases.html. 28
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·
Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
·
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
·
Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
·
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
·
MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
·
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
·
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
While all of the above references may be of interest to physicians who study and treat hemophilia, the following are particularly noteworthy.
The Combined Health Information Database A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to “Brochure/Pamphlet,” “Fact Sheet,” or “Information Package” and hemophilia using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years,” select your preferred language, and the format option “Fact Sheet.” By making these selections and typing “hemophilia” (or synonyms) into the “For these words:” box above, you will only receive results on fact sheets dealing with hemophilia. The following is a sample result:
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·
A Guide to First Aid for Children With Hemophilia Source: 1991. Contact: A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure provides school nurses with basic information on applying first aid to injuries and bleeds suffered by children with hemophilia. Management of blood is particularly important if the hemophiliac child is infected with Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS).
·
Questions and Answers About Blood Transfusions Source: 1991. Contact: Hemophilia Psychosocial Program HIV/AIDS Special Populations Consortium Training Program Hemophilia Council of California, 1507 21st St Ste 206, Sacramento, CA 95814. (916) 448-7444. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, PO Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure uses a question-and-answer format to present information about human immunodeficiency virus (HIV) infection and blood transfusions. It opens by explaining the difference between HIV infection and acquired immunodeficiency syndrome (AIDS). Readers who received blood transfusions between 1977 and 1985 are urged to take the HIV-antibody test, but the brochure also assures them that since 1985, the blood supply has become extremely safe. The brochure gives the symptoms of AIDS, but also explains that many people test positive and show no symptoms of the infection. HIV-positive persons should consult their doctors about treatment programs and their feelings about the diagnosis, and they should use caution in telling family members and friends of their diagnosis. The brochure also explains California's policy of protecting the rights of persons with AIDS (PWA's), including the right to work.
·
Safety of Therapeutic Products Used for Hemophilia Patients Source: in Morbidity and Mortality Weekly Report; Vol. 37, no. 29. 1988. p. 441-450. Contact: US Government Printing Office, P.O. Box 371954, Pittsburgh, PA 15250-7954. (202) 512-1800. Publication no. HHS (CDC) 88-8017;
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Approximate price range per copy: Under $5; Approximate yearly subscription: $50-$100. Massachusetts Medical Society Medical Publishing Group, CSP.O. Box 9121, Waltham, MA 02254. (617) 893-4610. Approximate praice range per copy: Under $5; Approximate yearly subscription: $50-$100. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This report summarizes information discussed at a January 11, 1988, meeting sponsored by the Centers for Disease Control and Prevention (CDC) to discuss the safety of therapeutic products used for treating hemophilia patients, focusing specifically on the transmission of Human immunodeficiency virus (HIV) and non-A, non-B hepatitis viruses. The purpose of the meeting was to share current epidemiologic and clinical trial data, to address therapeutic issues, and to review the safety of the manufactured blood components used for treating hemophilia patients. An editorial note reports that epidemiologic and laboratory data indicate that processed plasma derivatives currently available in North America, Europe, and Australia have a high degree of safety with regard to HIV transmission. It also presents the National Hemophilia Foundation's recommendations for United States physicians, developed after a review of the data presented at the CDC-sponsored meeting. ·
Research Priorities in Hemophilia : HCV and HIV Disease : A Blueprint for Action Source: 1999. Contact: National Hemophilia Foundation Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W. 32nd St., Fl. 11, New York, NY 10001-3212. (800) 424-2634. Summary: This brochure provides information concerning the need to study the impact of medical treatments for the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on persons with hemophilia. The brochure describes HCV and the available treatments, noting the lack of real knowledge about how HCV interacts with hemophilia. The brochure makes recommendations for research to discover more about HCV in hemophiliacs. It examines HIV/AIDS, its history among hemophiliacs, and the development of combination therapies to treat persons with this infection/disease. The brochure calls for research to be done concerning the impact and effectiveness of combination therapies on persons with HIV/AIDS and hemophilia. It supplies the readers with similar information concerning persons with hemophilia who are co-infected
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with HIV/AIDS and HCV. The brochure suggests an order for research priorities concerning people with all three of these afflictions. ·
Hemophilia and Sports Source: 1992. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. Publication No. ARC 2760. American Red Cross National Headquarters Health and Safety Services Office of HIV/AIDS Education, 8111 Gatehouse Rd., Falls Church, VA 22042-1203. (800) 375-2040. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This booklet reviews common attitudes and make recommendations concerning participation in sports and games by children and adults with severe hemophilia. Participation related to sports by a child with hemophilia presents certain risks, but is vital to his physical and psychological development. The general body build of the person, past clinical history, and present conditions of joints should all be considered when choosing a sport, with appropriate precautions taken in all cases. A list of various sports includes evaluative ratings on their safety. The booklet briefly discusses sports activities for persons with mild hemophilia.
·
Comprehensive Care for People With Hemophilia Source: 1991. Contact: National Hemophilia Foundation Hemophilia and AIDS Network for the Dissemination of Information, 110 Greene St., Ste. 303, New York, NY 10012-3832. (212) 431-8541. A photocopy of this material is available from the CDC National Prevention Information Network Document Delivery Service, P.O. Box 6003, Rockville, MD 20849-6003. (800) 458-5231. Summary: This brochure addresses comprehensive care for people with hemophilia; that is, continuing supervision by a multidisciplinary team of professionals overseeing all medical and psychosocial factors affecting persons and their families. The brochure discusses the functions of a comprehensive care center, the components of the team, essential resources, HIV infection and hemophilia, implementation of the treatment plan, and the benefits of comprehensive care.
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·
Survey report of hemophilia and HIV programs for adolescents Source: New York, NY: National Hemophilia Association. 1992. 66 pp. Contact: Available from Hemophilia and AIDS/HIV Network for the Dissemination of Information, 116 West 32nd Street, 11th Floor, New York, NY 10001. Telephone: (212) 328-3700 or (800) 42-HANDI / fax: (212) 328-3799 / e-mail:
[email protected] / Web site: http://www.infonhf.org. Available at no charge. Summary: This report presents the results of a survey by the National Hemophilia Foundation to determine the availability of HIV programs for adolescents in the hemophilia community, determine trends in program development to guide future programming, select model programs and ideas to serve as a basis for the development of new programs, and improve networking and communication about adolescents and HIV among interested hemophilia organizations. Descriptions of model HIV programs for adolescents in the hemophilia community and an overview of HIV prevention and support programs for adolescents in other communities and their applicability to the hemophilia community are also included.
The NLM Gateway30 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing “one-stop searching” for many of NLM’s information resources or databases.31 One target audience for the Gateway is the Internet user who is new to NLM’s online resources and does not know what information is available or how best to search for it. This audience may include physicians and other healthcare providers, researchers, librarians, students, and, increasingly, patients, their families,
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x. The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH).
30 31
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and the public.32 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “hemophilia” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category.
HSTAT33 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.34 HSTAT’s audience includes healthcare providers, health service researchers, policy makers, insurance companies, consumers, and the information professionals who serve these groups. HSTAT provides access to a wide variety of publications, including clinical practice guidelines, quick-reference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.35 Simply search by “hemophilia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
Coffee Break: Tutorials for Biologists36 Some patients may wish to have access to a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that Other users may find the Gateway useful for an overall search of NLM’s information resources. Some searchers may locate what they need immediately, while others will utilize the Gateway as an adjunct tool to other NLM search services such as PubMed® and MEDLINEplus®. The Gateway connects users with multiple NLM retrieval systems while also providing a search interface for its own collections. These collections include various types of information that do not logically belong in PubMed, LOCATORplus, or other established NLM retrieval systems (e.g., meeting announcements and pre-1966 journal citations). The Gateway will provide access to the information found in an increasing number of NLM retrieval systems in several phases. 33 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 34 The HSTAT URL is http://hstat.nlm.nih.gov/. 35 Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force’s Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 36 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 32
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may one day assist physicians in developing treatments. To this end, we recommend “Coffee Break,” a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.37 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.38 This site has new articles every few weeks, so it can be considered an online magazine of sorts, and intended for general background information. You can access the Coffee Break Web site at: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are a few examples that may interest you: ·
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
·
Image Engine: Multimedia electronic medical record system that integrates a wide range of digitized clinical images with textual data stored in the University of Pittsburgh Medical Center’s MARS electronic medical record system; see the following Web site: http://www.cml.upmc.edu/cml/imageengine/imageEngine.html.
·
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
·
MedWeaver: Prototype system that allows users to search differential diagnoses for any list of signs and symptoms, to search medical literature, and to explore relevant Web sites; see http://www.med.virginia.edu/~wmd4n/medweaver.html.
·
Metaphrase: Middleware component intended for use by both caregivers and medical records personnel. It converts the informal language
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 38 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 37
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generally used by caregivers into terms from formal, controlled vocabularies; see http://www.lexical.com/Metaphrase.html.
The Genome Project and Hemophilia With all the discussion in the press about the Human Genome Project, it is only natural that physicians, researchers, and patients want to know about how human genes relate to hemophilia. In the following section, we will discuss databases and references used by physicians and scientists who work in this area.
Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).39 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. Go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html to search the database. Type “hemophilia” (or synonyms) in the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. By following these links, especially the link titled “Database Links,” you will be exposed to numerous specialized databases that are largely used by the scientific community. These databases are overly technical and seldom used by the general public, but offer an abundance of information. The following is an example of the results you can obtain from the OMIM for hemophilia:
Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
39
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Genes and Disease (NCBI - Map) The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to re-visit it from time to time. The following systems and associated disorders are addressed: ·
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
·
Metabolism: Food and energy. Examples: Adreno-leukodystrophy, Atherosclerosis, Best disease, Gaucher disease, Glucose galactose malabsorption, Gyrate atrophy, Juvenile onset diabetes, Obesity, Paroxysmal nocturnal hemoglobinuria, Phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
·
Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
·
Transporters: Pumps and channels. Examples: Cystic Fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html
Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: ·
PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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·
Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
·
Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
·
Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
·
Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
·
PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
·
OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
·
Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
·
Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
·
ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
·
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
·
NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” In the box next to “for,” enter “hemophilia” (or synonyms) and click “Go.”
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Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database40 This online resource can be quite useful. It has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html you can also search across syndromes using an alphabetical index. You can also search at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database41 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “hemophilia” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms). This database is extremely technical as it was created for specialists. The articles are the results which are the most accessible to non-professionals and Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 41 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html#mission. 40
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often listed under the heading “Citations.” The contact names are also accessible to non-professionals.
Specialized References The following books are specialized references written for professionals interested in hemophilia (sorted alphabetically by title, hyperlinks provide rankings, information, and reviews at Amazon.com): · Blood and Circulatory Disorders Sourcebook : Basic Information About Blood and Its Components (Health Reference Series, Vol 39) by Linda M. Shin (Editor), Karen Bellenir (Editor); Library Binding - October 1998, Omnigraphics, Inc.; ISBN: 0780802039; http://www.amazon.com/exec/obidos/ASIN/0780802039/icongroupinterna · CRC Desk Reference for Hematology (CRC Desk Reference Series) by N. K. Shinton (Editor); Hardcover - September 1998, CRC Press; ISBN: 0849396816; http://www.amazon.com/exec/obidos/ASIN/0849396816/icongroupinterna · Clinical Laboratory Hematology by Shirlyn McKenzie; Hardcover - May 2002, Prentice Hall; ISBN: 0130199966; http://www.amazon.com/exec/obidos/ASIN/0130199966/icongroupinterna · Hematology for Students by Archie A. MacKinney (Editor); (Paperback June 2002), Harwood Academic Pub; ISBN: 9057026465; http://www.amazon.com/exec/obidos/ASIN/9057026465/icongroupinterna · Manual of Clinical Hematology by Joseph J., MD Mazza (Editor); Spiralbound, Lippincott, Williams & Wilkins Publishers; ISBN: 0781729807; http://www.amazon.com/exec/obidos/ASIN/0781729807/icongroupinterna · Microscopic Haematology: A Practical Guide for the Haematology Laboratory by Gillian Rozenberg; Paperback - 160 pages (August 1, 1997), Dunitz Martin Ltd.; ISBN: 9057022478; http://www.amazon.com/exec/obidos/ASIN/9057022478/icongroupinterna · Pioneering Hematology : The Research & Treatment of Malignant Blood Disorders by William C. Maloney; Hardcover - September 1997, Science History Publications; ISBN: 0881351954; http://www.amazon.com/exec/obidos/ASIN/0881351954/icongroupinterna · Williams Hematology by Ernest Beutler, M.D., Marshall A. Lichtman, M.D.; Hardcover - 1941 pages, 6th edition (November 28, 2000), McGrawHill Professional Publishing; ISBN: 0070703973; http://www.amazon.com/exec/obidos/ASIN/0070703973/icongroupinterna
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Vocabulary Builder Antiviral: Destroying viruses or suppressing their replication. [EU] Lymphadenopathy: Disease of the lymph nodes. [EU] Malignant: Tending to become progressively worse and to result in death. Having the properties of anaplasia, invasion, and metastasis; said of tumours. [EU]
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PART III. APPENDICES
ABOUT PART III Part III is a collection of appendices on general medical topics which may be of interest to patients with hemophilia and related conditions.
