Haemophilia and Haemostasis: A Case-based Approach to Management

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Haemophilia and Haemostasis

Special thanks to Novo Nordisk

Haemophilia and Haemostasis: A Case-based Approach to Management Compiled from the Haemostasis/Haemophilia Forum

EDITED BY

Harold Ross Roberts, MD Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

ASSOCIATE EDITORS

Daniel Carrizosa, MD Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

Alice Ma, MD Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

© 2007 by Blackwell Publishing Blackwell Publishing, Inc., 350 Main Street, Malden, MA 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Author to be identiﬁed as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 1 2007 Library of Congress Cataloging-in-Publication Data Haemophilia and haemostasis : a case-based approach to management / compiled from the Haemostasis/haemophilia forum ; edited by Harold Ross Roberts ; associate editors, Daniel Carrizosa, Alice Ma. p.; cm. Includes bibliographic references and index. ISBN 978-1-4051-6716-1 (alk. paper) 1. Hemophilia. 2. Hemostasis. 3. Blood coagulation disorders. I. Roberts, H. R. (Harold Ross) II. Carrizosa, Daniel. III. Ma, Alice. IV. Haemostasis forum. [DNLM: 1. Blood Coagulation Disorders, Inherited—therapy—Collected Works. 2. Thrombosis—therapy—Collected Works.—WH 322 H134 2007] RC642.H325 2007 616.1572—dc22 2007010316 ISBN: 978-1-4051-6716-1 A catalogue record for this title is available from the British Library Set in 10/13 Meridien by Charon Tec Ltd (A Macmillan Company), Chennai, India Printed and bound in the United Kingdom by TJ International Ltd, Padstow Commissioning Editor: Maria Khan Editorial Assistant: Jennifer Seward Development Editor: Elisabeth Dodds Production Controller: Debbie Wyer For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Blackwell Publishing makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check that any product mentioned in this publication is used in accordance with the prescribing information prepared by the manufacturers. The author and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this book.

Contents

List of Haemostasis Forum Editors, ix List of Contributors, xv Preface, xix 1 Haemophilia A and Haemophilia B, 1 General Overview Haemophilia and Immune Tolerance Therapy, 3 The Haemophilic Ankle: An Update, 5 The Haemophilic Knee: An Update, 15 Issues with Complicated Diagnoses Combined Haemophilia A and B Carrier, 23 A Complex Case of Haemophilia with HIV and Hepatitis C, 25 A Case of Haemophilia B, Mild VWD, and a Factor IX Inhibitor, 29 Premature Infant with Haemophilia B, 33 Haemophilic Carriers Haemophilic Carriers and Delivery, 35 Mild Haemophilia in Women, 37 Treatment of the Pregnant Haemophiliac, 41 Anticoagulation and Haemophilia Anticoagulation for Atrial Fibrillation in a Haemophiliac, 43 Anticoagulation for a Cardiac Valve in a Haemophiliac, 47 Cardiac Catheterization in a Haemophiliac, 49 Anticoagulation for a DVT in a Haemophiliac, 51 Treatment of Haemophiliacs DDAVP for Treatment of Mild Haemophilia during Surgery, 55 Haemophilia and Haemodialysis, 57 Haemophilia and Hepatitis C Treatment, 59 Haemophilia and Physical Therapy, 63 Haemophilia and Renal Bleeds, 65 Haemophilia and Scuba Diving, 67 Haemophilia and Ventricular Septal Defect Repair, 69 Haemophilia with Hepatitis C and Recurrent Bleeding, 73 Isotretinoin in Haemophilia, 75 Laser Eye Surgery in a Haemophiliac, 77 Managing Haemophilic Pseudotumours, 79 Continuous NovoSeven: Pros and Cons, 81

i

ii Contents

Complications of Treatment Haemophilia B and Immune Tolerance with Anaphylaxis, 85 rFVIIa (NovoSeven), 87 Thrombosis in PCCs vs. APCCs, 91

2 Von Willebrand Disease, 93 Epidurals and VWD, 95 Anticoagulation for a Cardiac Valve in a Patient with VWD Type 1, 97 VWD Type 2A and Pregnancy, 99 VWD Type 2B and Pregnancy, 101 VWD Type 2B vs. Platelet Type, 103 Prophylaxis in VWD Type 3, 105 Platelet Type VWD, 107

