Transfusion Medicine: A Clinical Guide

LANDES BIOSCIENCE

Table of contents 1. How to Order Blood

5. The Complex Patient

2. The Anemic Patient

6. The Obstetric Patient

3. The Coagulopathic Patient

7. The Pediatric Patient

4. The Thrombocytopenic Patient and Qualitative Disorders of Platelet Function

8. The Neonatal Patient

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Transfusion Medicine: A Clinical Guide

9. Other Special Patients 10. Transfusion Reactions

The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum.

Transfusion Medicine: A Clinical Guide

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Schexneider

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Katherine Schexneider

v a d e m e c u m

Transfusion Medicine

A Clinical Guide

Katherine Schexneider, MD

Naval Medical Center Portsmouth Portsmouth, Virginia, USA

LANDES BIOSCIENCE

Austin, Texas USA

VADEMECUM Transfusion Medicine: A Clinical Guide LANDES BIOSCIENCE Austin, Texas USA Copyright ©2008 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the USA. Please address all inquiries to the Publisher: Landes Bioscience, 1002 West Avenue, Austin, Texas 78701, USA Phone: 512/ 637 6050; FAX: 512/ 637 6079 In-text art by Kathryn Sauceda Cover art modification by Nicole Todd ISBN: 978-1-57059-703-9

Library of Congress Cataloging-in-Publication Data Schexneider, Katherine I. Transfusion medicine : a clinical guide / Katherine Schexneider. p. ; cm. -- (Vademecum) Includes bibliographical references and index. ISBN 978-1-57059-703-9 1. Blood--Transfusion--Handbooks, manuals, etc. I. Title. II. Series. [DNLM: 1. Blood Transfusion--Handbooks. WB 39 S328t 2008] RM171.S33 2008 615'.39--dc22 2008015993

While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication To S. Gerald Sandler, MD Teacher, mentor, scholar Thank you for everything.

About the Author...

Dr. Katherine Schexneider on a medical mission trip in rural South Africa, 2007.

KATHERINE SCHEXNEIDER, MD, is the Medical Director, Blood Bank at a tertiary care medical center. She is board-certified in Anatomic and Clinical Pathology and holds subspecialty boards in Transfusion Medicine. She received her medical degree from Uniformed Services University after studying history at UC Berkeley. Her interests are in management of massive transfusions and use of fresh frozen plasma in patients with mild coagulopathy. She particularly enjoys teaching transfusion medicine, whether at the bedside or in the lecture hall, to physicians and nurses at all levels of experience. She has previously authored a review manual covering all of clinical pathology and two articles on transfusion medicine topics. Outside of the hospital, Dr. Schexneider is a competitive runner (of no special ability) and avid baseball fan. She and her husband split time between their Portsmouth, Virginia and suburban Maryland homes.

Contents Preface ........................................................................ ix 1. How to Order Blood .................................................... 1 2. The Anemic Patient ...................................................... 7

2.1 Anemia without Ongoing Blood Loss........................................................ 8 2.2 Anemia with Ongoing Blood Loss ............................................................11 2.3 The Patient with Antibodies .......................................................................15 2.4 The Sickle Cell Anemia Patient and Autoimmune Hemolytic Anemia ........................................................................................17 2.5 The Surgical Patient ......................................................................................21

3. The Coagulopathic Patient ......................................... 25

3.1 Factor Deficiencies ........................................................................................26 3.2 The Warfarin Patient ....................................................................................29 3.3 The Liver Failure Patient and Chronic DIC ...........................................31 3.4 The Surgical Patient ......................................................................................35 3.5 The Patient Requiring Minor Procedures ................................................38

4. The Thrombocytopenic Patient and Qualitative Disorders of Platelet Function .................................... 41 4.1 Simple Thrombocytopenia..........................................................................42 4.2 Immune Thrombocytopenic Purpura .......................................................47 4.3 Thrombotic Thrombocyotpenic Purpura ................................................50 4.4 The Uremic Patient .......................................................................................54 4.5 The Patient on Anti-Platelet Agents .........................................................56

5. The Complex Patient .................................................. 59 5.1 Massive Transfusion......................................................................................60 5.2 DIC ..................................................................................................................66 5.3 The Septic and Critically Ill Patients .........................................................70

6. The Obstetric Patient—Special Situations .................. 75

6.1 Postpartum Hemorrhage ............................................................................76 6.2 Severe Postpartum Hemorrhage and Evolving Disseminated Intravascular Coagulation ...........................................................................77 6.3 Hemolysis, Elevated Liver Enzymes and Low Platelets .......................80 6.4 Maternal Immune Thrombocytopenic Purpura .....................................84

7. The Pediatric Patient—Special Situations ................... 89

7.1 The Pediatric Oncology Patient .................................................................90 7.2 The Critically Ill Child .................................................................................94 7.3 Thalassemia and Chronic Transfusions ....................................................98 7.4 The Pediatric Surgical Patient .................................................................. 102

8. The Neonatal Patient—Special Situations ................. 107

8.1 Hemolytic Disease of the Newborn ....................................................... 108 8.2 NAIT ............................................................................................................ 112 8.3 Dedicated Units ......................................................................................... 115 8.4 Neonatal Coagulopathy............................................................................ 117

9. Other Special Patients .............................................. 121

9.1 Autologous Donors ................................................................................... 122 9.2 Directed Donors ........................................................................................ 126 9.3 Jehovah’s Witnesses and Other Religious Considerations ................ 129

10. Transfusion Reactions .............................................. 135 Index ........................................................................ 145

Preface This book provides both scientific background and practical advice for the physician preparing to transfuse his/her patient. The background covers the basic pathophysiology and current research of transfusion medicine in a concise manner and refers the reader to well-written review articles for in-depth treatment. The advice is what I endorse from the authors referenced, major, well-respected trials published in peer-reviewed journals, and consensus statements and also my own recommendations, based on my experience as a board-certified transfusion medicine physician at a major medical center. The guidance I provide here is what I offer to physicians on a daily basis. It is specific. Yes, there are triggers throughout the book. That being said, responsibility for the decisions rests with you, and your own good clinical judgment is as much a part of the transfusion treatment plan as is this text. Although there are “classic patients,” each real patient is a variation on the theme, with unique features that require you to fine tune the standard approaches I offer. Transfusion medicine is more, far more, than medicine by the numbers. I probably use the word “integrate” more than any other word in this text besides “transfusion.” I’ll help you integrate as best I can. I have attempted to write for physicians at all levels and across the specialties, from the medical student (student doctor) to the attending. I would hope that a house officer could read the pertinent section of this book in the middle of the night, grasp the essential features of his patient’s disorder, then order blood appropriately, and even speak coherently about what he learned at morning rounds. What you learn here you may not have encountered before in your study of medicine. Didactic education in transfusion medicine is scant in most medical schools, and hospital-based instruction is too often catch-as-catch-can, with senior residents simply repeating what they remember to juniors, snippets of late-night conversations that they didn’t really understand the first time. I try to improve on that with clear, brief explanations (at 3:00 A.M., you can only handle so much blood banking, I know this) and rational, evidence-based consultation, so you can execute a treatment plan with some substance. Here is how the book is laid out. With the exceptions of the first and last chapters, each chapter discusses a patient type, i.e. the anemic patient, or the neonatal patient. Within each chapter are the more common disease states; there are few zebras in this book. The format tries to balance bullet-form text boxes with prose which explains major concepts in complete sentences. Thus, Key Principles, Role of Laboratory Tests and Treatment Plan are in box or

table format; these are the take-home messages of each section. The Chapter Overview, Basic Concepts and The Whole Patient are in paragraph form. Here, I try to explain transfusion medicine, pathophysiology, etc. in some detail so you understand what I am recommending and why. The Eight-Second Summary is transfusion medicine for one type of patient boiled down to one or two sentences. Quick Questions include the more common queries I have been asked by house staff and attending physicians alike. Good luck with your patients. Katherine Schexneider, MD Portsmouth, Virginia, USA

Acknowledgements My physician colleagues deserve the greatest credit for this book. Through their questions, requests for assistance and clinical insights, they helped shape my approach to transfusion medicine and made me recognize the need for a handbook. It has been a privilege to serve them these past several years, and broadly, I thank all of them for their input, but I must acknowledge several by name. The transfusion needs of patients in the intensive care units introduced me to some exceptional physicians, and I am particularly grateful to Pablo Pizzaro, MD, Abhik Biswas, MD and Bob Englert, MD as the heads of these units at my hospital. They added to my clinical knowledge far more than I increased their grasp of blood banking. Three others deserve special mention. Cindy Piccirilli, MD, has provided steady encouragement for me in my work. Jen Thompson, MD, continually reminds me that house officers desperately need instruction, didactic or curbside, in the basics of blood transfusion. Finally, Doug Miller, MD, was the inspiration for Quick Questions, and some of the examples in this book came directly from our conversations in the hallways. Two transfusion medicine physicians, S. Gerald Sandler, MD and Susan Roseff, MD, have both been superior mentors to me, always available, and always offering sound advice. Hundreds of consultations, formal and casual, laid the content for the book. The atmosphere of collegiality, the tone of enthusiastic cooperation set by the people above on their own wards on a daily basis, gave me the impetus to write. This was no solitary effort. I am also indebted to the publishing team. I thank Ron Landes, MD, for accepting it for publication and believing it will help physicians become better transfusionists. Cynthia Conomos and Celeste Carlton have guided the project from day one with professionalism and energy.

Disclaimer The views expressed in this book are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

CHAPTER 1

How to Order Blood Key Principles • The Type and Screen only provides information about your patient. It does not reserve blood for him. • The Type and Cross reserves packed red blood cells (RBC) for your patient, usually for 72 hours. • The Blood Bank does not crossmatch fresh frozen plasma (FFP), platelets or cryoprecipitate. • Irradiation only prevents Transfusion-Associated Graft Versus Host Disease. It has nothing to do with cytomegalovirus (CMV). • Leukoreduction reduces (does not eliminate) the risk of CMV transmission and Human Leukocyte Antigen (HLA) alloimmunization. • 10ml/kg of RBCs, FFP or platelets is a typical transfusion for neonates and infants.

Chapter Overview

This chapter outlines the correct terminology for ordering blood and explains briefly what your Blood Bank does with patient samples and blood products (RBCs, FFP, etc.) when you write orders. Perhaps the only time anyone taught you how to order blood was at 2:00AM on a medical student rotation, and by 2:15 a Type and Screen was indistinguishable from a Type and Cross, and you were too tired to think about blood banking any longer. In fact, I don’t even remember having a late night tutorial on ordering blood when I was a medical student or transitional intern. I learned this as a pathology resident and transfusion medicine fellow. It’s actually pretty straightforward, and it’s written down here, so you can flip through the pages of this chapter instead of racking your brain. I’ve provided some examples of correct orders at the end of this chapter as a go-by.

Basic Concepts The Type and Screen (T+S)

The T+S provides your patient’s ABO and Rh type from testing on the red blood cells, mixing them with reagent anti-A and anti-B antibodies. The Blood Bank also takes your patient’s plasma and mixes it with two or three reagent red cells to Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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determine if the plasma contains any clinically significant antibodies to antigens commonly found on red blood cells. These antibodies are not the anti-A in a group B person (we determine this in the typing), but rather anti-E in an E-negative person, for example. There are about a dozen of these antibodies which the Blood Bank tests for. While we make anti-A or anti-B naturally according to our own blood type, we make these other antibodies usually through exposure (transfusion or pregnancy), or sometimes naturally. The two or three reagent red cells have a mix-and-match of the dozen antigens on their surface. If your patient’s plasma reacts with any of the red cells, the Blood Bank performs the same test on 10-13 different red cells to isolate the offending antigen(s). If the initial antibody screen is negative, you can be reasonably confident that finding compatible RBCs will be quick and straightforward. If the screen is positive, the Blood Bank must check the antigens on red cells from a particular unit of blood prior to crossmatching it. If negative for the offending antigen, the technician will crossmatch the unit (more on this soon); if positive, he/she sticks that unit right back on the shelf and tries another. Remember that the T+S by itself only tests your patient’s blood; it does not match your patient’s blood (plasma) with units in the Blood Bank. That’s what the Type and Cross is for. Order a T+S if there is a small possibility (<50%) that your patient will need any blood products during his hospital stay. The T+S requires one tube of EDTA-anti-coagulated blood (rarely 2-3 tubes).

The Type and Cross (T+C)

This procedure includes both the T+S and the crossmatch of your patient’s plasma with a few drops of red cells from a unit of RBCs from the Blood Bank’s inventory. So if the T+S indicates that your patient is group A positive, then the Blood Bank technician (typically) pulls an A positive RBC unit out of the refrigerator, draws a few drops from something called a segment (a length of plastic tubing with blood in it) and mixes your patient’s plasma with those red cells. If there is no reaction, great. That unit is crossmatch-compatible and held in the Blood Bank with your patient’s name on it for a period of time, usually 72 hours. If your patient has a positive antibody screen, then this process takes a little longer, both because the unit must be phenotyped for the offending antigen (and found to be negative) and because the crossmatch is performed at room temperature and also 37˚C. Why even bother to crossmatch blood if the antibody screen is negative? Shouldn’t an A positive unit of RBCs be compatible for an A positive patient? Yes. However, the most feared mistake in transfusion medicine is giving ABO-incompatible RBCs, i.e., giving group A RBCs to a group O patient. Even though RBCs are typed twice before being put into the Blood Bank inventory, the technicians crossmatch before issuing RBCs (unless it is an emergency), because the crossmatch is the one last chance to identify and prevent an ABO-incompatible transfusion. OK, so a crossmatch involves the donor unit RBCs and your patient’s plasma. Thus, the Blood Bank does not crossmatch FFP, cryoprecipitate or platelets, as these products do not contain significant numbers of red cells. You may have heard about crossmatching platelets in cases of platelet refractoriness. This is not commonly done and not performed at all in many hospitals. We’ll discuss it briefly in Chapter 4. You ordered a T+S if there was a small chance that you might transfuse your patient with any blood product. Skip the T+S and order a T+C if there is at least

How to Order Blood

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a 50% chance that you will transfuse red cells and specify how many units (or mLs) of red cells you want the Blood Bank to crossmatch.

Ordering Fresh Frozen Plasma, Cryoprecipitate and Platelets

Order FFP or cryoprecipitate in the specific number of units you want and plan to transfuse these products within a few hours. Both FFP and cryoprecipitate are kept frozen in the Blood Bank, and thawing takes 30-60 minutes. While many Blood Banks have an adequate supply of FFP and cryoprecipitate, you don’t want to ask for units to be thawed unless you are pretty certain you will transfuse them. Unlike crossmatched RBCs, which can be moved back to the general inventory if unused, thawed FFP expires in 24-48 hours (depending on the Blood Bank), and pooled cryoprecipitate expires in four hours. These products will likely go to waste if you don’t transfuse them. Clearly, you don’t want to transfuse any blood product just so it doesn’t go to waste. That being said, think through your order for FFP or cryoprecipitate before you sign the order sheet. Order FFP as one or two units at a time. Order cryoprecipitate for adults as a 10-pack at a time. Order FFP for pediatric patients at 10mL/kg body weight. A rough estimate for cryoprecipitate is OK in kids. You may be able to have the Blood Bank set aside (tag) a platelet for your patient for use at some point in the next, say, 24 hours. While platelets aren’t crossmatched, they can be tagged for your patient, then either transfused or released back into the general inventory. Although many housestaff still order platelets as a 6-pack, a number of Blood Banks now carry almost exclusively apheresis platelets. These are drawn from a single donor, and one apheresis platelet is roughly equivalent to a 6-pack. Find out what your blood bank carries and then order either one apheresis platelet or a 6-pack. Platelets are typically in short supply in a Blood Bank. Only order one platelet (apheresis or 6-pack) at a time (more on this in Chapter 4), or 10mL/kg for pediatric patients, except in special cases (see Chapter 7). The Blood Bank needs to know the ABO type of your patient to prepare FFP and, in some cases, platelets. Ensure that either a T+S or T+C has been performed during the hospital stay.

Special Modifications-Irradiation

Irradiation prevents one disease only: transfusion-associated graft versus host disease ( TA-GVHD). It has no effect on cytomegalovirus transmission, human leukocyte antigen alloimmunization or the risk of any other type of transfusion reaction. Irradiation of cellular blood products (red cells and platelets) uses radioactive cesium or cobalt to intercalate the DNA in lymphocytes that are in the unit of blood (yes, even leukoreduced blood products have a few white blood cells (WBC) remaining) and render them incapable of replication. Thus, these donor lymphocytes cannot attack your patient’s own lymphocytes, a process called transfusion-associated graft versus host disease. TA-GVHD is distinct from organ transplant-related GVHD and carries a nearly 100% fatality rate. The indications for irradiating cellular blood products are: • Any hematologic malignancy patient (past or current) • Patients within 100 days, before or after, of a bone marrow/stem cell transplant (BMT/SCT). If the patient had a BMT for a hematologic malignancy, it’s reasonable to give them irradiated products permanently.

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• Patients with an absolute lymphocyte count of <500/μL (that’s right, lymphocyte count, not neutrophil count) • Patients receiving blood products from blood relatives (except the marrow or stem cell transplants themselves for reasons which ought to be intuitive). • Neonatal patients, when feasible. The above patients have an immune system that is quantitatively or qualitatively poorly able to fend off attack from viable donor lymphocytes. Why not just tack on “irradiated” to any order of RBCs or platelets? First, you want to practice good medicine, so order what is needed and don’t order what isn’t. Second, irradiation costs money and takes time; use medical resources judiciously. Does irradiation harm the patient when it’s not indicated? No, but I still don’t want you to order it unless the patient falls into one of the above categories. What if a new patient presents with pancytopenia and you think he might have leukemia, but you don’t have a diagnosis yet? Is it OK to preemptively order irradiated blood products then? Yes, that’s quite reasonable. If the patient turns out not to have leukemia, good for him, you can stop ordering irradiated products, no harm, no foul. Order irradiated products by writing the word “irradiated” after the blood product ordered.

Special Modification-Cytomegalovirus Seronegative

CMV-seronegative blood is given to patients known or presumed to be unexposed to the virus, who are also immunosuppressed and thus poorly able to control a CMV infection. Some blood centers test donors for anti-CMV antibodies and label cellular products as negative if the IgG titer is below a certain cutoff point. My interpretation of immunosuppressed here is broad, including BM or solid-organ transplant patients, neonates, and those with lymphocyte or neutrophil deficiency or dysfunction. Neutrophils are not key players in combating CMV infection (T lymphocytes are), but I am concerned about the overall immune status of the neutropenic patient. The risk of CMV transmission, even in CMV-seronegative units is small, but not zero. CMV, as you know, is a common and, once-acquired, lifelong infection. Thus, requesting this for children who are immunosuppressed and perhaps not yet exposed is reasonable. Ordering it on a 65-year-old man admitted for a chronic obstructive pulmonary disease exacerbation who needs red cells and isn’t really immunosuppressed is bad practice. You don’t want to waste a CMV-seronegative unit on someone who doesn’t need it. You can determine if your patient has been exposed by drawing a CMV IgG titer. Don’t draw a CMV DNA, which looks for active infection. Order this special modification by writing “CMV-negative” after the product ordered.

Special Modification-Leukocyte Reduced (LR) Products

Leukocyte reduction helps prevent platelet HLA alloimmunization, CMV transmission and febrile non-hemolytic transfusion reactions. Many blood centers, including the American Red Cross, leukoreduce all their RBCs as part of the collection process. Apheresis platelets are leukoreduced in the process of collection as well. If products are not leukoreduced by the time they get to the Blood Bank inventory, they can be issued with a bedside filter. Leukoreduction brings the WBC down to less than 5 X 106 per unit of either RBCs or platelets. Thus, the risk of the above-mentioned sequelae is low, but not zero. So, is LR equivalent to CMV-seronegative for CMV risk reduction? Roughly, yes. One study identified an incremental benefit in CMV-seronegative over LR (see Suggested Reading). I

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1 Quick Question What exactly is the Coombs test again? Is it the same thing as the DAT? The direct Coombs test looks for antibodies that are already attached to your patient’s red cells. The red cells are washed to remove any unbound antibody, then incubated with antihuman globulin (AHG) to make visible rosettes, spun and examined. If these rosettes or clumps are present, then your patient has IgG stuck to his red cells. This is the same test as the DAT, or direct antihuman globulin test. The indirect Coombs test is the same as the antibody screen. There, the Blood Bank looks at your patient’s plasma, not his red cells, for antibodies. Blood Banks don’t use the term “Coombs test” much any more. Look for these results to be reported as DAT or Antibody Screen.

Role of Laboratory Tests in Ordering Blood Test CMV titer

Absolute lymphocyte count

Use Determine if patient has been exposed to CMV already. Titer of >0.9 indicates exposure. <500/μL indicates immunosuppression justifying irradiated blood products. Obtain from CBC.

Limitations NA

Does not account for trend in lymphocyte count. Is count falling during chemotherapy and will be <500 soon?

think a reasonable situation in which to demand CMV-seronegative even if LR products are available is for an extremely premature neonate (<28 weeks EGA). For other patients, you can transfuse LR if CMV-seronegative is not available. As FFP and cryoprecipitate do not have any WBCs in them, LR does not apply to these products. Order by writing “Leukoreduced” after the product ordered.

The Whole Patient

In the remaining chapters, this section will discuss other considerations in your patient beyond the simple need for blood products.

Eight-Second Summary

I hope that every topic in this book can be boiled down to something you can repeat to yourself or recite on morning rounds in the span of eight seconds. So, in this chapter we learned the following: The T+S gives me information only about my patient, the T+C reserves RBCs for him, I’ll try to order FFP or cryoprecipitate only if I’m quite sure I’ll transfuse it, and I’ll follow the guidelines for ordering irradiated and CMV-seronegative products.

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Treatment Plan for Ordering Blood Examples of Correct Orders • • • • • • • •

Type and Screen Type and Cross 2U RBCs Type and Cross 2U RBCs, irradiated and LR Transfuse 1U RBC over 3 hours Transfuse 1U FFP Transfuse 10-pack cryoprecipitate Transfuse 1 apheresis platelet Transfuse 40 mL RBCs, CMV-negative, irradiated (for 4 kg infant)

Examples of Bad Orders I Have Seen • Type and Screen 2U RBCs (The T+S has nothing to do with blood in the Blood Bank.) • Type and Cross 4U FFP, irradiated (We don’t crossmatch FFP, and we only irradiate cellular products—RBCs and platelets.) • Transfuse 6-pack cryo now (adult patient) (Adults receive a 10-pack. While there’s nothing wrong with a 6-pack, it’s kind of like ordering half a Coke.) • Type and Cross 2U RBCs, 2U FFP, 2 platelets (The Noah’s Ark system suggests that the ordering physician didn’t consider his patient’s needs very carefully. Also, we don’t crossmatch FFP or platelets.)

Suggested Reading

1. Vamvakas EC. Is white blood cell reduction equivalent to antibody screening in preventing transmission of cytomegalovirus by transfusion? A review of the literature and meta-analysis. Transfusion Med Rev 2005; 19(3):181-199.

CHAPTER 2

The Anemic Patient Key Principles • Stable adult patients without ongoing blood loss or significant fluid shifts should show an increase of 1 g/dL in hemoglobin (Hb) or 3% in hematocrit (Hct) for each unit of RBCs transfused. • Selected patients may benefit from a Hct of 30%, but this is not a goal to be sought blindly for every patient. • The Hb and Hct are dynamic in unstable patients who may have ongoing blood loss and who are receiving RBCs and intravenous fluids (IVF). Interpret these laboratory values in their clinical context. • RBCs for patients with significant antibodies must be negative for the corresponding antigen (except in emergencies). Securing blood may be easily accomplished in the hospital blood bank or may require purchase of special units from a blood center such as the Red Cross. • Transfusing least-incompatible RBCs to patients with autoantibodies is commonly done if the need for transfusion is high. • Either fresh (<7 days old) or washed RBCs should be ordered for children uner 5 years of age undergoing surgery when there is a possibility of rapid transfusion.

Chapter Overview

Packed red blood cells (RBCs) are transfused to correct anemia and thus improve oxygen-carrying capacity. This chapter will discuss treatment of patients in whom anemia is the chief abnormality. It will include both medical and surgical patients, adults and children, and the acutely and chronically anemic. Patients who require multiple different blood products are covered in Chapter 5. I do not present whole blood as a transfusion option in this text. While it is used in some military hospitals in combat operations and in some trauma centers in developed countries, the great majority of hospital blood banks provide RBCs as component therapy (just the red cells). Nor do I cover the emerging field of blood substitutes, as these products are not yet licensed for use in the United States. Here, I’ll guide you through RBC transfusions for the stable patient with a negative antibody screen, through to more complicated cases, such as the sickle cell anemia patient with both allo- and autoantibodies who needs prompt intervention. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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2.1 Anemia without Ongoing Blood Loss 2

Basic Concepts

The single most important principle to understand in transfusing red blood cells (RBC) to the non-bleeding patient is the integration of evidence-based thresholds with clinical signs and symptoms. In this section, I will review one such trigger for patients in the intensive care unit (ICU) setting as defined by two landmark clinical trials and also provide reasonable triggers for other, more stable patients. As the former may be lower than what you are used to, I’ll review it in some detail. Set numerical thresholds are valuable starting points for your decision to transfuse. Your clinical assessment holds equal value. Red blood cells carry oxygen to tissues as passengers on the hemoglobin molecule, and one of the causes of tissue hypoxia is inadequate hemoglobin. The clinical symptoms of this are pallor, fatigue, dizziness, and shortness of breath, with chest pain or loss of consciousness being advanced sequelae. Diagnostic signs include tachycardia, tachypnea, hypotension if there is concurrent hypovolemia, and EKG changes. Your task here is to give appropriate weight to these signs and symptoms. I do not want you to over-transfuse because of very mild fatigue, nor withhold RBCs in the face of significant hypoxia or tachycardia. Neonatal patients, especially those with respiratory compromise, are transfused to a Hct of 40%, and I support this. Recall from Chapter 1 that a standard transfusion volume for pediatric patients for all blood products is 10 mL/kg body weight; this equates to about 3U RBCs in a 70-kg adult. It is difficult to estimate the incremental benefit of each transfusion in the neonate or infant, as these patients are far too small for the 3% rule to apply. A rough guide is that 10 mL/kg of RBCs should increase the Hb by 2-3 g/dL. However, neonatal patients frequently experience significant shifts in fluid volume, and this fact makes it challenging to interpret a post-transfusion H/H. If you do use the above rule, gauge the amount of intravenous fluids received since the pre-transfusion H/H and do your best to estimate if the desired effect was achieved. Unless the patient is markedly anemic, I recommend transfusing at 10 ml/kg and rechecking the H/H post-transfusion to determine if you have reached your target. Patients differ in their tolerance of anemia. Sickle cell anemia patients may feel normal with a Hct of 22%, and young adults or children with leukemia may grudgingly complain of mild fatigue at a similar Hct, while an older person with cardiac disease may experience significant distress at a Hct of 26%. Thus, a good rule of thumb for younger patients is to transfuse at a Hb/Hct (H/H) of 7/21 or perhaps 8/24. For older patients, particularly those with cardiopulmonary disease, the situation is more complex. One of the frequently referenced studies in transfusion medicine in the past decade is that by PC Hebert et al published in 1997. This controlled, randomized clinical trial (New England Journal of Medicine article) examined the outcome of mortality in patients in the intensive care unit (ICU) who were transfused at either a Hb of 7.0 g/dL, to a target of 7-9 g/dl, or 10.0 g/dL, to a target of 10-12 g/dl. Hebert found that although overall 30-day mortality was similar among the two groups, the rates were significantly lower in the restrictive transfusion group among those who were less acutely ill, as gauged by an

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Role of Laboratory Tests in Anemia without Ongoing Blood Loss Test Complete Blood Count (CBC)

Reticulocyte Count

Use H/H: assess severity if anemia WBC, plt counts: assess for pancytopenia, possible infection MCV, MCH, MCHC useful in determining etiology of anemia Assess marrow response to anemia

Limitations Dehydration falsely elevates H/H NA NA NA

APACHE II score of ≤20 and among those who were younger than age 55. Also, the mortality rate during hospitalization was significantly lower among those in the restrictive group than those in the liberal group. Hebert subsequently extracted data on those patients with cardiovascular disease in the ICU setting (Critical Care Medicine article). Here, he found similar rates of mortality at 30 days, 60 days, during hospitalization, and during ICU stay among patients with cardiovascular disease who were assigned to the same restrictive or liberal transfusion triggers and target hemoglobin values as used in the earlier study. He found slightly lower but nonsignificant absolute survival in the restrictive category in the subgroup that had severe ischemia. I think it is very reasonable to treat symptomatic anemia in those with severe ischemia at an H/H of 10/30, to a target of 10-12 g/dl for the hemoglobin and Hebert supports this approach. This no doubt resonates with you, as you will instinctively want to set a higher threshold in patients with significant cardiac disease. The challenge will be in defining what constitutes severe ischemia. It will be easy to assign this label to any patient with cardiovascular disease. You may well over-transfuse if you are more junior, with less experience treating patients with heart disease. I think an excellent approach in the non-urgent setting would be to read these referenced articles, discuss them on rounds in the context of your patient and solicit input from your attending on the best strategy. What kind of bang should you expect for your buck? The classic teaching is that one unit of RBCs should raise the Hb by 1.0 g/dL and the Hct by 3%. In the stable non-bleeding patient, you should expect this. Be aware though, that intravenous fluids will temper your post-transfusion bump. If you gave your patient a bolus of fluids, do not be alarmed if the increment is less than the 1 and 3 rule.

The Whole Patient

Obviously, the question you need to answer is: why is my patient anemic? You need not answer this fully before you transfuse. Clearly, if your patient is markedly and symptomatically anemic, you need to transfuse RBCs promptly. What you should do prior to transfusion is draw some basic laboratory tests that will help you characterize the anemia and perform a history and physical examination (H+P) to elicit red flags (dark stools for GI bleed, concurrent petechiae that suggests at least two cell lines affected, etc.). The various etiologies of anemia are not covered

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Quick Question Every patient I’ve ever admitted to the hospital has been dehydrated, and thus, the H/H always decreases a little after I give IV fluids? If someone has a Hb of 8.0 g/dl on admission and looks dry, is it reasonable to assume they are probably really at Hebert’s trigger of 7.0 g/dL? If they really are volume-depleted, I think that’s reasonable.

Treatment Plan for Anemia without Ongoing Blood Loss • • • • • • • • • •

T+S or T+C patient to determine the ABO, Rh type and antibody status. Assess need for transfusion, integrating H+P, CBC, clinical signs and symptoms. Consent patient or guardian prior to transfusion. Transfuse safely (a competent nursing staff ensures this). Reassess your patient. Check both clinical indicators (shortness of breath resolved?) and laboratory parameters (H/H). Transfuse for a Hb <7.0 g/dl for stable infants, children and adults. Target Hb: 7-9 g/dL. Transfuse for a Hb <10.0 g/dl for adults with severe ischemia. Target Hb: 10-12 g/dL. Expect that each unit will raise the Hb by 1 g/dL or Hct by 3% in adults. Transfuse for a Hct <40% in neonates with cardio-respiratory compromise or severe prematurity. Expect that each 10 mL/kg dose will raise the Hb by 2-3 g/dL, if volume status is stable (not always the case).

in this book; there are plenty of handbooks and texts that address this subject. For now, you should either know the cause of your patient’s anemia or have started to form a differential to pursue.

Eight-Second Summary

My patient with myelodysplastic syndrome is fatigued and light-headed with a Hb of 6.9 g/dL. I’m going to improve his oxygen-carrying capacity with 2U RBCs and expect an increase in his Hb to about 9.0 g/dL and relief of his symptoms.

Suggested Reading

1. Hebert PC, Wells G, Blajchman MA et al.A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340(6):409-17. 2. Hebert PC, Yetisir E, Martin C et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular disease? Crit Care Med 2001; 29:227-234.

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2.2 Anemia with Ongoing Blood Loss Basic Concepts

In this section, we will review the physiology of oxygen delivery and the compensatory mechanisms in anemia, and then turn our attention to the actively bleeding patient and see how these principles apply at the bedside. The mathematical formula for the delivery of oxygen to tissues provides a framework for understanding the causes of hypoxia (and thus how we can intervene to improve oxygen delivery), but it is neither as precise nor as predictive as we would like at the bedside. You probably first learned this equation as a freshman in medical school. Cardiac output (CO) and the arterial oxygen content of blood (Ca02) contribute to deliver oxygen as follows: D02 = CO x Ca02 D02 is the delivery of oxygen in mL/min. CO in dL/min is the product of heart rate (HR) and stroke volume (SV). Ca02 is the sum of arterial oxygen saturation (Sa02) as a percent times the hemoglobin concentration in g/dL multiplied by 1.34 (the oxygen-carrying capacity of hemoglobin), plus the solubility of oxygen in blood at 37ºC (0.003Pa02). Thus: D02 = HR x SV x (Sa02 x 1.34 Hb + 0.003Pa02) Looking at the equation and your own experience with anemic patients, it is intuitive that increasing one’s heart rate is the primary response to tissue hypoxia. Humans can do little else to increase total oxygen delivery on their own. The autonomic nervous system assists however, by redistributing blood flow away from the periphery (skin, muscles) toward vital organs (brain, heart). Madjdpour et al describe the compensatory effect of acute normovolemic hemodilution on Pa02 (Critical Care Med article), although the real benefit of this incremental increase in D02 is unclear. The authors of the American Society of Anesthesiologists Task Force on Blood Component Therapy Practice Guidelines (Anesthesia article) point out a major limitation of this classic equation: it reflects global rather than organ-specific oxygenation. They caution that one cannot measure oxygen transport to specific organs in the clinical setting. Nor can one predict the risk of significant morbidity or mortality conferred by anemia. Indeed, myocardial ischemia and ischemia of other organs may be silent, without changes in vitals signs. How then does this flawed mathematical model help the clinician at the bedside optimize oxygen delivery? Take a semi-quantitative approach with the equation. Set your calculator aside, march through the five parameters, and ask yourself which of them are flagging in oxygen transport. Then, try to fix them. A patient with symptomatic anemia will normally be tachycardic, but anti-adrenergic drugs such as beta-blockers will blunt this response. Stroke volume should increase when hypovolemia is corrected with intravenous fluids (IVF). In the patient with congestive heart failure/ventricular dysfunction, however, stroke volume may be low and exacerbate the effects of anemia. This may or may not already be maximized with an inotropic agent to boost cardiac ejection fraction (EF). Can or should you change the medication regimen to improve heart rate and stroke volume? You certainly won’t discontinue a beta-blocker in a patient with hypertension and a

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Hb of 6.8 g/dL so he can run his heart rate into the 130s and keep pace with his anemia, but you may stop it if he’s also hypotensive from hypovolemia. Next is oxygen saturation. What is the pulse oximetry reading? If it is low, supplement with oxygen or adjust ventilator settings. Improve the hemoglobin level with transfusion of red blood cells. Finally, the dissolved oxygen content will naturally increase with normovolemic hemodilution. You won’t take any action on this one. If you cannot improve one parameter, such as stroke volume in someone with advanced congestive heart failure, then you are justified in giving more RBCs because the Hb is something you can fix. Maybe you give three units instead of two if the EF is 35%. That’s it. That’s the semi-quantitative version of the sterile formula from medical school. It is not precise in the real world, but it does not have to be. Stripped of its mLs/min and zeros, it will guide you in a systematic review of your patient’s capacity for perfusing his vital organs and help you plan his transfusions. With this foundation clear in our minds, let us shift our focus to the patient with ongoing blood loss. The two key concepts to grasp here are: (1) that your patient is in a dynamic state, with his hemoglobin and hematocrit rising and falling with the transfusion of RBCs, continual blood loss and the administration of intravenous fluids (IVF); and (2) that he may need more from the Blood Bank than just RBCs, i.e., FFP, platelets or cryoprecipitate. Here are some points on the first concept. If your patient has gradually been losing blood over days or weeks, either from hemolysis or whole blood loss (slow GI bleed, heavy menses, slowly leaking aneurysm), then his H/H will reflect equilibration in the plasma compartment and thus will give you a good starting point for red cell replacement. You’ll need to give more RBCs than you would a stable patient, but not that much more. I recommend using the same triggers discussed in the previous section (they are repeated in the Treatment Plan box below). Acute, brisk blood loss, such as in a serious GI bleed, will likely bring the patient to your attention before the plasma component can compensate. Here, the hemoglobin value will be deceptively reassuring. Experience will prevent you from trusting the hemoglobin value in these cases, but you may feel at a loss because you cannot use well-established triggers to support transfusion. You must look to the vital signs, the hypotension and tachycardia that accompany hypovolemia, to assess the severity of blood loss. Unfortunately, I know of no useful equation to connect the vital signs and units of RBCs lost in bleeding. An empiric approach of 2-4 units of RBCs given to a patient with obvious bleeding who is decompensated is a reasonable start, but you may use the following model as a rough guide: one liter of whole blood lost requires three units of RBCs as replacement. As you correct the anemia with RBCs, you will simultaneously give IVF (do not ever, ever give anything but 0.9% NaCl through the same IV line as blood products). Thus, you will raise and lower the hemoglobin at the same time, and you will have ongoing blood loss as well. Do not depend on the 3% increase in Hct rule here. Recheck the hemoglobin frequently, every 4 hours in critical patients, to reassess where you are, and be aware that the H/H will probably downtrend slightly over 12-24 hours after an intense period of RBC and IVF administration, even if active bleeding has stopped. So, if you stop an esophageal varix from bleeding in a 63 year-old woman and transfuse her to a hematocrit of 30% (hemoglobin of 10 g/dL) by 7:00PM, and

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Estimating units of RBCs to replace EBL

2

then see that her 5:00AM next day’s hematocrit is 28%, do not quickly assume that she has re-bled. Assess her clinically, continue to monitor her hemoglobin and hematocrit to see where she is trending, and go from there. The question of whether to give additional RBCs beyond the initial transfusion is quantitatively more challenging in neonates and infants, as the 3% Hct rule doesn’t apply even in the stable patient. My best advice is to assess hydration first; if the patient is euvolemic, rely on the hemoglobin to guide the need for further RBCs. On the second point, once you have given 4-6 U RBCs, especially if you anticipate giving more, start giving FFP if your patient is losing whole blood, i.e., has a GI bleed, surgical blood loss, ruptured aneurysm, etc, but not hemolysis. Your (non-hemolyzing) patient is losing coagulation factors and platelets, and you must replace these to prevent coagulopathy. I will cover this fully in Chapter 5. If you are reading this section here as the fifth unit of RBCs goes into your patient, flip to Chapter 5 now. What about the hemolyzing patient, such as one with autoimmune hemolytic anemia (AIHA)? Patients can form antibodies to antigens or epitopes on their own red cells in a variety of settings: sickle cell anemia, lupus, chronic lymphocytic Role of Laboratory Tests in Anemia with Ongoing Blood Loss Test CBC Reticulocyte count Indirect bilirubin LDH Haptoglobin

Use H/H to assess the severity of anemia Marrow response to anemia Elevated ind bili supports hemolysis Elevated LDH supports hemolysis Decreased in hemolysis

Limitations In acute blood loss, H/H not reflective of degree of anemia NA NA Nonspecific test, may be elevated for other reasons Acute phase reactant, may be increased, confounding interpretation

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Treatment Plan for Anemia with Ongoing Blood Loss

2

• T+C for 2-4 U RBCs for adults and 10-20 mL/kg for infants and small children. • Assess the volume of RBCs you expect to transfuse (see Basic Concepts) • Consent patient or family member. • Order and transfuse RBCs • Intervene to stop ongoing blood loss • Reassess, integrating what you have put into the patient (RBCs, IVF) and what he has lost (RBCs only vs. whole blood) and how quickly he is continuing to lose blood, if at all. • Continue to transfuse, adding FFP, platelets, etc. as needed (Chapter 5). • Transfuse for a Hb <7.0 g/dl for stable infants, children and adults. Target Hb: 7-9 g/dL. • Transfuse for a Hb <10.0 g/dl for adults with severe ischemia. Target Hb: 10-12 g/dL. • Transfuse for a Hct <40% in neonates with cardio-respiratory compromise or severe prematurity.

anemia, or as a reaction to a drug. Often, the cause is unknown. Treatment may involve both pharmacologic interventions with corticosteroids, intravenous immunoglobulin (IVIg), and more potent agents; and RBC transfusions. In patients with AIHA, any RBC unit is likely to be incompatible. This is because the patient’s antibodies are often directed to some common red cell epitope (often resembling the e antigen). There is no special “rare blood from the Red Cross” that will be ideal for your patient. If your patient is decompensated from his anemia, give the least-incompatible blood your Blood Bank offers, know that some of those red cells will be hemolyzed, but some will survive, and consider trying to dampen his immune response with medications. You won’t get the 3% bump in Hct, but that’s OK. The patient with antibodies, alloimmune and autoimmune, is discussed more fully in the next section.

The Whole Patient

The primary tasks here are to identify the source of bleeding or recognize hemolysis, and to interrupt the process. You may need to call in consultants from gastroenterology, surgery or hematology. If you are reading this as a junior house officer, probably the most important message I can give you to to ask for help and ask quickly for unstable patients. One quick note—the GI bleeder who is supra-therapeutic on warfarin is an extremely common case. We will discuss correction of coagulopathy due to warfarin overdose in Chapter 3.

Eight-Second Summary

The patient with ongoing blood loss is in a dynamic state, and estimating the amount of RBCs he will need is a complex process involving quantitative laboratory data and clinical assessment.

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2.3 The Patient with Antibodies Basic Concepts

The patient with clinically significant antibodies to red cell antigens requires RBC units that are negative for the offending antigen(s). The important antigens which you should have a passing familiarity with are D, C, c, E, e (these are in the Rh family); K (Kell); Fya and Fyb (Duff y); Jka and Jkb (Kidd); and M, S and s (MNS family—N is rarely encountered). You may have heard of the Lewis antigens, Lea and Leb, being found in pregnant women. Anti-Lewis antibodies are rarely clinically significant and are not discussed further. There are dozens of other antigens on the surface of red blood cells, but they are either insignificant—that is, they do not cause significant hemolysis—or are rare. Individuals have some, rarely all, of the key player antigens listed above, and racial differences correspond to varying frequencies of these antigens. For example, K is found in 9% of whites, but only 2% of blacks, and so on. In most cases, patients develop antibodies upon exposure, by transfusion or pregnancy, to an antigen they lack. What does it mean when that T+S you ordered is “positive?” A positive antibody screen means that your patient’s plasma contains antibodies that have reacted with certain antigen(s) on the surface of reagent red blood cells, antigens from the list described above. The Blood Bank then incubates your patient’s plasma with a panel of 10-13 different reagent red cells to narrow down the antigen-antibody reaction to one or more specific antigens. Their next step is to phenotype RBC units in the Blood Bank’s inventory, i.e., determine if a particular unit is positive or negative for the antigen, and then crossmatch your patient’s plasma with a phenotypically-negative unit. In larger hospitals with a fair-sized Blood Bank, this is easily accomplished. If your patient has multiple antibodies or your Blood Bank carries a small inventory, the Blood Bank supervisor may need to call out to a larger blood center to purchase compatible units, and this usually takes a few hours. Unless you live in a remote area, this is not a showstopper. Why not phenotype all patients and all donors up front and only provide phenotypically-matched RBCs to patients? Wouldn’t this prevent patients from making antibodies in the first place? Probably, yes, but this is a laborious process which severely limits the potential units your Blood Bank can issue. For non-sickle cell anemia patients, most Blood Banks provide antigen-negative RBCs only to account for established, already-formed antibodies. We’ll discuss sickle cell patients in some detail in the next section. You do not need to specifically order antigen-negative blood for your patient. The Blood Bank takes care of this for you and maintains a history of antibodies formed by your patient. Antibody levels sometimes decline over time to the point where they cannot be detected on the antibody screen. In this case, the Blood Bank still Role of Laboratory Tests for the Patients with Antibodies Test Type + Screen, Type + Cross

Use Determine current antibodies

Limitations Does not pick up prior antibodies when levels have waned. Patient history card will cover this.

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Treatment Plan for the Patient with Antibodies

2

• Assess need for transfusion, with consideration of additional factor of extra time required to secure blood. • T+S or T+C, providing 2-3 tubes of EDTA blood for workup. • Order RBC transfusion, knowing that Blood Bank will handle phenotyping aspect. • Consent patient and transfuse safely. • Reassess. Unless there is ongoing blood loss/hemolysis, patients with antibodies should respond similarly to others with a 3% bump in Hct per unit.

honors the antibody and still provides antigen-negative RBCs. If they did not, antigen-positive red cells could elicit an anamnestic response and cause a delayed hemolytic transfusion reaction, with hemolysis of the transfused red cells some 7-10 days after the transfusion. Finally, let’s talk briefly about the emergent transfusion to a patient with an antibody, when there isn’t time to phenotype and crossmatch units of RBCs. How dangerous is it to give, say, six RBCs to someone with anti-E antibody, not knowing if those six units are E-positive or E-negative? If the patient is going to die without the RBCs, then you should give them, whether they are E-positive or not. The Blood Bank holds onto segments from all emergently released units and can phenotype them retrospectively, so you’ll know how many of the six were antigen-positive. Also, as you probably have 7-10 days before the anamnestic response takes hold, there is time to perform a red cell exchange transfusion to remove those E-positive red cells and replace them with all E-negative cells. This situation does not come up often at all, but it is manageable. It holds for the non-A and B antigens. You will never, ever give group A red cells to a group O patient (or any other ABO incompatible red cell transfusion), no matter what the situation, but for the other antigens discussed above, this is a viable card to play if the scenario warrants it.