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APPENDIX A. RESEARCHING YOUR MEDICATIONS Overview There are a number of sources available on new or existing medications which could be prescribed to patients with hemophilia. While a number of hard copy or CD-Rom resources are available to patients and physicians for research purposes, a more flexible method is to use Internet-based databases. In this chapter, we will begin with a general overview of medications. We will then proceed to outline official recommendations on how you should view your medications. You may also want to research medications that you are currently taking for other conditions as they may interact with medications for hemophilia. Research can give you information on the side effects, interactions, and limitations of prescription drugs used in the treatment of hemophilia. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
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Your Medications: The Basics42 The Agency for Health Care Research and Quality has published extremely useful guidelines on how you can best participate in the medication aspects of hemophilia. Taking medicines is not always as simple as swallowing a pill. It can involve many steps and decisions each day. The AHCRQ recommends that patients with hemophilia take part in treatment decisions. Do not be afraid to ask questions and talk about your concerns. By taking a moment to ask questions early, you may avoid problems later. Here are some points to cover each time a new medicine is prescribed: ·
Ask about all parts of your treatment, including diet changes, exercise, and medicines.
·
Ask about the risks and benefits of each medicine or other treatment you might receive.
·
Ask how often you or your doctor will check for side effects from a given medication.
Do not hesitate to ask what is important to you about your medicines. You may want a medicine with the fewest side effects, or the fewest doses to take each day. You may care most about cost, or how the medicine might affect how you live or work. Or, you may want the medicine your doctor believes will work the best. Telling your doctor will help him or her select the best treatment for you. Do not be afraid to “bother” your doctor with your concerns and questions about medications for hemophilia. You can also talk to a nurse or a pharmacist. They can help you better understand your treatment plan. Feel free to bring a friend or family member with you when you visit your doctor. Talking over your options with someone you trust can help you make better choices, especially if you are not feeling well. Specifically, ask your doctor the following: ·
The name of the medicine and what it is supposed to do.
·
How and when to take the medicine, how much to take, and for how long.
·
What food, drinks, other medicines, or activities you should avoid while taking the medicine.
·
What side effects the medicine may have, and what to do if they occur.
·
If you can get a refill, and how often.
42
This section is adapted from AHCRQ: http://www.ahcpr.gov/consumer/ncpiebro.htm.
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·
About any terms or directions you do not understand.
·
What to do if you miss a dose.
·
If there is written information you can take home (most pharmacies have information sheets on your prescription medicines; some even offer large-print or Spanish versions).
Do not forget to tell your doctor about all the medicines you are currently taking (not just those for hemophilia). This includes prescription medicines and the medicines that you buy over the counter. Then your doctor can avoid giving you a new medicine that may not work well with the medications you take now. When talking to your doctor, you may wish to prepare a list of medicines you currently take, the reason you take them, and how you take them. Be sure to include the following information for each: ·
Name of medicine
·
Reason taken
·
Dosage
·
Time(s) of day
Also include any over-the-counter medicines, such as: ·
Laxatives
·
Diet pills
·
Vitamins
·
Cold medicine
·
Aspirin or other pain, headache, or fever medicine
·
Cough medicine
·
Allergy relief medicine
·
Antacids
·
Sleeping pills
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Others (include names)
Learning More about Your Medications Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications your doctor has recommended for hemophilia. One such source
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is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the “U.S. Pharmacopeia (USP).” Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at www.usp.org. The USP currently provides standards for over 3,700 medications. The resulting USP DIÒ Advice for the PatientÒ can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database.43 While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopoeia. It is important to read the disclaimer by the United States Pharmacopoeia (http://www.nlm.nih.gov/medlineplus/drugdisclaimer.html) before using the information provided. Of course, we as editors cannot be certain as to what medications you are taking. Therefore, we have compiled a list of medications associated with the treatment of hemophilia. Once again, due to space limitations, we only list a sample of medications and provide hyperlinks to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to hemophilia:
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. You may be able to access these sources from your local medical library or your doctor’s office. Though cumbersome, the FDA database can be freely browsed at the following site: www.fda.gov/cder/da/da.htm.
43
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Reuters Health Drug Database The Reuters Health Drug Database can be searched by keyword at the hyperlink: http://www.reutershealth.com/frame2/drug.html. The following medications are listed in the Reuters’ database as associated with hemophilia (including those with contraindications):44
Mosby’s GenRx Mosby’s GenRx database (also available on CD-Rom and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Information from Mosby’s GenRx can be obtained at the following hyperlink: http://www.genrx.com/Mosby/PhyGenRx/group.html. Physicians Desk Reference The Physicians Desk Reference database (also available in CD-Rom and book format) is a full-text drug database. The database is searchable by brand name, generic name or by indication. It features multiple drug interactions reports. Information can be obtained at the following hyperlink: http://physician.pdr.net/physician/templates/en/acl/psuser_t.htm.
Other Web Sites A number of additional Web sites discuss drug information. As an example, you may like to look at www.drugs.com which reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. which allows users to download articles on various drugs and therapeutics for a nominal fee: http://www.medletter.com/.
Researching Orphan Drugs Orphan drugs are a special class of pharmaceuticals used by patients who are unaffected by existing treatments or with illnesses for which no known drug is effective. Orphan drugs are most commonly prescribed or developed 44
Adapted from A to Z Drug Facts by Facts and Comparisons.
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for “rare” diseases or conditions.45 According to the FDA, an orphan drug (or biological) may already be approved, or it may still be experimental. A drug becomes an “orphan” when it receives orphan designation from the Office of Orphan Products Development at the FDA.46 Orphan designation qualifies the sponsor to receive certain benefits from the U.S. Government in exchange for developing the drug. The drug must then undergo the new drug approval process as any other drug would. To date, over 1000 orphan products have been designated, and over 200 have been approved for marketing. Historically, the approval time for orphan products as a group has been considerably shorter than the approval time for other drugs. This is due to the fact that many orphan products receive expedited review because they are developed for serious or life-threatening diseases. The cost of orphan products is determined by the sponsor of the drug and can vary greatly. Reimbursement rates for drug expenses are set by each insurance company and outlined in your policy. Insurance companies will generally reimburse for orphan products that have been approved for marketing, but may not reimburse for products that are considered experimental. Consult your insurance company about specific reimbursement policies. If an orphan product has been approved for marketing, it will be available through the normal pharmaceutical supply channels. If the product has not been approved, the sponsor may make the product available on a compassionate-use basis.47 Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to hemophilia using the database managed by the National Organization for Rare Disorders, Inc. (NORD), located at www.raredisease.org. Simply go to their general search page and select “Orphan Drug Database.” On this page (http://www.rarediseases.org/cgi-bin/nord/searchpage) under “Enter a search term,” type “hemophilia” or a synonym into the search box. Under “Select a database,” check the box for “NORD Orphan Drug Designation The U.S. Food and Drug Administration defines a rare disease or condition as “any disease or condition which affects less than 200,000 persons in the United States, or affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug.” Adapted from the U.S. Food and Drug Administration: http://www.fda.gov/opacom/laws/orphandg.htm. 46 The following is adapted from the U.S. Food and Drug Administration: http://www.fda.gov/orphan/faq/index.htm. 47 For contact information on sponsors of orphan products, contact the Office of Orphan Products Development (http://www.fda.gov/orphan/). General inquiries may be routed to the main office: Office of Orphan Products Development (HF-35); Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857; Voice: (301) 827-3666 or (800) 3007469; FAX: (301) 443-4915. 45
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Database.” When you see a list of drugs, understand that not all of the drugs may be relevant. Some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box on the Web page: http://www.nlm.nih.gov/medlineplus/druginformation.html. Read about each drug in detail and consult your doctor to find out if you might benefit from these medications. You or your physician may need to contact the sponsor or NORD. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you or your physician should consult the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for hemophilia or related conditions:
Contraindications and Interactions (Hidden Dangers) Some of the medications mentioned in the previous discussions can be problematic for patients with hemophilia--not because they are used in the treatment process, but because of contraindications, or side effects. Medications with contraindications are those that could react with drugs used to treat hemophilia or potentially create deleterious side effects in patients with hemophilia. You should ask your physician about any contraindications, especially as these might apply to other medications that you may be taking for common ailments. Drug-drug interactions occur when two or more drugs react with each other. This drug-drug interaction may cause you to experience an unexpected side effect. Drug interactions may make your medications less effective, cause unexpected side effects, or increase the action of a particular drug. Some drug interactions can even be harmful to you. Be sure to read the label every time you use a nonprescription or prescription drug, and take the time to learn about drug interactions. These precautions may be critical to your health. You can reduce the risk of
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potentially harmful drug interactions and side effects with a little bit of knowledge and common sense. Drug labels contain important information about ingredients, uses, warnings, and directions which you should take the time to read and understand. Labels also include warnings about possible drug interactions. Further, drug labels may change as new information becomes available. This is why it’s especially important to read the label every time you use a medication. When your doctor prescribes a new drug, discuss all over-thecounter and prescription medications, dietary supplements, vitamins, botanicals, minerals and herbals you take as well as the foods you eat. Ask your pharmacist for the package insert for each prescription drug you take. The package insert provides more information about potential drug interactions.
A Final Warning At some point, you may hear of alternative medications from friends, relatives, or in the news media. Advertisements may suggest that certain alternative drugs can produce positive results for patients with hemophilia. Exercise caution--some of these drugs may have fraudulent claims, and others may actually hurt you. The Food and Drug Administration (FDA) is the official U.S. agency charged with discovering which medications are likely to improve the health of patients with hemophilia. The FDA warns patients to watch out for48: ·
Secret formulas (real scientists share what they know)
·
Amazing breakthroughs or miracle cures (real breakthroughs don’t happen very often; when they do, real scientists do not call them amazing or miracles)
·
Quick, painless, or guaranteed cures
·
If it sounds too good to be true, it probably isn’t true.
If you have any questions about any kind of medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov. This section has been adapted from http://www.fda.gov/opacom/lowlit/medfraud.html.
48
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General References In addition to the resources provided earlier in this chapter, the following general references describe medications (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·
Complete Guide to Prescription and Nonprescription Drugs 2001 (Complete Guide to Prescription and Nonprescription Drugs, 2001) by H. Winter Griffith, Paperback 16th edition (2001), Medical Surveillance; ISBN: 0942447417; http://www.amazon.com/exec/obidos/ASIN/039952634X/icongroupinterna
·
The Essential Guide to Prescription Drugs, 2001 by James J. Rybacki, James W. Long; Paperback - 1274 pages (2001), Harper Resource; ISBN: 0060958162; http://www.amazon.com/exec/obidos/ASIN/0060958162/icongroupinterna
·
Handbook of Commonly Prescribed Drugs by G. John Digregorio, Edward J. Barbieri; Paperback 16th edition (2001), Medical Surveillance; ISBN: 0942447417; http://www.amazon.com/exec/obidos/ASIN/0942447417/icongroupinterna
·
Johns Hopkins Complete Home Encyclopedia of Drugs 2nd ed. by Simeon Margolis (Ed.), Johns Hopkins; Hardcover - 835 pages (2000), Rebus; ISBN: 0929661583; http://www.amazon.com/exec/obidos/ASIN/0929661583/icongroupinterna
·
Medical Pocket Reference: Drugs 2002 by Springhouse Paperback 1st edition (2001), Lippincott Williams & Wilkins Publishers; ISBN: 1582550964; http://www.amazon.com/exec/obidos/ASIN/1582550964/icongroupinterna
·
PDR by Medical Economics Staff, Medical Economics Staff Hardcover 3506 pages 55th edition (2000), Medical Economics Company; ISBN: 1563633752; http://www.amazon.com/exec/obidos/ASIN/1563633752/icongroupinterna
·
Pharmacy Simplified: A Glossary of Terms by James Grogan; Paperback 432 pages, 1st edition (2001), Delmar Publishers; ISBN: 0766828581; http://www.amazon.com/exec/obidos/ASIN/0766828581/icongroupinterna
·
Physician Federal Desk Reference by Christine B. Fraizer; Paperback 2nd edition (2001), Medicode Inc; ISBN: 1563373971; http://www.amazon.com/exec/obidos/ASIN/1563373971/icongroupinterna
·
Physician’s Desk Reference Supplements Paperback - 300 pages, 53 edition (1999), ISBN: 1563632950; http://www.amazon.com/exec/obidos/ASIN/1563632950/icongroupinterna
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APPENDIX B. RESEARCHING NUTRITION Overview Since the time of Hippocrates, doctors have understood the importance of diet and nutrition to patients’ health and well-being. Since then, they have accumulated an impressive archive of studies and knowledge dedicated to this subject. Based on their experience, doctors and healthcare providers may recommend particular dietary supplements to patients with hemophilia. Any dietary recommendation is based on a patient’s age, body mass, gender, lifestyle, eating habits, food preferences, and health condition. It is therefore likely that different patients with hemophilia may be given different recommendations. Some recommendations may be directly related to hemophilia, while others may be more related to the patient’s general health. These recommendations, themselves, may differ from what official sources recommend for the average person. In this chapter we will begin by briefly reviewing the essentials of diet and nutrition that will broadly frame more detailed discussions of hemophilia. We will then show you how to find studies dedicated specifically to nutrition and hemophilia.