3 Factor Deficiencies, 109 Combined Factor V and VIII Deficiency, 111 DVT Prophylaxis in FVII Deficiency, 113 Menorrhagia in Factor VII Deficiency, 115 Anticoagulation for Atrial Fibrillation in FX Deficiency, 119 Management of Factor X Deficiency, 121 Anticoagulation for Atrial Fibrillation in a Patient with Factor XI Deficiency, 123 Factor XI Deficiency and Surgery, 125 Prophylaxis for Patients with Factor XIII Deficiency and Intracranial Bleeding, 127

4 Rare Platelet and Coagulation Disorders, 129 Coagulation Disorders Afibrinogenaemia, 131 Dysfibrinogenaemia, 135 Hypofibrinogenaemia, 139 Gardner–Diamond Syndrome, 141 Hereditary Haemorrhagic Telangiectasia, 145 Hereditary Vitamin-K-Dependent Coagulation Factors Deficiency and Pregnancy, 151 Platelet Disorders Glanzmann’s Thrombasthaenia and Gastrointestinal Angiodysplasia, 153 Glanzmann’s Thrombasthaenia and Pregnancy, 157 rVIIa (NovoSeven®) and Wiskott–Aldrich Syndrome, 159

5 Acquired Bleeding Diatheses, 161 Acquired Haemophilia and Second Pregnancy, 163 Developing a Factor IX Inhibitor, 165 End-Stage Liver Disease and Surgery, 167 Treatment for Acute DIC, 169

6 Miscellaneous Questions, 173 Bleeding Time vs. PFA-100, 175 Cocaine and DDAVP, 177

Contents iii

Hyponatraemia and DDAVP, 179 The Use of the INR, 181 Selective Serotonin Reuptake Inhibitors and Clotting Disturbances, 185 Work-up for Children with Intracranial Bleeding, 189

7 Thrombotic Disorders, 193 Are Asians Genetically Different from Westerners When it Comes to VTE?, 195 Treatment of Antithrombin Deficiency, 201 Anticardiolipin Antibody Questions, 203 Paediatric Antiphospholipid Syndrome and Recurrent Thrombosis, 205 Anticoagulation for Deep Venous Thrombosis in the Presence of an Intracranial Haemorrhage, 209 Clinical Probability Assessment for Thromboembolic Disease, 213 D-dimer in Thromboembolic Disease, 215 Progestins and Thrombosis, 217 Unknown Thrombophilia and Surgery, 221

Index, 223

Haemostasis Forum: Disclaimer

The material in this book was originally from a forum created for health care professionals only. The information contained herein is for scientific communications and educational purposes only. There is no warranty or guarantee as to the timeliness, sequence, accuracy or completeness of the information presented in these pages, or any linked pages. Additionally, there are no warranties, express or implied, as to the results to be obtained from use of such information. Neither Novo Nordisk A/S nor its information providers shall be liable, regardless of the cause or duration, for any errors, inaccuracies, omissions, or other defects in the information, nor for the untimeliness and inauthenticity thereof or for any claims or losses by any third parties arising there from occasioned thereby. In cases where drug indications are discussed the views expressed may not necessarily reflect the licensed indications and approved prescribing information for your country. You are advised to consult your country’s prescribing information and qualified health care professionals before acting on any information presented in these pages. If you have or suspect you may have any health problems you should consult your health care provider. Any change in medication or treatment should be made cautiously and only under medical supervision.

viii

List of Haemostasis Forum Editors

Editor-in-Chief Harold Ross Roberts Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

Associate Editors Louis M. Aledort

Jørgen Ingerslev

Mt Sinai School of Medicine New York, NY, USA

Haemophilia Center Department of Clinical Immunology University Hospital Skejby Aarhus, Denmark

Henri Bounameaux Department of Medicine University Hospital of Geneva Geneva, Switzerland

Charles R.M. Hay Department of Haematology Manchester Royal Infirmary Manchester, UK

Ulla Hedner Professor, University of Lund Malmo, Sweden; and Research & Development Novo Nordisk A/S, Denmark

Keith Hoots Gulf States Hemophilia & Thrombosis Center University of Texas Houston Health Houston, TX, USA

Nigel S. Key Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

Jeanne Lusher Wayne State University School of Medicine Detroit, MI, USA

Peir M. Mannucci A. Bianchi Bonomi Hemophilia & Thrombosis Center University of Milan Milan, Italy