The Whole Patient

The only major consideration here is whether to request one or more units of RBCs for the patient who needs multiply antigen-negative red cells. These may

Quick Question Why does the Blood bank make you repeat the T+S or T+C every 3 days for a patient with antibodies or if they’ve been transfused? Patients who have been transfused or who have established antibodies may develop new ones. These can pop up over the course of a few days, and the Blood Bank wants to be on top of a new antibody if it develops. Performing a T+S every day would be too often, but every 3 days will enable the techs to catch a new antibody early on.

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be hard-to-get units. Realize that the T+S for patients with antibodies is complex and takes time and sometimes requires a reference laboratory’s assistance. If your patient can manage without a transfusion, hold off on the lengthy laboratory work up and the purchase of an expensive (~$1000) unit of RBCs. Alternatively, if you do need to transfuse the patient with multiple antibodies, start this process early, and during daylight hours, as it will take several hours to secure and crossmatch appropriate units.

Eight-Second Summary

If my patient has formed antibodies to foreign red cell antigens, the Blood Bank will determine this from the antibody screen or from his history, and will provide antigen-negative RBCs, usually within a few hours. This is not the end of the world.

2.4 The Sickle Cell Anemia Patient and Autoimmune Hemolytic Anemia Basic Concepts

Here, we’ll cover the issue of phenotyping for sickle cell anemia (SCA) patients, the four classic types of transfusions for this population, and the provision of red cells for the patient with active autoimmune hemolytic anemia (AIHA). SCA and AIHA patients sometimes overlap, with autoimmune destruction compounding anemia in a patient who already has a hemolytic disorder, so I discuss the two groups in the same section. Phenotyping for sickle cell patients is usually either “limited”, with red cells matched for the patient’s own Rh and K antigens (D, C, E, c, and e), or “extended”, to include the Duff y, Kidd and S and s antigens. This up front phenotyping means that donor RBCs are matched even if your patient has not made antibodies to these antigens. Limited phenotyping is often abbreviated to just cover C, E and K, as matching for D is taken for granted, and most patients are c and e positive. I recommend RBCs phenotypically matched for C, E and K regardless of whether the patient has made antibodies to them, and antigen-negative for any established antibodies. This goes for all red cell transfusions. I view extended phenotyping as unnecessarily restrictive; it is costly and will delay procurement of blood for your patient. The four situations you will face with sickle cell anemia patients are: the well patient requiring interval red cell support, the patient in crisis who does not require transfusion, the crisis patient who does need RBCs (either simple transfusion or RBC exchange transfusion), and the patient presenting with brisk hemolysis due to autoantibodies. Sickle cell patients who are stable (not in crisis) may be supported with either chronic simple transfusions or planned red cell exchange transfusions. Not all patients suffer ongoing hemolysis which demands regular transfusion, but many do, and typically receive one or two units of RBCs as an outpatient on a monthly basis. By the age of about six, children are usually able to receive one whole unit of RBCs, and the 10 mL/kg rule is no longer employed. These transfusions help suppress marrow production of Hb S-rich red cells and improve quality of life. The risk with chronic simple transfusions is iron overload, which is inevitable after a cumulative load of roughly 100 units. The drugs desferrioxamine and deferasirox chelate excess iron to minimize overload, but compliance with desferrioxamine is sometimes poor, owing to its side effects. Serum ferritin should be monitored in

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all sickle cell patients, as levels above 2500 ng/mL are associated with damage to the heart, liver and pancreas, although chelation is often started well before this level is reached, perhaps at 1000 ng/mL. An alternative to chronic simple transfusions is the planned red cell exchange, which can be performed as an outpatient procedure in a few hours and replaces the patient’s own Hb S-rich red cells with 7-9 units of Hb A-rich RBCs (fewer units in smaller children). The iron balance is close to zero, as iron is removed and added in roughly equal measure. This procedure is performed by apheresis-trained nurses and usually requires placement of large-bore, long-term IV access, such as a dialysis-style catheter. Iron overload is discussed further in Section 7.3. The sickle cell patient who presents in crisis may not need a transfusion at all. For the patient presenting with pain as the chief complaint, who does not manifest neurologic signs, acute chest syndrome or priapism (these require urgent exchange transfusion), and in whom the H/H is at the patient’s baseline, the treatment of pain crisis is medical. Intravenous fluids, supplemental oxygen and analgesics are the cornerstones of therapy. Do not immediately equate the sickle cell patient in pain with the need for a red cell transfusion. Consider transfusion in the sickle cell patient in crisis whose Hb is below his baseline, once hydration, as these patients are often dehydrated, is corrected and an accurate H/H is obtained. Here, transfuse red cells as an adjunct to the standard medical therapy, with a target H/H of the patient’s baseline. Conditions for which there is consensus for a full red cell exchange are stroke, acute chest syndrome and priapism. An urgent/emergent red cell exchange takes several hours to arrange: up to 7-9 units of RBCs must be found and crossmatched, IV access which can support an apheresis procedure placed and hematology and the Blood Bank Medical Director consulted. If the patient is more anemic than is typical for him, giving one or two units of RBCs through a simple peripheral IV catheter while setting up for a full exchange is indicated. There are a variety of disease states associated with autoimmune hemolytic anemia (AIHA), sickle cell anemia being just one, but the pathophysiology is the same: these patients develop antibodies to epitopes of antigens on their own red cells and destroy them, sometimes at a brisk rate which overwhelms the bone marrow’s ability to keep pace with destruction. Consult hematology promptly for these complex patients. Here, the treatment strategy is two-fold: dampen the autoimmune response (if warranted) with intravenous immunoglobulin (IVIg) and/or corticosteroids, and be prepared to transfuse least-incompatible red cells. These patients may present with severe anemia with a Hb in the 3-4 g/dL range, a strongly positive direct antiglobulin test (DAT, or direct Coombs), and clinical signs and symptoms of decompensation such as marked fatigue, pallor, increased heart rate, etc. If the hemolysis is severe enough to warrant IVIg, you should give it up front, prior to RBC transfusion, to begin the process of cooling off the immune system. A useful guide for dosing is 1 g/kg body weight, divided into three doses: 50% on day one prior to the first transfusion, 25% on day two and 25% on day three. Again, the decision to administer IVIg should be made with your hematology consultant. In milder cases, IVIg may not be indicated, and corticosteroids, such as prednisolone at 1 mg/kg/day orally may be adequate. Once the appropriate medical therapies have been started, transfuse RBCs. Here, you may

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Role of Laboratory Tests with the SCA Patient and AIHA Test Hb, Hct

Hb S (electrophoresis)

Indirect bilirubin, LDH, haptoglobin

Use Compare with patient’s baseline to assess for worsening anemia Correlate Hb S level with patient’s symptoms and compare with previous Hb S levels Assess degree of hemolysis

Limitations Dehydration (common) gives falsely elevated H/H Takes time, possibly a few days

SCA patients are continually hemolyzing, need to compare with baseline values

not try to achieve the baseline Hb, either in SCA patients or others, but simply increase it from, say 4.2 g/dL to 6.8 g/dL. Certainly, as the patient will hemolyze some of the transfused red cells, the 3% Hct rule will not apply. One more point needs attention: the phenomenon of hyperhemolysis. This occurs rarely in sickle cell patients presenting with AIHA and can be catastrophic. It is a syndrome of worsening hemolysis with the transfusion of red cells; transfusion is analogous to pouring gasoline on a fire. Treatment, therefore, is to stop transfusing. A good approach to the specter of hyperhemolysis, when presented with a SCA patient with florid AIHA and a strongly positive DAT (3 or 4+), is to transfuse SLOWLY. Give a split unit of RBCs (½ unit) over three hours, and draw a peripheral blood Treatment Plan for the SCA Patient and AIHA

• T+C earlier rather than later. The work up in SCA patients takes time. Give the Blood Bank a head start if you have any plans to transfuse. • Secure IV access for IVF, simple transfusions. • Assess need for urgent exchange transfusion (CVA, ACS, priapism). • Assess degree of hemolysis to rule out AIHA. • Determine true H/H after hydration is complete. • Transfuse stable outpatient as either chronic simple or planned red cell exchange. • Treat pain crisis with IVF, oxygen and analgesics if patient is at baseline H/H. • Transfuse patient in crisis below baseline H/H back to baseline. • Perform urgent RBC exchange if indicated (see sample order sheet). • Consider IVIg (1 g/kg divided as described above in Basic Concepts) and/or prednisolone 1 mg/kg/day with taper for brisk hemolysis in AIHA. • Establish reasonable target Hb for patients with AIHA (may be lower than baseline). • Transfuse least-incompatible RBCs for patients with AIHA.

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Sample Order Sheet for Red Cell Exchange

2

DATE: _________________________ Pt NAME: ______________________ SSN: __________________ DOB: ______ Patient’s EBV: ___________________ HT: _______ WT: _______ Sex: _______ DIAGNOSIS: _______________________________ Referring MD: ___________ History:

Allergies: Lab data: Medications: Apheresis Consent on file: ® yes ® no Transfusion Consent on file: ® yes ® no ORDERS: Indication for Aphereisis: ____________________________________________ Goal for Apheresis: _________________________________________________ Frequency: ________________________________________________________ Access (IV): ________________________________________________________ Volume to Exchange/process: ________________________________________ Replacement Fluid: __________________________________________________ Lab Work: _________________________________________________________ Diphenhydramine 25 mg PO PRN for itching: __________________________ Acetaminophen 650 mg PO PRN for fever: _____________________________ PO Calcium supplement as needed: ___________________________________ Calcium 2 gm/250 mL NS or 4 gm/500 mL NS IV PRN: ________________ MD Signature: _________________________________ Date: _____________

sample 30 minutes into the transfusion so the Blood Bank can compare the plasma to the pre-transfusion sample and assess for worsening hemolysis. If the hemolysis is no worse, continue transfusing as you have been, the first ½ unit over three hours, the remaining ½ unit over another three hours, then each whole unit over four hours for the subsequent units. Finally, realize that if your patient is hemolyzing his own red cells at a rapid pace, he will likely show crossmatch incompatibility with any RBC unit available. There is no special unit held in a Red Cross vault that will be compatible, and washing the unit offers no advantage. I have transfused 3+

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incompatible RBCs to a SCA patient with a Hb of 3.6 g/dL to good effect, but I did this cautiously as described above and after a dose of IVIg.

The Whole Patient

Sickle cell patients often present with problems beyond their anemia. Pain obviously tops the list, and managing analgesic (narcotic) therapy can be challenging and frustrating for both patient and physician. Psychosocial issues also require attention, as they do in anyone with a chronic debilitating disease. Finally, infection should be suspected and explored in patients presenting in crisis, particularly if they are febrile. It is no easy task to simultaneously manage a complex medical disease, remain compassionate and avoid being manipulated by drug-seeking behavior, but that is what the sickler demands. Resist the temptation to disengage.

Eight-Second Summary

Phenotype for C, E, K and known antibodies; use your clinical skills to promptly identify emergencies requiring RBC exchange; and transfuse to a Hb level that provides symptomatic relief and a reasonable quality of life.

Suggested Reading

1. Provan D, Singer CRJ, Baglin T, Lilleyman J. Oxford Handbook of Clinical Haematology, 2nd ed. Oxford: Oxford University Press, 2004:117. 2. Vichinsky EP, Luban NL, Wright E et al. Prospective RBC phenotype matching in a stroke-prevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion 2001; 41:1086-1092. 3. Ballas SK, Marcolina MJ. Hyperhemolysis during the evolution of uncomplicated acute painful episodes in paitients with sickle cell anemia. Transfusion 2006; 46:105-110.

2.5 The Surgical Patient Basic Concepts

A comprehensive transfusion plan for the surgical patient includes three elements: the estimated blood loss (EBL); hemoglobin-based triggers; and tailored approaches for the preoperative, operative and postoperative periods. Such a plan need not be elaborate to include these elements. For many elective cases, it will be quite simple. Unstable patients and complex surgeries, though, require both forethought on your part and coordination with the Blood Bank. The plan summarized below will help you think ahead about transfusion in the same manner that you (if you are a surgeon) outline a surgical procedure in your mind before you pick up the first instrument. In this section, we will not discuss the pathophysiology of anemia; I have covered this topic in Section 2.2. Your first step in the transfusion plan is to determine the estimated blood loss for the procedure. You will predict the EBL using information about the specific operation, the patient’s bleeding diathesis, and the surgeon’s experience level. These will be ballpark estimates, but that’s OK. For instance, if a routine hemi-colectomy usually involves 500 mL EBL, and your patient stopped his warfarin several days ago but is still somewhat anti-coagulated, the EBL in his case may be 600-700 mL. If the surgeon has performed many hemi-colectomies, then you can anticipate 600-700 mL, no more. An important question to ask before going to the operating room is, how much blood loss is acceptable, and at what point do I need to replace

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2

shed blood with RBCs? For surgeries with significant blood loss, the schematic in Section 2.2 will get you started. Simply, replace one liter of unacceptable blood loss with three units of RBCs. You can use this rough mathematical model in the OR, but also in the preoperative period for the spontaneously bleeding patient, and postoperatively in the patient with percutaneous drains in place. The next step is to familiarize yourself with the evidence-based transfusion triggers. You will integrate these with the patient’s clinical status and his EBL as you decide whether to transfuse. In their article on perioperative RBC transfusions (Critical Care Medicine article, Table 2), Madjdpour et al provide hemoglobin-based triggers for five categories of patients and break each category out into intraoperative and an ICU versus postoperative on a general ward. In the OR or ICU setting, they suggest a trigger of 7 g/dL for all patients, 7-8 g/dL for patients over 80 years of age or with a fever or hypermetabolism, 8 g/dL for patients with severe coronary artery disease (CAD) or congestive heart failure (CHF), and 8-9 g/dL for those with an Sa02 <90%. The triggers in the postoperative period (general ward) are essentially 1 g/dL higher for each patient category. The authors further provide physiologic triggers for transfusion, including relative hypotension (mean arterial pressure <70-80% of baseline) and tachycardia (heart rate >120-130% of baseline). The quantitative triggers are valid, based on evidence, and they are straightforward to use. The qualitative components—severe CAD or CHF and hypermetabolism—are less so. You may be tempted to transfuse any patient with any degree of CAD. Step back. How severe is the CAD, really? Do the physiologic triggers support your decision? How about the EBL? Gather all the relevant pieces of data. Then, integrate. The third step is tailoring your transfusion plan to the preoperative, OR and postoperative periods. For surgeries where the expected blood loss is moderate, less than 1000-1500 mL, approach RBC transfusions as follows: optimize the preoperative hemoglobin as needed, replace red cells lost in the operating room during surgery to maintain adequate oxygenation, and complete red cell replenishment in the postoperative period (24-72 hours) as IVF and fluid shifts better reveal operative blood loss. For high-volume blood loss, greater than 1500 mL, refer to Chapter 5, as these patient will likely need multiple blood products. For many elective surgeries, preoperative transfusion of RBCs is unnecessary and is rarely done. Urgent or emergent surgeries in patients who may require surgical intervention because of bleeding, such as the GI bleeder requiring partial colectomy or the patient with a ruptured aneurysm often demand up front transfusion. If the blood loss is recent enough, within a few hours, the hemoglobin and hemaotcrit may not yet reflect the severity of anemia, and the preoperative transfusion strategy is empiric: do your best to estimate the patient’s blood loss and use the one liter of whole blood loss equates to about 3 U RBCs rule. The amount of time you have to transfuse prior to going to the operating room is obviously dictated by the patient’s clinical status; just transfuse as much as you can to replace what’s lost as quickly as is safe. In critically ill, markedly anemic patients, RBCs are given as fast as 5-10 min per unit.

∫

EBL (unacceptable) ∙ Hb triggers ∙ physiologic triggers ∙ patient history

The Anemic Patient

23

Role of Laboratory Tests in the Surgical Patient Test CBC

Prothrombin time (PT), partial thromboplastin time (PTT)

Use Assess degree of anemia, platelet count Assess potential coagulopathy

Limitations Acute blood loss, impending fluid shifts make this less accurate PT, PTT do not correlate with bleeding diathesis as accurately as once thought

*PT, PTT will be discussed fully in Chapter 3.

In the operating room, management of blood products is handled by the anesthesia team, which monitors estimated blood loss (EBL), anticipates the threshold of unacceptable EBL and communicates with the surgeons about the patient’s status. For the stable patient, an EBL of 1500-1800 mL or less may be acceptable and may not warrant transfused blood to maintain tissue perfusion. For longer cases involving steady losses and for abrupt losses, red cells are replenished to keep pace with EBL. Here, use both the one liter = 3 RBCs rule and hemoglobin-based triggers to guide you, but interpret real-time hemoglobins with caution. If the patient is hypovolemic, the hemoglobin will be falsely elevated. Remember that when you have transfused 4-6 RBCs, especially if more RBCs are anticipated, you must consider replacing coagulation factors and then platelets (see Chapter 5). The postoperative period is one of fluid shifts and is thus a dynamic state. The hemoglobin and hematocrit are moving targets. RBCs may be given at this time to correct for operative loss and will raise the H/H. Intravenous fluids, in the form of saline, electrolyte replacement and perhaps antibiotics, will lower them. So too will mobilization of third-space fluids. Monitoring the hemoglobin continually is critical to keeping on top of your patient’s oxygen-carrying capacity. All of these principles apply to the pediatric patient, with adjustments for volume and, typically, for good cardiopulmonary function at baseline. One aspect of perioperative transfusion is unique, however. Pediatric patients under the age of five who are to undergo surgery which may require rapid transfusion due to sudden and/or steady blood loss should receive either fresh (<7 days old) or washed RBCs. The extracellular potassium in older red cell units, which can be tolerated at moderate transfusion rates (2-3 hours), may overwhelm the pediatric patient. Fresh units have less extracellular potassium than older units. Alternatively, washing the unit removes the majority of the potassium. Many surgeons request 40 mL/kg of RBCs to be available in the operating room, and this is four times the typical transfusion volume. Clearly, an older unit of RBCs would give a huge potassium bolus if administered quickly. The Blood Bank can wash RBCs just prior to surgery. Once washed, the unit has a 24-hour expiration date, so washing just before surgery would make the unit available for the entire case and the early postoperative period. Washing takes 45-60 minutes, and this request should be made to the Blood Bank a day or two in advance (a heads up is always a good idea), and confirmed the morning of surgery. A full discussion of the pediatric surgical patient is found in Section 7. 4.

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Treatment Plan for the Surgical Patient

2

• Review preoperative labs: CBC, prothrombin time (PT), parital thromboplastin time (PTT) at a minimum; others (electrolyte, glucose, kidney function tests) as indicated by the patient’s clinical condition. • Transfuse RBCs preoperatively if needed to stabilize patient before surgery. Use 3 U RBCs per 1 liter blood loss as rule of thumb. • Transfuse RBCs during surgery if needed for intraoperative blood loss, using EBL as well as intraoperative H/H to guide you (see Madjdpour’s guidelines below). • Refer to Chapter 5 if EBL approached 40% of blood volume (2 liters in adults, roughly 35 mL/kg body weight in infants, 25-30 mL/kg in children. • Monitor H/H during postoperative period, anticipating a gradual decrease as IVF and fluid shifts increase intravascular volume. • Transfuse RBCs to target H/H if indicated (see Madjdpour’s guidelines below). • GUIDELINES adapted from Madjdopur: Patient Category All patients >80 yrs of age, or fever/hypermetabolic state Severe CAD or CHF Hypoxemia, <90% Sa02

OR or ICU Hb Trigger (g/dL) 7 7-8

General Ward Hb Trigger (g/dL) 8 8-9

8 8-9

9 9-10

The Whole Patient

Take a methodical, organ system-based approach to the history and physical of the surgical patient, evaluating for compromise and developing a treatment strategy for each system. This is fairly simple for the healthy patient undergoing elective surgery; much more complex for the debilitated one with a surgical emergency. It is beyond the scope of the book to cover this, and your training is no doubt adequate to conduct a preoperative assessment. The surgical patients with coagulopathy or platelet dysfunction are discussed in Chapters 3 and 4 respectively. For the unstable patient, you clearly need to consider a bleeding diathesis prior to going to the operating room, and the following chapters will assist you with these issues.

Eight-Second Summary

Transfuse RBCs preoperatively to the unstable patient to optimize oxygen-carrying capacity prior to anesthesia, replenish intraoperative losses using 3 U RBC per 1 liter EBL as a rough guide, and monitor for down trending H/H in the postoperative period, correcting as necessary.

Suggested Reading

1. Madjdpour C, Spahn DR, Weiskopf RB. Anemia and perioperative red blood cell transfusion: A matter of tolerance. Critical Care Medicine 2006; 34(55): S102-108.

CHAPTER 3

The Coagulopathic Patient Key Principles • Patients with disseminated intravascular coagulation (DIC) consume all factors, but fibrinogen is often disproportionately affected. • The relationship between the number of FFP units given and a patient’s International Normalized Ratio (INR) is nonlinear, with less effect on the INR seen with each unit of FFP given as the INR approaches normal values. • Calculate the number of international units (IU) of factor VIII or IX needed to correct a deficiency in a Hemophilia A or B patient, but realize that factors are usually given as whole vials that only approximate your dose. • Patients with poor liver synthetic function are deficient in most coagulation factors, with preservation of fibrinogen unless acute DIC is also present. • Consider FFP replacement to coagulopathic with PT > 1.5 times normal surgical patients preoperatively to minimize blood loss in open surgical procedures. • Patients with an INR of ≤2.0 can often undergo minor percutaneous procedures (central line placement, thoracentesis, biopsy) without further correction of the INR. • Correct warfarin overdoses with 2U FFP at a time, no more.

Chapter Overview

Treatment of coagulation disorders is not an exact science. There are mathematical equations and graphs in this chapter, yes, but they are simply starting points. This chapter will outline the treatment approach to the common coagulopathies: the inherited disorders of factors VIII and IX, patients with liver disease, patients supra-therapeutic on warfarin, and patients mildly coagulopathic but requiring either open surgical or percutaneous procedures. In the coagulopathic patient, I think you must rely on your clinical assessment (is the patient bleeding?) to guide therapy to a greater degree than you do in the anemic or thrombocytopenic patient. This is because plasma transfusion is imprecise. There is certainly not a 3% Hct rule for FFP, even in the stable patient. My guidance, therefore, though it is evidence-based and clear, will require your input as well. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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3.1 Factor Deficiencies Basic Concepts

3

This section discusses the more common inherited deficiencies of a single coagulation factor—hemophilia A, hemophilia B and von Willebrand disease (vWD), and outlines the use of factor concentrates to treat them. Treatment of factor deficiencies is the purview of hematologists; thus, this section provides only an overview. You will always present and obtain approval for treatment plans prior to implementing them. Hemophilia A and B are both X-linked recessive and are thus seen almost exclusively in males. Disease severity varies. Severe disease is characterized by factor VIII or IX levels of <1%, moderate by levels of 1-5%, and mild by 5-30%, respectively. Patients with severe disease often receive prophylactic treatment with factor replacement to prevent damage to joints from spontaneous hemarthroses. Those with mild disease may only need factor replacement for surgical procedures or after trauma. Von Willebrand disease is actually a group of disorders affecting the von Willebrand factor molecule. Most are inherited in an autosomal dominant fashion and are thus seen in both sexes. They are quite heterogenous in their presentation, and mild Type 1 vWD may go unnoticed for decades. The work up of vWD is more complex than that for the hemophiliac, because some forms (type 2 variants) are due to a qualitative defect or partial deficiency of certain vWF multimers. A battery of tests, including vWF activity, or ristocetin cofactor activity, ristocetin-induced platelet aggregation, and multimer analysis will normally classify the disease subtype. Remember that vWF is bound to factor VIII to protect the latter from enzymatic degradation, so if vWF levels are low enough, FVIII levels will fall as well. In the rare Type 3 vWD, characterized by a complete deficiency of vWF, FVIII levels may be so low as to strongly suggest hemophilia A. It is beyond the scope of this book to discuss the genetics and pathophysiology of these diseases further. Here, we will turn our attention to the use of factors in the treatment of the disorders. The main tasks in the treatment of the hemophiliac and von Willebrand disease are to calculate the proper dose of factor replacement and identify the historically prescribed brand of concentrate for the individual patient. Calculations involve simple math and give a precise number of international units (IU) for dosing. However, your Blood Bank or pharmacy will stock factor concentrates in vials containing a dose that probably won’t match your neat calculation. In most cases, you will give a whole vial(s) that most closely approximates your planned dose. To calculate the dose, you need to know the patient’s body weight in kilograms, his hemaotocrit and the target factor levels expressed as a percent. While it would be helpful to know his factor level at presentation, say at 3:00 a.m. when the patient presents with a hemarthrosis, this may not be possible. It is completely reasonable to assume a factor level for hemophiliacs of 0%. This certainly works for severe patients, who have a baseline of <1% anyway. For moderate cases, the difference between 0% and 1% or 5% when your target will likely be a factor level of 50%, is negligible. Let’s do some math.

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Patient: 11-year old boy with hemophilia A (severe) Body weight: 47 kg Hct: 42% Presenting complaint: hemarthrosis of right elbow Target factor level: 50% FVIII activity Current factor VIII level: 0% (assume) 1. Calculate blood volume (BV). The BV in children and adults is estimated at 70 mL/kg. 70 mL/kg X 47 kg = 3290 mL. 2. Calculate the “plasmacrit.” The factors are suspended in the plasma component of the blood. 100-42% = 58%. 3. Calculate the plasma volume. 0.58 X 3290 mL = 1908 mL. 4. Recall that 1 IU of factor VIII = 100% activity in 1 mL of plasma. 5. Calculate factor level to replenish. This is the target—current level, or 50%-0% = 50%. Let’s make this a decimal: 0.50. 6. Factor required: 0.50 X 1908 mL X 1 IU/mL = 954 IU. 7. Determine what brand of factor VIII the patient usually receives. Try to provide that same brand if at all possible. Let’s say it’s Recombinate. 8. Call the Blood Bank. Ask what strength they have of Recombinate. They say, “1036 IU vials. Is that OK?” You say, “Probably, but let me just run this by the pediatric hematologist covering the service. 9. Call the hematologist, wow him or her with your math and tell him/her that the Blood Bank can nearly match the planned dose. 10. A single dose may be sufficient for a hemarthrosis. Repeat if necessary in 12-24 hours. Factor IX replacement is just slightly more complicated because of the larger volume of distribution of the factor in the body. You will run the same high-speed math calculations you ran for factor VIII, then DOUBLE THE DOSE to account for that larger distribution. Let’s try it. Patient: 8-year old boy with hemophilia B (moderate) Body weight: 36 kg Hct: 40% Presenting complaint: hemarthrosis of left knee after trauma Target factor level: 50% FVIII activity Current factor VIII level: 0% (assume) 1. 2. 3. 4. 5.

Calculate blood volume (BV). 70 mL/kg X 36 kg = 2520 mL. Calculate the “plasmacrit.” 100-40% = 60%. Calculate the plasma volume. 0.60 X 2520 mL = 1512 mL. Recall that 1 IU of factor VIII = 100% activity in 1 mL of plasma. Calculate factor level to replenish. This is the target—current level, or 50%-0% = 50%. Let’s make this a decimal: 0.50. 6. Factor required: 0.50 X 1512 mL X 1 IU/mL X 2 (double the dose) = 1512 IU.

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Role of Laboratory Tests in Factor Deficiencies

3

Test Factor VIII level Factor IX level vWF:Ag

Use If time permits, check factor level to allow for accurate dosing.

Limitations Time may not permit in urgent cases. If so, assume factor level of 0%.

7. Determine what brand of factor VIII the patient usually receives. Try to provide that same brand if at all possible. Let’s say it Benefix. There are far fewer options with factor IX than with FVIII. 8. Call the Blood Bank. Ask what strength they have of Benefix. They say, “794 IU vials. Is that OK?” You say, “How many such vials do you have? Six? OK, giving two vials would be a 1588 IU dose, which is pretty close. Let me just run this by the pediatric hematologist covering the service.” Now, let’s turn our attention to vWF replacement. This may be accomplished by desmopressin (DDAVP), which stimulates release of vWF from endothelial cells, or by factors containing both FVIII and vWF. DDAVP is administered intravenously in the hospital setting, although patients may use the nasal spray for home use. It is particularly useful for patients with Type 1 vWD, somewhat useful for Type 2A, not indicated for Type 2B as it may worsen platelet aggregation, and not useful at all in Type 3. The dose for DDVAP is 0.3-0.4 μg/kg, repeated every 12 hours for surgical prophylaxis. If DDAVP is not indicated or not sufficient for vWD patients, the factor concentrate is given. Here, dosing is often done by the FVIII:C content for the vial, as if you were treating hemophilia A. As the dose of both FVIII and vWF are marked on the vial, be clear in your order what dose you Treatment Plan for Factor Deficiencies Dosing Parameters for Factors VIII and IX • Hemarthrosis: single dose, target: 30-50% activity. Repeat if necessary in 12-24 hours. • Superficial intramuscular hematoma: single dose, target: 50%. • Central Nervous System (CNS), retropharyngeal bleed: target 100% at onset, then 50-100% for 7-10 days. Give loading dose to achieve 100% activity, then ½ of loading dose Q8-12 hours to maintain 50-100% activity. • Major surgical procedure: target 100% prior to procedure, then 50-100% for 7-10 days. Give loading dose for 100% activity, then ½ loading dose Q8-12 hours. • Dental extraction: single dose. Target: 100%. Dosing Parameters for vWD • DDAVP: 0.3-0.4 μg/kg IV, Q12 hours for surgical prophylaxis. • vWF replacement: Use FVIII targets as guide. Dose Q12 hours with concentrate containing both FVIII and vWF.

The Coagulopathic Patient

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want. If you need 1000 IU of FVIII for a vWD patient, order (roughly) 1000 IU FVIII vial of Humate-P, one of the brands contining both FVIII and vWF.

The Whole Patient

The key issues in this patient population are transfusion-transmitted Human Immunodeficiency Virus (HIV), present in a diminishing number of patients who were infected in the 1980s; the debilitating sequelae of hemarthroses or other significant bleeding episodes; and the ongoing need for factor replacement in the severely affected patients. A subset of the hemophiliac population, and a very small subset of the vWD group have the poor quality of life that accompanies a chronic disease. Further, not all parents are socially or emotionally equipped to cope with the needs of their hemophiliac sons. Assisting your patients and their parents in getting access to information and support systems will greatly help.

Eight-Second Summary

For hemophilia or vWD patients presenting with either an acute bleed or a planned surgical procedure, the three-step plan is: (1) calculate the initial dose, (2) check with the Blood Bank to see what will best approximate the calculated dose, and (3) call the cognizant hematologist with your treatment plan before administering any factor.

Suggested Reading

1. Williams Hematology, 5th edition. Companion Handbook. W. Williams. New York: Mc Graw-Hill, 1996.

3.2 The Warfarin Patient Basic Concepts

Patients taking this commonly-prescribed medication may become supra-therapeutic and require urgent reversal of their coagulopathy with vitamin K and fresh frozen plasma (FFP). Your tasks for this patient are threefold: identify active or recent bleeding sites, correct the coagulopathy, and determine as best you can why the patient became supra-therapeutic. It is the second task that is our main focus here. But first, let’s briefly review the complications of warfarin therapy. The most feared sequela is an intracranial hemorrhage (ICH). Not only are supra-therapeutic patients at risk for a spontaneous ICH, but many of them are elderly, possibly unsteady, and are thus at risk for a fall that would precipitate a serious head bleed. So, while the ICH is less common than a GI bleed, you should always question the patient about trauma, headache, etc., and assess for mental status changes or neurologic deficits. Once you have addressed this issue, explore other sources of hemorrhage. These include the gastrointestinal tract, urinary tract (the two most common sites), retroperitoneum, and the skin, this last site being a unique thrombotic complication. Initiate correction of the INR in the patient who presents with a bleeding episode or an INR ≥5.0 with vitamin K. The standard dose is 5-10 mg IV. In some cases, where bleeding is not severe and there is no evidence of ICH, vitamin K alone is probably sufficient. If the INR is near 10, or if bleeding from any site is significant, then you should follow vitamin K with FFP administration. There is

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Role of Laboratory Tests in the Warfarin Patient

3

Test INR

Use Determine degree of warfarin excess. Risk of bleeding increases with INR >4.0.

Limitations INR <2.0 does not correlate well with clinical bleeding.

no useful mathematical equation for estimating the number of units or milliliters of FFP to give to bring an INR of 8.3 down to 2.5. Also, the effect of each unit of FFP diminishes as you approach a therapeutic INR, i.e., the effect is curvilinear rather than linear. I recommend that you give 2 units of FFP to the bleeding patient or the one at risk for a serious hemorrhage, whatever the INR is on admission, and then recheck the INR after those 2 units. See where you are. If you are not at your target INR, which partly depends on whether the patient requires a procedure (GI scope, etc.), then give 1-2 more. Do not blindly give 6-8 units of FFP to someone with an INR of 9.3 just because you think he must need that many units. He may not. Give 2 FFP and recheck the INR; repeat as necessary. Do not order FFP as 10 mL/kg body weight. FFP comes in units of roughly 300 mL each. You get full units for adults; that’s it. Finally, you may consider prothrombin complex concentrates (PCCs) or recombinant factor VIIa for the patient presenting with an ICH. These are potent medications that should be given only with an attending physician’s full approval. A rough dosing guide for PCCs is 35 IU/kg for a life-threatening bleed. For rFVIIa, a dose of 2.4 mg has been recommended for an adult with an ICH. Finally, you need to determine why or how your patient became supra-therapeutic on warfarin. Several drugs interfere with the metabolism of warfarin; thus, a complete medication history may provide the answer. Dosing of warfarin is individualized and not infrequently changed to try to achieve a target INR range. As such, an increase in the dose made 1-2 weeks ago may overshoot the Treatment Plan for the Warfarin Patient

• Check baseline coagulation parameters (PT, PTT, INR) • Assess for bleeding, with attention to possible ICH. • Give 5-10 mg vitamin K IV for a bleeding episode, or for an INR of ≥5.0 alone. • Give 2U FFP for significant bleeding or an INR approaching 10.0, in addition to vitamin K. • Establish target INR, based on need for an invasive procedure, presence of active bleeding. • Recheck INR after 2 U FFP, if given. • Repeat 2 U FFP if INR has not come down to your target. • Consider 2.4 mg rFVIIa IV for an ICH. • Consider 35 IU/kg Prothrombin Complex Concentrate (PCC) IV for ICH as an alternative to FFP or rVIIa.

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31

target. Finally, some patients on warfarin are elderly and on many medications, and they may mismanage otherwise appropriate dosing by taking too much warfarin.

The Whole Patient

The tasks that should be addressed in this patient are as follows: determine if the source of bleeding, if present, requires additional intervention beyond just correcting the coagulopathy; identify the cause for the supra-therapeutic INR; and probe for other possible medication issues that need attention. We have discussed above the need to identify any source of bleeding. The follow-on step is to diagnose “malignant” sources of bleeding, let loose by the coagulopathy. Examples of this are a lower GI tumor, bleeding excessively with the patient’s INR at 7.3; or a bladder cancer causing noticeable hematuria. Discuss the need for consultants as indicated to help you sort this out. We have covered the issue of why the patient is supra-therapeutic sufficiently in Basic Concepts. Finally, in the patient with multiple medical problems on polypharmacy, ask, “What else on this patient’s Problem List could be worse than it is at baseline?” If the patient has been unknowingly doubling up on his warfarin, has he been skipping some other medication? Is the patient able to manage his medications, or does he need help? Take some time to review these issues while you are waiting for the next INR to come back from the lab.

Eight-Second Summary

The primary treatment for warfarin overdose is 10 mg vitamin K, with FFP given two units at a time for significant bleeding. I expect to get less bang for my FFP buck as I approach a normal INR; therefore, I will not blindly pour FFP into a stable patient with an INR of <2.0 believing that, somehow, in my patient, this will achieve an INR of 1.0 by morning rounds.

Suggested Reading

1. Dzik WH Predicting hemorrhage using preoperative coagulation screening assays. Curr Hematol Rep 2004; 3:324-330.

3.3 The Liver Failure Patient and Chronic DIC Basic Concepts

Your primary task for the patient with chronic liver disease or chronic disseminated intravascular coagulopathy is to ensure adequate hemostasis, and your primary blood product for this task is fresh frozen plasma, although other pharmacologic adjuncts play a role as well. Maintaining or restoring clotting function in these patients requires a grasp of three issues: the pathophysiology of steady-state chronic liver disease and how it differs from chronic DIC; whether your particular patient is stable, is acutely bleeding from a single anatomic source, or has decompensated to diffuse bleeding; and whether an invasive procedure is indicated. In this section, we’ll review the pathophysiologic derangements in both these groups, the stable cirrhotic and the patient with low-grade DIC secondary to any of a number of underlying illnesses, including end-stage liver disease, as this frequently degenerates into DIC. A few key laboratory parameters will help

3

32

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Transfusion Medicine: A Clinical Guide

you distinguish these entities and guide your management. Prophylactic FFP is appropriate in many cases prior to an invasive procedure. This is covered fully in section 3.5, but we’ll discuss it briefly here. For both groups, clinical bleeding rather than coagulation test results will drive most of your decisions to transfuse apart from the invasive procedure scenario. While the patient with serious liver disease will be deficient in most coagulation factors and other plasma proteins as well, the patient with chronic DIC due to a non-hepatic etiology will show low levels of all factors, but should have normal levels of other plasma proteins. In the compensated cirrhotic patient, fibrinogen and FVIII levels are within the reference range or above it, as these factors are acute phase reactants. vWF levels are preserved as well. Thus, the fibrinogen level differentiates between the steady-state and the decompensated patient with liver disease. Again, smoldering DIC is not uncommon in late-stage liver disease, as Kujovich succinctly outlines in her review (Critical Care Clinics article), and a decreased fibrinogen level, coupled with an elevated D-dimer, support low-grade DIC or more fulminant decompensation. She recommends a baseline fibrinogen levels and serial testing to monitor for evolving DIC and suggests a level of <100-120 mg/dL as a breakpoint. Clearly, patients with chronic DIC for reasons other than liver disease will show the expected laboratory results-elevated PT, PTT and D-dimer; decreased fibrinogen and platelets; and perhaps schistocytes on the peripheral blood smear. Finally, systemic fibrinolysis is seen in a significant proportion of chronic liver disease patients. It is due to decreased synthesis of the fibrinolytic inhibitors α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor, and decreased clearance of tissue plasminogen activator (tPA). The clinical sequelae are variable, from minimal bleeding diathesis to persistent oozing, frequently stimulated by a surgical procedure releasing tPA. Thrombocytopenia is discussed in Chapter 4. Now that you understand the major pathophysiologic deficits that occur, consider the two clinical questions listed above. The first is whether your patient clinically stable at his baseline or acutely hemorrhaging or globally decompensated, and applies most often to the cirrhotic. Patients with chronic liver disease tend to be frequent fliers in the hospital, and you will need to approach each admission with fresh eyes, assessing for a new significant GI bleed or for more diffuse bleeding reflecting a decrement of liver synthetic function. Do not assume that the well-known cirrhotic will be in his usual state of suboptimal health every time you see him. He may not. The second, regarding a procedure, may apply to either patient type. Liver disease patients may require a biopsy to track progression of their chronic hepatitis, paracentesis to drain ascitic fluid, or an endoscopic procedure to evaluate or treat a bleeding varix. You will be placing lines, central and peripheral, doing a spinal tap in some cases, and so on in both groups. Prophylactic FFP should be considered prior to an invasive procedure if the INR is >1.7. This applies equally to the cirrhotic and the patient with chronic DIC for other reasons. As is discussed in section 3.5, you will affect the prothrombin time and INR very little with FFP if the INR is <2.0. Therefore, I recommend that if the INR is 1.7-2.0 that you give one unit of FFP shortly before the procedure—within an hour of starting—and then proceed. Do not wait until the FFP has been fully transfused, then wait some more while you recheck the

The Coagulopathic Patient

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INR. It may not fall appreciably, and you will be left wondering if you should give another unit or two. Perform the procedure and assess for clinical bleeding. If it is present, give another 1-2 U FFP. If you have no significant oozing, stop after that prophylactic unit is complete. You can check the post-transfusion INR if you wish, but do not be alarmed if it has not changed much. Keep your eye on post-procedure oozing and treat that. If the INR is >2.0, I would give 2 U FFP and recheck the INR, as patients with this degree of coagulopathy are at greater risk for bleeding with your procedure. Your approach to transfusion for the patient who does not require a procedure should be guided by the presence of clinical bleeding. I recommend FFP when clinical bleeding is present—from line sites, in the gastrointestinal or genitourinary tract, as pulmonary hemorrhage, or other sites, particularly if the INR is > 2.0, but perhaps at 1.5. FFP may be given prophylactically for a significantly elevated prothrombin time, equating to an INR >2.5, especially if the patient has recently bled. Because the effect of FFP on the PT and INR diminishes as one approaches the reference range, you drive down the INR very little giving 2 U FFP to a non-bleeding patient with an INR of 1.8 and getting a post-transfusion INR of 1.69 and you may do harm in term of volume overload, or acute lung injury FFP contains all the coagulation factors, the modulators of the hemostatic response, and the other needed proteins. It contains albumin, although in the markedly hypoalbuminemic patient, specific albumin replacement may be indicated to give this protein in a smaller volume of fluid than FFP. The primary limitation on giving FFP to the liver failure patient is volume overload. With poor oncotic pressure due to low albumin, and porto-systemic shunting, any IVF may be lost into the interstitium, lungs, or peritoneal cavity (ascites). Correcting oncotic pressure with albumin is no quick fix despite albumin administration. Thus, management of coagulopathy becomes a tightrope walk of optimizing oncotic pressure as well as you can, giving FFP judiciously and monitoring for fluid overload. You may consider alternate agents to treat both the cirrhotic and the chronic DIC patient. Cryoprecpitiate has a well-described role in the management of DIC and should be considered when the fibrinogen is <150 mg/dL. It should be given without hesitation for values below 100 mg/dL. DDAVP is used on occasion in patients with chronic liver disease prior to an invasive procedure. The increase in available vWF improves platelet function. I have no personal experience with DDAVP in this setting, however, and leave this to your discretion. Vitamin K has been recommended for the alcoholic with liver impairment, as a dietary deficiency is possible, and this may provide slight improvement in overall hemostasis; I support this recommendation as one with little downside. Finally, recombinant factor VIIa is used increasingly for intractable bleeding in many populations, not just those with hepatic dysfunction. If the patient is truly in extremis, I support its use at a dose of 90μg/kg body weight. The major risk is a thrombotic complication—uncommon, but a real threat. The other issue when considering rFVIIa is what to do when it wears off several hours later. If you are giving it to buy some time until a bleeding varix can be banded or peri-operatively during a liver transplant, I think this is reasonable. Do not rely on rVIIa as a long-term solution for the end-stage cirrhotic; that is not its purpose.

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Role of Laboratory Tests the Liver Failure Patient and Chronic DIC

3

Test PT, PTT, INR

Use Determine extent of coagulopathy

Limitations The INR was developed for patients on warfarin, but is used extensively for patient coagulopathic for other reasons. Also, the PT and INR do not predict clinical bleeding accurately near the reference range (<2.0 for INR)

You may support the patient in chronic disseminated intravascular coagulation with fresh frozen plasma as well. DIC is a consumptive coagulopathy, and current research favors replacement of coagulation factors and platelets. My advice here is the same as for the liver disease patient. Give FFP for clinical bleeding and consider FFP as the PT and PTT drift out (greater than 1.5-2 x normal) enough to make serious bleeding a real risk. Finally, we are discussing just coagulopathy in this chapter. Clearly, many patients in this group will need more than just FFP in terms of blood products. Chapter 5 discusses the complex patient in detail.

The Whole Patient

Unfortunately, the liver disease patient is at risk for decompensation in virtually every other organ system. This is especially true for the alcohol dependent. Severe hepatic dysfunction causes mental status changes due to hyperammonemia or thiamine deficiency. Alcoholic patients are at risk for aspiration pneumonia due to intoxication, and also from community-acquired agents, particularly of they are homeless. Dilated cardiomyopathy is the key concern in the cardiac system. Varices in the esophagus and ano-rectal region are the main vascular abnormalities of note. In the gastrointestinal tract, the stomach may demonstrate ulcers, and pancreatitis, either acute or chronic, can exacerbate an existing illness or wreak havoc on its own. In the hematopoietic system, alcohol is a direct marrow toxin, causing cytopenias. Splenic sequestration of platelets compounds this problem, and may result in significant thrombocytopenia. Indeed, managing blood transfusions maybe the easiest task in the care of the patient.