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Food and Nutrition: General Principles What Are Essential Foods? Food is generally viewed by official sources as consisting of six basic elements: (1) fluids, (2) carbohydrates, (3) protein, (4) fats, (5) vitamins, and (6) minerals. Consuming a combination of these elements is considered to be a healthy diet: ·
Fluids are essential to human life as 80-percent of the body is composed of water. Water is lost via urination, sweating, diarrhea, vomiting, diuretics (drugs that increase urination), caffeine, and physical exertion.
·
Carbohydrates are the main source for human energy (thermoregulation) and the bulk of typical diets. They are mostly classified as being either simple or complex. Simple carbohydrates include sugars which are often consumed in the form of cookies, candies, or cakes. Complex carbohydrates consist of starches and dietary fibers. Starches are consumed in the form of pastas, breads, potatoes, rice, and other foods. Soluble fibers can be eaten in the form of certain vegetables, fruits, oats, and legumes. Insoluble fibers include brown rice, whole grains, certain fruits, wheat bran and legumes.
·
Proteins are eaten to build and repair human tissues. Some foods that are high in protein are also high in fat and calories. Food sources for protein include nuts, meat, fish, cheese, and other dairy products.
·
Fats are consumed for both energy and the absorption of certain vitamins. There are many types of fats, with many general publications recommending the intake of unsaturated fats or those low in cholesterol.
Vitamins and minerals are fundamental to human health, growth, and, in some cases, disease prevention. Most are consumed in your diet (exceptions being vitamins K and D which are produced by intestinal bacteria and sunlight on the skin, respectively). Each vitamin and mineral plays a different role in health. The following outlines essential vitamins: ·
Vitamin A is important to the health of your eyes, hair, bones, and skin; sources of vitamin A include foods such as eggs, carrots, and cantaloupe.
·
Vitamin B1, also known as thiamine, is important for your nervous system and energy production; food sources for thiamine include meat, peas, fortified cereals, bread, and whole grains.
·
Vitamin B2, also known as riboflavin, is important for your nervous system and muscles, but is also involved in the release of proteins from
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nutrients; food sources for riboflavin include dairy products, leafy vegetables, meat, and eggs. ·
Vitamin B3, also known as niacin, is important for healthy skin and helps the body use energy; food sources for niacin include peas, peanuts, fish, and whole grains
·
Vitamin B6, also known as pyridoxine, is important for the regulation of cells in the nervous system and is vital for blood formation; food sources for pyridoxine include bananas, whole grains, meat, and fish.
·
Vitamin B12 is vital for a healthy nervous system and for the growth of red blood cells in bone marrow; food sources for vitamin B12 include yeast, milk, fish, eggs, and meat.
·
Vitamin C allows the body’s immune system to fight various diseases, strengthens body tissue, and improves the body’s use of iron; food sources for vitamin C include a wide variety of fruits and vegetables.
·
Vitamin D helps the body absorb calcium which strengthens bones and teeth; food sources for vitamin D include oily fish and dairy products.
·
Vitamin E can help protect certain organs and tissues from various degenerative diseases; food sources for vitamin E include margarine, vegetables, eggs, and fish.
·
Vitamin K is essential for bone formation and blood clotting; common food sources for vitamin K include leafy green vegetables.
·
Folic Acid maintains healthy cells and blood and, when taken by a pregnant woman, can prevent her fetus from developing neural tube defects; food sources for folic acid include nuts, fortified breads, leafy green vegetables, and whole grains.
It should be noted that one can overdose on certain vitamins which become toxic if consumed in excess (e.g. vitamin A, D, E and K). Like vitamins, minerals are chemicals that are required by the body to remain in good health. Because the human body does not manufacture these chemicals internally, we obtain them from food and other dietary sources. The more important minerals include: ·
Calcium is needed for healthy bones, teeth, and muscles, but also helps the nervous system function; food sources for calcium include dry beans, peas, eggs, and dairy products.
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·
Chromium is helpful in regulating sugar levels in blood; food sources for chromium include egg yolks, raw sugar, cheese, nuts, beets, whole grains, and meat.
·
Fluoride is used by the body to help prevent tooth decay and to reinforce bone strength; sources of fluoride include drinking water and certain brands of toothpaste.
·
Iodine helps regulate the body’s use of energy by synthesizing into the hormone thyroxine; food sources include leafy green vegetables, nuts, egg yolks, and red meat.
·
Iron helps maintain muscles and the formation of red blood cells and certain proteins; food sources for iron include meat, dairy products, eggs, and leafy green vegetables.
·
Magnesium is important for the production of DNA, as well as for healthy teeth, bones, muscles, and nerves; food sources for magnesium include dried fruit, dark green vegetables, nuts, and seafood.
·
Phosphorous is used by the body to work with calcium to form bones and teeth; food sources for phosphorous include eggs, meat, cereals, and dairy products.
·
Selenium primarily helps maintain normal heart and liver functions; food sources for selenium include wholegrain cereals, fish, meat, and dairy products.
·
Zinc helps wounds heal, the formation of sperm, and encourage rapid growth and energy; food sources include dried beans, shellfish, eggs, and nuts.
The United States government periodically publishes recommended diets and consumption levels of the various elements of food. Again, your doctor may encourage deviations from the average official recommendation based on your specific condition. To learn more about basic dietary guidelines, visit the Web site: http://www.health.gov/dietaryguidelines/. Based on these guidelines, many foods are required to list the nutrition levels on the food’s packaging. Labeling Requirements are listed at the following site maintained by the Food and Drug Administration: http://www.cfsan.fda.gov/~dms/labcons.html. When interpreting these requirements, the government recommends that consumers become familiar with the following abbreviations before reading FDA literature:49 ·
49
DVs (Daily Values): A new dietary reference term that will appear on the food label. It is made up of two sets of references, DRVs and RDIs. Adapted from the FDA: http://www.fda.gov/fdac/special/foodlabel/dvs.html.
Researching Nutrition 153
·
DRVs (Daily Reference Values): A set of dietary references that applies to fat, saturated fat, cholesterol, carbohydrate, protein, fiber, sodium, and potassium.
·
RDIs (Reference Daily Intakes): A set of dietary references based on the Recommended Dietary Allowances for essential vitamins and minerals and, in selected groups, protein. The name “RDI” replaces the term “U.S. RDA.”
·
RDAs (Recommended Dietary Allowances): A set of estimated nutrient allowances established by the National Academy of Sciences. It is updated periodically to reflect current scientific knowledge. What Are Dietary Supplements?50
Dietary supplements are widely available through many commercial sources, including health food stores, grocery stores, pharmacies, and by mail. Dietary supplements are provided in many forms including tablets, capsules, powders, gel-tabs, extracts, and liquids. Historically in the United States, the most prevalent type of dietary supplement was a multivitamin/mineral tablet or capsule that was available in pharmacies, either by prescription or “over the counter.” Supplements containing strictly herbal preparations were less widely available. Currently in the United States, a wide array of supplement products are available, including vitamin, mineral, other nutrients, and botanical supplements as well as ingredients and extracts of animal and plant origin. The Office of Dietary Supplements (ODS) of the National Institutes of Health is the official agency of the United States which has the expressed goal of acquiring “new knowledge to help prevent, detect, diagnose, and treat disease and disability, from the rarest genetic disorder to the common cold.”51 According to the ODS, dietary supplements can have an important impact on the prevention and management of disease and on the
This discussion has been adapted from the NIH: http://ods.od.nih.gov/whatare/whatare.html. 51 Contact: The Office of Dietary Supplements, National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: (301) 435-2920, Fax: (301) 480-1845, E-mail:
[email protected]. 50
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maintenance of health.52 The ODS notes that considerable research on the effects of dietary supplements has been conducted in Asia and Europe where the use of plant products, in particular, has a long tradition. However, the overwhelming majority of supplements have not been studied scientifically. To explore the role of dietary supplements in the improvement of health care, the ODS plans, organizes, and supports conferences, workshops, and symposia on scientific topics related to dietary supplements. The ODS often works in conjunction with other NIH Institutes and Centers, other government agencies, professional organizations, and public advocacy groups. To learn more about official information on dietary supplements, visit the ODS site at http://ods.od.nih.gov/whatare/whatare.html. Or contact: The Office of Dietary Supplements National Institutes of Health Building 31, Room 1B29 31 Center Drive, MSC 2086 Bethesda, Maryland 20892-2086 Tel: (301) 435-2920 Fax: (301) 480-1845 E-mail:
[email protected]
Finding Studies on Hemophilia The NIH maintains an office dedicated to patient nutrition and diet. The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature
Adapted from http://ods.od.nih.gov/about/about.html. The Dietary Supplement Health and Education Act defines dietary supplements as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb or other botanical; or a dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above; and intended for ingestion in the form of a capsule, powder, softgel, or gelcap, and not represented as a conventional food or as a sole item of a meal or the diet.”
52
Researching Nutrition 155
on dietary supplements such as vitamins, minerals, and botanicals.53 IBIDS is available to the public free of charge through the ODS Internet page: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. We recommend that you start with the Consumer Database. While you may not find references for the topics that are of most interest to you, check back periodically as this database is frequently updated. More studies can be found by searching the Full IBIDS Database. Healthcare professionals and researchers generally use the third option, which lists peer-reviewed citations. In all cases, we suggest that you take advantage of the “Advanced Search” option that allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “hemophilia” (or synonyms) into the search box. To narrow the search, you can also select the “Title” field.