Quick Question How long can you expect a couple of units of FFP to last in the patient before you need to transfuse again? Kujovich suggests 24 hours, but I think the effect can vary from patient to patient. The half-lives of the various factors are quite different, ranging from a few hours to a few days. This, coupled with the consumption of the factors in the transfused FFP, which may be rapid, or moderate or minimal, makes it difficult to estimate how long the FFP will last. You simply have to monitor both the PT/PTT and the clinical status each day and decide each day.

The Coagulopathic Patient

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Treatment Plan for the Liver Failure Patient and Chronic DIC • Check baseline coagulation parameters (PT, PTT, INR) • Assess for clinical bleeding. • If patient is coagulopthic (INR 1.5-2.5) and bleeding, give 1-2 U FFP, and reassess clinical bleeding, NOT the INR. If the INR is >2.5, recheck after giving FFP. • If bleeding has abated, hold off on transfusions of FFP and monitor. • If bleeding continues, consider additional 1-2 U FFP,as volume status allows. • If patient is coagulopathic (INR 1.5-2.5) and not bleeding, monitor but do not transfuse FFP. • If patient is significantly coagulopathic (INR >2.5) but not bleeding, assess risk for hemorrhage and consider prophylactic FFP, 1-2 U. • Pre-procedure: if INR is 1.7-2.0, assess for risk factors for bleeding—current significant bleeding, DIC, platelet count <50,000/μL. If risk factors are present, give 1 U FFP prior to procedure. Rechecking INR at this point may not give useful data. • Pre-procedure: if INR is <1.7, assess for risk factors for bleeding—current significant bleeding, DIC, platelet count <50,000/μL. If risk factors are present, consider giving 1 U FFP prior to procedure. Rechecking INR at this point may not give useful data. • Give cryoprecipitate for fibrinogen <100-150 mg/dL. • Consider vitamin K, 10 mg IM for patients with alcoholic liver disease. • Consider rVIIA, 90 μg/kg body weight, for intractable hemorrhage due to diffuse coagulopathy.

Eight-Second Summary

Clinical bleeding is the key driver for considering FFP transfusion in the patient with liver failure or chronic DIC, with the PT and INR as somewhat useful adjuncts.

Suggested Reading

1. Dzik WH Predicting hemorrhage using preoperative coagulation screening assays. Curr Hematol Rep 2004; 3:324-330. 2. Kujovich JL. Hemostatic defects in end stage liver disease. Crit Care Clin 2005; 21:563-587

3.4 The Surgical Patient Basic Concepts

The task in the surgical patient with coagulopathy is to minimize blood loss and tissue damage during surgery by replacing coagulation factors in the pre-, peri-, and postoperative periods as clinical bleeding and laboratory parameters dictate. We have discussed treatment strategies for patients with specific factor deficiencies, i.e., hemophilia A and B and vWD, and I refer you to section 3.1 for this population. Here, we will focus our discussion on patients with low levels of all factors, and we’ll recap our plan for the warfarin patient in the setting of an open surgical procedure.

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3

In the preoperative period, I recommend, as does the American Society for Anesthesiologists Task Force on Blood Component Therapy, correcting warfarin overdoses with FFP. These patients are fairly straightforward as their INR is typically above 2.0, as is should be when they are not under the knife. My approach is just the same for surgical candidates as it is for the rest of the warfarin patients: give 2 U FFP and recheck the INR. For those patients with a prothrombin time or partial thromboplastin time >1.5 times normal who have evident microvascular bleeding before going to the OR, FFP is also recommended by the Task Force. What if the PT or PTT is >1.5 times normal, but there is no evidence of bleeding? Here, I think you need to assess the consequences of microvascular bleeding which may develop on the operating table. If the patient has no other contributors to a bleeding diathesis (a low platelet count, for example) and is otherwise stable, I would hold off on FFP preoperatively and use it therapeutically if the patient starts to ooze in the OR. If the patient has multiple co-morbidities, is septic, or is thrombocytopenic (<50,000 μL), I think it is reasonable to give 1-2 U FFP in the preoperative setting, just before (within 2-4 hours) going to the OR. There is some risk involved in the “staying ahead of the curve” approach, as any transfusion can have adverse consequences. Use good clinical judgment. In the operative setting, where microvascular bleeding can be seen easily, follow the recommendations of the Task Force and correct bleeding when the PT or PTT is >1.5 times normal with 1-2 U FFP. You will recheck these laboratory parameters as a matter of course, but use the patient as your guide to the effectiveness of the FFP. If the bleeding has stopped, stop the FFP, even if the PT has not changed appreciably. It may not budge. If bleeding continues, look at the PT and PTT as well as the platelet count, and continue to follow the above guidelines. In the postoperative period, monitor for microvascular bleeding at incision and line sites. Follow the same recommendations as for the operative setting. As you learned in the section on the surgical patient in the last chapter, you will expect a gradual downtrend in the Hb in the 24-72 hours after major surgery as IVF and third-space mobilization manifest operative blood loss. Do not rush to interpret a falling Hb as evidence of bleeding that demands plasma for correction in a patient with a PT of 14.5 seconds. On the other hand, if you have a patient with multiple co-morbidities, sick as heck, who has a PT of 18.4 seconds but no noticeable oozing from incision sites, and you feel you have little or no margin for error, give 1 U FFP prophylactically to prevent bleeding. Role of Laboratory Tests Test PT, PTT, INR

Use Evaluate extent of coagulopathy

Limitations The INR was developed for patients on warfarin, but is used extensively for patients coagulopathic for other reasons. Also, the PT and INR do not predict clinical bleeding accurately near the reference range (<2.0 for INR).

The Coagulopathic Patient

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Treatment Plan

• Check baseline coagulation parameters (PT, PTT, INR). • Preop: If INR is >2.0, give 1-2 U FFP. Recheck INR prior to going to the OR. • Preop, OR, postop: If PT or PTT is >1.5 times normal and microvascular bleeding is present, give 1-2 U FFP and reassess clinically. Then, if bleeding has stopped, stop transfusing. If bleeding continues, give 1-2 U FFP again, and check platelet count. • Preop, OR, postop: If PT or PTT is >1.5 times normal and clinical bleeding is not apparent, evaluate for other contributors to a bleeding diathesis (platelet count <50,000/μL, sepsis, etc.) and overall clinical status of patient. Consider giving 1-2 U FFP prophylactically to prevent bleeding in unstable patients.

The Whole Patient

The main questions to address here are: (1) Does the patient have impaired liver synthetic function which will adversely affect wound healing? And (2) are additional blood products needed to support the patient? The first question is important if the patient is coagulopathic because he has liver disease. Such a patient may have a low albumin as well, and will likely heal poorly. Decide how you will approach this issue. The second question asks you to think through the decision to transfuse red cells or platelets, as they may or may not be needed. You may refer to sections 2.5 and, for more complex patients, 5.2 to help you with this.

Eight-Second Summary

Transfuse FFP to quickly correct warfarin effect and to minimize microvascular bleeding in patients with a PT or PTT >1.5 times normal. Consider its use in the non-bleeding patient with a PT >1.5 times normal if bleeding cannot be tolerated. Do not rely on the port-transfusion labs, but rather on clinical signs to help you assess the effectiveness of FFP.

Quick Question If you cannot get a PT/PTT back from the laboratory in a timely fashion and the patient is oozing more than you’re comfortable with, how often do you transfuse FFP empirically? In cases where the patient is heparinized, such as cardiac surgery cases, the answer is: often. For other cases, I would look at the preoperative PT/PTT and platelet count to try to determine if one or the other was borderline to begin with. You can probably transfuse 1U FFP in the time it takes to get coags back, and if you do that as an empiric strategy, I think that’s reasonable, but get some labs as soon as you can.

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Suggested Reading 3

1. Practice Guidelines for Blood Component Therapy: A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84:732-747. 2. Spahn DR. Strategies for transfusion therapy. Best Pract Res Clin Anaesthesiol 2004; 18(4):661-673.

3.5 The Patient Requiring Minor Procedures Basic Concepts

Most patients with mild coagulopathy, as designated by an elevation of the INR to the 1.7-2.0 range, can safely undergo a minor percutaneous procedure without attempts to correct the INR. Many physicians have been taught that an INR of 1.5 or less provides a measure of safety for bedside procedures and are thus reluctant to stick a needle in someone with an INR of 1.6. Many studies have examined this issue from all angles—the incidence of significant bleeding associated with specific procedures, the effect of plasma on laboratory tests (PT and INR), and the incidence of adverse reactions following FFP administration, to name three—and several authors decry the overuse and misuse of plasma in the hospital setting. In this section, I’ll summarize recent work by experts in the field. You will note that my recommendations are more conservative in this section than they are for the surgical patient undergoing an open procedure. I do think you can be more liberal with FFP for open procedures. First, what procedures have been studied? A systematic literature review by Segal and Dzik published in 2005 evaluated bronchoscopy, central vein cannulation, femoral angiography, liver and kidney biopsy, paracentesis, thoracentesis, and lumbar puncture. The review included one trial and 24 observational studies and was designed to determine if a prolonged PT or elevated INR predicted bleeding during the invasive procedure being studied. Segal and Dzik found comparable, and very small, rates of bleeding between those patients with normal or abnormal coagulation tests. They concluded that there was insufficient evidence to assume that an abnormal test result would predict bleeding. This is take-home point number one: for many common bedside procedures, there is no correlation with a mildly abnormal coagulation test result (in some studies an INR of >1.5 was the study group) and significant bleeding. Second, how does FFP affect the INR? A prospective study by Abdel-Wahab et al studied the effect of FFP transfusion in mildly coagulopathic patients. The results? FFP transfusion normalized the PT-INR in just 0.8% of patients and achieved 50% correction in only 15%. This study further showed no significant correlation between red cell loss requiring RBC transfusion and the pre-transfusion PT-INR. The study included patients with INRs ranging from 1.1-1.85. A similar study by Holland and Brooks mapped the effect of FFP on the INR over a range of 0.9 to 11.2. They found that patients with an INR of 2.0 achieved almost no decrease in the INR with administration of FFP, while patients with an INR of, say 6.0, would show a decrease in the INR of 2.0 after on unit of plasma. Further, patients with an INR of 1.3-1.6 showed small decreases (0.1) in the INR, whether or not they received FFP. Take-home message number two, then, is that FFP does

The Coagulopathic Patient

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Role of Laboratory Tests in the Patient Requiring Minor Procedures Test PT, PTT, INR

Use Evaluate extent of coagulopathy

Limitations The INR was developed for patients on warfarin, but is used extensively for patient coagulopathic for other reasons. Also, the PT and INR do not predict clinical bleeding accurately near the reference range (<2.0 for INR).

not significantly decrease the INR in patients who have only slight elevations, i.e., with an INR near 2.0. Finally, what is the risk of giving FFP? Many physicians are familiar with the infectious disease risks of transfusion, which are small, and the common febrile or allergic transfusion reactions. They are less cognizant of Transfusion-Related Acute Lung Injury ( TRALI), a new-onset acute event resembling adult respiratory distress syndrome. TRALI is discussed more fully in Chapter 10. The key message here is that indiscriminate FFP transfusion can have untoward results. A recent study looking at FFP transfusions in the intensive care unit setting found that new-onset acute lung injury was more frequent (18% vs. 4%) in patients transfused with FFP. So, not only will you be unlikely to prevent bleeding or correct the INR with FFP in mildly coagulopathic patients, but you may do harm. In summary, 1.5 is not a magic number. Here are some guiding principles which I believe are more useful. If a patient who requires a minor percutaneous procedure has an INR of ≤1.7, do not give FFP unless that patient is in DIC, actively bleeding with significant blood loss, or is markedly thrombocytopenic with a platelet count of <50,000/μL. If the INR is 1.7-2.0, consider the above extenuating circumstances; FFP is probably a good adjuvant therapy if the patient is obviously unstable. If he is stable, FFP may or may not prevent bleeding. If the INR is >2.0, give 1-2 U FFP prior to the procedure. What if you perform a central line placement on a patient with an INR of 1.82, but notice a moderate amount of oozing at the line site afterwards? Well OK, give 1 U FFP therapeutically. Your patient won’t ooze to death in the 45 minutes it takes the Blood Bank to thaw one FFP. If you get into the mindset of using plasma therapeutically versus prophylactically in mildly (INR <2.0) coagulopathic patients, you will transfuse less often, to the patient’s benefit.

The Whole Patient

Clearly, the greater issue in the mildly coagulopathic patient requiring an invasive procedure is about the procedure itself. For example, if the patient needs a thoracentesis, what is the nature of the pleural effusion? Is it malignant? Is a kidney biopsy being done to rule out Goodpasture’s syndrome? Once you have assessed the elevated prothrombin time or INR with the evidence-based guidelines provided here and taken appropriate action, you can confidently turn your attention to the procedure being done.

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Treatment Plan for the Patient Requiring Minor Procedures

3

• Check baseline coagulation parameters (PT, PTT, INR). • If INR is >2.0, give 1-2 U FFP. Recheck INR. • If INR is 1.7-2.0, assess for risk factors for bleeding—current significant bleeding, DIC, platelet count <50,000/μL. If risk factors are present, give 1 U FFP prior to procedure. Rechecking INR at this point may not give useful data. • If INR is <1.7, assess for risk factors for bleeding—current significant bleeding, DIC, platelet count <50,000/μL. If risk factors are present, consider giving 1-2 U FFP prior to procedure. Rechecking INR at this point may not give useful data. • If clinical bleeding develops or persists during or after the procedure, give 1 U FFP to patients with established coagulopathy (PT >1.5 times normal or INR >1.5).

Eight-Second Summary

Correlation between mildly elevated coagulation parameters and clinical bleeding associated with minor bedside procedures is poor. If the INR is <2.0 FFP is usually better used therapeutically for actual bleeding than prophylactically.

Suggested Reading

1. Segal JB, Dzik WH. Paucity of Studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005; 45:1413-1425. 2. Gajic O, Dzik WH, Toy P. Fresh Frozen Plasma and platelet transfusion for non-bleeding patients in the intensive care unit: benefit or harm? Crit Care Med 2006; 34:S170-173. 3. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006; 46:1279-1285. 4. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: the effect of plasma transfusion on coagulation test results. Am J Clin Pathol 2006; 126:133-139.

CHAPTER 4

The Thrombocytopenic Patient and Qualitative Disorders of Platelet Function Key Principles • For stable patients without ongoing platelet consumption, use established triggers as a starting point for the decision to transfuse and incorporate clinical findings to shape that decision. • Platelet transfusions are relatively contraindicated in immune thrombocytopenic purpura (ITP) and should be reserved for serious bleeding episodes. • Platelet transfusions are absolutely contraindicated in thrombotic thrombocytopenic purpura (TTP), and FFP must be given to replace the ADAMTS 13 gene product. • Platelet function can be optimized in uremic patients by transfusing RBCs to a Hct of 30% (if necessary), DDAVP and cryoprecipitate. • Rely on clinical bleeding as an indication for platelet transfusion in patients on antiplatelet agents (aspirin, GP IIb/IIa inhibitors, cardiac bypass). Not every patient requires platelets; those who bleed do.

Chapter Overview

This chapter covers the range of patients with either quantitative or qualitative platelet defects. More common disorders are emphasized: simple thrombocytopenia, immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura, the uremic patient, and the patient on an antiplatelet agent. For rare disorders, such as Bernard-Soulier disease or Glanzmann syndrome, please refer to a hematology text. Platelets are a relatively scarce commodity in any Blood Bank, and your decision to transfuse should include consideration of the impact on the rest of the hospital as well as your own patient’s needs. Blood Banks generally have plenty of FFP and cryoprecipitate, and a fair supply of RBCs. Platelets? They often have just enough to get by. The reasons for this have to do with the short shelf life of platelets and continual turnover of inventory. Thus, an indiscriminant platelet transfusion by your colleague might mean that your Blood Bank runs short as you’re admitting a patient with leukemia and a platelet count of 9,000/μL. Please be judicious. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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4.1 Simple Thrombocytopenia Basic Concepts

4

There are three major concepts to grasp as you treat the patient with simple thrombocytopenia, i.e., the patient on myelotoxic chemotherapy, the patient with aplastic anemia, or the patient with marrow failure due to an underlying disease such as myelodysplastic syndrome. The first is to know the triggers for prophylactic and therapeutic platelet transfusions. This issue has been studied extensively, and I will present the best-known trial on the topic, as well as a consensus statement as background for you. The second principle is the utility of leukoreduction as a means of reducing alloimmunization and platelet refractoriness. The benefit gained from leukoreduction is clear and broadly endorsed; the tactics to employ for the refractory patient are less so. The final theme is that of uncertainty. In the severely thrombocytopenic patient, there are a number of important clinical questions which you cannot answer with precision. I will outline those points of uncertainty, including the patient’s platelet count, the count at which he will sustain an ICH, the number of viable platelets in the unit, and whether therapeutic transfusion is superior to prophylaxis. Then I will recommend what I would do in your situation. Your goals in transfusing platelets are obvious: to prevent severe or life-threatening hemorrhage and to stop bleeding, whether minor or major, as it does occur. You would like to know exactly where your patient stands on the bleeding spectrum and the quantitative effect of your planned transfusion. Realize that there is some margin for error. The etiologies of thrombocytopenia in the patients described here are known (leukemia, chemotherapy effect, etc). If you do not know the reason for a low platelet count, stop and consider ITP, TTP and HIT(T) first before transfusing. Together, the trial by Rebulla (New England Journal of Medicine article) and the statement of the Edinburgh Consensus Conference (British Journal of Haematology article) set clear and broadly accepted triggers for platelet transfusions. Prior to the Platelet Transfusion Trigger Trial, many physicians used a trigger of 20,000/μL for prophylactic platelet transfusions in patients undergoing myelotoxic chemotherapy. Rebulla et al evaluated adolescents and adults receiving induction chemotherapy for acute myeloid leukemia (AML) excluding acute promeylocytic leukemia in two arms: at a trigger of 10,000/μL or 20,000/μL. Those in the lower threshold group would receive platelets for a count of 10-20,000/μL if they manifested fever, active bleeding, or if they required an invasive procedure. Rebulla and his group found that the rates of major bleeding, i.e., bleeding greater than petechiae, mucosal or retinal hemorrhage, were similar between the two groups, as were estimates of survival during induction chemotherapy and length of hospital stay. The lower threshold group received 21.5% fewer platelet transfusions. This study has gained wide acceptance and has been applied to groups beyond those with AML and on other regimens besides induction chemotherapy. I wholly endorse the triggers of 10,000/μL for the stable patient and 20,000/μL for the patient with fever (>38°C), bleeding or the need for an invasive procedure. Many physicians add absolute neutropenia (<500/μL) to the latter list. As the neutropenic patient is at risk for infection and quite possibly already febrile, I think the 20,000/μL trigger is reasonable here. In 1998, the Edinburgh Consensus Conference issued a statement on platelet use, referencing the Rebulla article and endorsing the 10,000/μL threshold in patients

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without additional risk factors. The group left open the numerical trigger to use for a septic patient, one on medications that impair platelet function, or requiring an invasive procedure. For massive hemorrhage, the group recommended a trigger of 50,000/μL. These parameters are quite straightforward and are clear, well-researched guidelines. Your only challenge is to clarify what constitutes “active bleeding’ in your patient. I caution you to consider carefully the decision to transfuse a patient with a platelet count of 18,000/μL with a few scattered petechiae. Your hospital’s supply of platelets is not endless, and you will want to choose wisely. The Trial to Reduce Alloimmunization to Platelets Study Group, or TRAP Study (New England Journal of Medicine article) established that leukoreduction, or ultraviolet B irradiation, significantly reduced the incidence of both alloimmunization to platelet antigens and refractoriness. The TRAP Study Group looked at four groups of patients, all of whom had no platelet alloantibodies at the start of the study. One group received unmodified platelets, and the other three were transfused with either leukoreduced random donor or apheresis units, or ultraviolet B irradiated products. I will remind you that UV-B irradiation is different from the irradiation used to prevent TA-GVHD, and is not available in the United States. The Study Group found that 13% of the patients in the control group developed alloantibodies and became refractory to platelet transfusions, compared with 3-5% of the patients in the treatment arms. Specifically, 3% of those receiving apheresis platelets and 4% receiving random donor platelets became refractory. A much higher percentage in all four arms formed antibodies, 45% vs.17-21% among the control and treatment groups, than actually suffered from poor increments. This study has also garnered wide acceptance. Platelets manufactured by apheresis are leukocyte reduced at the time of collections, but random donor units may not be. If you transfuse random platelets, the common 6-pack, at your hospital, transfuse with a bedside LR filter. What do you do if your patient does become refractory? This is a challenging problem for several reasons. First, the definition of refractoriness is a corrected count increment (CCI) of less than 5000 after two transfusions of ABO-compatible platelets, one of which has been on the shelf for only 48 hours. The formula for the increment is: CCI = (post-transfusion platelet count—pre-transfusion count) X BSA Number of platelets transfused X 1011 BSA is the body surface area of your patient. The number of platelets transfused may be obtained from the Blood Bank if the unit was collected by apheresis. This formula is rarely employed by transfusion medicine physicians typically use a rough estimate to assess for refractoriness, perhaps an increase of <15,000/ uL is viewed as poor and >15,000/uL as acceptable. The second difficulty is that apheresis platelets are now held from release until at least the 48-hour mark while they are cultured for bacterial contamination. Thus, the platelets recommended for assessment are hot off the shelf. The third obstacle is that ABO-compatible platelets may not be available in your facility on any given day, depending on your patient’s blood type. For example, a group B patient can certainly receive group A platelets, and will probably do just fine with them, but they are not considered ABO-compatible. These two issues have everything to do with your Blood Banks’

4

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Transfusion Medicine: A Clinical Guide

inventory. If your patient has a poor CCI, or is refractory by your rough estimate, and you are planning to give fresh, ABO-compatible platelets, call the Blood Bank first to find out if this is feasible. The final tactics are available in some larger institutions, but not always in medium or community-sized hospitals. These are HLA-matched platelets and crossmatching. HLA-matched platelets are drawn from regular donors whose HLA Class I antigen profile is known to be compatible with that of the patient. This does not always mean that the two match, but that at least the donor lacks antigens to which the patient has already made antibodies. Platelet crossmatching is roughly analogous to RBC crossmatching, although it is not supported as an effective strategy by some transfusion medicine physicians. I recommend trying the ABO-compatible route, using units as fresh as possible (they may not be 48 hours old, but 72 would be acceptable) if you have a patient with multiple poor increments on successive transfusions who is actively bleeding or has a count consistently below 10,000/μL. If your patient has a platelet count below 15-20,000/μL, he is in danger of serious hemorrhage, and you will not be able to quantify that danger with precision. Thus, you must make a decision about transfusion, and you will not be as well-equipped to make that decision as you would like. There are three points of uncertainty surrounding the severely thrombocytopenic patient. The first is the accuracy of the platelet counts at the low end of the analytic range of hematology analyzers. The analyzer with which I am familiar reports a coefficient of variation of up to 14% for platelet counts of 10-15,000 μL and does not report a specific count below 10,000/μL. This degree of variation is typical among analyzers in common use. Second, platelet counts at which thrombocytopenic patients have suffered an intracranial hemorrhage span a range. Stanworth et al reviewed studies on this issue and report that there is no clear association between ICH and the platelet count just before the bleeding episode (British Journal of Haematology article). Unfortunately, this is probably the single piece of data you would like to know. If you knew your patient would bleed into his brain at a count of 8,000/μL or 18,000/μL or 38,000/μL, you would transfuse him if he fell to that threshold. But you don’t know. Third, the number of functional platelets in a 6-pack can vary widely, and the quantity in an apheresis unit can be estimated, based on the unit count at the time of collection, but is not totally reliable. Studies to determine the recovery and survival of platelets have been conducted, but some of these use healthy volunteers as the donor and recipient (autologous transfusion). How many viable platelets are in the unit when it is hanging at the patient’s bedside, and how well these survive in a sick, thrombocytopenic patient is not clear. Given these unknowns, how do you manage the patient with a count, say, in the teens? If your patient has been clinically unstable, bleeding at platelet counts higher than 10,000/μL, bleeding from multiple sites, or with short-lived increments from transfusions, I would give yourself a little leeway with the triggers outlined in this section. Don’t break the (Blood) Bank, but err on the side of caution when you believe the patient is too unstable to tolerate the unknowns. One final issue that Stanworth raises regards the utility of prophylactic transfusions vice therapeutic interventions for clinically apparent bleeding. While Stanworth critically assesses the evidence of the published randomized controlled trials on the subject and finds it “tenuous,” I personally cannot endorse a policy based solely on therapeutic transfusions for active bleeding. Stanworth does not either, though he opens the question. I recommend prophylactic transfusions without hesitation.

The Thrombocytopenic Patient and Qualitative Disorders of Platelet Function

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Role of Laboratory Tests in Thrombocytopenia Test Platelet count HLA antibody test

Use Assess thrombocytopenia Assess for alloantibodies in workup of refractoriness

Limitations NA Sensitivity and specificity not optimal, results often not helpful in workup.

The Whole Patient

Two issues which merit your consideration here are the platelet inventory of your hospital and the management of end-of-life platelet transfusions. Platelets are no doubt the blood product in scarcest supply in your Blood Bank. An inappropriate transfusion on your part does not always mean that a patient on another ward will have to go without and risk bleeding into his brain just so your patient is covered. What it means far more often is that your Blood Bank will run short on platelets and have to order additional units from its supplier. This costs money and takes time. This does not happen with FFP or group A positive RBCs; it happens with platelets. Exercise good judgment with this valuable resource. A related issue is how to treat the patient at the end of his life, whose platelet count is dangerously low. Not infrequently, you will find yourself transfusing platelets to keep a patient alive for a short period of time,

Quick Question What does “out-of-group platelets” mean? This means one of two things. It can mean that your patient is group O and the platelets given to him are group A. Platelets carry ABO antigens on their surface, so the anti-A that your patient has in his plasma may destroy some of those platelets, causing a suboptimal bump. In practice, this does not have clinical significance in most cases, and I rarely try to match for this unless a patient is really thrombocytopenic and bleeding and we don’t see a good increment with group A or B platelets. It can also mean that your patient is group A (or B) and he receives group O platelets. The anti-A, B in the plasma in which those platelets are suspended may cause minor hemolysis of some of the patient’s RBCs. Also, this is rarely an issue, and if I do not have the platelets in my inventory, I do not match for this, except in neonates. Some transfusion medicine physicians do pay close attention to both of these issues, and I respect their opinions and practice. If your hospital is large enough, and has a big inventory of platelets, and your patient is getting poor increments from the first type of out-of-group platelets, then it’s reasonable to try ABO-compatible. It may help. In my hospital, many days, we only have group O or only group A, to offer, and the patients do OK with their increments and control of their bleeding.

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Treatment Plan for Thrombocytopenia

4

• CBC to assess baseline platelet count, with peripheral smear. • Order leukoreduced platelets for all patients who will require multiple platelet transfusions. • Order irradiated platelets for all patients with a hematologic malignancy or who will require/have received a bone marrow/stem cell transplant. • Transfuse platelets, one apheresis or one 6-pack, for a platelet count of <10,000/ μL. Recheck count at 30-60 minutes after completion. • Transfuse platelets, one apheresis or one 6-pack, for a platelet count of <20,000/μL in the patient with fever ≥38˚C, minor bleeding, the need for an invasive procedure (non-CNS), or neutropenia. Recheck count at 30-60 minutes after completion. • Transfuse platelets, one apheresis or one 6-pack, for a platelet count of <50,000/ μL in the patient with serious bleeding or the need for a lumbar puncture. Recheck count at 30-60 minutes after completion. • Transfuse platelets, one apheresis or one 6-pack, for a platelet count of <100,000/μL in the patient with a CNS bleed. Recheck count at 30-60 minutes after completion.

a few days perhaps, while he or she and family members prepare for the inevitable. Is this a justifiable use of the resource? I think so. The keys here are to set some limits on how many platelets will be transfused and for how long. I think if your Blood Bank can supply two platelets per day for a severely thrombocytopenic patient to prevent him from dying of an ICH, while he and his loved ones accept the ultimate futility of continued treatment interventions, then that is reasonable. More than two platelets is probably too many. If your Blood Bank is very short in its inventory, the patient and family should know that, too. How long? Several days to a week at most is my recommendation. By that point, death might intervene despite your efforts, or the family may be ready to let go. Coordinating cases such as this with your Blood Bank will help them manage their supply and plan ahead for you.

Eight-Second Summary

Treat simple thrombocytopenia with leukoreduced platelet transfusions according to well-established triggers. The value of your clinical assessment increases in the severely thrombocytopenic patient because the data points for decision-making are less precise than they could be.

Suggested Reading

1. Rebulla P, Finazzi G, Marangoni F et al. The threshold for prophylactic platelet transfusion in adults with acute myeloid leukemia. N Engl J Med 1997; 337:1870-1875. 2. Contreras M. The appropriate use of platelets: an update from the Edinburgh Consensus Conference. Br J Haematol 1998; 101(Suppl 1):10-12. 3. Trial to Reduce Alloimmunization Study Group. Leukocyte reduction and ultraviolet B irradiation to platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997; 337:1861-1869. 4. Stanworth SJ, Hyde C, Brunskill S, Murphy MF. Platelet transfusion prophyalxis for patients with haematologic malignancies: where to now? Br J Haematol 2005; 131:588-595.

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4.2 Immune Thrombocytopenic Purpura Basic Concepts

Immune thrombocytoenic purpura (ITP) is a relatively common autoimmune disease in which IgG antibodies are made to platelet glycoproteins, resulting in clearance of the antibody-coated platelets by the reticuloendothelial system. Platelet transfusions play an ancillary role in management except in severe cases with concomitant hemorrhage; the front line treatment is the purview of the hematologist. If you are not a hematologist, but rather a house officer or attending in another specialty, and a thrombocytopenic patient presents to you, you will want to accomplish these four tasks: quickly rule out other important causes for thrombocytopenia, grasp the fundamentals of the pathophysiology and the diagnostic work up, know the different treatment modalities, and decide when you will consider a platelet transfusion. The review article referenced here is excellent, comprehensive, clear and focused on treatment (New England Journal of Medicine article). What follows here is a significantly trimmed down version of the approach to ITP. For the adult patient, presenting acutely, I follow the authors’ recommendations to the letter. There is some variation in practice among pediatricians; here, I present the typical regimens in use, but refrain from endorsing any single strategy. The take-home message in the initial assessment of the thrombocytopenic patient is this: do not give platelets reflexively. This is particularly true for the adult, in whom thrombotic thrombocytopenic purpura ( TTP) is a key diagnostic consideration. Your first instinct is probably to give platelets. Don’t. Rule out TTP first, by the common laboratory studies at your disposal. Review a CBC, peripheral blood smear, LDH, and renal function tests; and perform a clinical examination for neurologic deficits. While you are interpreting the CBC and peripheral smear, you will rule out two other major causes of thrombocytopenia: acute leukemia and aplastic anemia. The treatment approach to TTP is covered fully in the following section, but platelets are contraindicated prior to plasma exchange; this is why I caution you so strongly to perform a brief work up before calling the Blood Bank. Once you have ruled out these disorders, and any other obvious causes for thrombocytopenia, such as drug-induced, move ITP up to the provisional diagnosis status. If you have a hematologist available to you, this is the time to place the consult. ITP is mediated by IgG antibodies which bind to platelet glycoprotein molecules and, although serologic tests are available, they lack sensitivity and specificity, making them poor diagnostic tools. Platelets bear several glycoproteins on their surface. GPIIb/IIIa is one that is probably familiar to you as a molecular target for antiplatelet drugs, and this was the first one to be discovered as an antigenic focus in ITP. Others include GPIb/IX, Ia/IIa, IV and V. Antibody-coated platelets, whatever the antigenic correlate, are culled out in the spleen by macrophages which bear FCγ receptors. The macrophages then process the antigen, present it to helper T lymphocytes along with the co-stimulatory molecule CD40. T cells then interact with B lymphocytes to generate antibody synthesis, completing the cycle. The pathophysiology is neatly outlined in the New England Journal of Medicine article, with a color schematic to facilitate understanding. The diagnosis of ITP, as Cines rightly points out, is one of exclusion. The direct assay for platelet-associated an-

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tibodies employs a reagent monoclonal antibody (MAB) to glycoprotein IIb/IIIa, which binds (in positive samples) to the patient’s platelet antigen, and then detects the IgG-GPIIb/IIIa-MAB complex with reagent anti-human globulin. Specificity for this type of assay is fair, and sensitivity often poor. My recommendation is to ask your own hematologist if he or she would find this test useful before you order it. I do not support ordering it up front. The salient points in the management of acute ITP in children are that controversy exists regarding the optimal approach to initial treatment and that the chance of sustained remission is better for children than for adults. The decision to treat a child will certainly be driven by the degree of thrombocytopenia, where a platelet count below 20,000/μL is a reasonable point to seriously consider intervention, and by the presence and risk of clinical bleeding. Treatment options include observation alone, intravenous immunoglobulin at a single dose of 0.8 g/kg body weight, and intravenous anti-D at either 25 μg/kg daily for two days or 75 μg/kg once. Cines reviews data on each of these options. Anti-D can only be employed in patients who are Rh-positive so remember to order an ABO/Rh type. Corticosteroids are used infrequently in children and should not be a consideration without input from a pediatric hematologist. As a house officer, I would perform a CBC, assess for clinical bleeding, study the options listed above and prepare a recommendation for the review of a specialist. Adults presenting acutely may be stratified by their platelet count and whether they are bleeding, according to the treatment algorithm in the New England Journal of Medicine article (Fig. 5). Patients with a platelet count >50,000/μL may be observed without treatment. Those with a count of 30-50,000/μL may be treated with oral prednisone 1-1.5 mg/kg/day, or simply observed. Those with counts below 30,000 but who are not bleeding may be treated with the same dose of prednisone and anti-D, 75 μg/kg as a single dose. Those who are bleeding will likely have a platelet count below 30,000/μl (Cines does not specify a count) and may be treated with platelet transfusion, IVIg, 1 g/kg/day for 2-3 days, and methylprednisolone, 1 g/day for 3 days. If the platelet transfusion can be delayed until some IVIg is onboard, survival of the platelets will be optimized, although the increment will not be 30,000. The decision regarding the duration of oral steroids should be made with input from a hematologist, if possible, and certainly a taper should be used. While most adults, one-half to three-quarters, respond initially to therapy, most then relapse, durable remission is rare. The management of remissions and the role of splenectomy are beyond the scope of this text. The decision to transfuse platelets in children can, I think, follow the same parameters provided here for adults: clinically apparent hemorrhage with severe thrombocytopenia ( platelet count <20,000/μL). Platelets are occasionally given as prophylaxis in ITP. I would consider a prophylactic transfusion at a count of <10,000/μL if the risk of bleeding was felt to be high, or as a temporizing measure if the patient was unresponsive to the initial medical intervention. I certainly recommend a prophylactic transfusion if the patient manifests wet purpura on mucosal surfaces, as this is a risk factor for intracranial hemorrhage. There is little in the way of guidance on this issue in the literature so this paragraph reflects my own guidelines.

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Role of Laboratory Tests in ITP Test Platelet count Platelet antibody assay

Use Assess thrombocytopenia Assess for autoantibodies to GPIIb/IIIa.

Limitations NA Sensitivity and specificity not optimal; results often not helpful in workup.

The Whole Patient

Beyond the initial episode, the longer term issues to consider differ between children and adults. In the child, who has a far better prognosis for remission than the adult, I think the main goals are to avoid corticosteroid therapy due to its side effects, to delay splenectomy per the guidelines of the American Society of Hematology, and to monitor for possible relapse at conservative intervals. In the adult, the issues involve both treatment alternatives and the search for an underlying etiology for the ITP. Splenectomy is a key option for adults, as are other steroid medications and immunosuppressive drugs, the latter bringing with them concerns for toxicity. The question of whether ITP in the adult is a secondary phenomenon due to any one of a number of diseases, including systemic lupus erythematosus, an immunodeficiency state or a lymphoproliferative disorder, should actually be performed early on, during the initial hospital stay, but you need not fire off a HIV test as an admission laboratory study. This work up can be conducted based on the likelihood of each disorder in the specific patient.

Eight-Second Summary

ITP is an autoimmune destructive disorder that is initially treated with steroids or immunoglobulins in the adult and observation or immunoglobulins in the child, once other key causes have been ruled out. While evidence-based guidelines are provided here, involving a hematologist at the outset is the right course of action.

Quick Questions Would HLA-matched platelets help in ITP? No. The autoantibodies are to common glycoproteins, not to specific HLA antigens, so that would not improve the increment after transfusion. I’ve read about the anti-CD20 agent, rituximab, being used to treat ITP. What do you think about that? Yes, it is used by some hematologists, and I think that the fact that it is well-tolerated is a plus from the patient’s perspective. We are still awaiting randomized clinical trials to compare rituximab to steroids, though. This decision would be the hematologist’s call at any rate.

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Treatment Plan for ITP

4

• Treatment Plan • CBC to assess baseline platelet count, with peripheral smear. • Rule out TTP with smear, LDH, indirect bilirubin, renal function tests. Rule out leukemia, aplastic anemia with CBC. • Assess patient for clinical bleeding, including careful examination of oral cavity to look for wet purpura. • For adults (adapted from NEJM article): – If platelet count is >50,000/μL, do not treat. – If platelet count is 30-50,000/μL, give prednisone, 1-1.5 mg/kg/day, or do not treat. – If platelet count is <30,000/μL, give prednisone, 1-1.5 mg/kg/day, and anti-D immune globulin, 75 μG/kg as a single dose. – If platelet count is <30,000/μL and patient is bleeding, transfuse platelets, one apheresis or one 6-pack at a time, rechecking platelet count after transfusion; and IVIg, 1 g/kg/day for 2-3 days; and methylprednisolone, 1 g/day for 3 days. • Transfuse platelets at a count of <10-15,000/mL prophylactically for wet purpura or if risk of ICH is high for other reasons (personal recommendation). • For children (adapted from NEJM article): – If platelet count is >50,000/μL, do not treat. – Consider observation, especially with a platelet count of >20,000/μL. – Consider IVIg as a single dose at 0.8 g/kg. – Consider anti-D at either 25 μg/kg/day for 2 days, or 75 μg/kg as a single dose. – Consider transfusing platelets at a count of <10-15,000/μL prophylactically for wet purpura or if risk of ICH is high for other reasons (personal recommendation).

Suggested Reading

1. Cines D, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346:995-1008

4.3 Thrombotic Thrombocyotpenic Purpura Basic Concepts

The three major principles to understand regarding thrombotic thrombocytopenic purpura ( TTP) are the classic pentad and its “downsizing,” the role of a disintegrin and metalloproteinase with thrombospondin-1-like domains (ADAMTS 13), and the use of fresh frozen plasma as primary treatment. The first of these principles may be the most important for you the clinician, as our developing knowledge has allowed a loosening up of the defining criteria for TTP and thus has increased our diagnostic sensitivity. We will briefly cover the pathophysiology of this interesting disorder and also the rationale and schedule

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for therapeutic plasma exchange. Your reliance on the Blood Bank will be great, as the course of treatment will require many units of plasma. Platelets, on the other hand, play virtually no role in therapy. They are, as I have said before, absolutely contraindicated in TTP at presentation, as they are likely to cause thromboses, worsening the patient’s clinical condition. Consider the diagnosis of TTP in any patient who presents with thrombocytopenia without an obvious cause; if microangiopathic hemolytic anemia is also present, immediately move TTP up on your differential. You will notice that these are only two criteria from the classic pentad of clinical findings in TTP. The other three, fever, renal impairment and neurologic findings, are variably seen in TTP and are not required for the diagnosis. Indeed, the latter two are sometimes late manifestations; waiting until the entire pentad is present may prove a fatal mistake. In his review, George defines TTP using MAHA and thrombocytopenia as the required features, and actually cites fever as uncommon (New England Journal of Medicine article). The value of “downsizing” the pentad is that it enables patients to begin plasma exchange more quickly, before they demonstrate renal failure, etc. For some, who may not show these other elements at all, just having two-fifths of the classic criteria may be their ticket to recovery. Beyond the pentad, the clinical symptoms are nonspecific and varied, although gastrointestinal complaints seem to be common. While these symptoms are valuable information and will be included in the H+P, they do not figure in the diagnosis. The diagnosis of TTP can thus be made with common laboratory studies available 24 hours a day in any hospital. The complete blood count will reveal thrombocytopenia and anemia, but also a normal WBC, which will help rule out acute leukemia. The peripheral smear should contain schistocytes; George quotes a study that sets two or more per 100 magnification field as a threshold to suggest MAHA (use the 100x oil immersion objective which actually provides a 1000x magnification when the 10x ocular magnification is included). Elevations of LDH and indirect bilirubin lend further support to a hemolytic process. A BUN and creatinine will help identify renal compromise. We will discuss testing for ADAMTS13 activity and inhibitors in the next section. Lastly, George encourages the clinician to continue, even after the diagnosis of TTP is made and treatment begun, to search for an alternative diagnosis, such as sepsis or disseminated malignancy. These have been found to be the true etiology for MAHA and low platelets in a significant minority of patients initially diagnosed with TTP. The metalloproteinase ADAMTS 13, which cleaves von Willebrand factor multimers, is frequently but not invariably deficient in patients with TTP. Inadequate levels of this enzyme result in vWF multimers which are unusually large and which interact with platelets to generate spontaneous thrombi. Congenital deficiency of ADAMTS 13 has been described, but adult TTP appears to be due to an acquired inhibitor. There are now laboratory tests to measure both enzyme activity and inhibitor levels. I recommend that you order these tests as part of the work up, with two caveats: you do not need a demonstrated deficiency of ADAMTS 13 to make the diagnosis of TTP, and sensitivity and specificity are such that equivocal or normal results do not rule the diagnosis out. George describes a wide range of results in TTP cohort studies, and also findings of deficiency states in persons without clinical TTP. My recommendation is to go ahead an order the tests, knowing that they will take

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4

a week to come back from the reference laboratory, and that you will not wait for them to make your diagnosis. If the tests come back as equivocal, stop and rethink the diagnosis, but do not halt treatment based solely on these assays. Therapeutic plasma exchange plays a dual role of removing ADAMTS 13 autoantibodies and replacing the ADAMTS 13 gene product to ensure enzymatic cleavage of vWF. The typical exchange is 1-1.5 plasma volumes. For an average adult, 3 liters for a one-volume and 5 liters for a 1.5 volume exchange are working estimates. You do not need to be precise. Plasma exchange is conducted daily until the platelet count reaches 150,000/μL and, per George’s algorithm, remains above this level for two consecutive days. At this point, many physicians decrease the frequency to every other day (George recommends stopping “gradually”) for several treatments, then perhaps twice weekly for a week, then halting. George discusses the addition of glucocorticoids to the regimen, either prednisone 1-2 mg/kg/day until remission or intravenous methylprednisolone 1 g/day for 3 days, recommending these for idiopathic TTP cases at least initially, but not for other (secondary) groups. For further guidance on steroid therapy, please refer to the review article, which includes an algorithm. This tool is an excellent starting point, but be mindful that there is significant variation in responses to therapy in TTP, and you should prepare to individualize treatment in each new case. Finally, once you have made a clinical diagnosis of TTP, you will want to notify the Blood Bank of your anticipated need for large volumes of FFP. A one-volume exchange, roughly 3 liters of plasma, will require pooling of 11-12 units of FFP, a 1.5 volume procedure some 20 units. If your patient is group AB, this is a logistical nightmare, if he is group B, somewhat less so, and if he is group A or O, you should be fine. Contacting the Blood Bank Medial Director up front and discussing the volume and frequency of exchanges will allow him or her to secure FFP for your patient. This communication is especially important after the transition to outpatient plasma exchanges. You certainly do not want your patient to show up and Role of Laboratory Tests for TTP Test Platelet count ADAMTS 13 level

ADAMTS 13 inhibitor Peripheral smear BUN, Cr WBC LDH, ind bili haptoglobin

Use Assess thrombocytopenia Identify deficiency. You do NOT need this test result to make the diagnosis. Presence helpful in diagnosis of acquired deficiency of ADAMTS 13. Evaluate for schistocytes Evaluate for renal impairment Rule out acute leukemia Assess for hemolysis

Limitations NA Some patients with clinical TTP have normal levels (sensitivity). Relatively new test. Sensitivity and specificity may improve in time. NA NA NA NA

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Treatment Plan for TTP (adapted from NEJM article)

• CBC to assess baseline platelet count, with peripheral smear. • LDH, indirect bilirubin, renal function tests. Test for ADAMTS 13 activity and inhibitor level. • Consult hematologist and nephrologist. • Once the diagnosis is made on clinical and laboratory grounds, proceed to plasma exchange, 1-1.5 plasma volumes daily until platelet count reaches 150,000/μL and stays above this mark for 2 consecutive days. • Consider prednisone 1-2 mg/kg/day until remission achieved, or IV methylprednisolone 1g/day for 3 days for idiopathic TTP in addition to exchanges • Taper plasma exchange and steroids once remission is achieved, individualized to patient’s status (platelet count, LDH). • Plan for follow-up with hematologist/nephrologist. Refractory cases are not covered here.

then have to wait the 2-3 hours it will take to thaw and pool the plasma. A quick phone call or email will streamline things immensely.

The Whole Patient

Because thrombotic thrombocytopenic purpura may be secondary to an underlying illness, such as systemic lupus erythematosus or other autoimmune disorders, or associated with certain medications, including some chemotherapy agents, or with hematopoietic stem cell transplant, it is important to follow the recommendation of George and pursue an underlying cause for the acute condition. Indeed, the development of TTP in the setting of another serious disorder may change the management strategy for that disorder. Further, plasma exchange is not indicated or efficacious for the syndrome of TTP in each of these other conditions. Thus, while idiopathic TTP is relatively straightforward in terms of treatment, secondary TTP syndromes are less so, and demand well-considered management.

Eight-Second Summary

TTP is a potentially fatal disorder of primary hemostasis which is due in some cases to a deficiency of a vWF-cleaving enzyme. Treatment with plasma exchange removes inhibitory autoantibodies and replaces the ADAMTS 13 enzyme. Platelet transfusions are contraindicated.

Suggested Reading

1. George JN. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354:1927-35. 2. Rock GA, Shumak KH, Buskard NA et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991; 325:393-397.

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4.4 The Uremic Patient Basic Concepts

4

Uremic patients suffer from both qualitative platelet dysfunction and, in up to half of cases, a moderate quantitative deficiency as well. A fraction of these patients require transfusion support to prevent or treat bleeding episodes. In this section, we will discuss the hemostatic disorders of this population, the pathophysiologic derangements underlying the platelet defects and the tactics to correct them, and the point at which you should consider a platelet transfusion. Interestingly, there are multiple interventions which improve primary hemostasis in the patient with renal failure, both from the Blood Bank and from the nephrology service. The platelet transfusion itself is likely to be a later-stage adjunct to the well-known treatments, and it will be employed more frequently for patients with additional reasons for thrombocytopenia than for the patient with uncomplicated uremia. While the chronic renal failure patient is prone to both hemorrhagic and thrombotic complications, we will focus on the bleeding diathesis here. Boccardo outlines these succinctly in his brief but comprehensive review on platelet dysfunction (Seminars in Thrombosis and Hemostasis article). Clinically, patients may manifest petechiae, ecchymoses, or oozing from mucosal surfaces or line sites, bothersome sequelae which may or may not require treatment. More serious episodes include gastrointestinal bleeding, which is fairly common, and pericardial or intracranial hemorrhage. Boccardo reports a range of 16 to 55% of uremic patients being thrombocytopenic. This is typically mild, and several studies give a lower limit platelet count of 80,000/μL Platelets are decreased for one or more of the intuitively obvious causes: underproduction, over-consumption due to mild ongoing bleeding, and losses from certain dialysis techniques. The simple fact that these patients often bleed at platelet counts which ought to assure hemostasis is the basis for our assumption that there must be a functional defect. Actually, there are many. Researchers have identified numerous, inter-related molecular abnormalities of platelet physiology which Boccardo classifies into those of the platelet itself and those of platelet and vessel wall interaction. Among the studies of platelet function, there appears to be consensus on a storage pool defect, with decreases in adenosine diphosphate (ADP) and serotonin, and an increase in the adenosine triphosphate (ATP) to ADP ratio. This could result in a defect of platelet activation. Secretion and aggregation defects are less clearly defined, as is the effect of uremia on thromboxane synthesis. Boccardo reviews many articles on the phenomenon of binding of platelets to the endothelium, describing a decrease in the content of platelet glycoprotein GPIb (the molecule that binds to fibrinogen to form the stable clot), increased endothelial-derived prostacyclin (PGI2), and increased nitric oxide levels, the latter two resulting in vasoldilation. He reports conflicting observations on the qualitative defect of von Willebrand factor (vWF), though the role of vWF in hemostasis, binding platelet GPIIb/IIIa, is established. The toxins removed by dialysis, such as guanidinosuccinic acid (GSA) and phenolic acids are thought to impair platelet function, and certainly patients bleed less when they receive dialysis, but studies attempting to correlate bleeding times and platelet adhesion with serum levels of these toxins have been

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Role of Laboratory Tests in Uremia Test

Use

Limitations

Platelet count

Assess thrombocytopenia

NA

BUN

Assess uremia

NA

disappointing. Finally, Boccardo discusses the role of anemia in platelet function. Red cells in a blood vessel push platelets to the periphery, where they more easily bind to damaged endothelial cells. There are several well-known strategies to improve function in the platelets the patient has, whatever his count. The first and most obvious is dialysis to remove the toxins described above. This does improve hemostasis, and serious bleeding is less frequent now that dialysis is widely available, as Boccardo points out. He does not, however, refer to the commonly used Hct target of 30% to enhance platelet margination by optimizing the hydrodynamics. Many physicians do use this target, however, and I support this tactic. Two approaches to correcting the defect of vWF are DDAVP at a dose of 0.3 μg/kg body weight IV, given once prior to an invasive procedure, regardless of the platelet count; and cryoprecipitate, one 10-pack given before a procedure or every other day for ongoing bleeding. Given that platelet function is impaired even when the patient receives dialysis, you can consider a prophylactic transfusion for a platelet count of <20,000/μL and treat active bleeding at a count of <50,000/μL. The former is an empiric recommendation, based on my own experience and consultation. I support raising the threshold from the standard of 10,000/μL to 20,000/μL in the face of multiple abnormalities of platelet physiology. The latter trigger is the same as you would use for any patient with major bleeding.

The Whole Patient

Your tasks with the uremic patient are obvious and twofold: correct the uremia with dialysis and identify, if you have not already, and treat the underlying cause. The sequelae of uremia are serious and well-familiar to you. They involve virtually every organ system. The more ominous include metabolic acidosis, disorders of electrolytes, pericarditis and mental status changes. Once you have tackled the immediate problem with dialysis, you will turn your attention to its etiology. A full discussion of the causes of renal failure is beyond the scope of this text. A few key questions to answer, though, are these: • Is this an isolated episode from which the patient will fully recover? • Will the patient require long-term dialysis? • Is the patient a transplant candidate?

Eight-Second Summary

Platelet dysfunction in uremia, though complex and not fully understood, is improved with dialysis, optimization of hydrodynamic flow (Hct of 30%), and either DDAVP or cryoprecipitate. Platelet transfusion may be an adjunct when thrombocytopenia further complicates the picture.

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Treatment Plan for Uremia

4

• CBC to assess baseline platelet count. • Perform dialysis to treat uremia. • Transfuse RBCs, if necessary, to achieve a Hct of 30% to optimize hydrodynamics. • Consider DDVAP, 0.3 μg/kg body weight, IV, prior to an invasive procedure. • Consider cryoprecipitate, one 10-pack per dose prior to an invasive procedure if DDAVP is unavailable, and every 2-3 days to optimize platelet function throughout the hospital stay. • Transfuse one apheresis or one 6-pack platelets to treat serious bleeding when platelet count is <50,000/μL. • Consider transfusing one apheresis or one 6-pack platelets as prophylaxis to prevent serious bleeding when platelet count is <20,000/μL.

Suggested Reading

1. Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost 2004; 30(5): 579-589.

4.5 The Patient on Antiplatelet Agents Basic Concepts

While the decision to give platelets to the patient on antiplatelet agents (APA) is empiric, there are three general guidelines to help direct your transfusion plan: give them when there is significant APA drug effect, give them when the patient is actively bleeding, and give them one unit at a time. Literature on the efficacy of platelet transfusions in this population is scant, as are consensus documents which might provide advice on patient management. Lecompte and Hardy’s review on antiplatlet agents and perioperative bleeding primarily addresses the risk of hemorrhage to patients on specific drugs or drug combinations and offers recommendations on the timing of doses before and after surgery (Canadian Journal of Anesthesia article). This is very useful advice and since I do not cover these issues, I refer you to their summary. The authors do advise on platelet transfusion, briefly and in broad terms, and I will discuss their opinions. In this section, then, we will cover the duration of effect of common APAs, the clinical triggers to support transfusion, and timing and dosing tactics. The major antiplatelet agents include acetyl salicyclic acid (aspirin, ASA), the thienopyridines and the GPIIb/IIIa inhibitors. Lecompte and Hardy report from other studies on aspirin that while full recovery of platelet function may take 10 days, primary hemostasis could recover as early as 48 hours after discontinuation of the drug. Before 48 hours, one should expect significant drug effect. They offer a period as long as five days for the disappearance of effect for the thienopyridines. For abciximab, a key GPIIb/IIIa inhibitor, the duration of action is much shorter, on the order of 12 hours. Lastly, as the turnover of platelet is 10% per day, each passing day that the patient is off an irreversible inhibitor of platelet function (ASA, thienopyridines) should bring improvement in primary hemostasis. Thus,

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Role of Laboratory Tests in the Patient on Antiplatelet Agents Test Platelet count

Bleeding time

Use Assess thrombocytopenia. If your patient has a quantitative deficiency as well as a qualitative one, you want to know this. Assess platelet function??

Limitations NA

4 This is a useless test. Do not use it to try to assess platelet function.

in a bleeding patient who is just off aspirin or clopidrogel for a day or two, drug effect is a reasonable etiology or contributing factor; at one week, move this down the list. The trigger for transfusion in all of the cases is significant clinical bleeding. Neither the authors referenced nor I support a policy of prophylactic transfusions. Whether the patient is surgical or medical, the advice is the same: assess for bleeding and consider platelet transfusion only if present and of worrisome severity. Timing a potential transfusion to a cardiac surgery patient will maximize the transfusion benefit. Lecompte and Hardy recommend waiting until the patient is off bypass, heparin has been neutralized, and surgical hemostasis has been achieved before considering transfusion. Then too, the decision will be based on the presence of significant bleeding. I differ from Lecompte and Hardy in the dosing regimen. While they support a dose of 5-7 X 1010 platelets per 7 kg of body weight, or two apheresis units (or two 6-packs), I favor giving a single apheresis unit or one 6-pack and observing for effect. A second unit may not be required. This would save the patient from additional exposure and save that second platelet for someone else.

The Whole Patient

The two issues which merit attention here are the severity of bleeding and possible sequelae from a hemorrhagic episode, and the requirement for ongoing anticoagulation in a patient with established thrombotic risk. If a patient presents with visible bleeding from the gums or noticeable petechiae, you will consider other sources as well: gastrointesintal, genitourinary and CNS are the key sites. You will determine how much of a work up is needed to rule out more serious hemorrhage, based on your initial findings. The key is to think about alternate and more ominous

Quick Question Will transfused platelets be affected by the APA in the patient’s system? Yes. The idea is that enough platelets, unaffected initially, will stop bleeding while the drug effect wears off.

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Treatment Plan the Patient on Antiplatelet Agents

4

• CBC to assess baseline platelet count. • Assess patient for significant clinical bleeding. • Determine duration of effect of the antiplatelet agent that the patient has been taking (see Basic Concepts). • Determine length of time patient has been off the APA. Is drug effect a possible cause for bleeding? • If yes, transfuse one unit apheresis or one 6-pack platelets. Evaluate for clincal effect on bleeding. Repeat if necessary. • If drug effect is unlikely and the platelet count is >50,000/μL, then platelet transfusion may not be the method to stop bleeding. Consider coagulation factor deficiencies or surgical bleeding first.

sites of bleeding while you are faced with perhaps minor stigmata in the patient in front of you. The second task is to reevaluate the management of the anticoagulation in the patient with significant cardiovascular disease. Lecompte and Hardy discuss this issue in some detail in their article, weighing the risks of hemorrhage with those of a thrombotic event in various patient types.

Eight-Second Summary

Consider platelet transfusions for the patient on antiplatelet agents only for substantial clinical bleeding and when the APA still retains some effect based on its duration of action. Give one unit of platelets and assess for hemostasis.

Suggested Reading

1. Lecompte T, Hardy JF. Antiplatelet agents and perioperative bleeding. Can J Anaesth 2006; 53:S103-S112.

CHAPTER 5

The Complex Patient Key Principles • Massive transfusion is defined as replacement of one blood volume (~5.0 L) or transfusion of 10 U RBCs in adults in a 24-hour period. Calculate one blood volume for pediatric patients as 85 mL/kg for infants and 100 mL/kg for premature neonates. • Practically, you should employ the principles of massive transfusion management in the unstable patient once you have transfused ~4-6 U RBCs. • Replace whole blood loss with all blood components: RBCs, FFP, platelets and cryoprecipitate in a 6:4:1:1 ratio. • Systematically reassess electrolyte, acid-base and thermal parameters in addition to blood component measures, and correct incipient abnormalities promptly. Do this continually until the patient is stabilized. • The septic patient chronically consumes platelets and in some cases coagulation factors; these should be monitored and replaced when indicated. • FFP, cryoprecipitate and platelets are indicated for the patient in acute DIC.

Chapter Overview

Be methodical. Integrate multiple pieces of data. Make decisions. Take action. If you are junior, ask for help. In this chapter, I will provide you with a brief discussion of the complexities of the massive transfusion along with a checklist to help you keep track of the many systems that are deranged in these patients. I will help you be methodical. Does a checklist mean you don’t have to think? Hardly. You are a physician because you are able to use algorithms and expand them to incorporate the unique aspects of your patient’s situation. When faced with a rapidly deteriorating patient, assess the situation and develop a treatment plan quickly. The layout of this chapter is to discuss massive transfusion without overt DIC in the first section and incorporate disseminated coagulopathy in the second. Just as significant operative losses sometimes deteriorate into DIC in a sequential fashion, so the first section will lead into the second. The last part covers the septic or otherwise critically ill patient who is not hemorrhaging. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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5.1 Massive Transfusion Basic Concepts

5

Massive transfusion has traditionally been defined as the replacement of one blood volume in a 24-hour period, accomplished by transfusion of 10 U RBCs and some combination of crystalloids and, hopefully, plasma. Hardy (Vox sanguinis article) offers alternative criteria of 4 or more RBCS in one hour with additional units anticipated, or 50% blood volume replacement in a three-hour span. These definitions make intuitive sense; one hardly needs to wait until the tenth unit of red cells has been transfused to shift into the massive transfusion mode, nor should one. This section outlines the approach to executing the high-volume transfusion, but stops short of treating the patient with obvious disseminated intravascular coagulopathy. This phenomenon, which may occur secondary to deterioration of a patient receiving a massive transfusion during elective surgery, following severe postpartum hemorrhage, subsequent to GI or vascular bleeds, or due to trauma, is covered in section 5.2. The guiding principle for the uncomplicated massive transfusion then, is to take a systematic approach to these three elements: replenish RBCs to support perfusion; prevent and correct incipient coagulopathy with FFP, platelets and cryoprecipitate; and manage the physiologic derangements of the large-volume transfusion. Your goal with red cell transfusions is to maintain adequate tissue oxygenation with hemoglobin, in concert with volume replacement, blood pressure and ventilatory support, and other adjuncts. There are several issues to address regarding RBC transfusions, but I believe the more important ones to think through prior to an actual case are those of emergency-release blood and group O-positive vs. group O-negative units. The key advantage of emergently released blood is obviously time. RBC units can be pulled and placed in a cooler in 5-10 minutes. As these units will always be group O, the real danger is that the patient may have an underlying alloantibody, say anti-E, and the RBCs in that cooler will be untested for the E-antigen. What is the potential outcome here? A delayed hemolytic transfusion reaction is the risk, with the patient generating an anamnestic response over the next 7-10 days, causing hemolysis of the E-positive red cells. I see this as a far less important issue than the urgent need for RBCs when you call the Blood Bank for an emergency-release. Uncrossmatched group O RBCs carry minimal risk to the patient. If you cannot wait 45 minutes for a T+C from scratch, or about 15 minutes for a crossmatch when a T+S is on file in the Blood Bank, ask for emergency-release RBCs and give them, period. The next concern is whether to give group O-negative RBCs to every patient in this circumstance. Some hospitals reserve group O-negative red cells for females of child-bearing potential (to include female children). The risk in giving group O-positive RBCs to males and older females is that they may have already formed anti-D from a previous exposure, either transfusion or pregnancy, and will generate an anamnestic response with hemolysis of the transfused RBCs in a week’s time. Alternatively, the risk of giving the entire group O-negative inventory in your hospital to a male patient is that you (the hospital) won’t have any group O-negative RBCs left for a younger woman who is either group O-negative or needs blood emergently. There are a few options here, the first of which is to restrict group

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O-negative to females with childbearing potential. A second is to issue 2 U RBCs as O-negative and have your Blood Bank type the pre-transfusion sample very quickly. Then, group-specific RBCs can be issued. A third is to honor the Rh-type from a previous hospital stay on males and older females; if they are known to be group A-positive, you can give group O-positive emergently, with little risk of a clerical mix up, until a current pre-transfusion sample confirms them as group A-positive. At that point, group specific RBCs can be issued. Other points regarding red cell transfusion are less controversial and involve administration of the units and the target Hct. Intravenous access may be achieved with either large-bore peripheral lines or a central line. An 8-Fr central line will allow 1000 mL of IVF or 500 mL of RBCs to be given per minute, although the blood infusion set must be compatible with the catheter lumen. Rapid infusion dictates use of a blood warmer, but beware that giving multiple units in succession will probably overwhelm the warming system, and hypothermia may follow. Use an in-line 170 μm filter to prevent clots from passing through the line. Finally, a target Hct of 35%, higher than the usual 30% you may be used to aiming for, may contribute to hemostasis by enhancing platelet margination. You will tackle the second element of massive transfusion, minimizing coagulopathy with a combination of fresh frozen plasma, platelets, and cryoprecipitate, with the dual goals of controlling clinical bleeding and achieving numerical targets for key laboratory parameters. Before we discuss blood product ratios and “good enough” platelet counts, let’s briefly look at some of the differences between elective surgery and the trauma setting as outlined by Hardy et al (Vox sanguinis article). In elective surgical cases, tissue trauma is controlled by the surgeon, blood is quickly available, normovolemia and normothermia are maintained, and importantly, coagulopathy is due to loss of coagulation factors rather than DIC. Trauma cases are quite different, with diffuse tissue damage, possible delay in initiating transfusion, frequent hypovolemia and hypothermia, and coagulopathy occurring due to DIC, which is precipitated by release of tissue factor and exacerbated by consumption of factors. Hardy stresses that DIC may be avoided in elective cases by preventing tissue anoxia and maintaining adequate blood pressure. The diagnosis of coagulopathy is made from both clinical and laboratory assessments. Oozing or overt bleeding from line sites, surgical incisions or wounds are all readily observed and valuable indicators of hemorrhage that may present well before laboratory results return. Numerical indices are still valuable however, and you will order the CBC, PT, PTT and fibrinogen frequently (every two hours is not too often) over the course of a case to track the patient’s progress. Near-patient or point-of-care testing may be performed with thromboelastography (TEG) and more sophisticated variants of this test. I leave the reader to Kozek-Langenecker’s (Minerva Anestesiologica) article for a thorough discussion of this method. A useful rule of thumb for replacing coagulation factors and platelets is to use the 6:4:1:1 ratio. That is, give six units of RBCs, four units of FFP, one apheresis (or 6-pack) platelet and one 10-pack of cryoprecipitate as a set, then repeat as necessary. This ratio will help you keep abreast of loss of coagulation factors and platelets, whether these losses are due to dilution or consumption. You may be thinking that your Blood Bank cannot always keep pace with requests for FFP, as these take time to thaw. Should you hold off giving RBCs or platelets to adhere

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to the 6:4:1:1 ratio until the FFP and cryoprecipitate are prepared? No, of course not. What you should do is call the Blood Bank as soon as a high-volume transfusion begins so they can start thawing frozen products. Hold to the 6:4:1:1 ratio as closely as you can. Keep a tally of products given as well, so that when the patient is more stable, you will know that you’ve given 14 RBCs and two platelets, but only five FFP and one 10-pack of cryoprecipitate, and that you should probably catch up on the coagulation factors. Your numerical targets are to achieve PT and PTT values close to normal (I think <17.0 and <45.0 seconds are fine), platelets >50,000/μL and fibrinogen >100 mg/dL. Clearly, weigh these numbers with the patient’s clinical status. If you’ve met your targets, but the patient is still bleeding, give more blood products. Alternatively, if you’re close to the above numbers, but the patient looks great, hold off. Of the many physiologic disturbances that follow massive transfusion, three demand your continual attention: acidosis/academia, hypothermia and hypocalcemia. Acidosis arises from lactate accumulation in poorly perfused tissues in the setting of tissue hypoxia or anoxia. It is compounded by hypoventilation, as may occur in the trauma patient not immediately resuscitated. It may be worsened also by rapid administration of stored RBCs. It is a prominent feature in the trauma patient, often upon arrival to a medical facility, and is an ominous sign there, as it is in the previously controlled patient who is deteriorating. Vigilant monitoring, pre-emptive treatment and prompt correction of acidosis is absolutely critical to preventing a downward spiral into DIC. Cold RBCs and cold FFP, thawed and stored for some time before transfusion, will cool the patient during a massive transfusion. This can occur even with a blood warmer in use, as this instrument cannot effectively warm multiple units given in rapid succession. Hypothermia, defined as a core body temperature of <35˚C, will slow enzyme reactions in the coagulation cascade, impact both platelet count and function, impede metabolism of citrate and enhance fibrinolysis. Prevention is obviously preferable to treatment, and you will certainly provide warmed IVF, apply external warming devices and use the blood warmer as you are able. Hypocalcemia is caused by the sodium citrate anticoagulant in RBCs chleating calcium in the patient. Although the human body can metabolize and excrete citrate, it cannot always keep up in a massive transfusion. Thus, hypocalcemia frequently complicates the high-volume transfusion and requires steady monitoring by either ionized calcium levels (preferred method) or serum calcium. Replacement with either calcium gluconate or calcium chloride, the latter through a central line, should prevent the neuromuscular and cardiac complications. The key concept to grasp in the pathophysiology of coagulopathy is the triad of acidosis, hypothermia and coagulopathy. This set of three related phenomena is self-perpetuating, each feeds on the others, and lethal if not interrupted. Acidosis, arising from lactate build-up in anoxic tissue and from transfusion of multiple RBC units, inhibits fibrin polymerization, so that formed clots are weak, subject to fibrinolysis. This leads to ongoing bleeding and more transfusions of cold RBCs, causing or worsening hypothermia. Hypothermia, in turn, slows the enzymatic reactions of the coagulation cascade, alters platelet function and decreases the

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Role of Laboratory Tests in Massive Transfusion Test CBC PT, PTT, fibrinogen ABG Ca2+

Use Assess Assess Assess Assess

Mg2+

Assess hypomagnesemia

H/H, platelet count coagulopathy degree of acidosis hypocalcemia

Limitations NA Takes time in lab NA Ionized preferable to serum Ca, especially if albumin is low Takes time in lab

platelet count and enhances fibrinolysis. The patient bleeds more, receives more cold blood, perfuses his tissues even less, worsening acidosis and hypothermia still more. It is an understatement to say that you want to stay off this wheel of death. If you work in a trauma facility, you may have no choice, but if you are managing a planned surgical procedure, even an urgent one, where bleeding has just become severe, aggressive early intervention to control coagulopathy and maintain thermal stability and tissue perfusion will save the patient’s life. Of the other significant abnormalities, probably the most important is hyperkalemia in small children. The potassium load in stored RBCs is significant, although this is rarely problematic in adults. Children under five years of age should be given fresh (less than 7-day old) RBCs whenever possible, or washed units if a high-volume transfusion is planned as part of a major surgical procedure. Hypomagnesemia frequently follows the massive transfusion as well and has been reported to induce arhythmias. Monitoring and replacement with magnesium sulfate will sufficiently address this issue. 2,3 diphosphoglycerate (DPG) levels fall in stored red cells, and this contributes to increased oxygen affinity, which is undesirable in the patient with poor tissue perfusion. However, 2,3 DPG levels rise on their own once the RBCs have been transfused, and there is little one can do to prevent this, short of transfusion only with fresh RBCs, whch is impractical.

The Whole Patient

The four priorities for you once the immediate crisis is over are: to complete the surgical procedure or fully stop the inciting hemorrhage—GI bleed, postpartum hemorrhage, etc; to assess for damage to vital organs, including CNS, liver or kidney from possible hypoxic insults; to watch carefully for re-bleeding from the surgical site or previous focus of hemorrhage; and to continue to monitor all parameters—CBC, coagulation, electrolytes, for the next 48-72 hours and correct these as needed. You will have the advantage of close nursing attention because the patient will be in the intensive care unit, and you will keep sufficient monitors in the form of arterial lines, abundant intravenous access and ventilatory support in place until it is safe to disconnect them. Expect that key indices of hemostasis, the H/H, platelet count, PT and PTT, and the electrolytes will downtrend over the next few days, as fluid shifts into the intravascular space dilute them.

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Quick Question

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If you start to transfuse someone with group O blood, and then find out that his blood type is actually group B, do you have to stick with group O? Not if you’re giving group O RBCs as component therapy. Your question is a throwback to the days when whole blood use was much more common than it is now. If you give a group B person group O whole blood, you’re giving anti-A,B antibodies. If you’ve given many units, then you don’t want to give him group B blood (whole or RBCS), because the anti-B will cause some hemolysis of the group B red cells. We don’t use whole blood often anymore, so this is rarely an issue. When we give group O RBCS, there is hardly any plasma in the unit, so anti-A,B is not a concern. So, if you’re starting with group O RBCs, then are able to switch to group B, just do it. Hemolysis is NOT a problem here.

Eight-Second Summary

Use a 6:4:1:1 ratio of RBCs, FFP, platelets and cryoprecipitate to provide an approximation of reconstituted whole blood during the massive transfusion. Aggressively monitor for, prevent and correct acidosis, hypothermia and hypocalcemia to optimize the patient’s own hemostatic mechanisms.

Suggested Reading

1. Kozek-Langenecker S. Management of massive operative blood loss. Minerva Anestesiol 2007; 73:1-15. 2. Hardy JF, de Moerloose P, Samama CM. The coagulopathy of massive transfusion. Vox Sang 2005; 89:123-127. 3. Spence RK, Mintz PD. Transfusion in Surgery, Trauma and Critical Care. In: Mintz PD, ed. Transfusion Therapy. Bethesda: AABB 2005.

Treatment Plan for Massive Transfusion

• Use the sheet on the next page to guide transfusion and electrolyte management. • When significant bleeding begins, empirically give either 2-4 U RBCs or start a 6:4:1:1 RBC; FFP: platelet:cryo set, depending on the amount of hemorrhage. • Inform Blood Bank of massive transfusion scenario. • Order CBC, coagulation tests including fibrinogen, electrolytes and ABG early to help assess patient’s status. • Assess the patient on the nine issues on the checklist, replenishing blood products and electrolytes as indicated, repeating this process until the patient is stable.

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STEP ONE: CALL THE BLOOD BANK TO ALERT THEM OF A MASSIVE TRANSFUSION Issue

Lab

Trigger

Consider Treatment

Anemia

H/H

Hct <30-35%

PRBCs, 2U per dose and 6 U per set with 6:4:1:1 ratio.

Dilutional coagulopathy

PT/PTT/INR

INR >1.5 or PT >1.5 times normal

FFP, 2 U per dose, 4 U per set. While the trigger is helpful, if significant blood loss is occurring start FFP EARLY.

Dilutional coagulopathy

Fibrinogen

<100 mg/dL

Cryoprecipitate, 10 pack per set

Dilutional coagulopathy

Platelet count

<80K

Apheresis platelets, 1 per set. Platelets are needed later than FFP in massive transfusions.

Dilutional coagulopathy

PT/INR

8U FFP, 2 plts, and Novoseven 90 μg/kg persistent clinical body weight coagulopathy (DIC)

Acidemia/acidosis

ABG

pH <7.20

NaHC03, 1 amp (50 mEq) IV

Hypocalcemia

Ionized Ca

<0.8 mmol/L

Ca gluconate IV, 1 gm or… CaCl2, 10 mL of 10% thru central line ONLY

Hypomagnesemia

Serum Mg++ <1.5 mg/dl

1-2G IV over 30-60 min

Hypothermia

NA

Warming interventions

T <35.0C

TIP: Correct factor deficiencies of coagulation first. If bleeding/oozing is not corrected with FFP, then consider platelet transfusion. TIP: When EBL reaches one half the patient’s EBV (2500 mL or 4-6 PRBCs given over several hours), begin to give FFP. Call the Blood Bank early to order FFP if significant blood loss is expected. TIP: Hand carrying lab specimens to the lab and walking them to the bench can speed TAT.

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5.2 DIC Basic Concepts

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Disseminated intravascular coagulopathy is defined as widespread thrombosis and subsequent microvascular hemorrhage and due to unchecked activation of the coagulation cascade and resultant consumption of factors and platelets. DIC occurs in a number of well-described settings, including trauma, particularly head injury; surgical or other hemorrhage which is uncontrolled; fat or amniotic fluid embolism; and in association with acute promyelocytic leukemia (APL). There are additional scenarios as well, but these account for a substantial proportion and will be the focus of our attention here. The approach to DIC will incorporate all the same elements that we just covered in the previous section, because the massive transfusion and DIC so frequently go hand-in-hand. To those principles, we will add three others: 1. Begin with the question: is the patient bleeding? 2. Intensify your regimen of replacement of coagulation factors and platelets, and your management of acidosis and hypothermia. 3. Consider use of newer adjuncts to control DIC, especially recombinant factor VIIa. Most of you have heard the pun of what DIC stands for: death is coming. While still true in a number of cases, better understanding of appropriate treatment strategies and some novel agents now available for use can hold DIC at bay. At its simplest, the key is to get off that wheel of death of acidosis, hypothermia and coagulopathy. DIC is characterized by clinical coagulopathy (microvascular bleeding and thrombosis), but if you identify any of the three features of the wheel, shift to aggressive support without delay. Let’s run through some of the common scenarios in which you will see DIC, starting with the relatively more stable patient and progressing to the trauma case and incorporate the principles above. Is the patient bleeding probably sounds like a ridiculous question of you are treating a trauma or some other surgical patient. Of course, they’re bleeding. Here, let’s go through the approach to the leukemic patient and the obstetric patient with an amniotic fluid embolism. What these patients have in common is that significant hemorrhage is not always present. Your task with them is two-fold. First, assess for hemorrhage. The new-onset APL patient may well have some mild mucosal bleeding, but perform the thorough history and physical examination to rule out gross hematuria, gastrointestinal bleeding, or a CNS bleed. If any of these are present, incorporate a recent bleed with the current degree of anemia, another feature of acute leukemia very likely to be found on CBC. Determine if RBCs should be given. For a younger patient, a Hb of <7.0 g/dL with mild-moderate bleeding can be corrected with 1-2 units of RBCs. If the patient is older and cardiac compromise is a complicating issue, transfuse to a Hb closer to 9-10 g/dL. The obstetric patient is more complex because of the risk for higher volume hemorrhage from the uterus. Here, the assessment for vaginal bleeding will be an integral part of the treatment of the woman, and you will not overlook it. Estimate the amount of bleeding and correct with RBCs, 3 units per liter of whole blood lost, while you are managing the coagulopathy.

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Your approach to the clinical picture of DIC in the elective or non-trauma surgical patient, with microvascular bleeding apparent and an INR or PT prolonged to >1.2 (minor) or > 1.5 (major) times normal, is to prevent acidosis and hypothermia and replace coagulation factors and later platelets, along with RBCs. Although tissue trauma is controlled in the elective surgical setting, some of these patients whose operative course has been complicated deteriorate into clinically evident DIC. Hardy et al (Canadian Journal of Anesthesia article) describe a small study of young healthy persons undergoing posterior spinal stabilization with massive transfusion, in which none suffered DIC. However, this is not always the case, particularly with older patients, those undergoing greater tissue manipulation, and those with underlying medical problems. Watch for developing DIC. Hardy does stress the importance of replacing fibrinogen, which is depleted to clinically significant levels before other factors in dilutional coagulopathy. From this, one can understand the central role of cryoprecipitate in transfusion support. Cryoprecipitate, as you recall, contains fibrinogen at a level of ~250 mg per unit, or 2500 mg per 10-pack, as well as factors VIII, XIII, vWF and fibronectin. Replacement of platelets is typically required later in the case, when the count falls below 80,000/μL with ongoing hemorrhage, or below 50,000/μL if the patient is more stable. The cardinal rule in the treatment of trauma patients from the transfusionist’s perspective is to give FFP and cryoprecipitate to replace lost coagulation factors. If you remember nothing else from this section, recall this: give FFP early and often. Proactive empiric and aggressive replenishment of FFP and cryoprecipitate is mandatory in the appropriate resuscitation of trauma patients. As Ho et al outline neatly in their excellent article on the use of factors in trauma (American Journal of Surgery article), these patients are likely to experience coagulopathy for three reasons beyond simple dilution with crystalloids. First, they are frequently hypothermic, and thus have suboptimal platelet aggregation and enzyme activity along the cascade. The studies they reference on performing a PT or PTT without pre-warming and at 32-33˚C bring up a useful clinical point. In your hypothermic patient, the blue-top tube will be pre-warmed to 37˚C, and then the test will be run. So the coagulation results, even though abnormal, may be falsely reassuring, and your patient may be even worse off than the results indicate. Second, trauma patients typically manifest some degree of consumptive coagulopathy due to the release of tissue thromboplastin and its triggering of the coagulation cascade. This is especially pronounced in cases of head trauma with brain thromboplastin igniting the fire. Finally, acidosis impedes effective clotting by decreasing the rate of factor X and prothrombin activation. Thus, the trauma patient can easily present to the hospital with all the features of the triad: coagulopathy, both dilutional and consumptive; hypothermia; and acidosis. You may be far behind the power curve before you even lay eyes on him/her. Ho and his colleagues rightfully decry the older doctrine of emphasizing RBCs and crystalloids for resuscitation, with FFP as an afterthought. I believe there are two reasons for this traditional approach. One is that we knew less about hemostasis a generation ago than we do now. Current surgical and trauma literature is replete with evidence to support the overwhelming preponderance of coagulopathy in the severely injured and the need for plasma to correct it. The other reason stems from the fear of using blood products in the wake of transfusion-transmitted AIDS. “Blood is dangerous” has

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been the predominant thinking for the past 25 years. With modern infectious disease testing platforms now in use, this statement simply no longer holds. Blood saves lives and the trauma patient needs it, all the components but especially coagulation factors, period. Finally, Ho recommends a 1:1 RBC: FFP ratio, which is slightly different than my recommendation of 6:4:1:1, which includes platelets and cryoprecipitate. Our strategies are quite close, and he recommends use of platelets, although he stresses that they may not be required until a later point in the treatment algorithm. When do you play the recombinant factor (rVIIa) card? At the time of writing this book, rVIIa is still relatively new. Some surgeons and anesthesiologists have used it and can comfortably decide when to add it to their arsenal. Others among you may never have seen it at work. rVIIa works by jump starting the coagulation cascade at the point where the extrinsic and common pathways meet (see schematic on inside cover). Its action is localized however, to sites of hemorrhage, making it a nearly ideal agent for microvascular bleeding episodes that are either focal or widespread. Here are two triggers to guide your decision. Give rVIIa at a dose of 90 μg/kg body weight after you have given two sets of FFP, cryoprecipitate and platelets, that is, 8 FFP and two each of the others, if clinical bleeding is not controlled. The other trigger is purely clinical and empiric. If you cannot get FFP and cryoprecipitate from the Blood Bank fast enough, and the patient exhibits profound DIC, give rVIIa. Just do it. You never stood idly by waiting for laboratory tests to come back when your clinical judgment demanded some intervention; you did what you deemed right. Do the same here. One aspect of rVIIa you do need to consider here is that this drug requires those common pathway factors to be present for it to work; these are X, V, thrombin, fibrinogen and XIII. FFP contains all these, so the more plasma (his own and FFP) the patient has onboard when you give rVIIa, the better. Can you tell how much of each of these factors the patient has when you give rVIIa? Not really. Both the PT and PTT reflect all the common pathway factors in addition to those of the extrinsic and intrinsic pathways, respectively. So we are back to the Nike slogan. If you feel compelled to give rVIIa and have not been able to give as much FFP as you would have liked, give it, give FFP as soon as you can, and hope for the best. You can expect to see the effect as early as a few minutes, but 30 minutes is a reasonable time to allow. The half-life is two hours, so you can consider re-dosing in 2-4 hours if hemorrhage persists. The Franchini article (Hematology article) discusses several other agents used in the treatment of DIC. His arguments that replacement therapy with platelets and FFP is the mainstay of treatment and that fears held previously about “fuel for the fire” are unfounded complement the positions of Ho and Hardy. The “fueling the fire” statement is a key point, as this tenet is still brought up occasionally in discussions of DIC. Franchini offers guidance on the use of heparin in chronic DIC to prevent thrombosis, but she cautions its use in APL as studies are conflicting on its efficacy. Antithrombin (no longer called antithrombin III) has been shown to have anti-inflammatory properties in addition to the primary one of inhibiting circulating thrombin. Recombinant interleukin-10 is another anti-inflammatory molecule, and this cytokine is being studied to determine its ability to staunch the endotoxin-induced effects on

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Role of Laboratory Tests for DIC Test CBC PT, PTT, fibrinogen ABG Ca2+

Use Assess Assess Assess Assess

Mg2+

Assess hypomagnesemia

H/H, platelet count coagulopathy degree of acidosis hypocalcemia

Limitations NA Takes time in lab NA Ionized preferable to serum Ca, especially if albumin is low Takes time in lab

coagulation in sepsis. Finally, experiments in animal models using anti-tissue factor and factor VIIa antibodies show some promise. For you, the clinician, these novel agents may be useful, common adjuncts at some point in the future, but are still a ways off for now.

The Whole Patient

If you can treat the underlying cause of the DIC, do so. This is perhaps most easily accomplished in the case of acute promyelocytic leukemia, where a specific agent, all-trans retinoic acid, is effective. In many other cases, you will simply try to stop the hemorrhaging, stabilize the patient and gradually withdraw the many supportive measures employed to keep him alive—pressors, ventilatory support, electrolyte and fluid replacement, and blood products. As you do with any massive transfusion case, assess the patient for vital organ damage subsequent to an anoxic injury. One final aspect of treatment is speaking with the family and other loved ones about the patient’s course. They must cope with a catastrophic event, one which they probably did not expect, in every case. In some cases, they must also contend with seeing their loved one massively fluid-overloaded, a bloated and unrecognizable transformation of their husband, daughter, or father. You have seen this already, no doubt, the patient 10-15 liters ahead, eyes swollen shut. From your perspective, it’s a victory that the patient is alive and in the ICU with a systolic

Quick Question What about the thrombotic risk with rVIIa? Yes, there is a well-documented risk of stroke or other thrombosis with this agent. A number of studies have looked at this, and found the risk to be small, less than 5%. You are giving rVIIa because of overwhelming bleeding that you cannot stop with conventional blood products. You are effectively saying that you are willing to take that risk, because the risk of the patient exsanguinating is far greater than the risk of a thrombotic complication. I think this is a reasonable risk to take in the massively hemorrhaging patient.

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Treatment Plan for DIC

• The treatment plan here is exactly the same as that for section 5.1, Massive Transfusion. Please refer to the previous sections green box and red table.

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blood pressure over 70 mmHg. Step back and think about how the family members will view the patient, and take a few moments to prepare them.

Eight-Second Summary

If your patient is not on the wheel of death, keep him off. If he is, get him off.

Suggested Reading

1. Franchini M, Manzato F. Update on the treatment of disseminated intravascular coagulation. Hematology 2004; 9(2):81-85. 2. Ho AM, Karmakar MK, Dion PW. Are we giving enough coagulation factors during major trauma resuscitation? Am J Surg 2005; 190(3):479-484. 3. Hardy JF, de Moerloose P, Samama CM et al. Massive transfusion and coagulopathy: patholophysiology and implications for clinical management. Can J Anesth 2006; 53(6):S40-S58.

5.3 The Septic and Critically Ill Patients Basic Concepts

Your two goals in transfusion support of the critically ill patient are to optimize tissue perfusion with red blood cells and to prevent serious bleeding with platelets and fresh frozen plasma. Unlike the patients in the previous sections of this chapter, the septic or otherwise critically ill person requires blood products only as an adjunct rather than as a core element of the treatment plan. You are caring for him or her because of urosepsis, a postoperative course complicated by “multiple medical problems,” pneumonia, and so on. This patient typically has several abnormalities on routine hematology and coagulation tests, and the decision you face is when to intervene with transfusion. What degree of anemia is tolerable? How many platelets are enough? If he is not actively bleeding, should you correct an elevated prothrombin time? In this section,we will discuss the approach to transfusion and lay out some reasonable triggers so you can achieve both goals listed above. We will also outline key issues in platelet dysfunction as this is a common and often complex problem in the ICU setting. Lastly, we will cover some of the newer medications in use, including activated protein C and rVIIa. In which patient do you incorporate the findings of the classic Hebert study and use a Hb of 7.0 g/dL as a red cell transfusion trigger? I discussed this study in Chapter 2 and find it applicable again here as we discuss the patient in the intensive care unit. To summarize, Hebert studied the 30-day all cause mortality and organ dysfunction in critically ill patients who were transfused RBCs either when their Hb fell below 7.0 g/dL and were maintained at a Hb of 7.0-9.0 g/dL (restrictive group), or when it fell below 10.0 g/dL and were maintained at 10.0-12.0 g/dL (liberal group). The findings were that the overall 30-day mortality was similar

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between the liberal and restrictive groups, and that the subgroup of patients with clinically significant heart disease had the same findings. However, the study also revealed lower death rates in the restrictive group in patients who were less acutely ill (APACHE II score <20) or were less than 55 years of age. While the evidence to support a lower transfusion trigger in younger, healthier patients was not surprising, the finding among patients with cardiovascular disease was, and other, though less well-designed studies present conflicting data. I support the recommendations of Drew (Clinics in Chest Medicine article) to employ the restrictive trigger of 7.0 g/dL for RBC transfusion in the ICU patient who is euvolemic, younger than 55, with an APACHE II score of <20, and has no ischemic heart disease. The liberal trigger of 10.0 g/dL can be used for the older (>65 years), sicker or ischemic patient. I commend Drew for offering very specific criteria for the restrictive threshold, as the decision to let a patient drift down to a Hb of 7.5 g/dL is a challenging one. Critically assess your patient for both qualitative and quantitative platelet dysfunction. In Chapter 4, we reviewed the qualitative impairment of platelets in uremia. If your patient is uremic, you may flip back to section 4.4 for guidance. The other commonly encountered patient in the ICU with suboptimal function is the one who is septic. Unfortunately however, the effect of bacterial products on platelets is unclear, and several studies mentioned by Vincent (Critical Care Medicine article) report either decreased or increased platelet aggregation in both animal and human models. As the range of satisfactory platelet counts varies so widely, with 50-450,000/μL usually sufficient for hemostasis, it will be nearly impossible for you to discern whether a patient with a count of 46,000/μL and tarry stools needs a platelet transfusion now. Are those platelets inadequate in number or function, or both, or are they just fine and the tarry stools are from a GI bleed two days ago? You can’t tell. You can assume that qualitative dysfunction may be a factor in the bleeding patient. My advice is to incorporate the patient’s clinical status (bleeding or not, as well as you can determine) to a greater degree than you would in the non-septic patient as you use numerical thresholds to decide on transfusion. In other words, give yourself a little leeway on the numbers. Quantitative platelet disorders in the critically ill have several causes, sometimes categorized as immune or non-immune. Four that should be well-familiar, because they are either common or demand prompt intervention, are sepsis-associated, heparin-induced (HIT), TTP and DIC. In the septic patient, platelet destruction is believed to be immune-mediated and also secondary to hemophagocytosis. The short lifespan of platelets of 7-10 days makes the onset of thrombocytopenia of new onset readily apparent over the course of just a few days. As Drews points out, evolving thrombocytopenia may be the herald of sepsis as it develops. Thus, a steadily falling platelet count in a patient with any reason to be septic should prompt a thorough search for an infectious agent. If the platelet count has fallen below 50,000/μL and the patient is either bleeding or requires an invasive procedure, this is the point at which to transfuse. The non-bleeding patient may be transfused at a count of 20,000/μL if febrile or with an active infection, and 10,000/μL is an appropriate trigger even if bleeding and fever are absent.