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: ·
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
·
The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
·
The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
·
The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
53
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·
The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
·
Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
·
Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
·
Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: ·
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
·
Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
·
Google: http://directory.google.com/Top/Health/Nutrition/
·
Healthnotes: http://www.thedacare.org/healthnotes/
·
Open Directory Project: http://dmoz.org/Health/Nutrition/
·
Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
·
WebMDÒHealth: http://my.webmd.com/nutrition
·
WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html
The following is a specific Web list relating to hemophilia; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: ·
Vitamins Vitamin E Source: Prima Communications, Inc. Hyperlink: http://www.personalhealthzone.com/pg000092.html
Researching Nutrition 157
·
Food and Diet Bruising Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsConditions/Hemo philiacc.html Fish Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsConditions/Hemo philiacc.html Fruit Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsConditions/Hemo philiacc.html
Vocabulary Builder The following vocabulary builder defines words used in the references in this chapter that have not been defined in previous chapters: Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Carbohydrates: A nutrient that supplies 4 calories/gram. They may be simple or complex. Simple carbohydrates are called sugars, and complex carbohydrates are called starch and fiber (cellulose). An organic compound—containing carbon, hydrogen, and oxygen—that is formed by photosynthesis in plants. Carbohydrates are heat producing and are classified as monosaccharides, disaccharides, or polysaccharides. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]
Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of
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the spinal axis, as the neutral arch. [EU] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Thermoregulation: Heat regulation. [EU] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]
Finding Medical Libraries 159
APPENDIX C. FINDING MEDICAL LIBRARIES Overview At a medical library you can find medical texts and reference books, consumer health publications, specialty newspapers and magazines, as well as medical journals. In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Before going to the library, highlight the references mentioned in this sourcebook that you find interesting. Focus on those items that are not available via the Internet, and ask the reference librarian for help with your search. He or she may know of additional resources that could be helpful to you. Most importantly, your local public library and medical libraries have Interlibrary Loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. NLM’s interlibrary loan services are only available to libraries. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.54
54
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries Open to the Public In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries that are generally open to the public and have reference facilities. The following is the NLM’s list plus hyperlinks to each library Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located):55 ·
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
·
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute), http://www.asmi.org/LIBRARY.HTM
·
Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
·
California: Kris Kelly Health Information Center (St. Joseph Health System), http://www.humboldt1.com/~kkhic/index.html
·
California: Community Health Library of Los Gatos (Community Health Library of Los Gatos), http://www.healthlib.org/orgresources.html
·
California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
·
California: Gateway Health Library (Sutter Gould Medical Foundation)
·
California: Health Library (Stanford University Medical Center), http://www-med.stanford.edu/healthlibrary/
55
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries 161
·
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
·
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: San José PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation), http://go.sutterhealth.org/comm/resc-library/sac-resources.html
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California: University of California, Davis. Health Sciences Libraries
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System), http://www.valleycare.com/library.html
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California: Washington Community Health Resource Library (Washington Community Health Resource Library), http://www.healthlibrary.org/
·
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.exempla.org/conslib.htm
·
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
·
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
·
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute), http://www.christianacare.org/health_guide/health_guide_pmri_health _info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine), http://www.delamed.org/chls.html
·
Georgia: Family Resource Library (Medical College of Georgia), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
·
Georgia: Health Resource Center (Medical Center of Central Georgia), http://www.mccg.org/hrc/hrchome.asp
·
Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library), http://hml.org/CHIS/
162 Hemophilia
·
Idaho: DeArmond Consumer Health Library (Kootenai Medical Center), http://www.nicon.org/DeArmond/index.htm
·
Illinois: Health Learning Center of Northwestern Memorial Hospital (Northwestern Memorial Hospital, Health Learning Center), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center), http://www.osfsaintfrancis.org/general/library/
·
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital), http://www.centralbap.com/education/community/library.htm
·
Kentucky: University of Kentucky - Health Information Library (University of Kentucky, Chandler Medical Center, Health Information Library), http://www.mc.uky.edu/PatientEd/
·
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation), http://www.ochsner.org/library/
·
Louisiana: Louisiana State University Health Sciences Center Medical Library-Shreveport, http://lib-sh.lsuhsc.edu/
·
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center), http://www.cmmc.org/library/library.html
·
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center), http://www.mmc.org/library/
·
Maine: Parkview Hospital, http://www.parkviewhospital.org/communit.htm#Library
·
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center), http://www.smmc.org/services/service.php3?choice=10
·
Maine: Stephens Memorial Hospital Health Information Library (Western Maine Health), http://www.wmhcc.com/hil_frame.html
·
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
·
Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre), http://www.deerlodge.mb.ca/library/libraryservices.shtml
Finding Medical Libraries 163
·
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Md., Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
·
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
·
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://medlibwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
·
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital), http://www.nebh.org/health_lib.asp
·
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital), http://www.southcoast.org/library/
·
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
·
Massachusetts: UMass HealthNet (University of Massachusetts Medical School), http://healthnet.umassmed.edu/
·
Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
·
Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
·
Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
·
Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center), http://www.cancer.med.umich.edu/learn/leares.htm
·
Michigan: Sladen Library & Center for Health Information Resources Consumer Health Information, http://www.sladen.hfhs.org/library/consumer/index.html
·
Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center), http://www.saintpatrick.org/chi/librarydetail.php3?ID=41
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·
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
·
National: National Network of Libraries of Medicine (National Library of Medicine) - provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
·
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
·
Nevada: Health Science Library, West Charleston Library (Las Vegas Clark County Library District), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital), http://www.rahwayhospital.com/library.htm
·
New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center), http://www.englewoodhospital.com/links/index.htm
·
New Jersey: Meland Foundation (Englewood Hospital and Medical Center), http://www.geocities.com/ResearchTriangle/9360/
·
New York: Choices in Health Information (New York Public Library) NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
·
New York: Health Information Center (Upstate Medical University, State University of New York), http://www.upstate.edu/library/hic/
·
New York: Health Sciences Library (Long Island Jewish Medical Center), http://www.lij.edu/library/library.html
·
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
·
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
·
Oklahoma: Saint Francis Health System Patient/Family Resource Center (Saint Francis Health System), http://www.sfhtulsa.com/patientfamilycenter/default.asp
Finding Medical Libraries 165
·
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center), http://www.hmc.psu.edu/commhealth/
·
Pennsylvania: Community Health Resource Library (Geisinger Medical Center), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System), http://www.hsls.pitt.edu/chi/hhrcinfo.html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System), http://www.upmc.edu/passavant/library.htm
·
Quebec, Canada: Medical Library (Montreal General Hospital), http://ww2.mcgill.ca/mghlib/
·
South Dakota: Rapid City Regional Hospital - Health Information Center (Rapid City Regional Hospital, Health Information Center), http://www.rcrh.org/education/LibraryResourcesConsumers.htm
·
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
·
Texas: Matustik Family Resource Center (Cook Children’s Health Care System), http://www.cookchildrens.com/Matustik_Library.html
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
·
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center), http://www.swmedctr.com/Home/
NIH Consensus Statement on Fresh Frozen Plasma 167
APPENDIX D. NIH CONSENSUS STATEMENT ON FRESH FROZEN PLASMA Overview NIH Consensus Development Conferences are convened to evaluate available scientific information and resolve safety and efficacy issues related to biomedical technology. The resultant NIH Consensus Statements are intended to advance understanding of the technology or issue in question and to be useful to health professionals and the public.56 Each NIH consensus statement is the product of an independent, non-Federal panel of experts and is based on the panel’s assessment of medical knowledge available at the time the statement was written. Therefore, a consensus statement provides a “snapshot in time” of the state of knowledge of the conference topic. The NIH makes the following caveat: “When reading or downloading NIH consensus statements, keep in mind that new knowledge is inevitably accumulating through medical research. Nevertheless, each NIH consensus statement is retained on this website in its original form as a record of the NIH Consensus Development Program.”57 The following concensus statement was posted on the NIH site and not indicated as “out of date” in March 2002. It was originally published, however, in September 1984.58
56 This paragraph is adapted from the NIH: http://odp.od.nih.gov/consensus/cons/cons.htm. 57 Adapted from the NIH: http://odp.od.nih.gov/consensus/cons/consdate.htm. 58 Fresh Frozen Plasma: Indications and Risks. NIH Consens Statement Online 1984 Sept 24-26 [cited 2002 February 19]; 5(5):1-12. http://consensus.nih.gov/cons/045/045_statement.htm.
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Fresh Frozen Plasma: Indications and Risks Fresh Frozen Plasma (FFP) is defined as the fluid portion of one unit of human blood that has been centrifuged, separated, and frozen solid at -18° C (or colder) within 6 hours of collection. Other single-donor plasma units, either frozen or liquid, may be substituted for FFP. Indications for these products are interchangeable with those for FFP except for coagulation factor V deficiency. For that reason, the term FFP in this statement otherwise applies to all single-donor plasma units. The use of plasma and its products has evolved over a period of four decades. The use of FFP has increased tenfold within the past 10 years and reached almost 2 million units annually. This trend may be attributable to multiple factors, possibly including decreased availability of whole blood due to widespread acceptance of the concept of component therapy. FFP contains the labile as well as the stable components of the coagulation, fibrinolytic, and complement systems; the proteins that maintain oncotic pressure and modulate immunity; and other proteins that have diverse activities. In addition, fats, carbohydrates, and minerals are present in concentrations similar to those in circulation. Although well-defined indications exist for the use of FFP in single or multiple coagulation deficiencies, indications for many of its other uses may be empiric. In an effort to resolve some of the questions surrounding the steadily increasing use of FFP, the National Heart, Lung, and Blood Institute, the Center for Drugs and Biologics of the Food and Drug Administration, and the Office of Medical Applications of Research convened a Consensus Development Conference on FFP on September 24-26, 1984. After a day and a half of presentations by experts in the field, a consensus panel drawn from the medical professions, blood banking organizations, and the general public considered the evidence and agreed on answers to the following key questions: ·
What are the currently recommended clinical indications for FFP?
·
What are the risks of FFP?
·
What alternative therapies exist?
·
What is the current scientific knowledge regarding the effectiveness of FFP?
·
What directions for future research are indicated?
NIH Consensus Statement on Fresh Frozen Plasma 169
Panel’s Conclusions The administration of FFP has increased dramatically in recent years despite the paucity of definitive indications for its use. This increase has occurred in the presence of mounting evidence of its potential risks, which include viral hepatitis and possibly AIDS. Many patients who receive FFP can be managed more effectively and safely with alternative modalities. Appropriate use of FFP must be justified on clinical grounds until better evidence is available. Research to develop safer FFP and alternative therapies is encouraged. There is no justification for the use of FFP as a volume expander or as a nutritional source. Safer alternative therapies exists. FFP is indicated for some documented coagulation protein deficiencies as well as for selected patients who require massive transfusions. It is indicated for patients with multiple coagulation defects as in liver disease, in conjunction with therapeutic plasma exchange for thrombotic thrombocytopenic purpura, for infants with protein-losing enteropathy, and for selected patients with other immune deficiencies. Its use in most other cases should be discouraged. Innovative educational efforts are needed to encourage appropriate use.
What Are the Currently Recommended Clinical Indications for FFP? Few specific indications for the use of FFP exist. These indications generally are limited to the treatment of deficiencies of coagulation proteins for which specific factor concentrates are unavailable or undesirable. In addition, circumstances exist in which FFP has been employed and is believed to be of therapeutic value, but data supporting its efficacy are limited or unavailable (e.g., multiple coagulation protein deficiencies in the uncontrollably bleeding patient). Because such patients are often critically ill and satisfactory alternative therapy may not be at hand, FFP may be appropriate. Indications for the use of FFP include the following:
170 Hemophilia
Replacement of Isolated Factor Deficiencies FFP is efficacious for treatment of deficiencies of factors II, V, VII, IX, X, and XI when specific component therapy is neither available nor appropriate. Requirements for FFP vary with the specific factor being replaced. For example, hemostatic levels of factor IX in a patient with severe deficiency are difficult to achieve with FFP alone, whereas patients with severe factor X deficiency require factor levels of about 10 percent to achieve hemostasis and are easily treated with FFP.
Reversal of Warfarin Effect Patients who are anticoagulated with warfarin are deficient in the functional vitamin K dependent coagulation factors II, VII, IX, and X, as well as proteins C and S. These functional deficiencies can be reversed by the administration of vitamin K. However, for anticoagulated patients who are actively bleeding or who require emergency surgery, FFDP (or single-donor plasma) can be used to achieve immediate hemostasis.
Massive Blood Transfusion59 Use of FFP in massive blood transfusion, for which there is less credible evidence of efficacy, appears to have increased in frequency in the past decade, possibly due in part to the relative unavailability of whole blood. Pathological hemorrhage in the massively transfused patient is caused more frequently by thrombocytopenia than by depletion of coagulation factors. The empiric use of FFP to reverse hemostatic disorders should be confined to those patients in whom factor deficiencies are presumed to be the sole or principal derangement. There is no evidence that the prophylactic administration of FFP decreases transfusion requirements in multiply transfused patients who do not have documented coagulation defects.
Use in Antithrombin III Deficiency FFP can be used as a source of antithrombin III in patients who are deficient in this inhibitor and are undergoing surgery or who require heparin for treatment of thrombosis.
59
>1 blood volume within several hours
NIH Consensus Statement on Fresh Frozen Plasma 171
Treatment of Immunodeficiencies FFP is useful in infants with secondary immunodeficiency associated with severe protein-losing enteropathy and in whom total parenteral nutrition is ineffectual. FFP also can be used as a source of immunoglobulin for children and adults with humoral immunodeficiency. However, the development of a purified immune globulin for intravenous use largely has replaced FFP.
Treatment of Thrombotic Thrombocytopenic Purpura FFP may be beneficial for the treatment of thrombotic thrombocytopenic purpura.
Risks of FFP The risks of FFP include disease transmission, anaphylactoid reactions, alloimmunization, and excessive intravascular volume. The potential viral infectivity of FFP probably is similar to that of whole blood and red blood cells. The rate of posttransfusion hepatitis--predominantly non A, non Bdepends on many factors, including donor selection. The incidence of nonicteric and icteric hepatitis following multiple transfusions probably ranges between 3 and 10 percent. In rare instances, acquired immunodeficiency syndrome (AIDS) is transmitted by blood transfusions and possibly by FFP. Allergic or anaphylactoid reactions can occur in response to FFP administration and may vary from hives to fatal noncardiac pulmonary edema. The potential for alloimmunization is present, as demonstrated by the infrequent formation of Rh antibodies. As with any intravenously administered fluid, excessive amounts of FFP may result in hypervolemia and cardiac failure.
What Alternative Therapies Exist? Evidence indicates that other plasma components (e.g., single-donor plasma) that do not meet the criteria of FFP may have adequate levels of coagulation factors and are suitable for patients in whom FFP is indicated. Single-donor plasma is efficacious in the treatment of mild deficiencies of stable clotting factors. It also is of value in treatment of multiple deficiencies as in reversal of warfarin effects or in liver disease.
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Safe and effective alternative treatment often exists so that FFP is no longer the therapy of choice in many conditions. Cryoprecipitate should be used when fibrinogen or von Willebrand factor is needed. For treatment of hemophilia A, cryoprecipitate or factor VIII concentrates, heated or unheated, are available. For treatment of severe hemophilia B, factor IX complex is preferable. Both of these concentrates are prepared from pooled plasma, and the risk of virus transmission is high. The factor IX concentrate carries the additional hazard of thrombogenicity. Crystalloid, colloid solutions containing albumin or plasma protein fraction, hydroxyethyl starch, and dextran are preferable to FFP for volume replacement. The practice of administering both packed red cells and FFP to the same patient should be discouraged, as this adds to the cost and doubles the infection rate. When conditions are appropriate, whole blood should be given. For nutritional support, amino acid solutions and dextrose are available. The most important alternative to the use of FFP is a comprehensive program of blood conservation. This includes measures such as autologous donation before elective surgery, the infusion of shed blood, and the realization that in many patients normovolemic anemia is not an indication for transfusion. Because of the special nature of neonatal requirements for blood and blood products, these issues were not addressed specifically in this report. Nonetheless, efforts should be exerted to continue to avoid undue exposure to multiple donor sources.
Current Scientific Knowledge Regarding the Effectiveness of FFP There is little scientific evidence to support the increasing use of FFP in clinical medicine. While FFP is a reliable solution for intravascular volume replacement in acute blood loss, alternative therapies are equally satisfactory and considerably safer. There is no documentation that FFP has a beneficial effect when used as part of the transfusion management of patients with massive hemorrhage. FFP contains the major plasma proteins, including the labile coagulation factors (V and VIII), but in clinical practice other blood components or derivatives usually provide greater efficacy.
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Directions for Future Research Research aims should be directed toward: ·
A national prospective study to identify the current patterns of use of FFP and related products.
·
Better understanding of the balance between coagulation and fibrinolytic systems, their activators and inhibitors, and their roles in the coagulopathies associated with liver disease and massive transfusion.
·
Definition of the etiology of uncontrollable hemorrhage in the massively transfused patient.
·
Clinical investigations to identify the factor(s) in FFP that appears to cause beneficial effects in patients who are undergoing apheresis for treatment of syndromes such as thrombotic thrombocytopenic purpura.
·
Blood and plasma salvage during operative procedures.
·
Production of the safest possible specific plasma constituents and substitutes.
·
Processes or methods to eliminate or inactivate viral and bacterial contaminants.
·
Technology involving membrane-separation techniques to separate cellular products more effectively.
·
Development of an efficient system by which a larger volume of FFP can be collected from a single donation thus lessening the number of donor exposures in single recipients.
The use of FFP is controlled locally and determined largely by existing practice. Attempts to alter FFP use frequently have been ineffective. The most successful attempts can be attributed to a strong local proponent of modern transfusion practices. Ongoing collaborative efforts, including component therapy workshops involving clinicians and blood bank directors, can do much to alter existing practices. Increased attention to the risks and benefits of component therapy in the medical schools and teaching hospitals also may change the use of FFP. When appropriate, information regarding potential risks and benefits of FFP and other blood products should be made available to patients who receive those products.
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Vocabulary Builder Edema: Abnormal fluid accumulation in body tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU]
Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour now often used of endocrine factors as opposed to neural or somatic. [EU] Immunity: The condition of being immune; the protection against infectious disease conferred either by the immune response generated by immunization or previous infection or by other nonimmunologic factors (innate i.). [EU] Labile: 1. gliding; moving from point to point over the surface; unstable; fluctuating. 2. chemically unstable. [EU] Oncotic: Pertaining to, caused by, or marked by swelling. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Pulmonary: Relating to the lungs. [NIH] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH]
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APPENDIX E. NIH CONSENSUS STATEMENT ON INFECTIOUS DISEASE TESTING FOR BLOOD TRANSFUSIONS Overview NIH Consensus Development Conferences are convened to evaluate available scientific information and resolve safety and efficacy issues related to biomedical technology. The resultant NIH Consensus Statements are intended to advance understanding of the technology or issue in question and to be useful to health professionals and the public.60 Each NIH consensus statement is the product of an independent, non-Federal panel of experts and is based on the panel’s assessment of medical knowledge available at the time the statement was written. Therefore, a consensus statement provides a “snapshot in time” of the state of knowledge of the conference topic. The NIH makes the following caveat: “When reading or downloading NIH consensus statements, keep in mind that new knowledge is inevitably accumulating through medical research. Nevertheless, each NIH consensus statement is retained on this website in its original form as a record of the NIH Consensus Development Program.”61 The following concensus statement was posted on the NIH site and not indicated as “out of date” in March 2002. It was originally published, however, in January 1995.62
This paragraph is adapted from the NIH: http://odp.od.nih.gov/consensus/cons/cons.htm. Adapted from the NIH: http://odp.od.nih.gov/consensus/cons/consdate.htm. 62 Infectious Disease Testing for Blood Transfusions. NIH Consensus Statement Online 1995 Jan 9-11[cited 2002 February 19];13(1):1-29. http://consensus.nih.gov/cons/099/099_statement.htm. 60 61
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Abstract Objective To provide physicians and other transfusion medicine professionals with a current consensus on infectious disease testing for blood transfusions.
Participants A non-Federal, nonadvocate, 12-member consensus panel representing the fields of hematology, infectious disease, transfusion medicine, epidemiology, and biostatistics and a public representative. In addition, 23 experts in hematology, cardiology, transfusion medicine, infectious disease, and epidemiology presented data to the consensus panel and a conference audience of 450.
Evidence The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience.
Consensus The panel, answering predefined consensus questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. Consensus Statement The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference.
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Conclusions The serum alanine aminotransferase test should be discontinued as a surrogate marker for blood donors likely to transmit posttransfusion non-A, non-B hepatitis infection since specific hepatitis C antibody testing has eliminated more than 85 percent of these cases. Anti-hepatitis B core antigen testing should continue as it may prevent some cases of posttransfusion hepatitis B; it also may act as a surrogate marker for HIV infection in donors and may prevent a small number of cases of transfusion-transmitted HIV infection. Syphilis testing should continue until adequate data can determine its effect on the rarity of transfusion-transmitted syphilis. Vigilant public health surveillance is critical in responding to emerging infectious disease threats to the blood supply.
What Is Infectious Disease Testing for Blood Transfusions? The United States has had an organized national blood collection system for 50 years. During this time, testing has been either mandated, recommended by regulatory authorities, or adopted voluntarily so as to make blood transfusions as safe as possible. Various strategies have been used during the past decade to exclude unsafe units from transfusion. These methods, which incorporate systems to ensure donor confidentiality, include refining and expanding the scope of the medical history, identifying behavior associated with high risk, and increased testing of donated blood. In the last 10 years alone, blood collection agencies have implemented five new tests applied to all donated blood: human immunodeficiency virus (HIV 1 and 2) antibodies, hepatitis B core antibody (anti-HBc), serum alanine aminotransferase (ALT), antibodies to human T-cell lymphotropic virus (HTLV I/II), and, most recently, antibodies to hepatitis C virus (HCV). At the time these tests were introduced, some were indirect tests, or “surrogates,” whereas others were specific for a particular infection. These actions have been extremely effective, and today the nation’s blood supply is safer than ever. The continuing contribution of some of these tests to the safety of blood transfusions is uncertain. The epidemiology of a disease may change with time, as may immunization status and other factors, so that the optimum combination of donor screening tests is also likely to change. Now that more specific assays are available, the continuing need for certain surrogate assays has been questioned. Both ALT and anti-HBc were introduced as surrogates for an infection that is now subject to more specific testing. Both of these nonspecific tests have a low positive predictive value with frequent false positive results. This leads to disposal of blood from normal donors and to
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deferral of the donors from future donation. False positive values not only contribute to the present blood shortage but also result in emotional, psychological, and financial costs to the donor. Another test, the serological test for syphilis (STS), was introduced to protect against transfusiontransmitted syphilis; at the present time it is retained primarily as a sign of risky behavior rather than as evidence for infection. STS, too, has a substantial false positive rate, leading to discarding blood and rejecting the donor with resultant distress. Moreover, the costs of these tests may make blood processing and blood transfusions needlessly more expensive. To maintain the safety of blood transfusion, it is also important to be alert to the possible introduction of new infectious diseases that may be blood-borne and therefore a hazard of transfusion. Thus, whereas one aim is to eliminate tests that are no longer useful, it is equally important to introduce whatever new screening procedures may be necessary to maximize the safety of blood transfusions. An example of such a challenge is the possibility of Chagas disease in donors. Because of immigration from Mexico, South America, and Central America and reports of several cases of Chagas disease resulting from transfusions, testing of donors for T. cruzi infection is now being considered by many blood banks. No general plans are in place, however, to deal with the introduction of agents that might threaten the safety of the blood supply. The purpose of this consensus conference was twofold: (1) to evaluate the need for continued use of ALT, anti-HBc, and STS tests in volunteer blood donors and (2) to develop a proposal for determining mechanisms to cope with the introduction into the community of an infectious agent that might threaten the blood supply. To address these issues, the National Heart, Lung, and Blood Institute, together with the Office of Medical Applications of Research of the National Institutes of Health, convened a Consensus Development Conference on Infectious Disease Testing for Blood Transfusions. The conference was cosponsored by the Transfusion Branch of the NIH Clinical Center and the National Institute of Allergy and Infectious Disease. After 1-1/2 days of presentations and audience discussion, an independent, non-Federal consensus panel composed of specialists and generalists from medical and other related scientific disciplines considered the evidence and formulated this consensus statement in response to the following four previously stated questions: ·
To what extent does the alanine aminotransferase test contribute to transfusion safety?
NIH Consensus Statement on Fresh Frozen Plasma 179
·
Should its use as in current practice continue or should its use be modified?
·
To what extent do tests for hepatitis B core antibody and for syphilis contribute to transfusion safety?
·
Should their use as in current practice continue or should their use be modified?
·
To manage potential threats to transfusion safety from emerging infectious diseases, what are the appropriate ways to identify of important diseases, to change in blood donor screening practices, and to introduce of new laboratory tests?
·
What are the highest priorities for research to improve transfusion safety by reducing the transmission of infectious disease?
Background for the Role of ALT and Anti-HBc Testing ALT and anti-HBc tests were introduced in 1986-87 in an effort to identify donors at risk of transmitting posttransfusion non-A, non-B (PT-NANB) hepatitis. Two major studies in the late 1970’s indicated that the rate of nonA, non-B hepatitis in transfusion recipients was higher in those receiving units from donors with high ALT levels than in those receiving units from donors with low ALT levels. In the Transfusion Transmitted Virus Study (TTVS) 45 percent of recipients of blood from donors with ALT in a high range (60-284 IU/L) developed PT-NANB hepatitis, whereas only 5 percent of recipients of blood from donors with ALT in a low range (1-14 IU/L) developed PT-NANB hepatitis. Intermediate rates of PT-NANB hepatitis were observed in recipients of units from donors with intermediate levels of ALT. In addition, recipients of units of blood from anti-HBc positive donors experienced a two- to threefold greater risk of PT-NANB hepatitis compared with recipients of units from donors without anti-HBc. A similar correlation between posttransfusion hepatitis and elevated ALT and the presence of anti-HBc in donors was observed at the National Institutes of Health. These two studies suggested that anti-HBc testing of donors, in concert with ALT testing, might eliminate 30-50 percent of PT-NANB hepatitis. Based on these studies, testing of volunteer donors for ALT and anti-HBc was begun by blood banks to reduce PT-NANB hepatitis. Several years later, HCV was identified, an anti-HCV test was developed, and HCV was shown to be responsible for most, if not all (> 90 percent) cases of PT-NANB hepatitis. The more sensitive second-generation test for anti-HCV combined with improved donor selection has effectively eliminated 85-90 percent of posttransfusion hepatitis due to HCV. It is likely that newer tests for anti-
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HCV will improve this level of protection against posttransfusion hepatitis C. The issue at present is whether these two surrogate tests (ALT and antiHBc) continue to contribute to transfusion safety. Does the Alanine Aminotransferase Test Contribute to Transfusion Safety? The panel reviewed the background data of changes in the risk of hepatitis following blood transfusion resulting from implementation of increasingly sophisticated tests for HCV infection. Also reviewed were data regarding the interpretation of an elevated ALT level in otherwise healthy blood donors. The potential utility of ALT testing is as follows: ·
To reduce the risk of posttransfusion hepatitis C not prevented by screening of donors for antibody to HCV;
·
To reduce the risk of posttransfusion hepatitis caused by other known hepatotropic viruses, such as hepatitis A and hepatitis B;
·
To reduce the risk of putative infectious agent(s) associated with posttransfusion non-A, non-B, non-C hepatitis.