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Platelet transfusion is not indicated in either type of heparin-induced thrombocytopenia (HIT), but the reasons are distinct. Type I HIT is characterized by a modest decrease in the platelet count within a few days of starting heparin, with a nadir still above 100,000/μL. It is less serious, as hemorrhagic or thrombotic complications are unlikely, and continuation of heparin therapy with monitoring of the platelet count, and expected recovery, is appropriate. Type II HIT occurs in a small but significant percentage of those on unfractionated heparin, 1-3%, and carries a risk of a thrombotic event for roughly half of those affected. Platelets are contraindicated because of the increased risk of thrombosis. Drews warns against overlooking type II HIT in patients with a normal platelet count, as occurs in 10-15% of cases, and stresses that this diagnosis should be considered in patients with a drop in their count of more than 50%. Treatment includes cessation of all heparin therapy including low molecular weight agents. For type II HIT, the diagnostic work-up is the heparin-induced platelet aggregation assay and an ELISA version which identify IgG anti-heparin-platelet factor 4 (PF4) antibodies. Either test will take several days and likely be performed by a reference laboratory. Thus, you will not wait for the results, but discontinue heparins until testing is complete. We have covered both TTP and DIC in other sections of this text. The point I would like to make here is to carefully consider these diagnoses in patients who are critically ill. TTP, as we discussed in Chapter 3, is not always readily apparent, as all five elements of the pentad may not be clinically obvious. Do not rush to transfuse platelets until you have ruled out TTP at least from a clinical standpoint. You will be more likely to consider DIC as it is more common. The guidelines for fresh frozen plasma transfusion in this setting are essentially the same as for more stable patients, with the emphasis being on therapeutic use for bleeding episodes and prophylactic use prior to an invasive procedure. While Drews uses an INR trigger of ≥2.0 in these patients, as well as those in DIC and those who have been massively transfused, I support a slightly more liberal policy, with an INR of >1.7 as reasonable in the unstable patient. As we discussed in Chapter 3, FFP makes little impact on either the INR or the predilection to hemorrhage in patients with only mildly elevated coagulation parameters. Giving 2 units of FFP to a non-bleeding patient with an INR of 1.92 and seeing it fall to 1.83 (and the patient is still not bleeding) really does the patient no benefit, and it may do him harm. In the patient who has recently bled, from the gastrointestinal, urinary, or respiratory tracts, or from line or wound sites, I think prophylactic FFP for an INR >2.0 is a valid consideration, but not mandatory. Of the novel agents now available and widely used, recombinant activated protein C (drotrecogin alfa; Xigris) has been shown to reduce mortality in patients with severe sepsis. Sepsis affects protein C in two ways: by decreasing absolute levels and by interfering with activation of the molecule. Because protein C is an anticoagulant (it inactivates factors Va and VIIIa) it is contraindicated in patients with active bleeding or recent hemorrhage, or at risk for these. In the non-bleeding patient, however, it is a useful adjunct to therapy. Recombinant factor VIIa, already described in some detail, is a potent drug to stop diffuse bleeding when traditional blood products have failed you. Two common situations where you will consider rVIIa are the patient with severe liver disease with widespread bleeding and the warfarin overdose where a life-threatening intracranial hemorrhage is suspected or

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Role of Laboratory Tests in Septic and Critically Ill Patients Test CBC PT, PTT, fibrinogen ABG Lactate HIT II Assay

Use Assess H/H, platelet count Assess coagulopathy Assess degree of acidosis Quantify degree of tissue perfusion Identify anti-heparin PF4 antibodies seen in HIT II

Limitations NA Takes time in lab NA Takes time in lab Send out test (reference lab), will take several days to a week.

confirmed. Dosing for this agent is 2.4 mg for rVIIa for intracranial hemorrhage, a significantly lower dose than the 90 μg/kg used for diffuse bleeding. An alternate medication in warfarin-associated bleeding is prothrombin complex concentrate (PCCs). PCCs contain factor IX in the greatest amount, and the other vitamin-K dependent factors II, VII and X. Dose this agent at 30-35 IU/kg for an ICH.

The Whole Patient

Your patient may not enjoy a swift recovery. Multiple medical problems and general poor health will likely be the baseline for him or her, with sepsis, or acute or chronic renal failure, or an exacerbation of any of several diseases only complicating the picture. A lengthy hospital stay should be anticipated. As a physician in any specialty, you are well-acquainted with the overall approach to this common Treatment Plan for the Septic and Critically Ill Patients

• Transfuse 1-2U RBCs to a patient with a Hb <7.0 g/dL if he is <55 years of age, has an APACHE II score <20 and has no significant coronary artery disease. Target Hb: 7.0-9.0 g/dL. • Transfuse RBCs to a patient with a Hb <10.0 g/dl if he is >65 years of age, or has an APACHE II score indicating severe illness, or has active ischemic heart disease, with a target Hb of 10.0-12.0 g/dL. • Before you transfuse platelets to any patient, STOP AND THINK. If TTP or HIT, either I or II, is still on the differential, DO NOT TRANSFUSE PLATELETS. • After clinically ruling out TTP and HIT, consider transfusion of one apheresis platelet for a count <50,000/μL with active bleeding or in preparation for an invasive procedure; <20,000/μL for fever or sepsis/infection; <10,000/μL as prophylaxis. • Transfuse FFP for active bleeding prior to a procedure with an INR ≥1.7 or PT ≥1.7 times normal. • Consider FFP as prophylaxis for an INR >2.0 or PT >2 times normal, particularly for a patient who has recently bled. • Consider activated protein C in septic patients who are not bleeding and not at risk for hemorrhage.

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5

scenario. You break down issues by organ system and outline a plan for each system. You make an effort to optimize function in organs that now function poorly at best, trying to achieve some quality of life for the short-term. You prevent nosocomial infections and iatrogenic damage as much as possible. When recovery is clearly unattainable, you discuss this compassionately with the patient and family and help guide them as they face imminent death. In this, the end-of-life situation, blood products can be a key strategy for buying time and comfort, until the patient and family are ready to let go. If you need to give a couple of extra platelets to prevent someone from bleeding into his brain while family members are flying in from out-of-state, that’s probably one of the best transfusion decisions you’ll make.

Eight-Second Summary

Transfusion plays an ancillary role in the treatment of the critically ill patient, but judicious use of red cells, platelets, plasma, and in selected circumstances newer agents, will improve tissue perfusion and hemostasis as you tackle the larger problem of the underlying illness.

Suggested Reading

1. Drews, RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Clin Chest Med 2003; 24:607-622. 2. Vincent JL, Yagushi A, Pradier O. Platelet function in sepsis. Crit Care Med 2002; 30(5):S313-317. 3. Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709.

CHAPTER 6

The Obstetric Patient—Special Situations Key Principles • It is reasonable to manage post-partum hemorrhage with RBCs alone up to 5-6 units; beyond this you are approaching a massive transfusion (refer to Chapter 5) and should transfuse FFP and possibly platelets. • Recognize promptly post-partum hemorrhage that is evolving into DIC, with diffuse microvascular bleeding, and start treatment with RBCs, FFP, cryoprecipitate and platelets as the severity warrants. • Hemolysis, elevated liver enzymes and low platelets (HELLP syndrome) require platelet transfusion if the platelet count is <20,000/μL; to a higher target for cesarean section or epidural catheter placement. • Maternal immune thrombocytopenic purpura (ITP) requires both pharmacologic and transfusion therapies and must be distinguished from other causes of thrombocytopenia such as HELLP syndrome.

Chapter Overview

A cardinal rule in obstetric medicine is to quickly recognize incipient catastrophe in what is usually a routine event (delivery of a baby), correctly identify the cause, and properly treat both mother and child. Obstetric transfusion is simply an adjunct treatment to this end. In this chapter, we’ll review the spectrum of post-partum hemorrhage, from moderate bleeding to disseminated intravascular coagulation; hemolysis, elevated liver enzymes and low platelets; and maternal immune thrombocytopenic purpura. For the obstetric patient requiring massive transfusion, Chapter 5 is a key reference as well, as the same parameters must be followed in any patient who receives massive resuscitation. The unique features in the obstetric patient are that they are often mildly anemic at baseline (when they present to the maternity ward), are often in good general health, and no one expects a bad outcome. I do not make this last comment flippantly; obstetricians face tremendous pressure to save their patients and deliver perfect babies. This is a different circumstance than that of the surgeon attempting to repair a ruptured abdominal aortic aneurysm in a 70-year-old male.

Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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6.1 Postpartum Hemorrhage Basic Concepts

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Uncomplicated postpartum hemorrhage can be managed with RBC transfusions if the Hb falls or is expected to fall below 7.0 g/dL. I use the term “uncomplicated” to mean two things here: that hemorrhage is ultimately controlled with pharmacologic agents and routine mechanical or surgical interventions short of hysterectomy, and that fewer than six units of RBCs are given. This section discusses moderate postpartum hemorrhage (PPH) then, while the next covers more serious bleeding in which multiple blood products are required, hysterectomy is considered and the mother’s life is at risk. As I am a pathologist and transfusion medicine specialist, I only discuss the use of blood products here. Obviously, you will manage these cases with oxytocin and other related agents. I will help you plan for transfusion as additional therapy. PPH is defined by the World Health Organization (WHO) as blood loss which is >500 mL within 24 hours of delivery. This level of blood loss is quite common, especially if a cesarean section is performed, where the EBL is easily near 1000 mL. The etiologies of hemorrhage are well-familiar to you—abnormal lie of the placenta, uterine atony or retained uterine contents, lacerations to the cervix, and disorders of coagulation. Uterine atony probably tops the list of causes of significant bleeding. Women progress to this trigger of 7.0 g.dL in one or more ways. First, most women presenting to the labor deck at term are at least mildly anemic, with a Hb in the 11-12 g/dL range. For some of your patients, those with sickle cell anemia or thalassemia, the anemia may already be close to or below 7.0 g/dL. Second, bleeding associated with delivery itself can be well over 500 mL. This is particularly true today as more cesarean sections are performed. Third, postpartum blood loss, manifested as steady vaginal flow or abrupt hemorrhage, often due to uterine atony, and sometimes occurring once the woman no longer has continual nursing care in her room, can quickly deplete the red cell volume, even if a STAT H/H does not yet reflect it. Finally, movement of fluid from the extracellular to intravascular space drives the Hb down further. Put in mathematical terms, a 75 kg woman at term with a 7500 mL blood volume and a 30% Hct at presentation who loses 2.0 L of blood during delivery and the postpartum period and is replaced with only 2.0 L of saline will have a Hct of 22% (Hb of 7.3 g/dL) before any third-spacing takes place. She is well on her way to at Hb <7.0 g/dL. Your role is to keep in mind the presenting Hb of your patient, estimate blood loss as accurately as possible and if you predict, either empirically or by calculation, that the woman will reach a Hb of <7.0 g/dL when intravascular volume has been replaced, then transfuse RBCs. Unless bleeding is very brisk, one or 2 Role of Laboratory Tests in Postpartum Hemorrhage Test CBC

Use Assess H/H at baseline on admission to labor deck and as needed during bleeding episodes and afterwards

Limitations NA

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Treatment Plan for Postpartum Hemorrhage

• CBC on admission to labor deck. • Transfuse 1-2 U RBCs for a Hb <7.0 g/dL, either current as diagnosed by a CBC, or expected by estimates of blood loss. • Recheck CBC 30-60 minutes after transfusion and daily during hospital stay. • Transfuse to achieve Hb goal of ≥8.0 g/dl.

6 units should be adequate to start. You can check the H/H after transfusing and at intervals during the hospital stay. You do not need to wait until the Hb has trended down to transfuse. If you reach 5-6 units of RBCs, especially if bleeding continues, then read ahead to the next section on severe PPH, as this management is more complex.

The Whole Patient

Your chief priority here is to prevent the need for hysterectomy to control bleeding. While red cell transfusion will support the patient who has lost some blood in the birthing process, it will certainly not achieve hemostasis. This you will manage with medications, uterine massage and minor surgical interventions. Even in the woman who has delivered her final child and may elect a sterilization procedure, avoiding hysterectomy is the desired outcome. Beyond this, a lesser issue may be concerns about receiving a blood transfusion by the patient or her family. Transfusions are less frequent now than a generation ago with delivery, and you may field questions about the safety of the blood supply. Assure your patient and her family that all blood, even that which is emergently released has been fully tested for HIV, HCV, HBV, HTLV and even West Nile virus prior to release. Yes, there are risks with any transfusion, but concern for acquiring an infectious disease should not be one of them.

Eight-Second Summary

Simple postpartum hemorrhage can be assessed with interval CBCs and estimates of blood loss and corrected if the Hb is or is expected to fall below 7.0 g/ dL with transfusion of 1-2 U RBCs initially to a target Hb of 8.0 g/dL.

Suggested Reading

1. Jansen AJ, van Rhenen DJ, Steegers EA, Duvekot JJ. Postpartum hemorrhage and transfusion of blood and blood components. Obstet Gynecol Surv 2005; 60(10):663-671.

6.2 Severe Postpartum Hemorrhage and Evolving Disseminated Intravascular Coagulation Basic Concepts

In this complicated patient scenario, I will emphasize three aspects of treatment: the prevention and correction of both coagulopathy and acidosis, two separate but very much related issues; and the decision to use activated factor VIIa as an adjunctive therapy. There are numerous consequences of high-volume

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transfusion to be addressed other than these three, of course. Please refer to section 5.1, Massive Transfusion for a full discussion. Your role, whether you are on the obstetric or anesthesiologist team, is to recognize simple postpartum hemorrhage that is deteriorating into DIC, and to intercede. Replacement of coagulation factors in the form of plasma and cryoprecipitate is paramount to successful intervention in intractable postpartum hemorrhage, just as it is in trauma and other settings of developing DIC. Many trauma centers now advocate in their literature and employ standardized protocols for administering a set ratio of RBCs, FFP, platelets and, if need be, cryoprecipitate. As this thinking is relatively new and represents a shift away from the rule of “crystalloids and then red cells as needed,” other specialties may be less familiar with the concept of replacing all the elements of blood with component therapy, that is, RBCs and FFP as separate products. The justification for balanced transfusion is twofold. First, whole blood is lost by the patient, so all of its constituents, RBCs, plasma and platelets must be replaced at that point where the remaining fraction is insufficient to maintain hemostasis. Put in mathematical terms, a 1600 mL EBL with delivery will reduce the patient’s coagulation factors by about one-third, and 66% is still an adequate level to ensure clotting in most people. However, a 3200 mL EBL reduces the level remaining to just 33%, which is perhaps just barely sufficient, or perhaps not. This patient is on the brink of coagulopathy. The second reason to replace coagulation factors besides whole blood loss is that tissue factor released with birth or surgical trauma will activate the coagulation cascade and can precipitate DIC. This will further deplete the level of factors available for necessary clotting. In the previous section I recommended adding FFP if blood loss prompted you to transfuse 5-6 units of RBCs. When you order the 5th-6th RBC units, request that FFP, 2-4 units, be thawed immediately. The second aspect of treatment to monitor and manage is acidosis. The primary reason from a transfusion perspective is that acidosis will worsen coagulopathy. Poorly perfused tissue will release tissue factor, further spurring DIC onward. In turn, coagulopathy exacerbates acidosis. These two, along with hypothermia, constitute a vicious cycle that will result in a fatal outcome unless prompt, aggressive interventions are made, and sometimes even if they are. Frequent, every 30 minutes is not too often, arterial blood gases (ABG), will allow the anesthesia team to track the pH and base deficit, and correct these with sodium bicarbonate (NaHC03) as indicated. The citrate in RBC units will lower the patient’s pH independent of unfolding coagulopathy, and thus an ABG should be performed early on, after 3-4 units of red cells have been given. The decision to give recombinant activated factor VIIa (rVIIa) should be made at the point where conventional transfusion therapy (RBC, FFP, platelets) is clearly inadequate to control the evolving DIC. This new pharmacologic agent, developed for hemophilia patients with inhibitors to factor VIII, has seen widespread use in many settings as an adjunct to control hemorrhage. Most of the literature comes from the trauma community, although use in obstetrics has been documented as well. Two articles referenced here describe the use of rVIIa in some detail. I support its use in intractable postpartum hemorrhage, but advocate caution with dosing in a population that is (or was) hypercoagulable due to the pregnant or postpartum state. My recommendation then is to give an initial dose of 4.8 mg at the point when the clinical scenario unquestionably indicates that blood products alone are insufficient

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Role of Laboratory Tests for Postpartum Hemorrhage and Evolving DIC Test CBC PT, PTT, fibrinogen

Use Assess H/H, platelets Assess coagulopathy

D-dimer

Specific for crosslinked fibrin which has been cleaved, a good marker for DIC Monitor pH and base deficit

ABG

Limitations NA Takes time to obtain results from lab Takes time to obtain results from lab NA

to control widespread bleeding, and to consider one or two additional 2.4 mg doses if bleeding does not abate within 30-60 minutes.

The Whole Patient

The three major tasks to address here are probably quite familiar to you once you have treated a case of severe postpartum hemorrhage: save the patient’s life, attend to the neonate even if the delivery itself was uneventful, and support the patient and other family members through a very different hospital experience than the one they were expecting. I hope that the guidance in this chapter and in section 5.1 provides useful direction for both the obstetrics and anesthesia teams. Certainly, massive transfusions are incredibly complex; I believe the methodical approach is the one to take to stay on top on multiple issues simultaneously. Once the immediate crisis is over, transfer to the ICU is clearly indicated for most, to provide ventilatory, pharmacologic and transfusion support until the patient has recovered. The pediatrics team will monitor the infant at a level appropriate to his clinical condition, NICU or observation nursery. The final task will fall to you after hours in the operating room and postoperative wards when you are likely exhausted: explaining, perhaps several times, to the family what has happened, what has been done, and what to expect in the coming hours and days. The best advice I can offer is to be clear, muster your empathy and employ your hospital’s chaplains to help.

Quick Question Some cases are obviously going to require massive transfusion from the get-go. Is it OK to tell the Blood Bank to starting thawing FFP and cryoprecipitate right away, rather than waiting until we’ve transfused 4 RBCs? Absolutely. A unique feature of obstetric medicine is how quickly situations develop. Your patients can decompensate in very short order. If, in your opinion, the patient will require multiple blood products, then by all means, get the Blood Bank going.

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Treatment Plan for Postpartum Hemorrhage and Evolving DIC

6

• For serious postpartum hemorrhage, give 2-4 U RBCs and crystalloids as initial treatment. • If obstetric bleeding persists, draw CBC, PT, PTT for updated labs and give 2 additional RBCs. Simultaneously order 2-4 FFP to be thawed (will take 45 minutes). • If 5 or 6 U RBCs have been given, give 1-2 FFP empirically, even if PT, PTT are not back from lab. • If bleeding abates, optimize volume status and replete red cells coagulation factors and platelets as laboratory parameters dictate to achieve Hct >24%, PT <16 sec, platelets >50,000/μL. • If bleeding persists or if microvascular bleeding develops, continue to transfuse RBCs, FFP and platelets at a ratio of 6:4:1. Platelets are given as either one apheresis or one 6-pack. Recheck CBC, PT, PPT, fibrinogen, D-dimer at this point. • Replace fibrinogen with cr yoprecipitate, one 10-pack at a time, if <100-150 mg/dL. • Consider rFVIIa 4.8 mg if above therapies are not correcting coagulopathy. Assess for effect in 30 minutes. • Monitor ABG Q 30-60 minutes as indicated by clinical status. Replace NaHC03 for pH <7.2. • Consider additional rFVIIa, 2.4 mg, if initial dose does not reduce microvascular bleeding.

Eight-Second Summary

Massive transfusion and incipient disseminated intravascular coagulation require transfusion of all the elements of whole blood: red cells, plasma as FFP and cryoprecipitate, and platelets. Activated FVIIa should be considered an adjunct in refractory cases.

Suggested Reading

1. Burtelow M, Riley E, Druzin M et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007; 47:1564-1572. 2. Ahonen J, Jokela R. Recombinant factor VIIa for life-threatening post-partum hemorrhage. Br J Anaesth 2005; 94:592-595. 3. Pepas LP, Arif-Adib M, Kadir RA. Factor VIIa in puerperal hemorrhage with disseminated intravascular coagulation. Obstet Gynecol 2006; 108(3 Pt 2):757-761.

6.3 Hemolysis, Elevated Liver Enzymes and Low Platelets Basic Concepts

Step one in the management of the syndrome of hemolysis, elevated liver enzymes and low platelets is to make the correct diagnosis. Step two is to initiate proper medical treatment, the mainstays of which are magnesium sulfate and corticosteroids. Step three is to transfuse platelets as necessary to achieve a count adequate for delivery, and other products to replenish losses from hemolysis or

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disseminated coagulation. Our focus in this section will be on steps one and three; medical management is the purview of the obstetrician. To make the diagnosis of HELLP syndrome, you must explore and rule out several mimickers, some of which have very different treatment regimens than what you will employ for HELLP. Your final step will be to accept that there is controversy in the diagnosis of this disorder but make the call anyway. Perhaps the most important disorder to rule out is acute fatty liver of pregnancy (AFLP). The nausea, abdominal pain and jaundice clinically resemble HELLP. Distinguishing features to help you diagnosis AFLP are lack of hypertension and, in the laboratory, normal urine protein, hypoglycemia and prolonged PT and PTT. Another key diagnosis to get off the board is TTP. Here, thrombocytopenia and hemolysis are more striking, and renal function may be impaired. Liver function should be normal. Although fever is a fairly reliable sign, neuralgic dysfunction is a late and ominous one, so you should not rely on it to make the diagnosis of TTP. Maternal ITP, discussed in this chapter in some detail, will be readily distinguished in many cases by more severe thrombocytopenia and lack of hypertension and transaminitis. Other disorders are outlined in the reference articles. Once you have ruled out to the best of your ability the above diagnoses, you may make the diagnosis of HELLP using the criteria in the Sibai article that I include here. Other authors have offered variations on the critieria, and some have outlined rather elaborate breakout categories when only some criteria are met. I support O’Brien’s position in his review article, which is that subcategorization is confusing to the clinician. His criteria are similar to Sibai’s, with the exception of the LDH, which he does not use. Sibai requires that all of the following are met: • • • •

Platelet count <100,000/μL AST >70 IU/L Abnormal peripheral smear LDH >600 IU/L or bilirubin >1.2 mg/dL

Your two priorities in terms of transfusion are (1) to raise the platelet count to >20,000/μL for any bleeding or for a vaginal delivery, >50,000/μL for a cesarean section, to >75,000/μL for placement of an epidural catheter (or to a set point established by your anesthesia team); and (2) to anticipate DIC, which complicates upwards of 15% of cases of HELLP and support coagulation factor and platelet losses as needed. The two ways you will raise the platelet count are by transfusion and by pharmacologic treatment with dexamethasone. Certainly, if the patient is bleeding at any count below 100,000/μL, you should transfuse. If she is not and delivery is not imminent, you may delay transfusion and plan to transfuse shortly before delivery to ensure survival of more of the platelets just before parturition. I further recommend giving an additional apheresis platelet during the actual delivery. The platelet count can also be optimized by the corticosteroid treatment that is a mainstay of therapy for HELLP. Several studies have reported improved counts with dexamethasone, both in the antepartum and postpartum periods. The mechanism for decreased consumption is complex. We think that the steroids reduce endothelial injury in the liver, thus improving local blood flow, thus preventing hepatocyte damage and platelet destruction. Given two methods for increasing the platelet count and the expectation of at least some ongoing platelet loss, can you estimate the platelet bump from an apheresis or 6-pack? No way; it’s a crap shoot. Follow the guidance here to

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Role of Laboratory Tests for HELLP Test CBC with peripheral smear

6

AST, LDH, indirect bilirubin

PT, PTT, fibrinogen D-dimer

Complete metabolic panel

Use Assess H/H, platelets Review smear for schistocytes Dx criteria: <100 K platelet count, schistocytes Assess for liver injury Dx criteria: AST >70 IU/L, LDH >600 IU/L or bilirubin >1.2 mg/dL Assess coagulopathy Specific for crosslinked fibrin which has been cleaved, a good marker for DIC Rule out AFLP, TTP, ITP

Limitations NA NA NA

Takes time to obtain results from lab Takes time to obtain results from lab NA

improve the woman’s platelet count toward the thresholds provided, recheck after transfusion, and go from there. One final complication bears mention; the specter of a subcapsular hematoma. This is clearly the worst sequela of HELLP. The clinical work-up and management of this potential catastrophe are covered cogently by O’Brien. My advice here is to contact the Blood Bank immediately upon confirmation of the hematoma and prepare for massive transfusion per the guidance in section 5.1.

The Whole Patient

Management of the patient with HELLP beyond delivery requires close monitoring in the first few days postpartum, and in the longer term, counseling and support regarding any future pregnancies. Sibai draws our attention to the risk of pulmonary edema in the first 48 hours after delivery, from transfusion of blood products and third-space mobilization, and also to renal impairment in the form of acute tubular necrosis. Thus, attentive nursing care and daily (or more frequent) laboratory studies to assess renal function, the platelet count, etc. are key elements to the treatment plan. In terms of risk of preeclampsia or HELLP complicating subsequent pregnancies, this is certainly a concern; the estimates are 20% and 2-19%, respectively. Additionally, the woman may suffer other untoward outcomes besides HELLP, including preterm delivery, fetal growth retardation, placental abruption, or even fetal loss. These can be discussed at a postpartum outpatient visit, when the mother and father have fully recovered from the ordeal.

Eight-Second Summary

HELLP is a potentially life-threatening complication of pregnancy which demands prompt medical intervention, transfusion of platelets to ensure adequate hemostasis during delivery and vigilant monitoring for signs of DIC and subcapsular hematoma formation.

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Treatment Plan for HELLP

• Draw appropriate labs for HELLP in patients with pre-eclampsia: AST, ALT, LDH, indirect bilirubin, PT, PTT, CBC with peripheral smear. Draw complete metabolic panel (CMP) to rule out mimickers of HELLP. • Rule in HELLP: platelet count <100,000/μL, AST >70 IU/L, abnormal peripheral smear, LDH >600 IU/L or indirect bilirubin >1.2 mg/dL. • Rule out key mimickers that require different treatment: acute fatty liver of pregnancy (low glucose, elevated PT, PTT, no proteinuria), TTP (elevated BUN, creatinine; severe thrombocytopenia), ITP (severe thrombocytopenia). • Initiate pharmacologic treatment of HELLP. • Transfuse platelets (one apheresis or 6-pack) for significant bleeding, for count <20,000/μL, for count <50,000/μL prior to cesarean section, for count <75,000/μL prior to epidural catheter placement.** • Transfuse platelets during delivery (one apheresis or 6-pack). • Recheck coagulation labs, CBC at intervals dictated by clinical status to anticipate DIC (Q4-12 hours). • Monitor platelets in postpartum period. Transfuse if count falls below 20,000/μL. • Notify Blood Bank immediately if subcapsular hematoma is diagnosed. If patient is stable, T+C 8 U RBCs. If rupture is suspected or diagnosed, plan for massive transfusion (Chapter 5, section 5.1). ** Platelet count acceptable to the anesthesia team for epidural placement may vary.

Suggested Reading

1. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 2004; 103(5):981-991. 2. O’Brien JM, Barton JR. Controversies with the diagnosis and management of HELLP syndrome. Clin Obstet Gynecol 2005; 48(2):460-477.

Quick Question Would you consider rVIIa as an adjunct for a ruptured subcapsular hematoma? Yes. Sibai did not mention rVIIa in his extensive list of blood products recommended for this catastrophe, and I do not have personal experience with such a case, but I would use it. These patients are at tremendous risk for exsanguination, and you should do anything you can to save them. I would use rVIIa without any hesitation.

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6.4 Maternal Immune Thrombocytopenic Purpura Basic Concepts

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Maternal immune thrombocytopenic purpura (ITP) causes significant thrombocytopenia in pregnant women, rarely in their fetuses, and may require both pharmacologic and transfusion therapy to ensure a safe delivery. The pathophysiology here is the same as in ITP in others: the patient makes IgG antibodies to platelet antigens (GP IIb/IIIa). Splenic macrophages bearing Fc receptors attach to the Fc portion of the IgG molecule, resulting in clearance of antibody-coated platelets by the reticuloendothelial system. Despite compensation by the bone marrow, seen as giant platelets on a peripheral blood smear, platelet counts often fall dramatically and may be near or below 20,000/μL when the woman presents in labor. The disease process accelerates in the third trimester; thus a prenatal screening CBC may show a normal or only slightly decreased count. As mild thrombocytopenia accompanies 5-10% of pregnancies, a platelet count of 100,000/μL would not, and should not cause great alarm. We can divide the diagnostic work-up of maternal ITP into two types: the non-urgent, when time allows for laboratory studies that will take several days to return; and the stat, when the woman presents in labor and/or at term. The routine approach attempts to confirm platelet-associated IgG and C3 with an immobilization assay, and some authors suggest a bone marrow biopsy to demonstrate megakaryocyte hyperplasia. I support the pursuit of assay, but my experience with this type of test in patients with ITP has been somewhat unrewarding, as the results are often negative (poor sensitivity). A marrow biopsy on a pregnant woman with thrombocytopenia is fraught with peril, and I cannot see the benefit of identifying a few extra megakaryocytes as outweighing the risk of biopsy in this patient, unless a more ominous disorder, such as aplastic anemia or acute leukemia is high on your differential. The work-up for the patient who is ready to deliver can be completed in a few hours at most and uses common laboratory tests, clinical assessment and consultation with your hematologist to confirm thrombocytopenia and rule out other key causes of the low platelet count. Your differential diagnosis should include incidental gestational thrombocytopenia; hemolysis, elevated liver enzymes and low platelets (HELLP syndrome); thrombotic thrombocytopenic purpura; and DIC. The degree of thrombocytopenia is helpful in distinguishing incidental gestational thrombocytopenia from from ITP, although there are reports of platelet counts in the former falling below 50,000/μL. Still, I would use this count as a cutoff ; a count below this would keep ITP on the list. HELLP syndrome can be moved down the list with a normal or near-normal lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), indirect bilirubin, and unremarkable red cell morphology on peripheral blood smear. Hemolysis affecting the H/H will be harder to gauge in the context of anemia at term. TTP, although rare, should also be ruled out. Here, the absence of fever and renal impairment, and a normal blood smear are reassuring. Neurologic abnormalities can be a late finding in TTP; thus a normal neurologic exam in itself should not carry too much weight. Laboratory tests will help explore DIC; the prolonged PT and PTT, low fibrinogen and elevated

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D-dimer are well-familiar to you. Obviously too, the patient in DIC is acutely ill and decompensating right before you. A rapid and useful laboratory work-up then consists of a CBC with peripheral smear, coagulation studies and a metabolic panel that will provide liver-associated enzymes and tests of renal function. Order these tests, assess the patient for petechiae and consult hematology to assist in diagnosis and management. Intravenous immunoglobulin (IVIg) and corticosteroids are the main pharmacologic adjuncts in treatment and are the purview of the hematologist. A dosing guide is provided in the treatment plan in the event you are on your own. You must also decide on a transfusion plan, the two key aspects being platelet count triggers and whether you can hold off on transfusion until at least some IVIg and/or corticosteroids are onboard. A good rule of thumb is to achieve a platelet count above 20,000/μL for a vaginal delivery, above 50,000/μL for a cesarean section and above 80,000/μL for placement of an epidural catheter. You probably already know that transfused platelets will also be culled out by the spleen prior to treatment of ITP. Patients with ITP often achieve very poor platelet increments after transfusion, but IVIg will help ensure the survival of transfused, as well as the patient’s own platelets. So, if the patient can wait until some portion of the IVIg has been given (this medication is administered over several hours), you can expect a better bump in the platelet count. The woman’s clinical condition will drive your treatment strategy. If she is very close to delivery, and her count is below the triggers, give platelets. If she is stable, give IVIg and then transfuse. It is prudent to transfuse platelets during the actual delivery, one apheresis unit for a vaginal and one or two for a cesarean section, even if you’ve achieved your parameters. Recheck a platelet count an hour after delivery and reassess the need for additional transfusions. Remember too, that your Blood Bank has a limited supply of platelets. Do not give platelets to a patient with a platelet count of 27,000/μL who hasn’t started IVIg yet because she might go to section a few hours from now; you’ll waste that unit and might not have another one later. Role of Laboratory Tests for Maternal ITP Test Platelet count Peripheral smear LDH, AST, ALT, indirect bilirubin BUN, creatinine PT, PTT, fibrinogen Platelet immobilization assay

Use Assess thrombocytopenia Evaluate for schistocytes to rule out HELLP, DIC Rule out HELLP with normal values Rule out TTP with normal values Rule out DIC with normal values Identify antibodies bound to platelets

Limitations NA NA NA NA NA Sensitvity not optimal

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Quick Question When the neonate has a low platelet count, is this the same as neonatal alloimmune thrombocytopenia (NAIT)?

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No. Thrombocytopenia in the neonate in maternal ITP is due to passive transfer of IgG that is directed against the GpIIb/IIIa antigens, an autoantibody. NAIT is an alloimmune process in which the fetus carries a platelet antigen that the mother lacks, and to which she has made alloantibodies. These IgG antibodies also cross the placenta by passive transfer. NAIT is distinguished from maternal ITP in two ways: the maternal platelet count in NAIT is normal, and thrombocytopenia in NAIT is often much more severe than it is in maternal ITP.

The Whole Patient

Beyond the usual issues to address in the pregnant patient, two others warrant discussion: other transfusion requirements for the mother and potential thrombocytopenia in the newborn. It is prudent to crossmatch RBCs for the mother prior to delivery, as you may encounter greater blood loss in this case than you would in a similar delivery if the platelet count were normal. As to thrombocytopenia in the fetus/newborn, this does occur, due to passive transfer of maternal IgG across the Treatment Plan for Maternal ITP

• CBC to assess baseline platelet count, with peripheral smear. • Chemistry and coagulation labs to rule out HELLP, TTP, DIC (LDH, AST, ALT, bilirubin, BUN, creatinine, PT, PTT). • Consult hemaotology once HELLP is off the board. • IVIg, 1 g/kg divided into two doses, 50% on day one over four hours, 50% on day two. • Prednisone, 1 mg/kg PO daily for 2 weeks. • Platelet transfusion, one apheresis unit at a time to achieve target counts: 20,000/μL for vaginal delivery, 50,000/μL for cesarean section, 80,000/μL for epidural catheter placement/removal. Give platelets after IVIg if possible. • Platelet transfusion, one unit during vaginal delivery, 1-2 units during cesarean section in addition to meeting target counts. • Cord blood platelet count on neonate at birth. Consider transfusion if <50,000/μL. • Recheck platelet count one hour after delivery and transfuse one unit if <20,000/μL. • Recheck platelet count daily for remainder of hospital stay, or more frequently is indicated. • Plan for follow-up with hematologist.

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placenta. Thankfully, significant platelet destruction is rare, and most neonates do not require transfusion. Now that this benign outcome is expected in the majority of cases, cordocentesis prior to delivery is no longer recommended, but a simple platelet count on cord blood at birth still is. A thorough evaluation on the delivery table for petechiae and cord blood platelet count will direct management for the pediatrics team. You’ll anticipate routine transfer to the observation nursery, but you will have managed the “second patient” appropriately. Finally, monitor the mother’s platelet count after delivery and through the hospital stay, and plan for follow-up with a hematologist.

Eight-Second Summary

Maternal ITP is an autoimmune-mediated process causing platelet destruction that is treated with IVIg and corticosteroids. Platelet transfusions ideally follow medical therapy with a goal of achieving set triggers prior to delivery.

Suggested Reading

1. Burrows RF. Platelet disorders in pregnancy. Curr Opin Ob Gyn 2001; 13:115-119. 2. Provan D, Singer CRJ, Baglin T, Lilleyman J, eds. Oxford Handbook of Clinical Haematology, 2nd ed. Oxford: Oxford University Press, 2004:388-389.

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CHAPTER 7

The Pediatric Patient—Special Situations Key Principles • Transfusion of red blood cells and platelets is a key adjunct to treatment of the child with cancer, providing marrow support during periods of myelophthisis and also marrow suppression from chemotherapy. • The stable patient in the PICU may be transfused at a hemoglobin trigger of 7 g/dL. • Unstable patients, those with severe hypoxemia, hemodynamic instability, active bleeding or cyanotic heart disease require a higher transfusion threshold. • The major task in the treatment of thalassemia and other hemoglobinopathies requiring chronic transfusion is the prevention and amelioration of iron overload and its sequelae. • The unique issues to consider in the pediatric surgical patient are undiagnosed hemoglobinopathies, potassium loads in massive or rapid transfusion settings, ABO compatibility in platelet transfusions, and directed donations from parents or other family members.

Chapter Overview

While transfusion practices designed for adults generally apply to pediatric patients, a handful of situations require a modified approach. Parameters for platelet transfusion in children treated for malignancies mirror those for adults, but red cell triggers may be lower in the pediatric patient who is otherwise healthy than in the older adult with co-morbidities such as coronary artery disease. The patient with a hemoglobinopathy requiring continual transfusion support is at risk for iron overload and its many complications. Certainly, chronically transfused adults share this risk, but it is in the pediatric population that this issue appears most acute. The young child needing rapid or massive transfusion of red cells is at risk for the complications of a severe potassium load, and thus requires either washed or fresh RBC units during resuscitation. This chapter discusses both the unique aspects of pediatric transfusion and the areas of overlap with the approach used in adults. Sickle cell anemia was covered in Chapter 2; there, I addressed the challenges of alloantibody and autoantibody formation. In this chapter, I outline iron overload as it applies to the sickler and thalassemic together. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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7.1 The Pediatric Oncology Patient Basic Concepts

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Your primary aim in transfusing the pediatric oncology patient is to provide marrow support to ensure adequate tissue oxygenation and prevent bleeding. As such, red blood cells and platelets will be the blood products you use; plasma and cryoprecipitate have no role in this setting unless the child becomes critically ill and coagulopathic. Likewise, I do not discuss granulocyte transfusions here, other than to mention that their use is somewhat controversial and their efficacy inconsistent. Your secondary aims are achieved with modifications to RBCs and platelets as cellular blood products and are threefold: to prevent transfusion-associated graft-versus-host disease with irradiation, to minimize HLA alloimmunization with leukoreduction, and to mitigate the risk of CMV transmission in the unexposed patient with either seronegative or leukoreduced units. For red blood cell support, a Hct trigger of 24% is reasonable during chemotherapy or radiation therapy. Here, I follow the guidance of Roseff (Transfusion article). She places strong and much-needed emphasis on the role of clinical signs and symptoms as the key drivers to red cell transfusion, not simply the morning’s Hct. A Hct of 24% is an appropriate starting point for children as they tolerate a lower Hct without effect than do adults in many cases. So, if you have a six-year old leukemic with a Hct of 22% who is not tachycardic and is playing happily in the ward’s day room, I would hold off on RBCs at that point. If you have a three-year old at 26%, a little tachycardic and tired-appearing, I would transfuse. Balance the triggers with the clinical scenario. For dosing, smaller children are usually transfused 10 mL of RBCs per kg body weight. Children from the age of 7 or 8 onwards are typically transfused a full unit of RBCs. A 10 mL/kg transfusion can be expected to raise the Hb by 2-3 g/dL (Hct by 6-9%) in the stable patient. Platelets form the core of transfusion support for the pediatric oncology patient, and the recent guidelines published by the American Society of Clinical Oncology (ASCO) (Journal of Clinical Oncology article) provide rational, evidence-based thresholds and management strategies to direct your treatment. The panel acknowledges that the studies used to form their recommendations were performed on adults and adolescents, but they believe it, “reasonable to use similar guidelines for children and older infants.” I agree. The topic of platelet transfusion is rather more complex than that of red cells. Let’s go through the major decisions of random vs. apheresis products, prophylactic transfusions, triggers for different patients and clinical situations, leukoreduction, refractoriness, and dosing. Remember that as cellular products, platelets should be irradiated and the CMV status considered for all transfusions. The ASCO guidelines judge the random donor (what the Blood Bank uses to make a 6-pack) and apheresis (single donor, one unit equals a 6-pack) platelets as equivalent in terms of infectious disease risk, posttransfusion increments, platelet survival and hemostatic effect. The main advantage of apheresis platelets is that each transfusion brings only a single HLA exposure, rather than several. This holds for leukoreduced units as they contain some white blood cells, as many as 5 x 106/apheresis unit. Recall that irradiation does not reduce or eliminate the risk of HLA alloimmunization. The cost of an apheresis unit, $400-500 is sometimes

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presented as a downside, as random units cost roughly half this amount, but given the costs of hospitalization and chemotherapy, I can hardly endorse this argument. Hospital blood banks vary in the type of platelet product they carry. Some offer both apheresis and random, many just one or the other. Thus, you may not be able to select the particular type of platelet you want for your patient, but as they are comparable, this should not be problematic. Prophylactic transfusions to prevent bleeding, as opposed to therapeutic transfusions to stop active hemorrhage, are the standard, well-accepted practice and supported by ASCO. Your goal here is obvious: to prevent bleeding into the central nervous system first and foremost, and to other sites, such as the respiratory, gastrointestinal, or genitourinary tracts and oral cavity to minimize the morbidity of chemotherapy-induced cytopenias. Incorporate the transfusion triggers presented below with the trend in the patient’s platelet count and his own bleeding history at specific counts as you decide to transfuse. Again, I concur with the panel’s consensus recommendations, although not with those of some of the studies they discuss. For patients receiving therapy for acute leukemia, the trigger is a platelet count of 10,000/μL if they are afebrile and clinically stable. If fever or minor bleeding is present, a count of 20,000/μL should be used. Recipients of bone marrow or stem cell transplants can be managed with these same guidelines. Some patients with solid tumors may be transfused at the above counts, the exceptions being patients with necrotic tumors that are prone to hemorrhage; these patients should be transfused at a platelet count of 20,000/μL regardless of their status. A level of 40-50,000/μL is sufficient for surgical or invasive procedures including central line placement, transbronchial or endoscopic biopsy, or open surgeries. For lumbar punctures (LP), the panel presents two studies advocating counts of 20,000 and 25,000/μL as adequate. I find this untenable and agree with the panels’ admonition that these counts may be acceptable for the most skilled physician, but not for all. I support a platelet count of at least 50,000/μL and am not opposed to 100,000/μL. What to do in cases where platelet refractoriness occurs, that is, when patients achieve a less than expected increment from a transfusion, is less clear. The ASCO panel recommends that at least two transfusions of ABO-compatible platelets, each less than 72 hours old, result in poor increments, defined as a corrected count increment (CCI) of <5000. This is problematic on several fronts. First, you may not have the option of always transfusing ABO-compatible platelets in your hospital if their inventory is small. If your patient is group O, and the only platelets available are group A, then your patient will receive group A, and the anti-A in his/her plasma may destroy some of the transfused platelets. Centers vary on how they manage this issue. I transfuse out-of-group platelets to infants over 4 months of age in order to manage an inventory of just 2-4 platelets at any time. Second, platelets that are less than 72 hours old have actually just been released to inventory and have two days of shelf life left. If your Blood Bank is issuing its fresher platelets and allowing others to expire, it is wasting a valuable resource, in my opinion. Finally, the CCI has been subject to criticism as a useful tool for assessing refractoriness. My recommendation is simpler and empiric. If your multiply-transfused patient on several occasions demonstrates an increase of only 10-20,000/μL when he is otherwise stable, I would consider that he is refractory. What are your options at

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this point? You may be able to secure HLA-matched platelets if your facility is large and has a pool of donors with known HLA types. Alternately, you may be able to have platelet crossmatching performed to assess compatibility in vitro prior to transfusion. Check with your hospital’s Blood Bank to see if they offer either of these services. If they do not, you may have to continue transfusing whatever platelets are available. In the critically ill patient at risk for serious hemorrhage, I think ABO-compatible is a good option in the short-term. Dosing of platelets for smaller children is 10 mL/kg. One can expect a rise in the platelet count of as much as 100,000/μL in the stable patient, but several caveats merit mention. As we just discussed, the refractory patient may not meet the expected target. Fever and minor or significant bleeding will consume platelets, making the post-count lower than expected. Finally, platelet counts in donors vary considerably, and this may impact the increment. Unless the bump is repeatedly poor in a non-bleeding, afebrile patient, I would not be overly concerned with an increase of 100,000/μL one day vs. one of 50,000/μL on the subsequent transfusion. The secondary aims of transfusion are easily achieved and, in terms of management, devoid of controversy. We reviewed TA-GVHD in Chapter 1. I will briefly remind you that this disorder is unique from marrow transplant-associated GVHD, that it manifests as donor lymphocytes attacking recipient (patient) lymphocytes which are unable to mount an effective counterattack, that it carries a 90% fatality rate, and that it is prevented by intercalating the DNA of the donor lymphocytes by irradiation. My recommendation for the duration of irradiating cellular blood products is from the moment you suspect leukemia, lymphoma or a high-grade solid tumor in a patient, continuing forever. Irradiation confers essentially no risk to the patient, especially if units are irradiated shortly before transfusion. We will discuss leukoreduction as a means to reduce HLA alloimmunization shortly, in the context of platelet transfusion. While cytomegalovirus can be acquired through casual contact, it can be devastating to the immunosuppressed patient, and thus the child who is not yet exposed should be protected from blood-borne transmission. As we learned in Chapter 1, this can be achieved in most cases by leukoreduction or by providing CMV-seronegative cellular blood products. Again, neither of these methods offers 100% protection, but they do minimize the risk. I recommend that you perform a CMV IgG titer on all new oncology patients. Do not test for CMV DNA in this instance, as this assesses active infection. An IgG level less than 0.90 units indicates naivety to the virus; greater than 0.90 is consistent with previous exposure. While you are waiting for the titer to come back, should you prophylactically order CMV-seronegative or leukoreduced products? Definitely. If the titer is found to indicate exposure, then you can stop ordering CMV-seronegative units. Because you will order leukoreduced blood regardless of CMV status, you are covered either way. The two advantages of leukoreduction (LR) are that it decreases both febrile non-hemolytic transfusion reactions (FNHTR) and alloimmunization against foreign HLA antigens. While FNHTRs are an inconvenience, alloimmunization leads to a refractory state to platelet transfusions, the latter increasing the risk of a hemorrhagic episode if safe platelet levels cannot be achieved. Leukoreduction mitigates but does not wholly eliminate this risk. This phenomenon was described in the well-designed Trial to Reduce Alloimminzation to Platelets (TRAP) and published in New England Journal of Medicine in 1997 (NEJM 337;1861-1869).