Now that sensitive tests for HCV infection in donors are available, the value of ALT must be questioned. In addition, the current policy of ALT testing results in the elimination of many acceptable donors and causes additional cost. Setting criteria for discarding units of donated blood because of ALT elevations has been problematic because modest elevations of serum ALT are common in healthy blood donors. Elevations may reflect acute or chronic liver disease of infectious or noninfectious etiologies. However, frequent alcohol consumption, obesity, or other factors not related to transfusiontransmitted diseases may cause ALT to rise to levels that lead to unnecessary exclusion of donors. Furthermore, studies in the United States and Europe have confirmed that values of ALT in normal males are considerably higher than those in normal females so that a single cutoff value for ALT rejects a higher proportion of men than women. Because several different methodologies are available to measure ALT activity, some variation in ALT results will occur even if the same sample is tested in different laboratories. Thus, the interpretation of an ALT level is affected by the assay and by the laboratory in which the determination is made. The lack of standardized interpretation of test results and cutoff
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values for these results contributes to inconsistent rules regarding the inclusion and exclusion of donors. ALT is a continuous variable, but the decision to discard a unit of blood is a binary one. Thus, healthy donors with borderline elevations of ALT may be deferred or permanently excluded from donating blood. Prior to the introduction of anti-HCV testing, surrogate markers including ALT may have reduced the overall posttransfusion hepatitis rate by 30-40 percent on a per unit basis. Improved donor recruitment and selection also contributed to this reduction. However, the preponderance of the available data indicates that, in the presence of anti-HCV testing, retention of ALT testing of blood donors has little additional value. Several observational studies failed to demonstrate an additional benefit of ALT testing in the prevention of posttransfusion hepatitis C. This conclusion was further supported by a prospective randomized study. With specific anti-HCV testing, the risk of posttransfusion hepatitis was equivalent in groups receiving blood screened with or without surrogate markers, pointing to the redundancy of ALT testing. ALT elevation has been proposed as a surrogate marker of HCV infection in the “window period” prior to anti-HCV seroconversion, because ALT rises approximately 4 weeks prior to production of anti-HCV. Implementation of newer, unlicensed anti-HCV tests (HCV 3.0) is expected to reduce this 4week window period. In spite of the theoretical window period, there are no data from clinical studies indicating that ALT screening would improve the margin of safety of blood transfusion. Even with anti-HCV testing of blood donors, a small but measurable risk of posttransfusion hepatitis remains (< 0.8 percent in both U.S. and Canadian studies). Possible explanations for this residual posttransfusion hepatitis include infection with new agents or known viruses presenting in an atypical fashion. Examples of the latter might include serotypic variants of HCV not currently detected by standard assays, HBV variants with mutations in the envelope protein that are not identified by standard HBsAg testing, and window period infections with HBV not detected by standard assays. In addition, some cases of apparent posttransfusion hepatitis may have a noninfectious etiology. Although the potential benefit of ALT for early detection of unknown hepatotropic viruses is intriguing, current data suggest that such testing will rarely, if ever, be helpful. The potential benefit of ALT for the detection of posttransfusion hepatitis A infection is also likely to be limited since the brief period of viremia largely precedes the rise in ALT.
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The direct cost of the ALT test is low. On the other hand, ALT testing incurs very high costs as measured by lost resources, both of discarded units (approximately 200,000 annually) and of donors temporarily deferred or permanently excluded (approximately 150,000 annually). Moreover, evaluation of donors with abnormal ALT represents an additional fiscal burden to the health care system. A substantial, but underappreciated, consequence of ALT testing is the direct psychological and financial impact on the deferred donor. A donor with borderline elevated ALT may be denied health and life insurance and may suffer from unwarranted anxiety and stress.
Recommendation ALT testing of volunteer blood donors should be discontinued. Persons previously deferred for an isolated elevation in ALT only may now be reevaluated for donor eligibility.
Do Tests for Hepatitis B Core Antibody and for Syphilis Contribute to Transfusion Safety? Anti-HBc Studies indicate that anti-HBc testing does not identify additional donors capable of transmitting HCV infection when such donors are also screened by the current, sensitive anti-HCV tests. However, anti-HBc screening of donors provides two additional benefits that may warrant its retention as a test used to screen blood donors. First, it is likely that anti-HBc testing contributes to the safety of blood transfusion by helping to reduce the risk of hepatitis B virus (HBV) infectious units entering the donor pool. Such units may come from two sources: (1) individuals chronically infected with HBV in whom HBsAg is not detectable and (2) donors with acute hepatitis B who are in the window period following disappearance of HBsAg and prior to the appearance of anti-HBs. Whereas relatively few HBV infectious units are likely to be excluded solely on the basis of anti-HBc testing, current use of anti-HBc screening probably contributes to the low rates of transfusion-transmitted hepatitis B in the United States. In addition, anti-HCV positivity may act as a surrogate marker for HBV infectious donors who are HBsAg negative.
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A second rationale for retention of anti-HBc testing relates to its activity as a surrogate marker for HIV infection. Its ability to serve as a surrogate marker for HIV is due to the overlapping epidemiology of HIV and HBV with common parenteral and sexual transmission risk factors. Given the availability of sensitive serologic markers for HIV infection, the value of antiHBc as a surrogate marker of HIV infection is restricted to recently infected donors who are in the window period of HIV infection prior to the detectability of HIV antibodies. Although window period donors are extremely rare (presently approximately 1:210,000-1:1,140,000), the severe consequence of transfusion-transmitted HIV infection supports the retention of the anti-HBc test for this purpose. Anti-HBc testing may currently be eliminating as many as one-third of HIV window period units. However, the value of anti-HBc testing as a surrogate for HIV is likely to decline with expanding HBV immunization and changing HIV epidemiology. Despite these potential benefits of anti-HBc screening, the present test for anti-HBc has many false positive results leading to the unnecessary deferral of tens of thousands of donors. This results in the loss of a large number of units of blood that are otherwise suitable for transfusion. In addition, donors are provided with confusing test results and are subjected to needless anxiety and medical expense, brought about by the mistaken thinking that they may have a contagious disease. Anti-HBs testing is helpful in confirming the specificity of anti-HBc testing: anti-HBc positivity in donors who also test positive for anti-HBs usually indicates prior HBV infection. Present data suggest that such donors are not likely to be infectious. On the other hand, a small proportion of donors who are anti-HBc positive in the absence of anti-HBs are HBV DNA positive and likely to be infectious. An argument may be made that donors positive for both anti-HBs and anti-HBc have a low probability of transmitting HBV and thus could be returned to the donor pool, but such a strategy would eliminate the potential value of anti-HBc screening in preventing HIV transmission. It would also complicate donor management. Thus the panel concluded that anti-HBs testing should not be a part of donor screening, although it will be useful in the medical evaluation of donors found to be anti-HBc positive. The value of the anti-HBc test in improving the safety of the blood supply is tempered by the impact of high false positive rates. Its positive predictive value for past or present infection with the hepatitis B virus must be improved.
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Recommendation Although there is no reason to retain the anti-HBc test to prevent posttransfusion hepatitis C, it is recommended that the anti-HBc test be retained for donor screening for the following purposes: Prevention of posttransfusion hepatitis B. Prevention of some cases of transfusion-transmitted HIV from donors who test negative for anti-HIV because they are in the window phase of the infection.
Syphilis Syphilis is one of the oldest recognized infectious risks of blood transfusion, and serologic tests for syphilis have been routinely carried out on blood donors for more than 50 years. In recent years, transfusion-transmitted syphilis has become exceptionally rare, with very few cases reported in the literature. In 1985, an FDA advisory panel proposed eliminating the requirement for serologic testing for syphilis. This proposal was not acted upon because of the possible value of the test as a surrogate marker of HIV. Given this, is it reasonable to continue donor screening for syphilis? Several factors probably contribute to the absence of reported cases of transfusion-transmitted syphilis. These include improved donor selection processes, the uniform application of serologic tests for syphilis to all donors, and a general shift from transfusion of fresh blood to transfusion of refrigerated blood components. The relative role of these three factors in excluding syphilis as an infectious hazard of blood transfusion is difficult to ascertain because of a paucity of data that specifically address these issues. In addition, uncertainty exists concerning the extent to which current surveillance practices would detect occasional cases of transfusiontransmitted syphilis. Antibiotics received by many hospitalized, transfused patients may partially treat transfusion-transmitted syphilis, obscuring the diagnosis but not necessarily preventing long-term complications of the infection. The general use of refrigerated blood for transfusion is often cited as an important factor in reducing the risk of transfusion-transmitted syphilis, as Treponema pallidum loses its viability within a few days in whole blood stored at 4° C. However, available data indicate that a small proportion of viable organisms may survive up to 96 hours under such storage conditions, and many units of blood are refrigerated for shorter time periods prior to transfusion. In addition, platelet concentrates are stored at room temperature
NIH Consensus Statement on Fresh Frozen Plasma 185
and no data are available concerning the survival of T. pallidum under these conditions. Thus, current blood storage conditions would not appear to provide an adequate margin of safety against transfusion-transmitted syphilis, should the donor screening test be eliminated. Further information concerning T. pallidum survival under blood and platelet storage conditions, and the application of molecular techniques to assess the presence of T. pallidum DNA in serologically positive units, would allow better assessment of this question. An alternative rationale often cited as a reason for retaining serologic testing of donors for syphilis is the potential ability of such tests to serve as surrogate markers of other transfusion-transmissible infections, especially HIV. However, cross-sectional studies and examination of prior donations from donors undergoing HIV seroconversion indicate that serologic tests for syphilis have very little value as surrogate markers for HIV infection in recently infected persons who have not yet developed detectable antibodies to HIV. Syphilis testing is likely to identify less than one such donor annually within the United States. This low efficacy of syphilis testing as a surrogate marker of HIV is not sufficient by itself to warrant its application to all blood donors. Low positive predictive values for HBV, HCV, or HTLV infections similarly do not support retention of syphilis testing as a surrogate for these infections.
Recommendation Because the contribution of serologic tests for syphilis in preventing transfusion-transmitted syphilis is not understood, the panel concludes that testing of donors for syphilis should continue.
Transfusion Safety Assurance of transfusion safety relies upon effective public health surveillance for emerging infectious diseases. Appropriate management of newer disease threats requires effective surveillance in combination with the rational use of screening measures to eliminate or minimize the risk of transfusion-associated disease transmission.
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Decisions regarding the appropriate response to a new infectious disease involve many considerations. The answers to the following three questions will direct a logical approach to a control strategy. Is the Disease Potentially Transmissible through Blood Products? Not every existing or emerging infectious disease is potentially transmissible through transfusion. On the other hand, diseases with a long and relatively asymptomatic period during which microorganisms are present in the blood are of particular concern to transfusion safety. Potential threats to transfusion safety from emerging infectious diseases can be identified in a number of ways. Case reports of infection following transfusion or infections appearing in patients who have received blood from multiple donors should prompt epidemiologic investigation. Even in the absence of such reports, if the disease has a significant period during which the causative microorganism is present in the bloodstream, it may be important to institute surveillance systems to detect transfusion-acquired infections. The potential survival of the organism in an infectious form during blood processing and storage should also be investigated. Is the Disease an Important Public Health Problem? The effort expended and resources committed to the disease threat will be determined by the severity, incidence, prevalence, and potential for secondary spread of infection. HIV infection, when it first appeared, affected only a small number of patients, yet the dire consequences of infection triggered a focused effort to exclude HIV from the blood supply. CMV infection is an example at the other end of the spectrum. CMV antibody is present in approximately 50 percent of donors, representing active infection in some, which can in turn be transmitted to recipients. CMV antibodypositive donors are retained since infection in immunocompetent adult recipients is usually mild, and exclusion of CMV positive donors would drastically reduce the nation’s blood supply. Only in immunocompromised patients is CMV potentially fatal, and in these patients blood components lacking CMV infection are preferentially transfused. The incidence and prevalence of the infection in the donor population are also critical determinants. The approach to a widespread infection will require strategies different from those required for a rare or regionally concentrated infection. An example of the latter is T. cruzi infection, a
NIH Consensus Statement on Fresh Frozen Plasma 187
proven transfusion threat currently limited to blood from donors who were born in or resided for prolonged periods in Mexico, Central America, or South America. Thus, regionality, habits, travel history, country of birth, medical history, and perhaps other indices of donor behavior are important considerations in the potential of any infectious agent to emerge as a threat to the blood supply. Another consideration in evaluating the public health importance of an emerging infection is the potential of that infection for secondary spread.