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Role of Laboratory Tests in the Pediatric Cancer Patient Test CBC HLA typing

Use Determine H/H, platelet count Provide information for HLA-matched platelets

CMV IgG titer

If <0.90, patient considered naïve. If >0.90, patient considered exposed.

Limitations NA Takes time, but will be performed anyway if BMT is being considered. NA

The trial randomized newly diagnosed AML patients to receive pooled random donor platelets (not LR), pooled LR platelets, apheresis LR platelets, or pooled random donor platelets that were UVB irradiated. Note that UVB irradiation is not the same as the cesium/cobalt irradiation used to prevent TA-GVHD, and that UVB is not available in the US at this time. The three groups receiving modified platelets showed a statistically significant reduction in anti-HLA antibody formation. They made antibody 17-21% of the time, while the group receiving non-LR platelets made antibody 45% of the time. The ASCO panel gives its strongest recommendation to provide leukoreduced platelets to patients with AML, as well as to other leukemics and other oncology patients on chemotherapy. There is no controversy here.

The Whole Patient

The issues facing the child with cancer can be broadly grouped into three categories: the medical complications of the disease and treatment process, the psychosocial burden of a long illness and frequent hospitalizations, and, unfortunately for some, those surrounding the end-of-life. The sequelae of cancer arise from the disease itself in some cases, with CNS damage associated with some brain Treatment Plan in the Pediatric Cancer Patient

• Draw CMV IgG titer to determine patient’s exposure status. • Order CMV-seronegative (if patient is not yet exposed or status is unknown), leukoreduced and irradiated for all RBC and platelet transfusions. • Consider transfusing RBCs for Hct <24% during chemotherapy or radiation therapy. • Transfuse platelets to maintain levels >10,000/μL in the stable, afebrile patient on chemotherapy or undergoing BMT/SCT. • Transfuse platelets to maintain levels >20,000/μL in the febrile, neutropenic or mildly bleeding patient. • Transfuse platelets to maintain levels >40-50,000/μL for major invasive procedure or open surgical procedure (see text for list). • Transfuse platelets to patients with solid tumors on chemotherapy to >10,000/μL, or >20,000/μL if tumor is necrotic and likely to bleed.

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tumors, etc. More often, though, the impact of marrow suppression and the side effects of chemotherapy constitute the greater challenges. You will alleviate some of these with transfusion support, but certainly will be devoting much of your attention to treating nausea, mucositis and the like. Hospitals now provide excellent social services to assist children and their families with the emotional challenges of cancer and its treatment. Your role will be to direct the patient and family to them, but also to understand that no oncology ward playroom, no matter how cool, beats a Saturday morning soccer game with friends, outdoors, without fear of minor cuts or bruises or tiring out because your Hct is only 24%. Lastly, the many successes that pediatric cancer patients enjoy with today’s regimens are still punctuated by painful failures. Transfusion plays a valuable part in this scenario however, as it enables the child to have at least some level of energy, via red cells, and it prevents fatal bleeds, with platelets, for a time. Delaying impending death is not much of a moral victory, but you will do everything you can to make the transition as painless as possible.

Eight-Second Summary

Use evidence-based guidelines, integrated with the patient’s clinical status to plan a transfusion strategy that will optimize tissue perfusion and minimize the risk of serious hemorrhage.

Suggested Reading

1. Roseff SD, Luban NL, Manno CS. Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 2002; 42:1398-1413. 2. Schiffer CA, Anderson KC, Bennett CL et al.Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19(5):1519-1538.

7.2 The Critically Ill Child Basic Concepts

A restrictive strategy for red cell transfusions is appropriate for the stable child in the pediatric intensive care unit, and adult guidelines are generally applicable for other blood products, including FFP, platelets and cryoprecipitate. In this section we will discuss in some detail the findings of the recently published clinical trial of erythrocyte transfusion parameters (New England Journal of Medicine article) and the patients for whom you may employ the restrictive approach. We will review rational use of other major blood products following the guidelines of the American Society of Anesthesiologists Task Force on Blood Component Therapy (Anesthesiology article). Finally, we will cover the use of activated factor VII in the PICU setting, based chiefly on my own experiences with this agent. The literature analyzing transfusion therapy in pediatric critical care is sparse, and surveys have revealed, not surprisingly, a wide range of practices and thresholds among pediatric intensivists and other specialists. I believe the reasons for this broad span of acceptable hemoglobin values is twofold: first, physicians cannot quantitatively characterize tissue perfusion to major organs with accuracy and must infer whether or not adequate oxygenation is taking place; and second, the physician’s own comfort level is a part of many decisions to transfuse. This

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is to be expected. As we gain experience in medicine, we incorporate it into our gut and feel increasingly confident with decisions that might have intimidated us a few years prior. What I provide here is a rational, and in the case of RBC transfusions evidence-based, set of guidelines to use as a foundation for your own transfusion strategy. Lacroix et al determined in a large, well-designed, prospective controlled trial that stable critically ill children may be transfused at a Hb threshold of 7 g/dL without increasing the incidence of multiple organ dysfunction, thereby decreasing their transfusion requirements. This two-armed noninferiority trial enrolled 637 stable but critically ill children, ages 3 days to 14 years, with a Hb <9.5 g/dL within 7 days of admission to a tertiary-care PICU. The restrictive-strategy group was transfused RBCs at a Hb trigger of 7 g/dL, with a post-transfusion target of 8.5-9.5 g/dL. The liberal-strategy group had the threshold set at 9.5 g/dL, with a target of 11-12 g/dL. The stable patient was defined as having a mean systemic arterial pressure not less than 2 SD below the normal mean for age and not requiring increased cardiovascular treatments for at least 2 hours before enrollment. Each group of patients remained in the protocol for up to 28 days of stay in the PICU, or until the death of the patient, if this occurred within 28 days. Physicians had the option of temporarily suspending the protocol for the following conditions: active and clinically significant bleeding, surgical procedure, severe hypoxemia, or hemodynamic instability. These conditions did not disenroll the patients, however; once they were stabilized, the restrictive protocol was resumed. The primary outcome was new or progressive multiple organ dysfunction syndrome (MODS). Secondary outcomes included deaths, nosocomial infections, mechanical ventilation, duration of ICU stay and reactions to RBC transfusions. The results were that there were no statistically significant differences between the restrictive and liberal groups in either the primary or any of the secondary outcomes, and that there was a 96% reduction in the number of patients transfused and a 44% decrease in the number of RBC transfusions given in the restrictive group. The authors concluded with an endorsement of the restrictive strategy with a few key exclusions: premature infants; and children with severe hypoxemia, hemodynamic instability, active bleeding or cyanotic heart disease. Three points merit discussion here: the strength of this study, the issue of pre-storage leukoreduction of red cell units, and the breakpoint between the stable and unstable patient. While most of the articles referenced in this book are reviews or consensus statements, a few are trials. I have selected them carefully. The Lacroix study complements the Hebert trial (conducted in critically ill adults) to provide the same superior quality of research and results for the pediatric ICU population. The Hebert paper is a classic, and I expect that the Lacroix article will be similarly regarded. Second, Lacroix briefly alluded to the possible adverse effect of cytokines in red cell units that have not been pre-storage leukoreduced. In his trial, all units were leukoreduced, and he hypothesizes that this may partially account for the equivalence in in-hospital deaths in his pediatric study, compared to Hebert’s adult study, where the units were not leukoreduced and there were more in-hospital deaths in the liberal strategy group. While you may not have a choice of ordering pre-storage LR red cells for your patients, I

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recommend that you find out if your Blood Bank carries them, and if they do, request this for your PICU patients. If your hospital purchases its blood from the American Red Cross (ARC), the units will all be pre-storage LR, as this is the ARC standard practice. Bedside filters remove most of the WBCs, but do not eliminate cytokines already released by WBCs while the units have been sitting in storage. Thus, pre-storage leukoreduction is superior to bedside filtration. Finally, where is the point at which hypoxemia is too severe, the hemodynamics too labile, or bleeding too great for you to maintain the patient at a Hb of 7 or 8 g/dL? I suspect you will have a far easier time recognizing stability and deciding to adhere to the restrictive strategy. There is no mathematical model or algorithm I can offer to help you quickly and precisely mark the point at which to suspend the restrictive protocol and increase the Hb target to 11 or 12 g/dL. You will integrate the numerical indicators of cardio-respiratory status (ventilator settings or nasal oxygen requirements, blood pressure and doses of pressors, heart rate, etc.); the patient’s current clinical status and his/her history during the hospitalization, how labile he/she has been; and your own comfort level with sick children. You will make your decision based on these factors. If the patient is stable, use the restrictive guidelines. If your integration causes you to say, “Enough,” then give more red cells. For fresh frozen plasma, platelets and cryoprecipitate, you may follow the ASA guidelines. Transfuse FFP to treat microvascular bleeding, or to provide factors when a specific concentrate is not available, if the PT or PTT are >1.5 times the normal value. While the PT is very nearly at adult values from birth onward in normal neonates, the reference range for the PTT is roughly 30-55 seconds in the one-day-old full-term neonate and does not approximate adult values until six months of age. Ensure that you have an age-adjusted reference range as you interpret these test results. ASA does not offer guidance on when to discontinue FFP if coagulation parameters are still prolonged but bleeding is, for the moment, controlled. In this situation, I support continuing FFP for 24-48 hours if the PT or PTT remains elevated to minimize the risk of re-bleeding. At that point, reassess and consider holding FFP while you continue to monitor both clinical and laboratory parameters. Transfuse platelets to treat microvascular bleeding if the platelet count is less than 50,000/μL per ASA. I fully support transfusing to a count above 100,000/μL for active, recent or potential intracranial hemorrhage. I think it is reasonable to apply the same 24-48 hour plan to the patient who has recently bled. If the patient was bleeding yesterday at a platelet count of 24,000/μL , stopped bleeding with a platelet transfusion, and today has a count of 35,000/μL but is currently not hemorrhaging, consider giving another platelet today. Certainly, the severity of the hemorrhage will factor into your decision. The decision to transfuse cryoprecipitate is the most straightforward. Transfuse 10 mL/kg body weight for a fibrinogen less than 100 mg/dL. In the setting of DIC, strongly consider transfusion at 150 mg/dL. For small children and infants, you may opt for one unit of cryoprecipitate per 10 kg body weight for convenience sake; this will give you a slightly higher dose than 10 mL/kg. Activated factor VII is a potent adjunct to conventional blood products that you may consider when microvascular bleeding is severe and life-threatening, and FFP

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Role of Laboratory Tests in the Critically Ill Child Test CBC PT, PTT, fibrinogen

Use Assess anemia, thrombocytopenia Assess coagulopathy

Limitations NA NA

and cryoprecipitate are either inadequate to control hemorrhage or not available quickly enough in the rapidly decompensating patient. Dosing practice for rVIIa varies widely among physicians, not a surprising finding as this is a fairly new drug. I recommend a dose of 35 μg/kg body weight to be administered once. Repeat this dose only if severe bleeding recurs several hours later (the half-life of rVIIa is 2 hours). 35 μg/kg is lower than the typical dose of 90 μg/kg used for adults; I present this dose as what I am familiar with in the PICU patient. If you are a house officer reading this, you MUST have approval of your attending physician to order this medication. If you are an attending and have never used rVIIa, consider it in the patient in extremis to stop life-threatening hemorrhage.

The Whole Patient

Broadly, the two issues to review here are the adjunctive role of blood products and the concerns that family members may have regarding transfusion. The critically ill child’s underlying disease will command the majority of your clinical skills and efforts. Transfusion support is just that, an ancillary tool to ensure tissue Treatment Plan in the Critically Ill Child

• CBC, PT, PTT on all patients. Fibrinogen if DIC suspected. • Transfuse RBCs, 10 mL/kg to stable patients for a Hb <7 g/dL, with a target of 8.5-9.5 g/dL. • Transfuse RBCs, 10 mL/kg to patients with severe hypoxemia, hemodynamic instability, active and significant bleeding for a Hb <9.5 g/dL, with a target of 11-12g/dL. • Transfuse RBCs, 10 mL/kg to patients with cyanotic heart disease for a Hb <10-11 g/dL. • Transfuse FFP, 10 mL/kg for microvascular bleeding and concurrent elevation of PT or PTT to >1.5 times normal. • Consider continuing FFP for 24-48 hours after bleeding is controlled for persistently prolonged PT or PTT. • Transfuse platelets, 10 mL/kg for microvascular bleeding and a platelet count of <50,000/μL (100,000/μL for CNS bleeds). • Consider continuing platelets for 24-48 hours after bleeding is controlled for a platelet count persistently <50,000/μL (100,000/μL for CNS bleeds). • Transfuse cryoprecipitate, 10mL/kg for fibrinogen <100 mg/dL. In DIC, consider trigger of 150 mg/dL. • Consider rVII at a dose of 35 μG/kg body weight for severe microvascular bleeding unresponsive to FFP, platelets, and cryoprecipitate.

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perfusion and to prevent or stop bleeding while you attend to the primary disease. As such, you will spend an appropriate amount of time and thought putting together a transfusion plan, write your orders, and move on. As a physician who has ordered blood many times before, you probably do not concern yourself so much with the risk of AIDS transmission or the fact that your patient is about to receive blood from a total stranger. Parents, on the other hand, sometimes show great anxiety once they are asked to sign the transfusion consent, or when they see the actual unit of blood being raised to the IV pole. Take a few moments to understand and allay their fears. With current infectious disease testing platforms, the risk of contracting AIDS from a transfusion is exceedingly small, on the order of 1 in 2 million. I address the issue of directed donations in section 4.4 in this chapter and also in Chapter 9. A brief, compassionate discussion with parents or other family members is usually enough to reassure them of the safety of the blood you are giving to their child.

Eight-Second Summary

Apart from the case of the stable but anemic pediatric patient, for whom there is solid, evidence-based guidance, you must rely upon guidelines designed for adults to help you generate a transfusion plan. In conjunction with the clinical context of the patient, these guidelines work just fine.

Suggested Reading

1. Lacroix J, Hébert PC, Hutchison JS et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609-1619. 2. Desmet L, Lacroix J. Transfusion in pediatrics. Crit Care Clin 2004; 20:299-311. 3. Practice Guidelines for Blood Component Therapy: A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84:732-747.

7.3 Thalassemia and Chronic Transfusions Basic Concepts

While the transfusion strategy for anemic patients with thalassemia, sickle cell anemia or selected other hemoglobinopathies is straightforward, the prevention and management of the complications of chronic transfusion are complex, challenging and, in many cases, costly. In this section, I will briefly outline the pathophysiology of the thalassemias as a group. I will then discuss the major sequelae of iron overload, its diagnostic work-up and therapeutic interventions. My aim here is to provide the house officer or perhaps medical student with a general context for treatment of the patient with thalassemia. The intricacies of iron chelation therapy and the approach to monitoring for complications are the purview of the pediatric hematologist, and I give only the broadest guidance on these matters. If you are a resident reading this as you prepare to meet your first thalassemic patient, I believe this section and the two reference articles will provide you with a solid foundation. My area of expertise, transfusing the patient, is the easy part in this population. What to do with all that excess iron is another story. It is a story that applies equally well to the sickle cell anemia patient, whose other issues (antibodies) I covered in Chapter 2. Here is the brief version.

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The thalassemias are characterized by decreased globin chain synthesis due to gene mutations, the typical case in β-thalassemia; or gene deletions, the case in α-thalassemia. You will recall that hemoglobin A is a tetramer of two α-chains and two β-chains, and that this is the predominant hemoglobin in normal adults. The consequences of inadequate chain production are either increased synthesis of an alternate chain, such as the γ-chain to make HbF (α2γ2), excess production of one chain type, or the formation of single chain tetramers, such as β4 which are unable to carry oxygen. In homozygous β-thalassemia, often called thalassemia major, the ability to make HbF in far greater amounts than normal adults ever make allows for survival, with some transfusion support. Excess α-chains are synthesized in these patients as well and cause early apoptosis of erythroid precurors in the marrow, so that erythropoiesis is ineffective. In contrast, the accumulated β-chains in α-thalassemia with two or three gene deletions do not cause apoptosis, but rather degrade the red cell membrane with resultant hemolysis. This pathophysiology of decreased globin sysnthesis is different from the mechanism in sickle cell anemia and many of the other hemoglobinopathies, such as HbE, HbO or HbD, which are due to point mutations. Those hemoglobins are all α2β2 but with an abnormal, usually β, chain. The thalassemias which usually require transfusion support are β-thalassemia major and intermedia, the latter being either a homozygous state with a little HbA production or a heterozygous state with marked anemia; α-thalassemia with three gene deletions (HbH disease), and some double heterozygous forms of β-thalassemia, such as with HbE. The diagnostic work up of iron overload is typically based on serum ferritin levels, although correlation of this marker with true iron burden is suboptimal. Some recommend a liver biopsy with iron quantification by atomic absorption spectrometry. While this is likely to be more accurate, it may not be feasible and may not be covered by the patients’ medical insurance. New patients may be further evaluated by less invasive tests by adding a serum iron, total iron binding capacity and iron saturation to the ferritin. If you are going to monitor the patient with serial ferritin levels, which I think is reasonable, these other tests may not add much to your knowledge base. Evaluation of cardiac function should include an echocardiogram with measurement of ejection fraction and T2-weighted magnetic resonance imaging. Endocrine function should be assessed by routine serum or plasma levels of the relevant hormones. The deleterious effects of iron overload on the heart, liver and endocrine systems cause the bulk of the morbidity and mortality in the chronically transfused patient. Cardiovascular complications head the list and account for the leading cause of death in thalassemia patients in some studies. Arrhythmias and congestive heart failure are the key forms of heart disease, and these are due to chronic anemia and pulmonary hypertension as well as iron overload. The clinician should monitor the patient with serial left ventricular ejection fraction studies, and Schrier (Annual Review of Medicine article) designates either a decrease by 10% or an absolute value of <45% as points at which to begin aggressive chelation to improve left ventricular function. Iron overload in the liver leads to hepatic fibrosis ultimately, but simple iron deposition may be reversed. Endocrine dysfunction involves the pancreas, thyroid, parathyroid glands and the gonads. In his recent publication, Delea (Transfusion article) projects the complications in patients who have a typical but

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Test CBC Ferritin

Use Assess degree of anemia Assess iron load

Liver biopsy, AAS for iron Endocrine panel

More accurate reflection of hepatic iron load Assess damage to thyroid, parathyroid, pancreas, gonads

Limitations NA An imperfect correlate to true iron load. It is inexpensive, quick and commonly used to track iron overload, but is not an ideal marker. Patient discomfort, time NA

unfortunately suboptimal pattern of deferoxamine use, 169 infusions per year. He anticipates diabetes in 54%, hypothyroidism in 28%, and hypogonadism in 81%. He also predicts that if the drug were used as indicated (260 infusions per year, or 5 times weekly), that these rates would fall to 9, 14 and 47 percent, respectively. More telling is his prediction for cardiac sequelae, where 96% of thalassemics could expect this at the usual interval of treatment, but only 60% if infusions were done 5 times per week. The financial burden of non-compliance with iron chelation therapy is difficult to estimate, but Delea uses the figure of $20,000 per year per patient. One hopes that the new oral medication available in the US now will improve compliance, decrease complications and enhance the quality of life of the thalassemic population. Schrier offers a reasonable hemoglobin target of 9-12 g/dL, with transfusions given once the hemoglobin falls below 7.0 g/dL. I support this threshold. Transfusion therapy provides fewer challenges to the clinician treating thalassemia, compared with sickle cell disease. This is because of the red cell antigen profile of the demographic groups often affected with thalassemia. They are less likely to form antibodies to significant red cell antigens, and obtaining units for them is usually straightforward. Thus, the issue of iron overload comes squarely to the forefront as the major obstacle. Red cell exchange in lieu of chronic simple transfusion offers the key advantage of an even iron swap. If the patient has an elevated ferritin level, chelation may be continued for a time while transfusions are given as part of an exchange procedure, and one should expect the ferritin to decrease. Bone marrow and stem cell transplant has been employed to effect a cure in thalassemic patients for over two decades now. Schrier reports a 20-year thalassemia-free survival in 68% of a large group of 1003 patients who underwent marrow or stem cell transplant from 1981 to 2003. He further discusses the prospect of gene therapy, with the goal being to insert either α- or β-globin genes into hematopoietic stem cells. This is an exciting theory, but as of the writing of his article, it was conducted successfully only in a murine model. Other alternative therapies under review are those which would overcome the normal downregulation of

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Treatment Plan for Thalassemia

• Transfuse patients with a Hb <7.0 g/dL to a target Hb of 9-12 g/dL. • Initiate or continue iron chelation therapy with deferoxamine as a subcutaneous infusion 250 nights/year (5 nights/week) or deferasirox (Exjade, Novartis) in patients over 2 years of age at a dose of 20-30 mg/kg/day. • Evaluate iron stores with serum ferritin at intervals selected by the cognizant hematologist. • Consider echocardiogram and T2-weighted magnetic resonance imaging to assess cardiac function in cases of iron overload. • Consider liver biopsy with iron staining and atomic absorption spectrometry to assess liver iron burden. • Perform routine endocrine laboratory studies, including TSH, fasting glucose, PTH as directed by the cognizant hematologist to assess for endocrine dysfunction.

γ-globin gene synthesis, thereby allowing increased production of HbF; these include hypomethylating agents and histone deacetylase inhibitors.

The Whole Patient

Your priorities in management of the thalassemic or any chronically transfused patient include both medical and psychosocial issues. We have outlined the major physiologic sequelae of chronic transfusion, and you will emphasize the cardiovascular, hepatobiliary and endocrine systems in your treatment program, trying to limit damage to these organs and optimize function. I see the emotional challenges facing the thalassemic patient and his/her family as somewhat different from those affecting the sickler, because pain crises and pain management are less of a problem in the former. Perhaps more prevalent is the problem of short stature as an endocrine manifestation of the disease. This may cause more distress in boys than in girls. The other sequelae of iron overload, such as decreased exercise tolerance from cardiac compromise (and also from anemia), are likely similar between thalassemics and sicklers. Not being able to “keep up” with school mates may be a significant source of frustration for some children. Thus, a large part of your job is to mobilize support for the patient and family to help them cope.

Eight-Second Summary

Iron overload and its serious clinical consequences to the heart, liver and endocrine system can be prevented and partially ameliorated with iron chelation therapy, now available in oral form in the United States.

Suggested Reading

1. Schrier SL, Angelucci E. New strategies in the treatment of the thalassemias. Annu Rev Med 2005; 56:157-171. 2. Delea TE, Edelsberg J, Sofrygin O et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion 2007; 47:1919-1929.

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7.4 The Pediatric Surgical Patient Basic Concepts

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The approach to the pediatric surgical patient mirrors that for the adult with a few key exceptions: preoperative testing may include screening for a hemoglobinopathy, a pre-emptive strategy to avoid potassium and anticoagulant loads is advised, a formula for the maximum allowable blood loss facilitates transfusion decisions, and directed donations by parents may be considered. In this section, we will discuss the rational use of the common blood products—red cells, plasma, platelets and cryoprecipitate—and cover the exceptions listed above. Unfortunately, there are few studies available that specifically address blood support of the pediatric patient in the surgical suite, save for those on cardiac procedures and those geared toward the sickle cell anemia sufferer. The excellent review article by Hume and Limoges (American Journal Therapeutics article) raises this point, and the authors propose the use of guidelines set forth by the Canadian Medical Association (CMA) (1997) and the American Society of Anesthesiologists (ASA) Task Force on Blood Component Therapy (1996). While the CMA guidance is directed to both adults and children, the ASA parameters are set for adults. Hume and Limoge argue what I believe is a critical point: recommendations which are evidence-based and rational can be applied in the pediatric setting (excluding infants under four months of age) when used in concert with sound clinical judgment. The emphasis on integrating the specific clinical scenario into the decision is well-said and is solid advice. Let us outline the use of the four main blood products in the perioperative period and then briefly discuss alternatives to allogeneic transfusion. The issues to address in red blood cell support include: preoperative laboratory testing, the use of washed or fresh RBCs, irradiation and CMV-seronegative products, the maximum allowable blood loss, RBC dosing, and when to add FFP to the transfusion plan. I recommend a CBC on every patient for any case beyond the most minor procedure, while Hume follows clinical indicators if the patient is over 12 months of age to guide this decision. As Hume correctly points out, iron deficiency anemia is relatively common, as is the mild effect of some hemoglobinopathies, such as β-thalassemia trait. Detecting this preoperatively is in your interest. She further advises screening for sickle cell anemia if indicated. Next, the greatest transfusion risk in the pediatric population is their inability to handle a high potassium load in a rapid transfusion. The solution is either to provide fresh RBC units, less than 2-3 weeks old per Hume, or washed units to young children. My own practice is to wash one RBC unit just prior to surgery any time the physician requests >15 mL/kg to be available in the operating room. Washing just before the case gives you 24 hours to use the RBCs, ample time for long cases with time left over to cover the early postoperative period and a possible return to the OR. Fresh units are just as appropriate. I use five years of age and under as the group to receive washed or fresh units. Irradiation should be performed on cellular products for all infants under four months of age, and for older children if they have (or may have) a cellular immune deficiency, are receiving chemotherapy or a stem cell transplant, or are receiving cellular blood products from a blood relative. Finally, it is reasonable to provide CMV-seronegative RBCs to a child as your inventory allows, although if the patient is not immunosuppressed, the risk of overwhelming CMV infection is extremely small.

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Begin RBC transfusion support at any of the following points: when the Hb falls below 6.0 g/dL, when the maximum allowable blood loss (MABL) has been exceeded or is about to be, or when the Hb is between 6.0 and 10.0 g/dL and ongoing bleeding or the patient’s oxygenation status indicate that he is unstable. The formula, provided by Hume for the MABL is: MABL = EBV (HO – HL) HO EBV is the estimated blood volume for the patient. Use 85 mL/kg for infants, and 70 mL/kg for children over one year. HO is the preoperative Hct, and HL is the lowest acceptable Hct. Hct should be expressed as a decimal. For example, if you have an 8 kg infant with a 680 mL EBV and a preoperative Hct of 0.40, and you determine that 0.24 is the lowest Hct you will tolerate, then the MABL is 272 mL. You will estimate the EBL for each case based on your experience and research. If the expected EBL approaches the MABL, plan for transfusion by ordering washed or fresh RBCs from the Blood Bank with advance notice so they will have the blood ready as you begin the case. Dosing for RBCs is simple; give 10 mL/kg, and expect, in the stable patient, a rise in Hb of 2.5 g/dL if CPDA is the anticoagulant and 1.8 g/dL if it is AS. If ongoing bleeding is present, of course these increments will not hold. Your strategy here is to give 10 mL/kg, then recheck the H/H and determine if these values, coupled with the clinical status of the patient, are satisfactory. If not, transfuse another 10 mL/kg. Transfuse fresh frozen plasma to treat microvascular bleeding when coagulation parameters (PT, PTT) are elevated, or when they are not quickly available as in the case of a massive transfusion or serious hemorrhage. This is the recommendation of CMA and ASA, and I concur with it fully. I further advise, however, that you transfuse or at least strongly consider prophylactic use of FFP in surgical cases of high-volume (>50% blood volume) estimated blood loss (EBL) after 20 mL/kg of RBCs have been transfused. Such cases would include the lengthy craniosynostosis and posterior spinal fusion, for example. In my hospital, we give 10 mL/kg of FFP after 20 mL/kg of RBCs for the craniosynostosis procedures and avoid dilutional coagulopathy. Plasma should be ABO-compatible with the patient’s blood type, and your Blood Bank will ensure that it is. Dosing is typically 10 mL/kg, and this can be expected to raise the coagulation factors by 20%. There are two caveats to the 20% prediction, however. The first is that ongoing consumption and dilution by blood loss in the surgical patient will lower that 20% immediate bump over time. The second is that factor levels in individuals vary widely, and you have no idea what levels of factors have been transfused in the 10 mL/kg, so factor VII may rise by 45%, but thrombin by only 10%. As I stated in Chapter 3, correcting coagulopathy with FFP is not an exact science. Follow the guidelines here, transfuse at 10 mL/kg doses and assess carefully for clinical bleeding as a key to your decisions. Platelets should be transfused in the thrombocytopenic patient preoperatively to achieve a platelet count of at least 40-50,000/μL (ASCO guidelines, see section 7.1) and for microvascular bleeding for counts below 50,000/μL (ASA guidelines). In the unstable patient or in the neurosurgical case, a count of 100,000/μL is a reasonable trigger. Hume recommends dosing by either one random donor unit per 10 kg body weight or 5 mL/kg for apheresis units to achieve a rise in the platelet count of

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50,000/μL. I support the dose for random platelets, although I usually give 10 mL/kg with the apheresis platelets we carry in my facility. If you are transfusing platelets in a surgical case, it is either because the preoperative count was borderline or low, or because you are encountering significant hemorrhage. As such, I would transfuse at 10 mL/kg for apheresis units. Ideally, you will transfuse ABO-identical platelets to your patient. Recall that platelets carry ABO antigens on their surface and are suspended in plasma with some level of anti-A or anti-B depending on the blood type of the donor. Thus, group A platelets transfused to a group O child may result in a suboptimal increment because the child’s anti-A will destroy some of those platelets. In practice this is rarely an issue, and post-transfusion platelet counts are satisfactory. If group O platelets are given to a group A child, the anti-A in the plasma may effect some degree of hemolysis of the child’s red cells. I follow this restriction only in neonates. In all other patients, I provide plasma-compatible (to protect the patient’s red cells) whenever possible as the inventory allows. In larger hospitals with larger platelet inventories, you may be able to transfuse plasma-compatible or even ABO-identical platelets. In smaller facilities, you may have to transfuse what you have. My own opinion is that out-of-group platelets are well-tolerated and effective. Finally, if you must give Rh-positive platelets to an Rh-negative patient, administer RhIG within 72 hours to protect against anti-D formation. Some recommend this only for female patients, but I support this for both males and females. It is simple and inexpensive. The dose is one vial of 300 μG, given intramuscularly. Cryoprecipitate is rarely used in routine surgical cases, although it may be required in lengthy case with high-volume blood loss. I recommend following the fibrinogen and transfusing cryoprecipitate when it falls below 100-150 mg/dL. For the long surgical cases, you will certainly have time to await laboratory results. In cases where the patient has developed DIC with obvious diffuse microvascular bleeding, it is reasonable to transfuse without waiting for the fibrinogen result. Hopefully, these will be rare events. Dosing can be either 10 mL/kg or one unit of cryoprecipitate per 5-10 kg body weight. Each single bag of cryoprecipitate contains approximately 15 mL, so the latter dose, as recommended by Hume is somewhat higher than the standard dose of 10 mL/kg for all blood products. Frankly, either dose is appropriate. Recheck the fibrinogen after transfusing to ensure it is above the target of 100-150 mg/dL. Role of Laboratory Tests in the Pediatric Surgical Patient Test CBC

Sickledex test or Hb electrophoresis PT, PTT

Fibrinogen

Use Assess H/H, platelet count, MCV (consider iron deficiency or thalassemia) Screen for hemoglobinopathy in selected patients Assess coagulopathy during case Assess coagulopathy

Limitations NA

Takes time for electrophoresis May not be immediately available during rapid hemorrhage Same as above

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Quick Question I am cautious about giving sodium bicarbonate to infants with mild acidemia (pH 7.3) because I want to avoid hypotension. What do you recommend? Pediatric patients can usually tolerate mild acidemia, down to a pH of 7.2. Below this level, you may either administer bicarbonate, and then hyperventilate to expel the excess C02, or alternatively, give thiomethamine (THAM) which will absorb the excess hydrogen ions.

Alternatives to allogeneic blood transfusion include autologous donation and directed donations. Cell salvage techniques may be another option, although the blood lost must be of sufficient volume to recover, wash and return, and this is not always the case in pediatric surgeries. Autologous donation is a viable plan in older children, particularly for orthopedic procedures such as surgery for scoliosis. Parents often desire to donate for their children. They may believe, as Hume writes, that their own blood is safer in terms of infectious disease risk, than that from the general population. Studies have shown this not to be the case. I contend that another factor for parents is an unconscious desire to shed blood along with their child to share in his or her suffering. At an emotional level, I understand this, but do not feel that directed donations are necessary. What is absolutely necessary, Treatment Plan for the Pediatric Surgical Patient

• Perform a preoperative CBC to rule out anemia and to determine MABL. • Perform sickle cell anemia screening if demographics dictate. • Request washed or fresh RBCs at 10-40 mL/kg in advance form the Blood Bank if EBL is expected to exceed MABL. • Transfuse RBCs at 10 mL/kg dose for Hb <6.0 g/dL, when MABL is approaching, or when blood loss is brisk and patient is becoming unstable. Recheck H/H after transfusion. • Consider FFP at 10 mL/kg after giving 20 mL/kg of RBCs in high-volume EBL cases. • Transfuse FFP at 10 mL/kg for microvascular bleeding with concomitant elevation of PT or PTT, or when hemorrhage is brisk and you cannot wait for PT/PTT to be performed. • Transfuse platelets at 10 mL/kg for a platelet count of <40-50,000/μL prior to surgery or in the perioperative period. Use a trigger of 100,000/μL for neurosurgical cases. • Transfuse cryoprecipitate for a fibrinogen of <100-150 mg/dL. • Provide irradiated products to infants less than four months of age, immunocompromised patients, and those receiving blood from family members. • Refer to checklist in section 5.1 if you are approaching a massive transfusion.

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however, is to irradiate any cellular product from a blood relative to remove the risk of TA-GVHD.

The Whole Patient

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The tasks here are straightforward and involve the physiologic consequences of large-volume transfusions and general perioperative and postoperative care. You may refer to section 5.1, Massive Transfusions, for a discussion of the hemostatic, acid-base and electrolyte disturbances that may follow the transfusion of multiple red cell units or 10 mL/kg doses. If the surgery has not required as much blood, say just one 10 mL/kg dose of RBCs, simply checking coagulation parameters, an arterial blood gas and electrolytes (Ca, Mg) upon arrival to the ward and the following morning should be sufficient. You may find that you need to replace calcium and/or magnesium early in the postoperative course if you have given red cells. The checklist for routine postoperative care is well-familiar to you, and I can add nothing to it.

Eight-Second Summary

If the expected EBL is greater than the MABL, request washed or fresh RBCs for children less than five years of age. Transfuse RBCs and other products at 10 mL/kg per dose, if laboratory parameters and the clinical status of the patient so dictate.

Suggested Reading

1. Hume HA, Limoges P. Perioperative blood transfusion in pediatric patients. Am J Ther 2002; 9:396-405.

CHAPTER 8

The Neonatal Patient—Special Situations Key Principles • Consider an exchange transfusion for hemolytic disease of the newborn (HDN) if the bilirubin rises to 20 mg/dL or is rising by 0.5 mg/dL/hr in the first 24 hours of life. • Neonatal alloimmune thrombocytopenia (NAIT) should be suspected in any case of a low platelet count in a neonate and often requires urgent platelet transfusion to prevent intracranial hemorrhage (ICH). • Units dedicated to a specific neonate are used for the duration of their shelf life (35-42 days) and limit exposure to multiple donors. • Coagulopathy in the neonate is managed with the goal of preventing IVH/ICH using a few rule-of-thumb guidelines, although these in no way guarantee a perfect outcome.

Chapter Overview

Two broad categories of neonatal transfusion are those required subsequent to maternal antibody destruction and those secondary to illnesses common in the premature patient. Mothers may form antibodies to paternally-derived antigens which they themselves lack and which enter their circulation during pregnancy. Maternal IgG can cross the placenta and cause both fetal red cell and platelet loss and will cause residual destruction in the neonate until these antibodies wane or are consumed. Two examples of this phenomenon that are probably familiar to you are hemolytic disease of the newborn (HDN) due to anti-D or ABO-incompatibility and neonatal alloimmune thrombocytopenia (NAIT). Less common is red cell antigen incompatibility where the mother lacks a very common antigen, such as the e antigen. In these cases, support is typically limited to the specific component being destroyed. More complex in terms of blood transfusion is the critically ill neonate. These patients frequently require multiple different components, and steady iatrogenic blood loss from necessary lab draws demands additional transfusions to maintain an adequate hemoglobin level. Intravenous volume constrictions provide a further challenge, particularly in the low-birth weight neonate.

Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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8.1 Hemolytic Disease of the Newborn Basic Concepts

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Hemolytic disease of the newborn (HDN) is due to maternal IgG antibodies crossing the placenta, attaching to antigens on the surface of the fetal red blood cells, and causing hemolysis. Here, we’ll discuss the types of HDN, the approach to treatment and the mathematics involved in ordering an exchange transfusion. HDN can be conveniently separated into three groups: ABO-incompatibility, antibodies to clinically significant red cell antigens which can be determined during pregnancy, and classic anti-D HDN. ABO incompatibility between mother and fetus is common, and very mild HDN affects neonates without the disease ever coming to attention on a regular basis. Group O persons make anti-A and anti-B antibodies of the IgG class, sometimes in high titer, which can cross the placenta, while group A and group B persons rarely make IgG against their opposite antigen, instead making IgM. Thus, it is usually the group O mother with a group A or group B fetus presenting with ABO HDN. You may wonder why this type of HDN is so often mild, when giving incompatible RBCs or plasma is catastrophic. The primary reason is that fetal red cells show weak expression of the A and B antigens. Another reason is that hemolysis is extravascular, rather than the intravascular hemolysis seen with IgM antibody reactions. The bilirubin is typically normal at birth, but rises quickly in the first 24-48 hours of life, causing apparent jaundice. The diagnosis of ABO HDN is by a positive DAT on the neonate, showing anti-A or anti-B. Testing on the mother is not helpful here, as the routine antibody screens don’t test for high titer IgG against the A or B antigens. The initial treatment is phototherapy to convert unconjugated bilirubin to the conjugated form, which is water-soluble and can be excreted in the urine. The important decision for you to make is when to transfuse and when to perform an exchange transfusion. Consider simple transfusion with RBCs if the Hb falls below 9-10 g/dL, and perform an exchange transfusion if the bilirubin rises to 20.0 mg/dL or is rising by a rate of 0.5 mg/dL/hr on serial measurements. Simple transfusion is occasionally required for ABO HDN, as this disease can be moderate-severe. Exchange transfusion is rarely needed as an adjunct to phototherapy, but you should keep it in mind. Do not be lulled into a false sense of security by the fact that ABO HDN is usually mild. Monitor these neonates closely. Antibodies which can be detected during pregnancy and monitored, apart from anti-D, include anti-C, E, c, e, K, Fya, Jka, and the MNSs group. The Blood Bank will detect these on the routine pre-natal antibody screen. Your Blood Bank should automatically perform a titer on any of these antibodies, as they are clinically significant, meaning they cause HDN. Obstetricians vary on what constitutes a significant titer, but most consider either 16 or 32 worrisome and warranting close follow-up with serial titers through the pregnancy and cranial dopplers to evaluate for anemia. This group differs from ABO HDN in that you as the pediatrician can anticipate hemolysis in the neonate prior to delivery. While the severity of hemolysis does not correlate perfectly with the titer, it is a useful place to start. I recommend performing a CBC and

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DAT on a neonate born to a mother with an antibody titer of 8 or 16 or greater for this group as a first step. If the Hct is reassuring, the DAT 2+ or less, then following the bilirubin and clinical condition is reasonable. If the neonate is anemic at birth, and/or the DAT is 3-4+, then begin to think about simple transfusion and the possibility of exchanging the patient. Clearly, good communication between the pediatricians and obstetricians is critical to managing these neonates successfully. The third group is classic HDN due to anti-D and, although rare in the developed world today, it is potentially the most devastating. Like HDN due to the rest of the non-A,B antibodies just discussed, anti-D HDN occurs with exposure to the D antigen. This most often happens during pregnancy with mixing of fetal and maternal blood, but transfusion of Rh-positive red cells to an Rh-negative woman will achieve the same result. A very small volume of Rh-positive red cells on the order of 0.1 mL, can initiate the immune response. The mother’s primary response consists of predominantly IgM production, not a threat to the fetus, but subsequent pregnancies and re-exposure will elicit an anamnestic response with IgG which can cross the placenta. Prevention of anti-D is a genuine success story in medicine. Rh-negative women are given 300 μg of RhIG at 28 weeks gestation, when the Rh type of the fetus is unknown, and within 72 hours of delivery if the newborn is Rh-positive. These women are also given RhIG following abortion or miscarriage, or other events which may cause feto-maternal hemorrhage (FMH), including accidents and obstetric procedures. Despite the availability of RhIG in developed countries, anti-D HDN still occurs, not infrequently. The reasons are failure of RhIG to achieve prophylaxis (rarely); refusal of RhIG by the patient; and missed administration as may happen when a woman miscarries at home and does not receive medical care or is not provided RhIG after an elective abortion. If a woman demonstrates anti-D on an initial prenatal antibody screen and has not received RhIG in the past six months (rarely longer), she is presumed to be alloimmunized, and at this point is no longer a candidate for RhIG. The Blood Bank should perform an anti-D titer, and the obstetrician should follow titers closely, every 4-8 weeks until delivery. As the pediatrician receiving a newborn with anti-D HDN, you should perform a CBC, bilirubin and DAT promptly after delivery, and prepare for the possibility of an exchange transfusion. Anti-D HDN is the most severe form of hemolysis in neonates, so your threshold should be lower than for ABO HDN. Here, if in the first 12 hours of life the Hb falls below 10 g/dL or the bilirubin is rising by >0.5 mg/dL/hr even with phototherapy, perform an exchange. Petertec in the referenced article provides a chart with guidelines for performing an exchange beyond the 12 hour mark. A double-volume exchange transfusion will remove up to 90% of the fetal red cells, but only 50% of the bilirubin, due to the presence of bilirubin in tissues and subsequent re-equilibration. Your Blood Bank should be able to run the calculations for reconstituting whole blood and will wash the RBCs to minimize the potassium and anticoagulant load prior to adding compatible plasma. To calculate the total volume of reconstituted whole blood you need, recall that the

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blood volume of a term neonate is 85 mL/kg body weight, and for a premature neonate it is 100 mL/kg. Here is the formula:

Exchange Transfusion Math

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Total volume whole blood (WB in mL) = neonate’s wt in kg X 85 mL/kg X 2 (for double volume exchange) Absolute volume of RBCs = WB vol (mL) X 0.45 (Hct of WB to transfuse) Actual volume of RBCs = absolute volume RBCs/Hct of washed RBC unit Volume of FFP to add = total volume WB – actual volume RBCs Let’s try this out using a practice patient, a term infant weighing 2400 gm with anti-K HDN and a bilirubin of 13.2 g/dL at 12 hours of life.

Exchange Transfusion Math Example

1. Total volume whole blood (WB in mL) = neonate’s wt in kg X 85 mL/kg X 2 (for double volume exchange). The neonate weighs 2.4 kg and is 38+3 weeks, so the blood volume is 2.4 X 85 = 204 mL. X 2 for a double volume exchange is 408 mL. The Blood Bank needs to send up 408 mL of reconstituted whole blood, made from RBCs and FFP. 2. Absolute volume of RBCs = WB vol (mL) X 0.45 (Hct of WB to transfuse). 408 mL X 0.45 = 184 mL. If the RBCs had a Hct of 100%, they would take up 184 mL of the unit of whole blood. 3. Actual volume of RBCs = absolute volume RBCs/Hct of washed RBC unit. When the Blood Bank washes a red cell unit, the Hct is still close to the typical 55-60% of a plain RBC unit off the shelf. Let’s call the Hct 57%. Thus, 184 mL/0.57 = 323 mL. 4. Volume of FFP to add = total volume WB – actual volume RBCs. The Blood Bank adds thawed FFP to the washed red cells to make reconstituted whole blood. So, 408 mL WB – mL RBCs = mL FFP. Here, 408 mL – 323 mL = 85 mL. The Blood Bank adds 85mL FFP to the washed RBCs to give an final Hct of 45%. 5. Call the Blood Bank. Tell them you need 408 mL of reconstituted whole blood for an exchange and you want a Hct of 45%. If they cannot run the other calculations themselves, then you know how to walk them through it.

The Whole Patient

Because severe HDN with kernicterus is rare, the approach to the majority of cases you will see can be to evaluate and treat the hyperbilirubinemia and anemia until maternal antibody levels wane and broaden your focus to the neonate’s other systems. It is difficult to assess the duration of maternal antibody, but it is clearly far shorter than the four months expected for other antibodies. Further, I do not think it is useful to try to assess residual antibody levels. Rather, track the H/H and bilirubin. When the hemoglobin stabilizes and bilirubin trends consistently

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Role of Laboratory Tests for Hemolytic Disease of the Newborn Test Complete Blood Count (CBC) Maternal antibody screen DAT

Neonatal bilirubin Reticulocyte Count

Use H/H: assess severity of anemia Detect clinically significant antibodies in prenatal period Detect maternal antibodies on neonate’s red cells Assess degree of hemolysis Assess marrow response to anemia

Limitations NA Does not detect ABO antibodies May be falsely negative if all antibody-coated RBCs have been cleared NA NA

downwards, resolution is occurring. If the neonate is otherwise healthy and has not suffered the catastrophic effects of kernicterus, this chapter is closed. Attention can then be turned to the parents and their plans for future children. If this was a case of ABO-HDN, it can certainly recur in future pregnancies and depends on the father’s genotype. If he is AA or BB, there is a 100% risk of HDN; if he is AO or BO, then the risk is 50% with each child. Because the pathophysiology involves high titers of IgG in the mother, and she can cause HDN of a similar severity with future pregnancies, I would recommend a CBC and DAT on future children at birth as a pre-emptive move. With other antibodies and certainly with anti-D, antibody screens and serial titers are indicated. Certain antibodies in addition to D, such as K and Fya, can cause severe HDN and warrant close monitoring with Treatment Plan for Hemolytic Disease of the Newborn

• CBC, DAT, bilirubin on neonate at birth if HDN is suspected (maternal titer of >8-16). • Perform immediate double-volume exchange if maternal Rh titer is >64, cord bilirubin is >5 mg/dL, cord Hb is <12 g/dL, or clinical hydrops is present. Consider exchange for these same parameters if antibody is other than D. • Initiate phototherapy per your hospital’s guidelines, based on bilirubin. • If immediate exchange is not indicated, recheck bilirubin Q4 hours. Calculate rate of rise. If >0.5 mg/dL/hr, perform double-volume exchange. If rate of rise is slower, continue to monitor bilirubin Q4-8 hours as indicated by most recent bilirubin. • Perform double-volume exchange at 2-3 days of life if: bilirubin is >9-12 mg/dL for birth weight <1250 gm), >12-13 mg/dL (1250-1499 gm), >13-15 mg/dL (1500-1999 gm), >15-17 mg/dL (2000-2499 gm), >18-20 mg/dL (≥2500 gm). (Petertec article) REFER TO EXCHANGE TRANSFUSION MATH ON PREVIOUS PAGE FOR CALCULATIONS.

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cranial dopplers and/or amniocentesis. Discussion of intrauterine transfusion is beyond the scope of this text.

Eight-Second Summary

HDN due to non-A, B antibodies can be anticipated from the maternal antibody screen and typically presents in multiparous women, whereas ABO HDN may occur in the first pregnancy. The CBC, DAT and bilirubin are the key labs to assess these neonates and plan for a simple or exchange transfusion.

Suggested Reading 8

1. Petertec SM. Perinatal hematology: management of neonatal Rh disease. Clin Perinatol 1995; 22:561-92.

8.2 NAIT Basic Concepts

Neonatal alloimmune thrombocytopenia (NAIT) is an antibody-mediated disorder that is analogous to hemolytic disease of the newborn. It is not uncommon, affecting 1 in 1500-5000 live births. The important features to grasp are these: NAIT occurs in the first pregnancy in 60% of the cases and cannot be anticipated with routine prenatal laboratory studies; thrombocytopenia may be severe, with significant risk of intracranial hemorrhage (ICH) and thus demands prompt intervention; treatment includes either washed maternal platelets or off-the-shelf platelets. As a pediatrician, your primary goal is to prevent ICH by transfusing platelets. NAIT occurs when there is a discrepancy in the antigen profile between fetal and maternal platelets. These antigens are in the human platelet antigen (HPA) system, not the GpIb or GpIIb/IIIa antigens with which you are already familiar. The mother lacks an HPA antigen which the father and fetus carry, and she makes IgG antibodies against the foreign protein which cross the placenta causing platelet destruction in the fetus. Residual maternal antibody will continue to deplete platelets in the neonate until levels are exhausted. The most common antigen causing NAIT is HPA-1a (78% of NAIT cases), which is found in ~98% of the population; thus, the mother has a rare platelet phenotype. HPA-5b is the second most frequent cause (19% of cases), and a handful of others have been identified. The routine prenatal antibody screen looks for antibodies to red cell antigens and will not identify incipient NAIT, nor will a maternal platelet count, as the mother is not destroying her own, antigen-negative platelets. The work-up is complex and probably cannot be performed in your hospital. It includes platelet phenotyping of both parents to identify the antigen present in the father but absent in the mother, and a platelet antibody panel on the mother to specify the antigen-antibody mismatch. Testing takes 1-2 weeks and will not impact your management of the neonate in new cases, although it will provide useful information for subsequent pregnancies. Because the laboratory work-up will not be completed during the neonate’s hospital stay, you will make a clinical diagnosis of NAIT. Consider the diagnosis in a neonate with a platelet

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Role of Laboratory Tests for NAIT Test Platelet count

Platelet antigen typing Platelet antibody panel on mother

Use Perform as soon as NAIT is suspected clinically in new cases, at birth in established cases Phenotyes both mother and father Identify antibodies as the cause of neonatal thrombocytopenia

Limitations NA

Takes 1-2 weeks Takes 1-2 weeks in some labs. Antibodies against less common implicated antigens may not be identified except in very sophisticated reference labs

count <100,000/μL and/or petechiae or purpura. Quickly rule out other causes: sepsis should be at the top of your list, followed by maternal ITP or drug abuse further down. When other etiologies are off the table, make a clinical diagnosis of NAIT and proceed with maternal platelet transfusion as feasible, and consider IVIg for the neonate as a supplement to random platelet transfusions. Maternal IgG can easily leave the fetus/neonate with severe thrombocytopenia, counts less than 20,000/μL and the clinical sequelae which follow, from simple petechiae to fatal ICH. Several articles have reported a10% mortality with ICH, and lasting neurologic damage at 20%. Thus, your immediate treatment plan will be to transfuse platelets emergently for a count of <30,000/μL and probably urgently for a count of <50,000/μL. If you notice petechiae on a newborn on routine examination and find severe thrombocytopenia on your stat CBC, do not mull over the etiologies at this point: TRANSFUSE. Once the platelets are onboard, then consider your differential of sepsis, etc. By no means should you waste valuable time trying to secure maternal platelets in a neonate with a platelet count of <30,000/μL. Give off-the-shelf platelets from the Blood Bank to start, get the platelet count above 50,000/μL, and then talk to the mother.

The Whole Patient

The two issues here which should command your attention are bleeding in the neonate secondary to thrombocytopenia and where to obtain platelets for transfusion. As intracranial hemorrhage is your overarching concern, plan on ordering an ultrasound of the newborn’s head at an early opportunity, once a platelet count is back and necessary transfusions have been given. You will also assess for petechiae and other sources of bleeding, such as from the respiratory, gastrointestinal and genitourinary tracts as a matter of course. As to platelets, you have a few options. Your first option is to give platelets “off-the-shelf ” from the Blood Bank. Again, these are likely to be positive for the offending antigen, but some of them will survive; they are a good choice. Second, if the mother is physically able to donate apheresis platelets, draw them and use them. Drawing platelets from a woman

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Quick Question Can you estimate the expected platelet increment with “off-the-shelf” platelets, or how long they will last?

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No. You really cannot tell how much maternal antibody is onboard at any point in time, so you can’t guess how many of these platelets will survive. With “off-the-shelf” and also for maternal platelets, check a platelet count 30 minutes after the transfusion and at set intervals (4-12 hours) afterwards based on the newborn’s clinical status, and go from there.

who has just delivered a baby is technically challenging, however, so you should not take for granted that she will return to the postpartum ward in a couple of hours having provided a perfect “6-pack.” If she is physically unable to donate, do not worry; go back to option 1. Finally, you may be approached by well-meaning family members who want to donate. If the case of NAIT is a new diagnosis to the family (and you), this plan will probably not work for a few reasons. First, you will not be able to find out if the family member is negative for the platelet antigen in question in sufficient time to use his/her platelets, as this test takes 1-2 weeks. Second, while it is acceptable to give untested (for HIV, etc) blood from mother to child, you really cannot do this with family members, and if you wait two days for the platelets to be tested for infectious diseases, you still won’t know the antigen profile. For these new cases, politely thank the family member and decline. However, if you are preparing for delivery of a second child where NAIT has been diagnosed and the antigens determined, a family member may be able to help, especially if a cesarean section is planned and a donation can be scheduled a couple of days ahead of time. Treatment Plan for NAIT

• Perform platelet count as soon as petechiae are noted, or at birth in previously diagnosed cases. • Transfuse platelets immediately for platelet count <30,000/μL. Do NOT wait for washed maternal platelets. Recheck count 30 minutes after completion. • Perform ultrasound of head to assess for ICH. • Consider other causes of severe thrombocytopenia prior to soliciting maternal platelets or starting IVIg. • Once NAIT diagnosis has been made on clinical grounds, assess mother for platelet donation. If she is able, draw, wash and transfuse these platelets. Recheck count 30 minutes after completion. • Consider IVIg, 1 g/kg body weight. • Recheck platelet counts Q4-12 hours between transfusions. • Transfuse to maintain platelet count >30,000-50,000/μL.

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Eight-Second Summary

NAIT is a serious antibody-mediated disorder which can cause marked thrombocytopenia in the fetus and newborn. It is treated with emergent platelet transfusion and, if possible, washed maternal platelets, with a goal of preventing intracerebral hemorrhage.

Suggested Reading

1. Rothrnberger S. Neonatal alloimmune thrombocytopenia. Therapeutic Apheresis 2002; 6(1):32-35. 2. Kiefel V, Bassier D, Kroll H et al. Antigen-positive platelet transfusion in neonatal alloimune thrombocytopenia (NAIT). Blood 2006; 107(9):3761-3763.

8.3 Dedicated Units Basic Concepts

The major points to understand about dedicated units for neonates are these: the key advantage is reduced donor exposure; these are RBC units only, not other blood products; they are appropriate for typical transfusions of 10-15mL/kg; and they should be requested only if multiple transfusions are anticipated for the patient. While most hospitals set aside fresh (< 7day-old) RBC units for use in neonates/infants, some facilities will dedicate a fresh unit to a specific patient, usually in the neonatal ICU (NICU) setting, for the entire shelf life of the unit. This is either 35 or 42 days, depending on the anticoagulant and preservative in the unit. Thus, a neonate requiring red cells weekly due to losses from phlebotomy and anemia of prematurity will be exposed to just one donor over roughly a five-week span, rather than five. The referenced article describes reduction of donor exposure to 1.1 on average for neonates at high risk for blood transfusion. While the blood supply is very safe in terms of infectious disease risk, there is still some threat of CMV transmission. Also, every cellular blood product, RBC and platelets, exposes the recipient to foreign HLA antigens, even if the units are leukoreduced. Transfusing RBCs from these units up till the expiration date is safe in terms of potassium and preservative loads as well at small-medium volume transfusion of 10-15 mL/kg. Dedicated units are only available for RBCs. Plasma, once thawed, has a 24-48 hour shelf life. Platelets have just a five-day shelf life. The 35-42-day shelf life of red cells makes them a viable option for tagging to a specific neonate. For large-volume transfusions, those >15 mL/kg, either a fresh or washed RBC unit should be prepared. For many Blood Banks, the washing process is set for a full RBC unit, not one which has several small aliquots removed. Thus, if a neonate who has 50% of his/her dedicated unit remaining requires surgery and needs 40 mL/kg RBCs ready for the operating room, ask the Blood Bank to wash a separate unit and prepare, say, 80 mL of RBCs for your 2.0 kg patient. The neonate’s dedicated unit can be kept right where it is and saved for other transfusions.

Role of Laboratory Tests for Dedicated Units for Neonates Test Type and Rh

Use Determine neonate’s ABO/Rh type

Limitations NA

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Quick Question Can a family member donate to provide the dedicated unit?

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This is probably a bad idea. The primary reason is that a family member would expose the neonate to foreign HLA antigens, with (possible) subsequent antibody formation. You’re thinking, wouldn’t this happen with any unit? Yes. However, in the event that the child needed a marrow/stem cell transplant at some later point in life and was looking to a family member as a donor, he might already have formed anti-HLA antibodies to that person’s WBCs. Other reasons are that cellular units from family members must be irradiated to prevent TA-GVHD, and that directed units are three times more likely to test positive for an infectious diseases marker than random units are. I recommend against this practice.

In my hospital, we set up dedicated units at the request of the neonataologists. Our Blood Bank sets these without question for newborns <1000 gm. In other cases (larger neonates), the neonatologist will relay the justification to the Blood Bank. This system prevents a request by nurses for a dedicated unit on every admission to the NICU and overwhelming the Blood Bank’s inventory.

The Whole Patient

Three points merit brief discussion here. First and most obvious is the expectation of transfusing other blood products to the premature or very ill neonate. Iatrogenic blood loss for laboratory studies is a loss of red cells, plasma and platelets, and you will monitor H/H, platelets and coagulation parameters on a regular basis to determine if FFP, platelets, or even cryoprecipitate are indicated. Second, many very premature infants spend 2-3 months in the neonatal intensive care unit, and will require more than one dedicated RBC unit because their current unit either expires or is used up. Coordinate with the Blood Bank when this happens. Third, the parents of these patients often feel an added measure of support (and safety) knowing that their child has blood set aside for him/her.

Eight-Second Summary

Dedicated RBC units reduce the number of donor exposures in neonates who receive multiple red cell transfusions and can easily be set up by your Blood Bank. Treatment Plan for Dedicated Units for Neonates

• Request a dedicated RBC unit for neonates <1000 gm or if multiple RBC transfusions are expected based on clinical condition. • Indicate “dedicated unit” on each request for RBCs. • Coordinate with Blood Bank when unit will expire and decide if another dedicated unit will be necessary.

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Suggested Reading

1. Van Straaten HL, de Wildt-Eggen J, Huisveld IA. Evaluation of a strategy to limit donor exposure in high risk premature newborns based on clinical estimation of transfusion need. J Perinat Med 2000; 28(2):122-128.

8.4 Neonatal Coagulopathy Basic Concepts

The key concepts to grasp regarding neonatal coagulopathy are the differences in levels of coagulation factors in the newborn compared to an older child and the implications for the neonate once bleeding begins, the differential diagnosis for coagulopathy, and the approach to management. Many of the coagulation factors are at decreased levels in the neonate compared to adult levels, though fibrinogen, and factors V, VIII, and vWF are essentially at adult marks. This is reflected in prolongation of the prothrombin and partial thromboplastin times. Reference values for newborns on day of life 1 are in the range of 10.6-16.2 (preterm) and 10.1-15.9 (term) seconds for the PT, and 27.5-79.4 (preterm) and 31.3-54.5 (term) seconds for the PTT. Reduced levels of anticoagulant proteins C, S and antithrombin even out this relative deficiency, and the result is balanced hemostasis, with the term infant fairly resistant to hemorrhage. The downside of this natural phenomenon is that the neonate has little reserve of either pro- or anticoagulant proteins. Thus, a bleeding event which consumes these factors can quickly render the patient especially vulnerable to catastrophic hemorrhage, either into an anatomic space ( intracranial hemorrhage) or diffusely (DIC). The differential diagnosis of bleeding in the neonate should include both inherited and acquired disorders of both platelets and factors, and encompass both infectious and physiologic etiologies. Hereditary disorders of platelets should be considered in the otherwise well neonate with mucosal or petechial bleeding and would include Bernard-Soulier disease, Glanzmann thrombasthenia, Wiskott-Aldrich syndrome and platelet storage disorders. Acquired platelet disorders will likely be far more common in the NICU setting. Here, infection and sepsis, liver disease, NAIT and medication effect will be your primary suspects. Defects in secondary hemostasis can be approached in the same fashion, with an otherwise healthy male infant who manifests oozing from heel sticks or circumcision suggesting hemophilia A or B. Although severe von Willebrand disease may present in the neonate, this would probably be Type 3, which is rare. I would not rush to explore Type 1 or even 2 in the NICU or nursery setting unless family history and clinical scenario strongly drove you down this path. Acquired coagulation deficiencies are critical to consider in the NICU. You should keep vitamin K deficiency, liver disease and overt DIC at the top of your list. Anticipation of liver failure and DIC is critical. Herpes simplex and CMV are key causes of liver disease in the neonate, and both carry a high mortality. DIC can arise from overwhelming infection; another major cause is hypoxic-ischemic encephalopathy (HIE). Neonates born with a significant anoxic insult should be monitored very closely for development of coagulopathy, so that replacement therapy may begin immediately.

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Vitamin K-deficiency bleeding ( VKDB) results from the naturally low vitamin K1 stores present in all newborns, exacerbated by poor hepatic function and suboptimal hemostasis in premature infants. Three discrete syndromes may be seen. Early VKDB, presenting in the first day of life, affects infants whose mothers had low vitamin K stores themselves due to poor absorption or medication taken during pregnancy, and manifests in the neonate with skin, GI tract or intracranial bleeding. Classic VKDB, seen in the first week of life, is due to inadequate placental transport of vitamin K to the fetus (antenatal aspect) and breast-feeding with delivery of milk lacking in vitamin K (postnatal aspect). Late VKDB is seen 1-8 weeks into life, and may be due to breastfeeding and antibiotic exposure alone, but may also have an additional component, such as biliary atresia or a malabsorption syndrome. The approach to treatment should be guided by one over-arching goal, prevention of intracranial hemorrhage, followed by support directed to the remaining organ systems and general hemostasis. One part of your strategy will be to avoid what has been shown not to work. What doesn’t work? Prophylactic FFP, given within two hours of birth and again at 24 hours did not improve survivability or lessen severe disability at two years of age in a large trial in the UK (Lancet article). Platelet transfusions, given for a count <50,000/μL, did not have an impact on major hemorrhage in a recent retrospective study (Murray article in Transfusion Medicine), although a safe lower limit platelet count was not suggested. Finally, a few studies are being published now exploring the use of recombinant factor VIIa as a prophylactic adjunct for preventing IVH in premature neonates. It is too early to endorse this medication at present. What is a reasonable strategy, then? I suggest you do three things. Follow the guidelines by Murray for platelets, by Roseff for FFP for prophylaxis and treatment (see Treatment Plan); monitor the CBC, CMP and coagulation parameters closely for evolving liver failure or DIC, which will require ongoing transfusion support; and continue appropriate treatment of sepsis, necrotizing enterocolitis, etc. which will consume platelets and may precipitate hepatic compromise or DIC. I deviate from Murray in supporting 100,000/μL as a reasonable trigger for IVH/ICH, either active or imminent (he favors 50,000/μL). These guidelines are a sound starting point and developed by sound research, but are not hard and fast rules. They must be placed in the clinical context of your specific patient. Role of Laboratory Tests to Assess Neonatal Coagulopathy Test CBC PT, PTT

Use Assess and monitor platelet count Assess secondary hemostasis

Fibrinogen

Useful in DIC, values are comparable to those in adults Useful in DIC

D-dimer

Limitations NA Review normal values for neonates, both term and preterm, as these vary from adult values NA May take time to perform this test in the lab

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Quick Question What kind of increments in platelet count or PT/PTT should I expect after transfusion? It’s hard to say. The bump in platelet count and decrease in PT/PTT are dictated by two things: the plasma volume of the infant, which can vary as other IVF are given; and ongoing consumption of the blood products due to underlying illness. If you see poor increments after transfusion, then it’s probably safe to assume that the platelets or coagulation factors are being used up, and you may need to give more.

The Whole Patient

The two major tasks here are to treat the underlying cause for the coagulopathy and to realize that a bleeding diathesis in a neonate, especially a preterm or otherwise critically ill one, may portend a poor prognosis, a situation which requires extra support to be given to the family. Hypoxic ischemic encephalopathy and neonatal HSV are just two examples of catastrophic events of the early neonatal period which can rapidly turn into fulminant disseminated intravascular coagulation and demand intense supportive care as well as acyclovir in the latter case. Treatment Plan for Neonatal Coagulopathy

• CBC, PT, PTT, fibrinogen to assess coagulopathy. • Vitamin K 0.2 mg IM if not already given (appropriate for all neonates). • Assess clinical bleeding, from lines sites, GI/GU/respiratory tracts, CNS. Perform US for IVH/ICH as indicated by clinical condition. • Transfuse platelets, 10-15 mL/kg, according to the following triggers (adapted from Murray): – Maintain >100,000/μL for CNS bleed or CNS surgery, or at high-risk for a CNS bleed. – Transfuse even if >50,000/μL for serious active bleeding of GI, GU or respiratory tract. – Maintain >50,000/μL for sick preterm neonate with active bleeding or requiring invasive procedure. – Maintain > 30,000/μL for stable neonates. • Transfuse FFP, 10-15 mL/kg according to the following triggers (adapted from Roseff): – PT or PTT 1.5 times mid-range normal value in bleeding patient or one requiring invasive procedure. – With overt bleeding when time does not allow for laboratory results. – Transfuse cryoprecipitate, 10-15 mL/kg, according to the following trigger: Fibrinogen <100 mg/dL or <150 mg/dL with active DIC.

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The high transfusion requirements only add to the acuity of care. If you are able, and this is often not the case, to turn the tide on the underlying disease process, transfusion needs will subside. Communication with and empathy for the parents and other family members is part and parcel of the neonatologist’s job, and both interpersonal skill and time are needed. Again, developing hemorrhage merely ups the ante in an already high-stakes situation, as the infant’s status becomes even more precarious.

Eight-Second Summary

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While many neonates do not bleed despite prolonged coagulation laboratory values due to their balance of hemostatic factors, their reserve of these factors is low, making them vulnerable to hemorrhage once a bleeding episode begins. There is no regimen to guarantee hemostasis, but adherence to several guidelines will support the neonate without excessive transfusions.

Suggested Reading

1. Nuss R, Manco-Johnson M. Bleeding disorders in the neonate. Neo Reviews 2000; 1(10)e:196-200. 2. Murray NA, Roberts IA. Neonatal transfusion practice. Arch Dis Child Fetal Neonatal Ed 2004; 89(2):101-107. 3. Roseff SD, Strauss R, Sloan S, Hume H, Eder A. Blood components, hemostatic disorders. In: Roseff SD, ed. Pediatric Transfusion: A Physician’s Handbook. 2nd ed. Bethesda: AABB, 2006:18-30, 102-109. 4. Murray NA, Howarth LJ, McCloy MP et al. Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med 2002; 12:35-41. 5. Northern Neonatal Nursing Initiative (NNNI) Trial Group. Randomized trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: Outcome at 2 years. Lancet 1996; 348:229-32.

CHAPTER 9

Other Special Patients Key Principles • Screen autologous donors having elective surgery to select those who will likely require peri- or postoperative RBC transfusion using a preoperative Hb of 11.0-13.5 g/dL and the likelihood that they will regain their baseline Hb prior to surgery as general guides. • The optimal situations for directed donations include maternal-neonatal rare phenotypes (Chapter 8) and children with chronic transfusion requirements at risk for forming alloantibodies to red cell antigens. • Jehovah’s Witnesses and other religious groups vary in their acceptance of blood products. Certain products, such as factor concentrates, are acceptable to most, and some Jehovah’s Witnesses make exceptions to the tenets of their faith when faced with an absolute need for transfusion.

Chapter Overview

This chapter provides guidance on miscellaneous patients who request or require blood support outside of the regular channel of allogeneic blood provided by the Blood Bank. The common theme among these patients is that they prefer their own blood, or that of selected loved ones, to blood from an unknown donor. The disaster of transfusion-transmitted acquired immunodeficiency syndrome (AIDS) from blood transfusion has driven some to this position, although the current risk of acquiring AIDS from a blood transfusion in the US is about 1 in 2,000,000. A related issue is that of control. Being a patient means that others make decisions for you. One way to maintain some personal control is to dictate the terms under which blood, the symbol of life, is introduced to your body. For certain patients, the theme of control is understood in religious or spiritual terms. Finally, parents sometimes feel a need to share in the physical suffering of their child undergoing surgery by providing blood, although they may explain their desire to donate blood in terms of safety and infectious disease risk. Your role is to integrate the medical need, or risk, for a special blood product or no blood at all, and the emotional and religious needs of the human beings you are caring for. This is not an easy task.

Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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9.1 Autologous Donors Basic Concepts

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Preoperative autologous donations (PAD), in which patients donate one or more units of blood to be available for their use alone for up to 42 days, are most commonly made prior to orthopedic surgeries, usually total joint arthroplasties, and less often for gynecologic, general or other special surgeries. Your decision to request an autologous donation for your patient should take into account several issues, as this has become a somewhat controversial topic. I do not hold a strong opinion on autologous donations and support judicious use of this alternative to allogeneic blood by my orthopedic and occasionally general surgery colleagues. Your transfusion plan will be judicious if it includes the following seven elements: it is individualized to each patient; the predicted EBL makes transfusion likely (≥50% chance); the patient’s preoperative hemoglobin and functional status have been evaluated and his suitability to donate screened, the feasibility of iron supplementation and erythropoietin (EPO) has been explored, the potential for allogeneic transfusion in addition to autologous has been discussed, the possibility of autologous blood not being used has been presented, and the decision to transfuse either autologous or allogeneic blood includes both clinical and laboratory parameters. Let’s go through each of these in turn. The transfusion strategy you employ, whether it involves autologous or allogeneic blood, both, or neither, should be unique for each patient. Stulberg describes this concept neatly in his review (The Journal of Arthroplasty article, vol. 22, number 4). He rightly emphasizes that some patients, such as males undergoing a primary total knee arthroplasty (TKA), may require no blood at all. Further, he encourages each surgeon to estimate his own blood loss for particular cases in his own facility, as practitioners differ according to their level of experience and technique. This principle obviously applies to the non-orthopedic patient as well. The remaining six factors will map out the approach you may use for your patient. I recommend that autologous donation only be considered in cases where the likelihood of transfusion is at least 50%. This is the usual cutoff point for ordering a Type + Cross. Here, your estimated blood loss will be the key data point. If you are an experienced orthopedic surgeon who has performed many joint arthroplasties, you can accurately predict your EBL. For others, this may be more challenging, especially if you are considering PAD in a less common procedure, such as the resection of a hemangioma of the liver. Refer to the literature for an average EBL for less common surgeries and integrate this with your own skill level to come up with an estimate. The two main factors in suitability for PAD from the patient’s perspective are his preoperative hemoglobin and hematocrit and his overall functional status. A frequently used parameter for autologous donors is a Hb of 11-14 g/dL. At my facility, we use 11.0-13.5 g/dL as the criteria for joint replacement surgery patients. By American Association of Blood Banks regulations, an autologous donor must have a Hb of ≥11.0 g/dL and a Hct of ≥33% on the day of donation. The upper end Hb is designed to prevent us from drawing an autologous unit from a patient who will likely be able to tolerate the EBL without requiring a transfusion. If your patient has a Hb <11 g/dL or >14 g/dL, he is probably not a suitable candidate.

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Second, the patient must have adequate cardio-respiratory reserve to endure a blood donation. Well-controlled hypertension is not a show-stopper, but significant cardiovascular or respiratory disease is. I do not use a strict APACHE II score to screen patients; appropriateness can be determined on a case-by-case basis. The single most important question to try to answer is this: can the patient return to his baseline hemoglobin value prior to surgery after he has donated? If the answer to this is “no,” then the patient should not donate, as he would be better off just keeping the 450 mL of blood in his body. There are three tactics you can employ to maximize his chance of regenerating the donated red cells. First, time the donation(s) as close to 42 days (if your Blood Bank uses additive solution RBCs) prior to surgery as possible. Give yourself a few days of leeway to allow for transfusion on postoperative day 2 or 3. This gives the patient’s marrow some time to rebound. Second, provide the patient with oral iron supplementation to facilitate RBC production. Third, use EPO, at 600 IU/kg subcutaneously on days 21, 14, and 7 before the day of surgery, and the last dose on the day of surgery (Stulberg’s protocol). If you cannot use erythropoietin, rethink PAD. This medication will be an important adjunct to help the patient regain his baseline Hb prior to going to the operating room, and it will probably be more critical in women than in men. Nydegger’s small study (Seminars in Hematology article) supports the use of EPO as a supplement in PAD, as do several other articles. Autolgous donations do not always obviate the need for allogeneic blood, and the patient should understand this and make clear his position on allogeneic products with you. In Keating’s recent trial (The Journal of Arthroplasty article, vol. 22, number 3) comparing PAD to preoperative EPO use, 14% of PAD patients received allogeneic transfusions, while the rate was 3% in the EPO group. Note that in his trial, the autologous donors group did NOT receive erythropoietin; they did receive oral iron, however. In a trial by Horowitz in gynecologic surgery patients (Obstetrics and Gynecology article), 3 of 106 patients who had donated autologous units received allogeneic transfusions. In many conversations with autologous donors, I have not encountered adamant refusal of allogeneic blood, although some patients will decline. Broach the subject beforehand to find out where your patient stands. Perhaps the strongest argument against PAD is that a great percentage of units are wasted, not transfused to the patient. Regulations prohibit unused autologous blood from being released into the general blood inventory, so if a unit is not transfused to the patient who donated it, it is discarded. Keating cites a usage rate of 62% of patients ( joint arthroplasty cases), while Horowitz’s study saw only 14% receive their donated blood (benign and oncologic gynecology cases). There are two issues to consider here. The first is rational use of a valuable resource. Collecting a unit of blood when there is only a 14% chance that it will be transfused is poor resource management, and this is why I ask that you anticipate at least a 50% chance of transfusion before considering PAD. Tied to the issue of wastage is that of cost-effectiveness. Numerous studies have explored this angle, comparing EPO’s bill to that of PAD, autologous vs. allogeneic outlays, etc. I do not see the issue of cost containment as rivaling what is the best treatment strategy for the patient, particularly as the cost differential is at most a few hundred dollars. The seventh element in your transfusion plan is whether the patient expects to receive his blood back and whether you as his physician feel compelled to transfuse

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it because it “belongs to him.” Obviously, many units are not transfused back to the patient, hence the high wastage rates. Interestingly though, Keating found that despite equivalent Hb parameters for transfusion in his study between the PAD and EPO groups (8 g/dL), the PAD group received more transfusions than the EPO group. Physicians could order transfusions at a Hb >8 g/dL for blood loss, fatigue, hypotension, shortness of breath, and other reasons. They did so, but they did it more often in the group with their own blood sitting in the hospital Blood Bank; 34 transfusions were given to the PAD group for blood loss, including 7 that were allogeneic, while none were given to the EPO group for this reason. Yet, the EBLs were comparable between the two groups. Most strikingly, the pre-transfusion Hb was 8.13 g/dL for the EPO group and 8.97 g/dL in the PAD group. Stulberg encourages the physician to rely on the physiologic assessment (his italics) of anemia, not simply to transfuse based on laboratory parameters. This is sound advice, and we have been using it throughout this book. In Keating’s study though, and perhaps in your own experience, the clinical triggers changed when the patient had his own blood available. This is not a cardinal sin, but I will exhort you to be objective in these situations. The take-home messages for you then are to apprise your patient that his blood may not be used if a transfusion is not indicated and then follow through on your statement.

The Whole Patient

Once the surgery is complete, the primary focus becomes a smooth postoperative course. The decision to transfuse may be a central one as you work to get the patient back on his feet. This is particularly true in the orthopedic patient, who must have the stamina to engage in rehabilitation, but holds as well for other surgical patients. Here, you execute the last element of the judicious transfusion plan: incorporating the clinical signs and symptoms into the algorithm along with the morning’s hemoglobin value. While I cautioned you in the last paragraph of Basic Concepts not to transfuse an autologous unit just because it was available and you did not want it to go to waste, I present the other side of the argument here. If your patient is fatigued and reluctant to move forward with is recovery for this reason, he will probably benefit from a red cell transfusion, whether it is his own blood or an allogeneic unit.

Eight-Second Summary

Preoperative autologous donation is a reasonable option to consider in patients who meet certain criteria, and who understand and consent to the use of allogeneic blood if it is likely they will need it, and also to the prospect of their blood being discarded. Role of Laboratory Tests for PAD Test CBC PT, PTT

Use Assess H/H, platelet count preoperatively/ on admission. If patient is coagulopathic, he is more likely to need blood products.

Limitations NA NA

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Treatment Plan for PAD

Autologous Donation Should Not Be Considered • Your facility allows that all patients meeting set parameters may donate in PAD program (lack of patient and case-specific guidelines). • The predicted EBL makes transfusion unlikely (<50% chance). • The patient’s preoperative Hb is <11 or >14 g/dL, or his functional status is such that donation is risky. • PO iron cannot be tolerated, or EPO cannot be administered, or compliance with these will likely be poor. The patient is unlikely to regain his pre-donation H/H. • The patient only desires PAD if it guarantees that he will avoid allogeneic blood, and this scenario is unlikely due to a high EBL. “Doc, if I’m going to get 2 or 3 units from the Blood Bank, why not just get them all from there?” • The patient opposes his blood being discarded, and the possibility of this is high. • You plan to transfuse the PAD unit(s), no matter what.

Treatment Plan for PAD

Autologous Donation May Be Considered • Your facility has an individualized program to select patients for PAD. • The predicted EBL makes transfusion likely (≥50% chance). • The patient’s preoperative Hb is ≥11 and ≤14 g/dL, and his functional status is such that donation can be tolerated. • PO iron can be tolerated, EPO can be administered, and compliance with these will likely be good. The patient is likely to regain his pre-donation H/H. • The patient understands that PAD does not guarantee that he will avoid allogeneic blood, and this scenario is likely due to a high EBL. “Doc, if I need to get 2 or 3 units from the Blood Bank after you give me my own blood back, do whatever you need to do.” • The patient accepts his blood may be discarded if transfusion is not indicated clinically. • You plan to transfuse the PAD unit(s), if it is clinically indicated by laboratory parameters and physiologic assessment.

Suggested Reading

1. Stulberg BN, Zadzilka JD. Blood management issues using blood management strategies. J Arthroplasty 2007; 22(4):95-98. 2. Keating EA, Callaghan JJ, Ranawat AS et al. A randomized parallel-group, open-label trial of recombinant human erythropoietin vs. preoperative autologous donation in primary total joint arthroplasty. J Arthroplasty 2007; 22(3):325-333. 3. Horowtiz NS, Gibb RK, Menegakis NE et al. Utility and cost-effectiveness of preoperative autologous blood donation in gynecologic and gynecologic oncology patients. Obstet Gynecol 2002; 99(5):771-776. 4. Nydegger U. Enhanced efficacy of autologous blood donation with epoetin alfa. Semin Hematol 1996; 33(2 Suppl 2):39-40.

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9.2 Directed Donors Basic Concepts

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Directed donations are those in which an individual provides one or more units of blood for transfusion to a specific patient. The donor is frequently a family member, usually a parent if the patient is a child, but is occasionally a close friend. The practice of directed donations is controversial and is not endorsed by all physicians, hospitals or larger institutions. You will want to learn your own facility’s policy on directed donations prior to discussing the issue with a patient. In this section, we will outline four aspects of directed donations: the key drivers or motivating forces behind the desire to donate; the rates of deferrals, positive infectious disease markers and wastage; the risk of receiving blood from a family member; and the selected populations most likely to benefit from this practice. A grasp of these issues will allow you to speak cogently to patients and loved ones alike. The two key drivers in the majority of requests are concerns for safe blood products and a psychological need to shed blood alongside a loved one. One can surmise that transfusion-transmitted AIDS did more to spur on directed donations, and autologous ones, than any other event in the history of blood transfusion. Many people in the 1980s feared that the blood supply was unsafe, and at that time there was good reason for their concern. Their response was to assume that blood from a relative or close friend was safer than blood from a volunteer donor. Today, there are problems with both parts of this reasoning. With current testing methodologies, which for HIV include an antibody test for HIV-1 and HIV-2 and also a nucleic acid test for the virus itself, the risk of contracting AIDS from a blood transfusion is exceedingly remote, on the order of 1 in 2 million. The risk for the hepatitis C virus (HCV) is roughly the same. Secondly, as we will explore in the following paragraph, blood from directed donors is no safer than that from anonymous volunteers. In some studies, the rate of positive infectious disease markers is equal to that of volunteer donors, and in others it is higher in directed donors. For many of your patients and their families however, the specter of Ryan White still looms, and you may need to go over the numerical risks with them to convince them that your hospital’s blood is safe. The other key driver will not be raised by the prospective donor, most often the parent for this issue. It can be inferred though, and I believe it is a strong force in parents of sick children. No parent wants to see his child suffer, and so it is natural and wholly understandable that a parent who foresees bleeding in his child may want to shed some of his own to replace what his son or daughter has lost. This act fulfils a dual function of healing for the child and concomitant suffering by the parent. Parents may also feel a sense of responsibility when their child is sick or requires surgery, and giving blood may alleviate their guilt, ill-founded though it is. Again, I do not hear parents verbalize this argument, but I think it’s real. A quantitative analysis of directed donations reveals that blood is underutilized and that no added measure of safety is conferred. The study by Wales et al (Journal of Pediatric Surgery article) at a children’s hospital recorded a wastage rate of 63.6% from directed donations, compared to only a 7% rate from volunteer donations. I do not offer utilization rates from other studies, but certainly the results from this one are an example of poor conservation of a valuable resource. Their research did

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show a benefit of decreased donor exposure, as 28% of the transfused patients in the hospital during the study period received multiple units from a single donor, although this benefit was not specifically observed in general surgery patients. Deferral rates were found to be higher than that in the volunteer donor population. Their data included higher rates of reactivity (a positive initial screening test) for infectious diseases in directed vs. volunteer donors (1.2% vs. 0.47%) and higher true-positives after confirmatory testing (1.2% vs. 0.10%). Including other deferrals for reasons such as ABO-incompatibility, malaria and high-risk behavior, only 61% of parents who requested were able to provide blood for their child. Several other studies have reported either a higher or equivalent incidence of infectious disease markers when they compared directed to volunteer donors. While the residual risk of infectious disease transmission is small because the great majority of prospective donors carrying HIV or other transmissible diseases will be screened out, the risk of transfusion-associated graft-versus-host disease and HLA alloimmunization remain. TA-GVD results from HLA haplo-identity between the donor and recipient and can easily occur between blood relatives. The mechanism is discussed in Chapter 1, but I will briefly review it here. The recipient’s (patient’s) immune system fails to recognize donor lymphocytes as foreign if they (the donor) are homozygous for one of the HLA haplotypes that the recipient has. If the recipient is heterozygous, then the competent donor lymphocytes will identify the recipient’s WBCs as foreign and mount an immune attack (TA-GVD). Irradiation effectively prevents a possible attack by interfering with the replication of the donor lymphocytes. So yes, the risk of TA-GVD can be virtually eliminated. However, the donor WBCs and their HLA antigens are still transfused, and some remain even in leukoreduced RBC and platelet units. If the donor’s HLA profile differs from that of the recipient (the donor is not homozygous here), and it probably carries one unique and one identical haplotype if the donor is the biological parent, then the child is exposed to foreign HLA antigens. He or she can generate antibodies to those antigens. The potential problem here is that should the child ever need a bone marrow or stem cell transplant, he would have already made antibodies against just the HLA antigens he would likely receive in anything less than a 6/6 HLA match, if the transplant donor was a blood relative. How likely is this scenario? Not very, but I employ this line of reasoning with parents when discussing directed donations, which my own hospital does not allow. Wales presents two circumstances where directed donation offers an advantage over allogeneic blood from the hospital’s Blood Bank. The first is for young children who require chronic transfusions, such as those with hemoglobinopathies or congenital hemolytic anemias. The rationale for directed donations from family members is that a relative likely matches for red cell antigens and would partially obviate red cell alloantibody formation. These are different from the HLA antigens we’ve been discussing, and you’re right when you argue that you are risking HLA alloimmunzation to prevent red cell antibody formation. That’s a fair trade-off, and here’s why. The incidence of red cell antigens varies among ethnic groups, and a relative from the same group is likely to share the antigen profile. The second group is children who require major surgery and can expect multiple transfusions. Here, the number of donor exposures may be reduced, as a small child could receive several aliquots of RBCs from his directed donor.

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Role of Laboratory Tests for Directed Donation Test CBC

Use Assess H/H, platelet count preoperatively/ on admission.

Limitations NA

The Whole Patient

9

Two issues to consider here are the transfusion needs of the patient who has blood set aside for him and the awkward situation of a potential donor whose blood cannot be used for one reason or another. Some donors, both autologous and directed, believe that their donated blood is similar to money in a bank account. They may think that it will definitely be transfused to the intended recipient. This is not always the case. As the physician caring for the patient, you will make your transfusion decisions based solely on the patient’s clinical needs. If he needs the RBCs, transfuse them, if not, do not. Do not give a transfusion that is not indicated so as not to waste the donation or placate a parent. Make sure that the parent or other donor understands that their blood may not be used before they donate to avoid a misunderstanding. As we saw from the referenced article, some potential donors are deferred because of positive infectious disease tests. This is the case even if the result is a false-positive, and false-positives occur regularly. You may have to tell a parent that his blood cannot be used because it tested positive for the AIDS virus, that, no, no, he doesn’t really have AIDS because the confirmatory test was negative, but you still can’t use the blood. Think for a moment how you might handle such a situation, and how the donor will explain this to his wife and anyone else who thought he was doing this wonderful thing for his daughter. It’s enough to make you back off the entire directed donation scheme altogether.

Quick Question Can directed donations be used with all blood products, like platelets and FFP? The usual case for both autologous and directed donations is that the whole blood donated is processed into RBCs, which are labeled and saved, and FFP which is discarded. This may vary in your hospital; check to find out, but do not assume that the directed donation will automatically be made into one RBC, one FFP and a random platelet (one-sixth of a 6-pack). It is rare that either FFP or platelets are required for blood support in pediatric or orthopedic surgery, the two more common situations where directed donations are made. Thus, many Blood Banks will not go to the extra effort to make and label FFP when it is highly unlikely to be used. Platelets are even less likely to be manufactured. Ensure that the donor understands which part of his or her blood will be available to the patient. We discussed directed donations of platelets in Chapter 8.

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Treatment Plan for Directed Donation

• Estimate the expected blood loss for surgical cases where a directed donation is requested and the likelihood that blood will be needed. If the EBL is small, it is not cost-effective to secure a directed unit. • Perform CBC to assess baseline H/H. • Discuss risks and benefits of a directed donation with the potential donor. • If the reduction in donor exposure is a likely outcome (multiple RBCs transfusions anticipated in a small child) and is deemed to outweigh the risk of HLA alloimmunization, the Blood Bank will consent and screen the donor for a directed donation. (If your hospital purchases its blood from a supplier, such as the American Red Cross, the donation will be performed outside of the hospital.) • Set clear parameters for transfusion for the patient. These are the same as for any patient—the clinical status and Hb values. DO NOT feel compelled to transfuse donated blood just because it has been donated. Transfusion decisions are driven by the patient’s needs.

Eight-Second Summary

Directed blood donations are not safer than those from the general population of blood donors and pose certain risks to the patient apart from infectious disease transmission. However, they may be indicated in selected cases where multiple transfusions are anticipated.

Suggested Reading

1. Wales PW, Lau W, Kim PC. Directed blood donations in pediatric general surgery: is it worth it? J Pediatr Surg 2001; 36(5):722-725.