What Are the Appropriate Responses to the Threat? Identification of an emerging transfusion-transmitted infectious disease and assessment of its magnitude will determine the balanced response required to ensure the continuing safety of blood components while maintaining an adequate supply. Management of an emerging threat to the blood supply involves refinement of donor recruitment and selection practices, donor testing, and blood processing. Recipient surveillance may also be important. The appropriate strategy is based on careful assessment of the risk: benefit ratio, cost-effectiveness, and availability of procedures to remove that threat from the donor pool. Each intervention must be tailored to the epidemiology and microbiology of the infection. The intervention strategy that may have the greatest potential efficacy is refinement of the donor history. Data from the early 1980’s demonstrate that a substantial reduction in the incidence of posttransfusion hepatitis B, hepatitis C, and HIV transmission occurred following redesign of donor recruitment and selection practices as well as improved transfusion practice. The efficacy of this approach is further corroborated by recent studies on Chagas disease, which show that careful design and validation of historical questions can separate high-risk from low-risk donors. Further studies on the development and validation of this instrument should be encouraged. The next step in screening for potential transfusion-transmitted infection is implementation of new laboratory tests of donor blood. Ideally such tests should be very sensitive, in order to lead to the rejection of all dangerous donors, and also very specific, in order to achieve a strong positive predictive value and minimize unnecessary deferral of otherwise acceptable donors. In the absence of reliable assays specific for the infection in question, it may be necessary to institute surrogate testing as was done for posttransfusion hepatitis. Implementation of revised donor questionnaires and introduction of laboratory testing must be accompanied by evaluation of outcomes demonstrating that the interventions favorably influence
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component safety and supply. Ineffective or inefficient interventions should be discontinued if their impact is negative or neutral. Implementation of a response to an emerging infectious disease threat to the blood supply requires a wide range of activities. Once a strategy is adopted, personnel must be trained, equipment and supplies obtained, procedures and policies prepared and validated, and appropriate documentation prepared. In view of the fact that any change per se may induce a higher error rate for some time, close supervision is critical at this phase. Numerous other effects result from changes in donor screening strategy. For example, the donor will now be required to answer additional or different questions, or may receive notification of the result of unfamiliar tests. Planning must include these considerations.
Recommendations In the absence of any formal mechanism by which transfusion medicine evaluates the threat of a potential transfusion-transmitted infection, it is recommended that: ·
The blood transfusion community arrange for periodic communication with the Centers for Disease Control and Prevention to proactively review emerging infectious disease threats to the United States and its borders.
·
The appropriate responses once a potential threat to transfusion safety is identified include: - Evaluation of transmissibility by transfusion - Assessment of public health significance - Definition of responses appropriate to the potential transfusion safety risk.
What Are the Highest Priorities for Research? The panel believes that the following issues represent important needs in improving transfusion safety. Recognizing that research is already under way in most of these areas, the panel wishes to provide a comprehensive list of research issues, not in any priority. ·
T. pallidum in relation to transfusion
·
Definition of the incidence and causes of bacterial contamination of blood
NIH Consensus Statement on Fresh Frozen Plasma 189
·
Better methods for eliminating or inactivating infectious agents in blood components
·
Improved direct tests for infectious agents
·
Definition of the biology and natural history of non-A, non-B, non-C, posttransfusion hepatitis
·
Prevalence of residual hepatitis B and hepatitis C posttransfusion hepatitis; large-scale, prospective donor repositories and recipient surveillance
·
Implications of transfusion-transmitted diseases in neonates
·
Evaluation of the risk of nonenveloped viruses in patients receiving plasma derivatives
·
Epidemiology of Chagas disease in the United States
·
Design of questionnaires to elicit evidence of risk in donors
·
Impact of deferral on donors
·
Improved understanding of donor motivation and recruitment practices
·
Development of artificial blood components
Conclusions ·
Since the determination of ALT has not been shown to be a useful surrogate marker in the present setting, the panel recommends that it be discontinued.
·
Anti-HBc testing does have the potential to prevent some cases of posttransfusion hepatitis B. It may also act as a surrogate marker for HIV infection in donors and may prevent a small number of cases of transfusion-transmitted HIV infection. However, it has a high false positive rate, which results in the deferral of many acceptable donors. The panel therefore recommends that the test be continued but that its specificity be improved. Since disease prevalence in populations is in constant flux, the accuracy of direct and indirect tests for disease also changes. The panel therefore also recommends periodic critical reevaluation of the utility of these tests.
·
The test for syphilis has been used for many years, and data are inadequate to ascertain whether it accounts for the rarity of transfusiontransmitted syphilis. The panel therefore recommends that use of the test continue, but also recommends that research be done to determine if seropositivity is predictive of spirochetemia and to define the extent to which the organism remains viable and infective in blood components.
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·
Public health surveillance, and collaboration between public health and transfusion medicine specialists, is critical in responding to emerging infectious disease threats to the blood supply.
·
An organized multidisciplinary approach to these threats must be formulated (including Federal and State public health agencies, the medical community in general, and the transfusion medicine community).
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries and glossaries. The National Library of Medicine has compiled the following list of online dictionaries: ·
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
·
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
·
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
·
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
·
On-line Medical Dictionary (CancerWEB): http://www.graylab.ac.uk/omd/
·
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
·
Terms and Definitions (Office of Rare Diseases): http://rarediseases.info.nih.gov/ord/glossary_a-e.html
Beyond these, MEDLINEplus contains a very user-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia Web site address is http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a) and drkoop.com (http://www.drkoop.com/). Topics of interest can be researched by using keywords before continuing elsewhere, as these basic definitions and concepts will be useful in more advanced areas of research. You may choose to print various pages specifically relating to hemophilia and keep them on file. The NIH, in particular, suggests that patients with hemophilia visit the following Web sites in the ADAM Medical Encyclopedia:
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Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries and glossaries: ·
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
·
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
·
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
·
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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HEMOPHILIA GLOSSARY The following is a complete glossary of terms used in this sourcebook. The definitions are derived from official public sources including the National Institutes of Health [NIH] and the European Union [EU]. After this glossary, we list a number of additional hardbound and electronic glossaries and dictionaries that you may wish to consult. Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]
Adsorption: The attachment of one substance to the surface of another; the concentration of a gas or a substance in solution in a liquid on a surface in contact with the gas or liquid, resulting in a relatively high concentration of the gas or solution at the surface. [EU] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anthropology: The science devoted to the comparative study of man. [NIH] Antibodies: Specific proteins produced by the body's immune system that bind with foreign proteins (antigens). [NIH] Antibody: An immunoglobulin molecule that has a specific amino acid sequence by virtue of which it interacts only with the antigen that induced its synthesis in cells of the lymphoid series (especially plasma cells), or with antigen closely related to it. Antibodies are classified according to their ode of action as agglutinins, bacteriolysins, haemolysins, opsonins, precipitins, etc. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized Tlymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Aqueous: Watery; prepared with water. [EU]
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Arthropathy: Any joint disease. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Lack or loss of strength and energy, weakness. [EU] Asymptomatic: Showing or causing no symptoms. [EU] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bilirubin: A bile pigment that is a degradation product of HEME. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Blindness: The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. [NIH] Carbohydrates: A nutrient that supplies 4 calories/gram. They may be simple or complex. Simple carbohydrates are called sugars, and complex carbohydrates are called starch and fiber (cellulose). An organic compound—containing carbon, hydrogen, and oxygen—that is formed by photosynthesis in plants. Carbohydrates are heat producing and are classified as monosaccharides, disaccharides, or polysaccharides. [NIH] Cardiac: Pertaining to the heart. [EU] Catheter: Thin, flexible medical tube; one use is to insert it into a blood vessel to measure blood pressure. [NIH] Cell: Basic subunit of every living organism; the simplest unit that can exist as an independent living system. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chronic: Of long duration; frequently recurring. [NIH] Coagulation: 1. the process of clot formation. 2. in colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. in surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colorectal: Pertaining to or affecting the colon and rectum. [EU]
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Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Cytokines: Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. [NIH] Cytomegalovirus: A genus of the family herpesviridae, subfamily betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU]
Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Edema: Abnormal fluid accumulation in body tissues. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU]
Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH] Empiric: Empirical; depending upon experience or observation alone, without using scientific method or theory. [EU] Encephalopathy: Any degenerative disease of the brain. [EU] Endogenous: Developing or originating within the organisms or arising from causes within the organism. [EU] Enzyme:
Substance, made by living cells, that causes specific chemical
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changes. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other health-related event occurring in such outbreaks. [EU] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Fatal: Causing death, deadly; mortal; lethal. [EU] Fetus: Unborn offspring from 7 or 8 weeks after conception until birth. [NIH] Fibrinogen: A plasma protein that is converted into fibrin by thrombin in the presence of calcium ions. Fibrin is responsible for the semisolid character of a blood clot. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrosis: Process by which inflamed tissue becomes scarred. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Granulocytopenia: Agranulocytosis. [EU] Haemophilia: A haemorrhagic diathesis occurring in two main forms : (1) haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; (2) haemophilia B (factor IX deficiency, Christmas disease), also X-linked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [EU] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood
Glossary 197
clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Pertaining to the liver. [EU] Hepatitis: Inflammation of the liver. [EU] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Heredity: 1. the genetic transmission of a particular quality or trait from parent to offspring. 2. the genetic constitution of an individual. [EU] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homosexuality: Sexual attraction or relationship between members of the same sex. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour now often used of endocrine factors as opposed to neural or somatic. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH]
Hypertension: High blood pressure (i.e., abnormally high blood pressure tension involving systolic and/or diastolic levels). The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines hypertension as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or taking hypertensive medication. The cause may be adrenal, benign, essential, Goldblatt's, idiopathic, malignant PATE, portal, postpartum, primary, pulmonary, renal or renovascular. [NIH] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Idiopathic: Results from an unknown cause. [NIH] Immunity: The condition of being immune; the protection against infectious disease conferred either by the immune response generated by immunization or previous infection or by other nonimmunologic factors (innate i.). [EU] Immunization: Protection from disease by administering vaccines that induce the body to form antibodies against infectious agents. [NIH]
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Immunogenetics: A branch of genetics which deals with the genetic basis of the immune response. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] Inertia: Inactivity, inability to move spontaneously. [EU] Infarction: 1. the formation of an infarct. 2. an infarct. [EU] Inflammation: Response of the body tissues to injury; typical signs are swelling, redness, and pain. [NIH] Infusion: The therapeutic introduction of a fluid other than blood, as saline solution, solution, into a vein. [EU] Intestinal: Pertaining to the intestine. [EU] Intramuscular: Within the substance of a muscle. [EU] Intravascular: Within a vessel or vessels. [EU] Intravenous: Within a vein or veins. [EU] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]
Labile: 1. gliding; moving from point to point over the surface; unstable; fluctuating. 2. chemically unstable. [EU] Lymphadenopathy: Disease of the lymph nodes. [EU] Lymphoma: Cancer of the lymph nodes. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaise: A vague feeling of bodily discomfort. [EU] Malignant: Tending to become progressively worse and to result in death. Having the properties of anaplasia, invasion, and metastasis; said of tumours. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Melanoma: A tumour arising from the melanocytic system of the skin and other organs. When used alone the term refers to malignant melanoma. [EU]
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Membrane: Thin, flexible film of proteins and lipids that encloses the contents of a cell; it controls the substances that go into and come out of the cell. Also, a thin layer of tissue that covers the surface or lines the cavity of an organ. [NIH] Metabolite: process. [EU]
Any substance produced by metabolism or by a metabolic
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Nasal: Pertaining to the nose. [EU] Nausea: An unpleasant sensation, vaguely referred to the epigastrium and abdomen, and often culminating in vomiting. [EU] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatology: infant. [NIH]
A subspecialty of Pediatrics concerned with the newborn
Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of the spinal axis, as the neutral arch. [EU] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Oncotic: Pertaining to, caused by, or marked by swelling. [EU] Orthopaedic: Pertaining to the correction of deformities of the musculoskeletal system; pertaining to orthopaedics. [EU] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH]
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Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Pathogen: Any disease-producing microorganism. [EU] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of Pneumocystis carinii pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects. [NIH]
Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Pharmacokinetics: The action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The entire physical, biochemical, and physiological makeup of an individual as determined by his or her genes and by the environment in the broad sense. [NIH] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Prenatal: Occurring before birth. [NIH] Prophylaxis: The prevention of disease; preventive treatment. [EU] Protease: any enzyme that catalyses the splitting of interior peptide bonds in
Glossary 201
a protein. [EU] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]
Proviruses: Duplex DNA sequences in eukaryotic chromosomes, corresponding to the genome of a virus, that are transmitted from one cell generation to the next without causing lysis of the host. Proviruses are often associated with neoplastic cell transformation and are key features of retrovirus biology. [NIH] Pulmonary: Relating to the lungs. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Receptor: 1. a molecular structure within a cell or on the surface characterized by (1) selective binding of a specific substance and (2) a specific physiologic effect that accompanies the binding, e.g., cell-surface receptors for peptide hormones, neurotransmitters, antigens, complement fragments, and immunoglobulins and cytoplasmic receptors for steroid hormones. 2. a sensory nerve terminal that responds to stimuli of various kinds. [EU] Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Refractory: Not readily yielding to treatment. [EU] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Serum:
The clear portion of any body fluid; the clear fluid moistening
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serous membranes. 2. blood serum; the clear liquid that separates from blood on clotting. 3. immune serum; blood serum from an immunized animal used for passive immunization; an antiserum; antitoxin, or antivenin. [EU] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Surgical: Of, pertaining to, or correctable by surgery. [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]
Systemic: Relating to a process that affects the body generally; in this instance, the way in which blood is supplied through the aorta to all body organs except the lungs. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Thrombocytopenia: Decrease in the number of blood platelets. [EU] Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombosis: The formation, development, or presence of a thrombus. [EU] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]
Glossary 203
Tonic: 1. producing and restoring the normal tone. 2. characterized by continuous tension. 3. a term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU]
Toxic: Pertaining to, due to, or of the nature of a poison or toxin; manifesting the symptoms of severe infection. [EU] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU] Transfusion: The introduction of whole blood or blood component directly into the blood stream. [EU] Ulcer: A local defect, or excavation, of the surface of an organ or tissue; which is produced by the sloughing of inflammatory necrotic tissue. [EU] Vaccine: A suspension of attenuated or killed microorganisms (bacteria, viruses, or rickettsiae), administered for the prevention, amelioration or treatment of infectious diseases. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viruses: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. [NIH] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] Withdrawal: 1. a pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) a substancespecific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU]
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General Dictionaries and Glossaries While the above glossary is essentially complete, the dictionaries listed here cover virtually all aspects of medicine, from basic words and phrases to more advanced terms (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·
Dictionary of Medical Acronymns & Abbreviations by Stanley Jablonski (Editor), Paperback, 4th edition (2001), Lippincott Williams & Wilkins Publishers, ISBN: 1560534605, http://www.amazon.com/exec/obidos/ASIN/1560534605/icongroupinterna
·
Dictionary of Medical Terms : For the Nonmedical Person (Dictionary of Medical Terms for the Nonmedical Person, Ed 4) by Mikel A. Rothenberg, M.D, et al, Paperback - 544 pages, 4th edition (2000), Barrons Educational Series, ISBN: 0764112015, http://www.amazon.com/exec/obidos/ASIN/0764112015/icongroupinterna
·
A Dictionary of the History of Medicine by A. Sebastian, CD-Rom edition (2001), CRC Press-Parthenon Publishers, ISBN: 185070368X, http://www.amazon.com/exec/obidos/ASIN/185070368X/icongroupinterna
·
Dorland’s Illustrated Medical Dictionary (Standard Version) by Dorland, et al, Hardcover - 2088 pages, 29th edition (2000), W B Saunders Co, ISBN: 0721662544, http://www.amazon.com/exec/obidos/ASIN/0721662544/icongroupinterna
·
Dorland’s Electronic Medical Dictionary by Dorland, et al, Software, 29th Book & CD-Rom edition (2000), Harcourt Health Sciences, ISBN: 0721694934, http://www.amazon.com/exec/obidos/ASIN/0721694934/icongroupinterna
·
Dorland’s Pocket Medical Dictionary (Dorland’s Pocket Medical Dictionary, 26th Ed) Hardcover - 912 pages, 26th edition (2001), W B Saunders Co, ISBN: 0721682812, http://www.amazon.com/exec/obidos/ASIN/0721682812/icongroupinterna /103-4193558-7304618
·
Melloni’s Illustrated Medical Dictionary (Melloni’s Illustrated Medical Dictionary, 4th Ed) by Melloni, Hardcover, 4th edition (2001), CRC PressParthenon Publishers, ISBN: 85070094X, http://www.amazon.com/exec/obidos/ASIN/85070094X/icongroupinterna
·
Stedman’s Electronic Medical Dictionary Version 5.0 (CD-ROM for Windows and Macintosh, Individual) by Stedmans, CD-ROM edition (2000), Lippincott Williams & Wilkins Publishers, ISBN: 0781726328, http://www.amazon.com/exec/obidos/ASIN/0781726328/icongroupinterna
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·
Stedman’s Medical Dictionary by Thomas Lathrop Stedman, Hardcover 2098 pages, 27th edition (2000), Lippincott, Williams & Wilkins, ISBN: 068340007X, http://www.amazon.com/exec/obidos/ASIN/068340007X/icongroupinterna
·
Tabers Cyclopedic Medical Dictionary (Thumb Index) by Donald Venes (Editor), et al, Hardcover - 2439 pages, 19th edition (2001), F A Davis Co, ISBN: 0803606540, http://www.amazon.com/exec/obidos/ASIN/0803606540/icongroupinterna
206 Hemophilia
INDEX A Adolescence ....................21, 22, 193, 200 Adsorption .............................................88 Analgesic ...............................56, 111, 197 Anemia ...27, 28, 30, 31, 42, 61, 101, 111, 118, 132, 172, 202 Antibodies...13, 40, 48, 65, 70, 71, 72, 73, 74, 75, 81, 87, 88, 89, 96, 171, 196, 197 Antibody .....17, 18, 48, 73, 80, 81, 89, 94, 95, 96, 109, 125, 193, 195, 197 Antigen ....................21, 81, 193, 196, 197 Aqueous ................................................87 Arthropathy ........................13, 72, 84, 112 Assay.....................................................62 Asthenia.................................................61 Asymptomatic ............................61, 62, 63 B Bacteria ...22, 80, 113, 150, 193, 202, 203 Bilirubin ..................................................62 Biochemical .............................75, 81, 200 C Capsules..............................................153 Carbohydrates .............150, 157, 168, 194 Cardiac ........................................110, 171 Cell ..... 11, 22, 28, 30, 31, 41, 61, 66, 69, 70, 72, 73, 75, 76, 80, 81, 82, 101, 111, 132, 157, 194, 195, 198, 199, 201 Chromosomal ..................................67, 72 Chronic ......13, 48, 49, 62, 63, 72, 78, 109 Cognition ...............................................29 Condoms .......................................24, 109 Confounding ..........................................70 Cytokines .........................................65, 69 D Diarrhea.........................................24, 150 Diathesis ..................................40, 70, 196 Disposition .............................................62 Dystrophy ................................30, 31, 132 E Edema .................................................171 Efficacy .......49, 50, 56, 61, 71, 73, 74, 75, 167, 169, 170, 172, 195 Elective ................................................172 Electrophoresis......................................88 Empiric.........................................168, 170 Encephalopathy.....................................12 Endogenous ....................................66, 74 Enzyme..................62, 63, 82, 90, 92, 200 Epitopes.................................................65
F Fatal ................................ 12, 42, 171, 202 Fetus ................................................... 151 Fibrinogen ......................... 85, 86, 90, 172 Fibrinolytic................................... 168, 173 Fibrosis ........................................... 30, 31 G Gingivitis ............................................. 112 Granulocytopenia.................................. 61 H Haemophilia ........ 28, 40, 98, 99, 100, 196 Hematology............................... 10, 25, 28 Hemorrhage ...... 12, 13, 22, 41, 170, 172, 173, 201, 202 Hemostasis ......................................... 170 Heparin ............................................... 170 Hepatic................................ 48, 62, 63, 70 Hepatitis .... 12, 25, 28, 33, 47, 49, 63, 77, 78, 94, 126, 169, 171 Hepatocytes .................................... 66, 84 Histocompatibility............................ 69, 71 Homologous.......................................... 66 Humoral .............................................. 171 Hypertension........................... 30, 40, 197 I Ibuprofen............................................... 47 Idiopathic....................................... 40, 197 Immunity ............................................. 168 Immunization ................ 82, 174, 197, 202 Incubation ........................................... 109 Indicative....................................... 42, 203 Indinavir .......................................... 46, 68 Infarction ............................... 74, 174, 203 Inflammation ................................... 32, 33 Infusion ............................. 13, 87, 89, 172 Intestinal........................ 41, 119, 150, 198 Intramuscular .... 40, 72, 74, 174, 196, 200 Intravascular ......................... 74, 171, 172 Intravenous ..... 65, 77, 78, 84, 171, 174, 200 Intrinsic.................................................. 85 L Labile .......................................... 168, 172 Lymphoma ............................................ 28 M Malabsorption ............................... 24, 132 Malaise.................................................. 61 Malignant ........................ 40, 41, 197, 198 Melanoma ..................................... 41, 198 Membrane......................... 75, 85, 86, 173 Metabolite ..................................... 63, 154
Index 207
Molecular ....... 69, 82, 88, 123, 130, 131, 174, 196, 201 N Nasal .....................................................65 Nausea ..................................................61 Neonatal ........................................70, 172 Neural ..................................151, 174, 197 Neuropsychology...........................22, 199 Niacin...................................................151 O Oncotic ................................................168 Orthopaedic .........................................110 Overdose .............................................151 P Parenteral ............................................171 Pathogen .....................................113, 198 Perinatal ..........................................24, 96 Pharmacokinetics ......................48, 63, 74 Pharmacologic.......................................47 Phenotype .......................................66, 71 Plasmapheresis ...................................107 Pneumonia ..................................113, 200 Poisoning.........................................30, 32 Polymorphic...........................................72 Potassium............................................153 Preclinical ........................................72, 74 Prenatal ...............................................112 Prophylaxis ......................13, 98, 174, 203 Protease ..................................56, 68, 198 Proteins ..... 21, 26, 73, 75, 77, 78, 80, 81, 82, 92, 150, 152, 168, 169, 170, 172, 193, 195, 199, 203 Proteolytic ..............................................90 Prothrombin .........................49, 62, 87, 90 Proviruses..............................................76 Psychiatry ..............................................22 Psychology ..............................22, 29, 199 Pulmonary .............40, 171, 174, 197, 203
R Receptor ........................... 66, 72, 80, 193 Recombinant................. 12, 74, 75, 76, 84 Refractory ............................................. 69 Riboflavin ............................................ 150 Rubella.................................................. 25 S Sanitation .............................................. 31 Selenium ............................................. 152 Serum ............................... 63, 78, 82, 202 Species ............................. 72, 82, 89, 202 Surgical ................................... 22, 33, 199 Synergistic ...................................... 89, 91 Systemic ....................... 72, 118, 174, 203 T Tetanus ................................... 25, 41, 202 Thalassemia.................................. 27, 101 Thermoregulation................................ 150 Thrombocytopenia ...................... 101, 170 Thromboplastin ..................................... 87 Thrombosis ..... 22, 74, 170, 174, 202, 203 Thyroxine ............................................ 152 Tolerance ............................ 47, 65, 69, 73 Tonic ..................................................... 85 Toxic ...... 61, 82, 89, 113, 151, 158, 200, 201, 203 Toxicity...................................... 70, 72, 77 Transaminase ....................................... 61 Transfusion ...... 10, 12, 14, 90, 107, 109, 122, 170, 172, 173 Transplantation ............................... 11, 28 V Vascular ........................................ 76, 101 Vein......................................... 21, 81, 198 Venereal.......................................... 30, 32 Viruses ..... 12, 76, 94, 113, 126, 136, 193, 203 W Warfarin ...................................... 170, 171
208 Hemophilia
Index 209
210 Hemophilia