9.3 Jehovah’s Witnesses and Other Religious Considerations Basic Concepts

There are three elements to a respectful and medically sound approach to transfusion in Jehovah’s Witnesses ( JW) or in others who refuse “blood” on religious grounds. First is an understanding of the primary components of blood as defined by The Watchtower Bible and Tract Society. Next is a familiarity with the alternatives acceptable to many JWs. The third is partnering with each patient, whatever his professed affiliation, as he makes a personal decision regarding his care plan, which may or may not mirror the strict doctrines of his church. Before I cover these three elements, I will offer a few general words of advice, as this situation arises infrequently and when it does, it often causes anxiety among the health care team. Do not panic. While you may not have much experience with religious objections to blood transfusion, others have and they have provided solid advice. The articles referenced in this section are current, specific and apply to your real-world situations. Do not assume homogeneity among JWs. It is easy to fall into the trap of thinking that everyone of a particular religious group, especially if it is one removed from the mainstream, thinks and behaves in uniform fashion. This is not always the case. The Roman Catholic Church prohibits the use of birth control, but we as physicians accept that many of our Catholic patients make exceptions to this

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teaching; we do not assume that every Catholic follows every dictum all the time. We are more comfortable with the Catholic patient because we know them and have personal experience with a range of interpretations of church teaching. It’s more challenging with the first Jehovah’s Witness we’ve ever met, whose faith is unfamiliar to most of us. This section will give you a brief introduction to the JW religion, some advice on others with similar concerns about blood, and strategies for managing blood loss for this patient population. The four primary components of blood constitute the baseline of blood products to be refused by JWs. Sniecinski refers to the Watchtower publication in his brief commentary (Anesthesia and Analgesics article), which defines the “primary components” of blood as red blood cells, white blood cells, platelets and plasma. The Watch Tower Society, which promotes church doctrine, has set these components as unacceptable for transfusion. You are probably thinking that this pretty well covers everything, but read on. The Society deems fractionated blood products as potentially acceptable. This most clearly includes protein fractions such as coagulation factors VIII and IX, Rh immune globulin, and even cryoprecipitate. JW members are instructed to look to their own conscience to determine if such preparations are acceptable. The Society’s acceptance of these components seems to hinge on the fact that some proteins move naturally from mother to fetus. As Sniecinski points out, this opens the door for several products derived from plasma to be offered to the JW patient. It is unclear to me what about the process of fractionation makes these plasma-derived proteins acceptable from a religious standpoint. It is also very possible that your particular patient is not well-versed in blood manufacturing practices and may have no idea how cryoprecipitate is different from FFP. I would suggest that in your discussion, you let them know that some protein fractions are acceptable and considered a personal decision. A broader interpretation of the term “fractionated” opens the door further. In the follow-up editorial to Sniecinski’s article, Lee Elder, affiliated with a group called Associated Jehovah’s Witnesses for Reform on Blood, states that JWs have the option of accepting everything from a unit of blood as long as it is sufficiently fractionated (pp. 757-758 of the same issue of Anesthesia and Analgesics). As the medical director of a blood bank, I can tell you that all the blood products you will use, save for whole blood, are fractionated. Centrifugation and separation are how we make components. As the fraction which we call RBCs is still a primary component, his statement, which is derived from the Watchtower power of attorney document, muddies the picture. If a patient brings you such a document and asks you about fractionation, I suggest you explain that all blood products have been fractionated, but that you understand that RBCs, platelets, and FFP are still considered primary components, and then ask the patient how he feels about RBCs (or platelets or FFP) specifically. Second, alternatives to conventional blood products include derivatives from plasma besides cryoprecipitate and blood conservation techniques. Derivatives include an agent discussed in other sections of this book, rVIIa, which Sniecinski reports using to good effect in cardiopulmonary bypass surgeries in the same journal referenced above (pp. 763-764). Recombinant factor VIIa is a powerful hemostatic drug, and while it is more effective when other common pathway factors are present in adequate amounts, it is certainly a good option in the bleeding patient who refuses FFP. Cryoprecipitate, if acceptable, would be a helpful adjunct to rVIIa in this situation. Antithrombin in the cardiovascular surgery setting is another agent

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likely to be acceptable, and antifibrinolytics may also play a role. Shander outlines numerous blood conservation strategies for the JW patient (Current Opinion in Hematology article) throughout the operative course for patients undergoing surgery. Preoperatively, these include optimizing red cell mass with erythropoietin and iron, avoiding medications that impair clotting, limiting blood draws and using preoperative autologous donation. In the operating room, autologous options may include acute normovolemic hemodilution and use of cell-saver technology. Remember that strict adherence to JW doctrine requires that the blood remain in continuous contact with the patient through sterile tubing. Disconnecting the collection unit from the patient would violate that doctrine. Good surgical technique to minimize blood loss and maintaining euvolemia are obvious tactics you will use. In the postoperative period, erythropoietin and iron may be restarted, blood draws ordered judiciously and all remaining shed blood re-infused. Clearly, it is preferable to identify the patient with religious restrictions to conventional blood products in the weeks prior to surgery, so that medications can be started and plans for cell-saver use, etc. made well in advance. Third, whether you are in a preoperative appointment for a planned surgery or at the bedside admitting the patient for an illness or injury, you will want to discuss clearly and openly the options available to him or her at your hospital in terms of blood alternatives, and work with the patient to develop an individualized transfusion plan. JW patients may adamantly refuse everything derived from blood, they may refuse only the primary components, or they may accept these as they are fractionated, if they are in extremis. They may even suspend all restrictions and accept whatever you as the physician deem necessary in their care. They are guided by their faith but are also individuals who must decide how best to manifest that faith in challenging circumstances. Enter into the discussion with an open mind, as you really don’t know what the patient will or will not allow. Document his wishes clearly, in writing, on your hospital consent form, including whatever protein derivatives have been termed as acceptable, such as rVIIa or antithrombin. Some recommend, and I concur with them, having this discussion in private, with you, the patient and a witness present. Other family members sometimes try to influence the decisions of their loved ones, and may talk them into or out of a procedure against their wishes. If the patient is competent, he or she alone may accept or refuse medical interventions. You may want to include your hospital chaplain in the discussion however, as he or she has experience in just these situations, can guide you through the conversation and help you do what is ethically right. In the difficult situation of parents refusing life-saving transfusions for their child, involve the chaplain and legal counsel immediately to assist you. You will occasionally encounter patients who may consider refusing blood for religious reasons who are not Jehovah’s Witnesses, and I favor a different approach for them. These patients sometimes belong to small sects whose practices are even less familiar than those of the JW community. At times, the theological underpinnings of their position on blood are baffling. As blood transfusions were not part of medical practice in either Old or New Testament times, it is difficult to interpret biblical dictums to abstain from blood (Genesis 9:3,4, Leviticus 7:26,27 and Acts 15:28,29) as an injunction against a unit of RBCs from the Red Cross. Blood is certainly a potent symbol in the Bible. Life was believed to reside in blood, and

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Role of Laboratory Tests for Jehovah’s Witnesses Test CBC

PT, PTT

9

Use Assess H/H, platelet count preoperatively/ on admission to know your starting point before counts fall with blood loss. Assess coagulapathy preoperatively/on admission. If patient is coagulopathic to start, you have less of a reserve if factors are depleted.

Limitations NA

NA

both of these belonged to God, so blood was nothing to treat casually. The Old Testament commandment against consuming blood actually referred to drinking the blood of animals; that part was to be sacrificed to God, from whom the animal’s life came. From this dietary practice, some religious persons have adopted the policy of refusing transfusion. This is the basis of the JW faith position, too, although their emphasis on fractionation and derivatives makes them somewhat unique and open to more options from the Blood Bank. Patients with a passionate faith may well bring powerful imagery with them to the hospital room, of animals laid on an altar, or Christ dying on the cross. To then see that same substance in a sterile bag plastered with labels and hanging on an IV pole, and perhaps treated no differently by you than a dose of gentamicin, is probably frightening. To enable such patients to consider accepting a necessary transfusion, you may need to construct a theological bridge from Leviticus to your treatment plan. Try presenting blood in a new context for them. Explain that the unit of RBCs, while it is indeed blood, is a medication, pure and simple, and is quite different from the blood of sacrificed animals or the blood of Christ (the latter are sacred, the former is certainly not). Your bag of blood is in no way trying to imitate that currency of life described in the Bible. It is simply another adjunct we humans use to try to treat sick people. This may help them cross that bridge. If it does not, I would go back to the conservation strategies used with JW patients.

The Whole Patient

The two pertinent issues here are the effects of untreated anemia or coagulopathy on the patient and the opportunity for the patient who has refused blood products to change his mind during his hospital stay in light of his condition. It will be prudent to review the patient’s functional status and underlying illnesses in the context of possible anemia or a bleeding diathesis. For example, a Hb of 6.5g/dL will likely be tolerated by a young, healthy person recovering from an elective surgery but could be catastrophic for an older person with underlying coronary disease. Anticipate such scenarios and incorporate them into the preoperative or admission H+P conversation. A related issue is whether the patient may suspend his refusal if he becomes symptomatic or concerned for his well-being. You certainly do not want to ask the patient each morning at rounds if he will receive a transfusion today, as that would not respect his faith, but you may want to present the option of revisiting the decision during the hospital stay if his blood parameters become dangerously abnormal. Patients sometime regret the decisions they have made. We see this in cancer patients regularly, as they decide to discontinue chemotherapy when their

Other Special Patients

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Quick Question How exactly do you start this discussion? Here are some options: I see that you are a Jehovah’s Witness, Mrs. Smith. I know that there is some variation in how Jehovah’s Witnesses approach the issue of blood transfusion, and we have a number of options to support you during your surgery/hospital stay, including several fractionated blood products. Have you thought much about what you would feel comfortable with? Why don’t we think through these options together, one-by-one, and I can explain how they are derived from whole blood, how they would affect you, and what might happen if you decided that you did not wish to receive each one. I respect your decision to decline red blood cells as a primary component, but with your surgery, you may become quite anemic, even with our cell-salvage techniques, and you may feel some discomfort. I want to make sure you know you have the right to change your mind. If you and I together feel that you are suffering or your condition becomes dangerous to you, we can revisit this consent. How does that sound?

Treatment Plan for Jehovah’s Witnesses

• CBC, PT, PTT to assess baseline blood counts and levels of coagulation factors. • Discuss privately with the patient his desires regarding transfusion should it be medically indicated, explaining all blood derivatives and conservation strategies available. • Enlist the assistance of your hospital chaplain as necessary to aid you in the discussion.

prognosis is grim. The oncologist typically understands and supports their choice. I think the same principle applies here.

Eight-Second Summary

Integrate the tenets of your patient’s particular religion with his personal understanding of that faith, discuss the full range of transfusion options available to him/her at your facility, and generate a treatment plan together.

Suggested Reading

1. Sniecinski RM, Levy JH. What is blood and what is not? Caring for Jehovah’s Witness patient undergoing cardiac surgery. Anesth Analg 2007; 104(4):753-754. 2. Watch Tower Bible and Tract Society. Questions from Readers. Watchtower 1978; 15:30-31; 1990; 1:30-31; 2004; 15:22. 3. Rogers DM, Crookston KP. The approach to the patient who refuses blood transfusion. Transfusion 2006; 46:1471-1477. 4. Shander A, Goodnough LT. Objectives and limitations of bloodless medical care. Curr Opin Hematol 2006; 13:462-470.

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CHAPTER 10

Transfusion Reactions Key Principles • Pre-medication with acetaminophen does not prevent febrile non-hemolytic transfusion reactions to the degree once thought. Do not use it on every patient. • Stop all transfusions where the patient’s temperature rises above 1.0˚C or 2.0˚F from the baseline (pre-transfusion vital signs) and initiate a transfusion reaction work-up, regardless of the patient’s fever curve or subjective symptoms. • ABO incompatibility, bacterial contamination and anaphylaxis are potentially fatal reactions that demand immediate aggressive intervention. • Febrile non-hemolytic transfusion reactions (FNHTR) are mediated by cytokines and/or antibodies to human leukocyte antigens (HLA). • Allergic and anaphylactic reactions are mediated by plasma proteins in the donor unit and IgE antibodies in the recipient. • Transfusion-related acute lung injury (TRALI) is an acute reaction manifested by non-cardiogenic pulmonary edema and clinical respiratory compromise. It demands aggressive management. • Delayed hemolytic transfusion reactions typically occur 7-10 days after transfusion and vary in severity, occasionally requiring additional RBC support for the patient.

Chapter Overview

This chapter outlines the actions to take when you are informed by a nurse, or discover yourself, that your patient may be reacting to a transfusion, and it describes the major transfusion reactions in adequate detail for you as a practicing clinician. Your primary task is to treat a patient experiencing anything from mild urticaria to acute hypotensive collapse. Your secondary task is to determine if additional blood products are required, once the offending unit has been disconnected and returned to the Blood Bank. Most transfusion reactions are mild in terms of signs and symptoms, thankfully, but you should approach each one as potentially severe until you have fully evaluated the patient. I divide reactions into the acute, which you’ll be called about by the nurse and which are covered more comprehensively, and the less common delayed reaction, which I’ll touch on briefly. Transfusion Medicine: A Clinical Guide, by Katherine Schexneider. ©2008 Landes Bioscience.

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Basic Concepts Pre-Medication

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You will not prevent every febrile non-hemolytic transfusion reaction with pre-medication with acetaminophen, so do not order it on all your patients. Many physicians have been taught that pre-treating patients with 650 mg acetaminophen and 25 mg diphenhydramine per os prior to transfusion is a standard order, and one which will likely prevent the development of that minor fever which interrupts a transfusion. When a patient develops a fever during a transfusion, you are called to the bedside to evaluate him/her when you have many other patient-care tasks to complete already, and the transfusion of needed blood is delayed while the Blood Bank does the reaction work up. Better to avoid this if at all possible, right? Yes, but…pre-medication with acetaminophen does not really blunt the febrile reaction. Tobian’s 2007 review on this topic showed that the rates of febrile non-hemolytic transfusion reactions (FNHTR) and allergic reactions (ATR) to be similar, or even increased with pre-medication (Transfusion article). The largest study reviewed found a rate of 17.8% (FNHTR + ATR) in the treatment group vs. 19.3% in the controls. I suggest that you avoid ordering acetaminophen except in the following situation: if your patient has an established fever prior to transfusion, acetaminophen may dampen the fever curve long enough for you to complete the transfusion without a spike that will cause the transfusion to be interrupted. This might be a neutropenic fever patient on the oncology ward or a postoperative patient with an infection. Order it then. For all other patient’s it’s reasonable to skip the acetaminophen. If they develop a fever, then give it; you probably would NOT have avoided this situation anyway.

What Is a Transfusion Reaction and What Do I Do?

A transfusion reaction is an adverse patient response during or shortly after infusion of blood products. While most often manifested by an increase in the patient’s temperature, it also includes chills, urticaria, shortness of breath and tachypnea, pain in the flanks or at the infusion site, hypotension, tachycardia, and other symptoms of discomfort. When are any of these signs severe enough that you should stop the transfusion and call a reaction? A hard rule that I use is to stop ALL transfusions if the patient’s temperature increases ≥1.0˚C or 2.0˚F from the baseline, pre-transfusion temperature recorded by the nurse. The only way the Blood Bank (and you) can rule out an acute hemolytic transfusion reaction, the ABO-incompatible RBCs disaster, it to stop the transfusion and complete the work-up. I hold to this rule even when the patient has been febrile earlier that day, when the RBCs are labeled as group O, when everyone is certain that this is just a benign fever. You should follow this rule too, every time. What about the other signs and symptoms? Here, you have some leeway and should use your good judgment. If a cachectic elderly woman experiences mild chills while a unit of 3˚C RBCs go into her veins, but her temperature is stable, it might be reasonable to give her an extra blanket and monitor her closely as the transfusion proceeds. Also, you can stop any transfusion at any time for any reason if you suspect that the patient is in distress. The patient’s discomfort may be unrelated to the transfusion, but the Blood Bank will sort that out. Better to be safe than sorry.

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What should you do when the nurse calls a transfusion reaction? We just covered Step One, which is to stop the transfusion. Step Two for you is to assess the patient and determine if this is a serious reaction, requiring urgent medical intervention to stabilize the patient. The key signs would be hypotensive collapse and, in some cases, high fever (>2-3˚F above the baseline). We will discuss below the causes of the serious transfusion reaction. What you need to do is quickly check the vital signs, responsiveness and symptoms. If the patient is decompensating, maintain IV access and treat as you would any case of acute collapse, with IVF, pressors, respiratory support, etc. If fever is present, draw blood cultures once you have addressed the tasks above. If you are a house officer, call your staff. Thankfully, the above reaction happens very rarely. Far more frequently, you will be called to the bedside of someone with a moderate increase in temperature, chills, and perhaps some subjective complaints that are completely indistinguishable from those voiced at the three-hour H+P you struggled to complete a few nights ago when you admitted the patient. Here, stop the transfusion, keep the IV line open with a fluid rate that the patient can tolerate. Step Three is to ensure that the nursing staff draws blood samples from the patient (usually 1-2 EDTA tubes, but this may vary in your hospital) calls the Blood Bank to report a transfusion reaction, completes a reaction form, and sends the form, the samples and the remaining blood (even a virtually empty bag is OK) to the Blood Bank. Step Four is for you to speak to the Blood Bank physician about the results of the work-up and make him/her aware of additional blood products you need. If your patient was anemic but only received one-third of a unit of RBCs before the reaction, you probably want another unit. Communicate this to the Blood Bank physician. Also, discuss performing cultures on the unit, if it was RBCs or platelets; and on the patient if he/she had an increase in temperature as part of the reaction. I recommend culturing patients if they were not febrile in the 24-48 hours prior to the transfusion, or if the temperature spike is significant, say >1.5˚C or 3.0˚F from the baseline. I do not think you need to culture a patient with an established fever curve who goes up 1.1˚C from his baseline in every case. Step Five is to give additional blood products as needed once the work-up is complete. What exactly does the Blood Bank do in the work-up? First, they review the paperwork on the patient, his ABO history and the transfusion paperwork attached to the unit of blood, to ensure that the right blood went to the right patient. Next, they look for gross hemolysis in one of the EDTA tubes sent with the reaction form. They also perform a DAT on the patient, looking for antibodies attached to the transfused RBCs, and compare this to a DAT run on the pre-transfusion sample. Some patients have a positive DAT at their baseline, so the technicians are looking for a newly positive, or at least much stronger reaction. The Blood Bank also rechecks the ABO and Rh types of the patient as a method of confirming the identity of the recipient. If the ABO of the transfused patient does not match that of the intended recipient, that’s a problem. The Blood Bank may recheck the ABO type of a RBC unit, although this task is performed two or three times prior to labeling. Finally the unit may be sent to the microbiology section for cultures of the Blood Bank physician orders this. In my Blood Bank, I do not request a

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urine sample for hemolysis unless I really think there has been an ABO mismatch, which thankfully I have not experienced. These tasks take less than one hour in most Blood Banks and are all geared toward ruling out ABO incompatibility. The reason you need to wait for your Blood Bank to get these done is to avoid making the ABO-incompatible error twice. Now, let’s run through the specific types of transfusion reactions. The first three we’ll cover are the acute disasters which require immediate, aggressive intervention by you.

Acute Hemolytic Transfusion Reaction

10

The acute hemolytic transfusion reaction (AHTR) classically occurs when ABO-incompatible red cells are transfused to a recipient. This is a disaster and is frequently fatal. It is the reason that Blood Banks are so darn picky about patient samples and starting transfusions with two nurses. The pathophysiology is described clearly by Davenport as occurring in three phases ( Transfusion Reaction book chapter). First, antibodies bind to red cell antigens, with or without complement activation. Next, the antibody-coated red cells interact with phagocytic cells and cause in the third phase the release of inflammatory mediators, including interleukin 1 (IL-1), IL-6 and tumor necrosis factor (TNF). Complement activation plays the central role in causing hypotension, via the anaphylatoxins C3a and C5a. TNFα plays a key part in initiating DIC. The mechanism of renal failure is not solely due to the actions of free hemoglobin, although it can cause constriction of afferent arterioles by reducing local nitric oxide. The effects of hypotension and thrombi generated in DIC are the drivers of renal compromise. Your primary task, once you have stopped the transfusion, but before the diagnosis of AHTR has been established in the Blood Bank, is to maintain blood pressure and renal perfusion. Have the nurses send blood samples to the Blood Bank, but just support the patient. Once the results come back that this is an AHTR, continue IVF and renal perfusion with dopamine and begin to diurese briskly with furosemide or mannitol. If DIC is present and causing clinical hemorrhage, consider giving FFP and platelets. In severe cases, a red cell exchange will be indicated to remove the incompatible red cells.

Bacterial Contamination

Occult bacteremia or skin flora from blood donors can grow in RBC or platelet units and cause immediate (minutes) or rapid-onset (few hours) clinical sepsis in recipients. The common agents cultured from red blood cell units are gram-negative rods, including Yersinia enterocolitica, Serratia spp. Pseudomonas spp. Enterobacter spp. and Escherichia coli, among others. In platelets, the organisms are often gram-positive cocci, such as Staphylococcus aureus, coagulase-negative staphylococci, and streptococci. Typically, clinical sepsis is more severe with gram-negative organisms. The patient usually develops fever, often high, hypotension, nausea and vomiting, and rigors during the transfusion. This sounds just like the presentation for AHTR. You do not need to distinguish between AHTR and bacterial contamination in the first minutes of the reaction, Stop the transfusion, maintain IV access and begin fluid resuscitation, treating for evolving shock. The Blood Bank will be able to determine if this is an AHTR within a short time (30 minutes). If the patient is crashing with a fever and it is not AHTR, presume sepsis

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and begin broad antibiotic coverage in addition to resuscitative efforts. Draw blood for cultures before starting antibiotics and have someone ensure that the Blood Bank cultures the offending unit. When culture results are available from your laboratory, you can specifically direct your antibiotic therapy. Platelet contamination is less frequent since bacterial culturing of all apheresis platelets began in 2004, but is can still occur, and red cells are not cultured.

Anaphylaxis

Anaphylaxis occurs when a specific plasma protein is transfused to a patient with high levels of IgE antibody against that protein. This is the third acute collapse to know about. It is an example of Type I hypersensitivity, and a key feature is the lack of fever. The main features are respiratory, with stridor, wheezing, dyspnea and anxiety; cardiovascular, with hypotension, tachycardia and shock; and gastrointestinal, with nausea, vomiting and diarrhea. The classic description of the anaphylactic reaction is in patients who lack IgA and have formed anti-IgA antibodies of the IgE class. However, many anaphylactic, or anaphylactoid reactions lack a clear etiology, as the patient’s IgA levels are found to be normal. I believe the IgA issue to be a moot point at the time of the reaction. Your role is to provide immediate cardio-respiratory support to the patient with epinephrine, volume expansion, dopamine as needed, and endotracheal intubation if necessary to maintain the airway. Your first question when you are called to the bedside to a rapidly decompensating patient will be, is there a fever? If there is not, suspect anaphylaxis and focus your attention on the airway and ensuing hypotension. You still need to send a sample to the Blood Bank to rule out AHTR, but the afebrile patient, particularly if he/she is demonstrating respiratory distress, needs epinephrine, not mannitol and not antibiotics. Send labs for the patient’s IgA levels when the crisis has passed.

Febrile Non-Hemolytic Transfusion Reaction

Febrile non-hemolytic transfusion reactions (FNHTR) are common, benign febrile reactions which are mediated by recipient antibodies to human leukocyte antigens on WBCs in the donor unit or by cytokines and other biologic response modifiers in the unit itself. Researchers determined 50 years ago that patients who had formed antibodies to antigens on WBCs from a previous transfusion or from pregnancy could react to donor WBCs in a unit of either RBCs or platelets and cause release of pro-inflammatory cytokines—Il-1, IL-6 and TNFα. Another, related mechanism is that those same antigen-antibody interactions activate complement and subsequent cytokine release from recipient macrophages. Finally, WBCs in a donor unit of RBCs or platelets will release these cytokines over time in storage and may play a role in development of fever, although this last mechanism is not wholly clear. The symptoms of the FNHTR—fever, chills, occasionally headache or GI upset—typically occur well into the transfusion, or even in the couple of hours after completion. However, the fever is usually moderate, less than 2˚C up from the baseline, and the patient is otherwise stable. Remember, a fever in a patient receiving a blood transfusion cannot be assumed to be a FNHTR until the Blood Bank has completed the work-up. The task here is the same. Stop the transfusion, assess the patient, initiate the reaction work-up and treat the fever with acetaminophen as the patient can tolerate.

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Allergic and Urticarial Reaction

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The allergic or urticarial reaction is the mild end of the spectrum of IgE-mediated reactions. The patient has preformed IgE to some protein in the plasma of the unit. Upon exposure, the patient develops urticaria and pruritis, often on the face, arms or trunk. There is mild discomfort. Fever is not a component of this reaction. These reactions may be rate-dependent, and slowing the infusion of FFP or platelets, if these are the products being transfused, may allow you to continue transfusing that particular unit. In this case, your actions are to stop the transfusion, but do not disconnect the unit. Assess the patient for possible anaphylaxis. When you are confident that he/she is stable and simply manifesting wheals, treat with diphenhydramine, 25-50 mg PO, and wait for resolution of the symptoms. If the patient improves, you may continue the transfusion of the same unit at a somewhat slower rate, observing closely that the symptoms do not recur or worsen. In this case alone, you need not call the Blood Bank and report a transfusion reaction, although if you wish to have the assistance of the Blood Bank physician in evaluating the case, that’s fine. Does one allergic/urticarial reaction mean that this patient should always be pre-medicated with diphenhydramine prior to a transfusion? I don’t think so. Chronically transfused patients, such as those with leukemia or myelodysplastic syndrome, often tolerate many transfusions without incident, and then experience urticaria on an isolated occasion. It is likely there was a protein in that one unit that matched up with the patient’s IgE. Will that same protein be in the next unit? Who knows. I recommend offering standing orders for diphenhydramine to patients with recurrent allergic reactions, especially if they are increasing in intensity, but not for isolated events.

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury ( TRALI) is a newly-described complication of transfusion characterized by respiratory embarrassment due to non-cardiogenic pulmonary edema. It has two, probably overlapping, theories of pathogenesis. Both involve a two-hit hypothesis. The first hit is the priming of the patient’s neutrophils and their localization to pulmonary endothelial cells and is the same for both theories. One theory holds that the second hit is due to antibodies in the donor unit which attach to corresponding HLA or human neutrophil antigens (HNA) on the neutrophils, causing the release of oxygen radicals. This leads to a pulmonary capillary leak syndrome and subsequent pulmonary edema. The alternate theory suggests that biologically active lipids, which have accumulated in units stored for several weeks, cause neutrophil priming as well, leading to the same capillary leak syndrome. While the first (antibodies to HLA/HNA) theory helps explain TRALI occurring with platelet and FFP transfusions, the lipid mediator theory applies better to TRALI where the implicated unit is RBCs. The Blood Bank investigation of TRALI is complex, costly, and often unrewarding. Samples from the patient are required to determine his/her HLA phenotype, and samples must also be obtained from all donors (if there were multiple units given around the time of the symptoms) to test for anti-HLA or anti-HNA antibodies. Frequently, one or more donors are found to have broadly reactive anti-HLA antibodies; it is rare that a clean antigen-antibody match is identified.

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How does TRALI present clinically? The reaction occurs within six hours of transfusion, often within two hours. Respiratory symptoms, dyspnea and cough, dominate the picture, and fever is common as well. Blood pressure changes are variable, and both hypertension and hypotension have been described. If the patient is intubated already, you may see pink, frothy sputum coming from the endotracheal tube. Oxygen saturation drops, and supplemental oxygen or increased ventilatory settings are required to maintain adequate saturation. Chest radiographs reveal bilateral infiltrates. If a pulmonary artery catheter has been placed, an occlusion pressure of ≤18 mm Hg, supports the diagnosis, in keeping with TRALI as non-cardiogenic pulmonary edema. Evidence of left atrial hypertension is absent. Hypoxemia is defined as a PaO2/FiO2 ratio of ≤300 mm Hg or O2 saturation of ≤90% on room air. TRALI is a clinical diagnosis, using the above criteria. The laboratory work-up will take 1-2 weeks and may be non-contributory. Ultimately, laboratory confirmation is not required to render this diagnosis. Thus, your treatment approach will be based on clinical suspicion. Your tasks are to assess each patient with a transfusion reaction for respiratory compromise and provide support for as long as the patient requires. Two aspects of respiratory management are imperative to keep in mind. First, the extent of pulmonary edema is variable from patient to patient and can progress rapidly over hours. Monitor any patient with dyspnea after a transfusion very closely for worsening of symptoms and prepare to transfer him/her to the ICU, to intubate if necessary. Second, diuretics are not indicated in the treatment of TRALI and may cause catastrophic hypotension. You do use diuretics in simple cases of fluid overload, and you are familiar with this approach. If the pulmonary artery catheter pressure supports TRALI, avoid furosemide and maintain arterial blood pressure at around 60 mm Hg with IVF. What if you can’t distinguish between fluid overload and TRALI? Use the PA catheter to help you. Also, use the patient’s history. If this was a previously healthy person who now has florid respiratory failure after a transfusion and does not yet have a PA catheter, think TRALI before fluid overload. If it is someone with a well-known history of congestive heart failure who has received a large volume of fluids, then it’s reasonable to try diuresis first.

Delayed Hemolytic Transfusion Reaction

The delayed hemolytic transfusion reaction (DHTR) occurs 7-10 days after transfusion of red cells which carry an antigen to which the recipient has made antibodies from a previous exposure. An anamnestic response with quickly rising titers of antibody against the antigen causes mild-moderate hemolysis of the transfused red cells. A classic example of this type of reaction involves the Kidd antigens. Here’s how it works. A patient negative for, say, Jka, would have been transfused in the past with Jka positive RBCs and formed anti-Jka antibodies. These particular antibodies often wane over time, and when the patient was tested at your hospital Blood Bank, he/she showed no evidence of the antibody, and was inadvertently given Jka positive red cells again. At this point, the anamnestic response takes hold, over several days, resulting in clinical hemolysis and a drop in Hct. As the DHTR occurs a week or so out from the transfusion, the patient may not be in the hospital to manifest the lower Hct. If the reaction is fairly mild, he/she may not even notice the effects of relative anemia and jaundice. If your patient is still in-house and you

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Role of Laboratory Tests for Transfusion Reaction

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Test DAT

Use Blood Bank evaluates for antibodies on the transfused red cells

Blood cultures

If bacterial contamination is suspected, perform on both patient and unit of RBCs or platelets Decrease in haptoglobin, increase in other labs support hemolysis

Haptoglobin, serum/urine hemoglobin, indirect bilirubin, LDH

Limitations If all the red cells have been hemolyzed, or if patient has an existing positive DAT, less useful NA

Somewhat less useful in patients with pre-existing hemolysis (HbSS disease), but helpful in all other cases

note these findings, call the Blood Bank. They will test your patient for current antibodies and can test the offending unit for its phenotype. You will support the patient with additional transfusions, of antigen-negative red cells, as needed. The primary way that Blood Banks prevent DHTRs is by honoring past antibody formation, even if the patient does not show a specific antibody on the current T+S. It is usually when a patient is new to a particular hospital Blood Bank and has undetectable antibody levels that the DHTR happens. You will not be called about this reaction in the middle of the night, and thankfully, the DHTR is usually mild. What is important is that you notify the Blood Bank if you suspect it, so they will not issue additional antigen-positive units to someone whose immune system is now activated. That would result in significant hemolysis.

The Whole Patient

The key question to ask here is: what effect will the transfusion reaction have on my patient’s treatment plan and hospital course? The answer may be simple; if it is a FNHTR, and your patient is still anemic or thrombocytopenic, order additional blood products to complete the transfusion plan. If the reaction is serious, one of the big three I outlined, then unfortunately you must treat hemolysis, bacterial sepsis

Quick Question Will pre-medication or a leukoreduction filter help prevent a DHTR due to an antibody identified on the T+S? No. Giving antigen-negative red cells will prevent the delayed hemolytic transfusion reaction. Pre-medication may or may not, as we learned, prevent FNHTR or ATR. The LR filter reduces the number of WBCs transfused in a RBC or platelet unit. It has no effect on the antigens on the red cells.

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Treatment Plan for Transfusion Reaction

• STOP the transfusion. • Assess the patient: review vital signs, auscultate lungs, ask about subjective complaints. • Maintain IV access. • Treat acute hemolysis (AHTR) with aggressive IVF, furosemide or mannitol for diuresis, and renal-dose dopamine (1-5 μg/kg/min). • Treat bacterial sepsis with IVF and pressors to support BP initially. Once AHTR has been ruled out, consider broad coverage antibiotics until cultures turn positive. • Treat anaphylaxis with epinephrine: 0.3-0.5 mL of a 1:1000 solution SQ, Q20-30 minutes for less severe reactions; 5 mL of a 1:10,000 solution IV, Q 5-10 minutes for intractable hypotension. • Treat bronchospasm with aminophylline 6 mg/kg IV as a loading dose. • Treat FNHTR with acetaminophen, 650 mg PO. Severe rigors may be managed with Demerol. • Treat allergic reactions with diphenhydramine 25-50 mg PO, IM, or IV. • Treat suspected TRALI with respiratory support, close monitoring of respiratory status, and intubation if required. Avoid diuretics.

or anaphylaxis as well as the patient’s primary disease. Thankfully, these reactions are very rare. Far more often, the transfusion reaction is a brief bump in the road. Use the guidelines provided, stop to think (I know you thought I was going to say, “Stop the transfusion.”), assure yourself that the reaction is not one of the big three, treat the patient and move on.

Eight Second Summary

Stop the transfusion, assess all patients for acute decompensation, provide supportive care as required and call the Blood Bank for assistance.

Suggested Reading

1. Tobian AA, King KE, Ness PM. Transfusion premedications: a growing practice not based on evidence. Transfusion 2007; 47:1089-1096. 2. Popovsky MA, ed. Transfusion Reactions. Bethesda: AABB, 2007:1-156. 3. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury: a review. Chest 2004; 126:249-58.

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INDEX

ABO-compatible platelet 43, 44, 91 ABO-type 3, 137 Acetaminophen 20, 135, 136, 139, 143 Acidosis 55, 62-67, 69, 73, 77, 78 Activated factor VII 94, 96, see also Recombinant factor VIIa Activated protein C 70, 72, 73 Acute chest syndrome 18 Acute hemolytic transfusion reaction 136, 138 ADAMTS 13 41, 50-53 Adenosine diphosphate (ADP) 54 AIDS 67, 98, 121, 126, 128 Allergic/urticarial reaction 140 Allogeneic blood 105, 121-125, 127 Aminophylline 143 Anaphylaxis 135, 139, 140, 143 Anemia 7-15, 17-19, 21-23, 42, 47, 50, 51, 55, 65, 66, 70, 76, 84, 89, 97-102, 105, 108, 110, 111, 115, 124, 127, 132, 141 Antibody 1, 2, 4, 5, 7, 10, 13-18, 21, 43-45, 47-49, 64, 69, 72, 73, 84, 85, 86, 93, 98, 100, 107-116, 126, 127, 135, 137-142 Antibody screen 2, 5, 7, 15, 17, 108, 109, 111, 112 Antigen 1-3, 7, 13-18, 43, 44-49, 60, 84, 86, 92, 100, 104, 107-109, 112-116, 121, 127, 135, 138-142 Antiplatelet agent (APA) 41, 56-58 duration of effect 56, 58 Arterial blood gas (ABG) 63-65, 69, 73, 78-80, 106 ASCO guideline 90, 91, 93, 103 Aspirin 41, 56, 57 Autoimmune hemolytic anemia (AIHA) 13, 14, 17-19

Autologous blood 122, 123 Autologous donor 121-123

B Bacterial contamination 43, 135, 138, 142 Bacterial sepsis 142, 143 Bible 129, 131, 132 Blood conservation 130, 131 Bronchospasm 143

C Cardiac disease 8, 9 Cell salvage 105 Cell-saver 131 Cesarean section 75, 76, 81, 83, 85, 86, 114 Chelation 18, 98-101 CMV titer 5 Coagulopathy 13, 14, 23-25, 29, 31, 33-36, 38-40, 59-63, 65-67, 69, 73, 77-80, 82, 97, 103, 104, 107, 117-119, 132 Congestive heart failure (CHF) 11, 12, 22, 24, 99, 141 Coombs test 5 Coronary artery disease (CAD) 22, 24, 73, 89 Corticosteroid 14, 18, 48, 49, 80, 81, 85, 87 Crossmatch 1-3, 6, 15-17, 20, 60, 86 Cryoprecipitate 1-3, 5, 6, 12, 35, 41, 55, 56, 59-62, 64-68, 75, 78-80, 90, 94, 96, 97, 102, 104, 105, 116, 119, 130 Culture 137, 139, 142, 143 Cytomegalovirus (CMV) 1, 3-6, 90, 92, 93, 102, 115, 117

INDEX

A

146

D

INDEX

Dedicated unit 115, 116 Deferasirox 17, 101 Deferral rate 127 Delayed hemolytic transfusion reaction (DHTR) 16, 60, 135, 141, 142 Desferrioxamine 17 Dexamethasone 81 Dialysis 18, 54, 55, 56 Diphenhydramine 20, 136, 140, 143 Direct antiglobulin test (DAT) 5, 18, 19, 108, 109, 111, 112, 137, 142 Directed donation 89, 98, 102, 105, 121, 126-129 Disseminated intravascular coagulation (DIC) 25, 31-35, 39, 40, 59, 61, 62, 65-72, 75, 77-86, 96, 97, 104, 117-119, 138 Diuretic 141, 143 Donor exposure 115, 116, 127, 129 Dopamine 138, 139, 143

E Electrolyte 23, 24, 55, 59, 63, 64, 69, 106 Emergency-release 60 Epidural catheter 75, 81, 83, 85, 86 Epinephrine 139, 143 Erythropoietin (EPO) 122-125, 131 Estimated blood loss (EBL) 13, 21-24, 65, 76, 78, 103, 105, 106, 122, 124, 125, 129

F Febrile non-hemolytic transfusion reaction (FNHTR) 4, 92, 135, 136, 139, 142, 143 Ferritin 17, 99, 100, 101

Transfusion Medicine: A Clinical Guide

Fever 20, 22, 24, 42, 46, 51, 71, 73, 81, 84, 91, 92, 135-141 Fibrinogen 25, 32, 33, 35, 54, 61-65, 67-69, 73, 79, 80, 82, 84, 85, 96, 97, 104, 105, 117-119 Formula for the delivery of oxygen 11 Fractionation 130, 132 Fresh frozen plasma (FFP) 1-3, 5, 6, 12-14, 25, 29, 30-41, 45, 50, 52, 59-62, 64-68, 70, 72, 73, 75, 78-80, 94, 96, 97, 102, 103, 105, 110, 116, 118, 119, 128, 130, 138, 140

G Gestational thrombocytopenia 84 GPIIb/IIIa inhibitor 56

H Hemolysis 12-20, 45, 52, 60, 64, 75, 80, 81, 84, 99, 104, 108, 109, 111, 137, 138, 141-143 Hemolytic disease of the newborn (HDN) 107-112 Hemophilia A 25-28, 35, 117 Heparin 57, 68, 71-73 Heparin-induced platelet aggregation assay 72 Heparin-induced thrombocytopenia (HIT) 42, 71-73 Hepatitis C virus 126 Herpes simplex 117 Human immunodeficiency virus (HIV) 29, 49, 77, 114, 126, 127 Human leukocyte antigen (HLA) 1, 4, 44, 45, 49, 90, 92, 93, 115, 116, 127, 129, 135, 140 alloimmunization 4, 90, 92, 127, 129

Index

I Iatrogenic blood loss 107, 116 IgA 139 IgE 135, 139, 140 Immune thrombocytoenic purpura (ITP) 41, 42, 47-50, 75, 81-87, 113 maternal 81, 84-87, 113 International normalized ratio (INR) 25, 29-40, 65, 67, 72, 73 Intracranial hemorrhage (ICH) 29, 30, 42, 44, 46, 48, 50, 54, 72, 73, 96, 107, 112-114, 117-119 Intravenous immunoglobulin (IVIg) 14, 18, 19, 21, 48, 50, 85-87, 113, 114 Iron overload 17, 18, 89, 98-101 Irradiation 1, 3, 4, 43, 90, 92, 93, 102, 127

J Jaundice 81, 108, 141 Jehovah’s Witnesses 121, 129-133 Joint arthroplasty 122, 123

L Leukoreduction 1, 4, 42, 43, 90, 92, 95, 96, 142 Liberal strategy 95 Lumbar puncture 38, 46, 91

M Magnesium sulfate 63, 80 Mannitol 138, 139, 143 Massive transfusion 59-67, 69, 70, 75, 78-80, 82, 83, 89, 103, 105, 106 Maternal ITP see Immune thrombocytoenic purpura (ITP) Maximum allowable blood loss (MABL) 102, 103, 105, 106 Microvascular bleeding 36, 37, 66-68, 75, 80, 96, 97, 103-105

N Neonatal alloimmune thrombocytopenia (NAIT) 86, 107, 112-115, 117 Neonatal coagulopathy 117-119 Neonatal patient 4, 8, 107

O Out-of-group platelet 45, 91, 104 Oxygen delivery 11

P Parents 29, 89, 98, 102, 105, 111, 112, 116, 120, 121, 126-128, 131 Pediatric oncology patient 90 Percutaneous procedure 25, 38, 39 Phenotypically-matched RBC 15 PICU 89, 94, 95, 96, 97 Platelet 1-4, 6, 12-14, 23, 24, 26, 28, 32-37, 39-75, 78-94, 96, 97, 102105, 107, 112-119, 124, 127, 128, 130, 132, 137-140, 142 functional defect 54 Platelet-associated IgG 84 Platelet refractoriness 2, 42, 91 Postpartum hemorrhage (PPH) 60, 63, 76-80

Index

Human neutrophil antigen (HNA) 140 Human platelet antigen (HPA) 112 Hydrodynamics 55, 56 Hyperhemolysis 19 Hypotensive collapse 135, 137 Hypothermia 61-67, 78 Hypoxic-ischemic encephalopathy (HIE) 117, 119 Hysterectomy 76, 77

147

148

Potassium 23, 63, 89, 102, 109, 115 Pre-medication 135, 136, 142 Preoperative autologous donation (PAD) 122-125, 131 Priapism 18, 19 Primary component 129-131, 133 Prophylactic transfusion 44, 48, 55, 57, 90, 91 Prothrombin complex concentrate (PCC) 30, 73

R INDEX

Recombinant factor VIIa (rVIIa) 30, 33, 66, 68-70, 72, 73, 78, 83, 97, 118, 130, 131 Red blood cell (RBC) 1-10, 12-24, 38, 41, 44, 45, 56, 59-64, 66-68, 70, 71, 73, 75-80, 83, 86, 89, 90, 93, 95, 97, 102, 103, 105, 106, 108-111, 115, 116, 121, 123, 127-133, 135-142 RBC exchange 17, 19, 21 Renal failure 51, 54, 55, 73, 138 Respiratory distress and respiratory compromise 8, 10, 14, 39, 135, 139, 141 Restrictive strategy 94-96 Rh immune globulin (RhIG) 104, 109, 130

S Sepsis 37, 51, 69, 71-73, 113, 117, 118, 138, 142, 143 Sickle cell anemia (SCA) 7, 8, 13, 15, 17-19, 21, 76, 89, 98, 99, 102, 105 Stroke 11, 12, 18, 69 Subcapsular hematoma 82, 83 Surgery 7, 14, 21-24, 35-37, 56, 57, 60, 61, 67, 91, 102, 105, 106, 115, 119, 121-124, 126-128, 130-133

Transfusion Medicine: A Clinical Guide

T T+C 2, 3, 5, 10, 14, 16, 19, 60, 83 T+S 1-3, 5, 6, 10, 15-17, 60, 142 TA-GVHD 3, 43, 92, 93, 106, 116 Thalassemia 76, 89, 98-102, 104 Thienopyridine 56 Thrombotic thrombocytopenic purpura (TTP) 41, 42, 47, 5053, 71-73, 81-86 Tissue perfusion 23, 63, 70, 73, 74, 94, 97 Transfusion reaction 3, 4, 16, 39, 60, 92, 135-143 Transfusion-related acute lung injury (TRALI) 39, 135, 140, 141, 143

U Uremia 54-56, 71 Uterine atony 76

V Vitamin K 29-31, 33, 35, 117-119 Vitamin K-deficiency bleeding (VKDB) 118 von Willebrand disease (vWD) 26, 28, 29, 35, 117 von Willebrand factor (vWF) 26, 28, 29, 32, 33, 51-55, 67, 117

W Warfarin 14, 21, 25, 29-31, 34-37, 39, 72, 73 Washed maternal platelet 112, 114, 115 Washed RBC 7, 23, 110, 115 Wastage 123, 124, 126 Whole blood loss 12, 22, 59, 78

LANDES BIOSCIENCE

Table of contents 1. How to Order Blood

5. The Complex Patient

2. The Anemic Patient

6. The Obstetric Patient

3. The Coagulopathic Patient

7. The Pediatric Patient

4. The Thrombocytopenic Patient and Qualitative Disorders of Platelet Function

8. The Neonatal Patient

BIOSCIENCE

LANDES BIOSCIENCE

V ad eme c um

V ad e me c u m

LANDES

V ad e me c u m

Transfusion Medicine: A Clinical Guide

9. Other Special Patients 10. Transfusion Reactions

The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum.

Transfusion Medicine: A Clinical Guide

The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine.

The Landes Bioscience Vademecum books are intended to be used both in the training of physicians and the care of patients, by medical students, medical house staff and practicing physicians. We hope you will find them a valuable resource.

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Schexneider

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Katherine Schexneider