Victor Marder School of Medicine at UCLA Los Angeles, CA, USA

ix

x List of Haemostasis Forum Editors

Claude Négrier

Carmen Luisa Arocha-Piñango

Edouard Herriot University Hospital Lyon, France

Emeritus Researcher Instituto Venezolano de Investigaciones Cientiﬁcas Caracas, Venezula

Johannes Oldenburg Institute of Experimental Haematology and Transfusion Medicine University Clinic Bonn Bonn, Germany

Margaret Ragni Division of Hematology/Oncology University of Pittsburgh Physicians Pittsburgh, PA, USA

E. Carlos Rodriguez-Merchan Consultant Orthopaedic Surgeon Department of Orthopaedics and Hemophilia Unit La Paz University Hospital and Associate Professor of Orthopaedics Autonoma University Madrid, Spain

Guenter Auerswald Comprehensive Care Center for Thrombosis and Haemostasis Klinikum Bremen-Mitte Professor Hess Children’s Hospital Bremen, Germany

Ross Baker Thrombosis & Haemophilia Service Royal Perth Hospital Perth, Australia

Angelika Batorova National Haemophilia Center Bratislava, Slovakia

Kenneth A. Bauer Inge Scharrer Department of Haematology University of Mainz Mainz, Germany

VA Boston Healthcare System; and Beth Israel Deaconess Medical Center Harvard Medical School Needham, MA, USA

Erik Berntorp

Editorial Board Tom Abshire Department of Pediatric Hematology Emory University School of Medicine Atlanta, GA, USA

Malmo University Hospital; and Department for Coagulation Disorders Lund University Malmo, Sweden

Rául Pérez Bianco National Academy of Medicine Buenos Aires, Argentina

Pantep Angchaisuksiri Divison of Hematology Department of Medicine Ramathibodi Hospital Bangkok, Thailand

Paula Bolton-Maggs University of Manchester Manchester, UK

Brigit Brand Jovan Antovic Karolinska University Hospital & Institute Stockholm, Sweden

Haemophilia Center University Hospital Zurich, Switzerland

List of Haemostasis Forum Editors xi

Juan R. Cabrera

Joan Gill

Abel Santamaría Cuadrado University Hospital Pinar del Rio, Cuba

Blood Center of Wisconsin Milwaukee, WI, USA

Jenny Goudemand Marco Cattaneo University of Milan Milan, Italy

Hopital Cardiologique Lille, France

Walter B. Greene Donna M. DiMichele Pediatric Hematology/Oncology New York Presbyterian-Weill Cornell Center New York, NY, USA

Ivo Elezovic Institute of Haematology Clinical Center of Serbia Serbia, Yugoslavia

Miguel A. Escobar Assistant Professor of Medicine and Pediatrics University of Texas Health Science Center at Houston Associate Medical Director Gulf States Hemophilia & Thrombophilia Center Houston, TX, USA

Augusto B. Federici Associate Professor of Hematology Angelo Bianchi Bonomi Hemophilia Thrombosis Center Department of Internal Medicine University of Milan Milan, Italy

OrthoCarolina Charlotte, NC, USA

Philip G. de Groot Department of Haematology University Medical Center Utrecht, The Netherlands

John Hanley Department of Haematology Royal Victoria Inﬁrmary Newcastle Upon Tyne, UK

Michael Heim The National Hemophilia Center Sheba Medical Center Tel Hashomer, Israel

Kathy High Division of Hematology Childrens Hospital of Philadelphia Philadelphia, PA, USA

Jørgen Jespersen Department of Clinical Biochemistry Ribe County Hosp-Esbjerg Esbjerg, Denmark

Peter Jones Charles Forbes Ninewells Hospital & Medical School Scotland, UK

Royal Victoria Inﬁrmary Newcastle Upon Tyne, UK

Carol Kasper Paul Giangrande Oxford Haemophilia Centre Oxford, UK

Emeritus Professor of Medicine University of Southern California Pasadena, CA, USA

xii

List of Haemostasis Forum Editors

Kaan Kavakli Department of Pediatric Hematology Ege University Hospital Izmir, Turkey

Christine Kempton Emory University/CHOA Comprehensive Hemophilia Program Atlanta, GA, USA

Gili Kenet The National Hemophilia Center Sheba Medical Center Tel Hashomer, Israel

University of Pennsylvania Philadelphia, PA, USA

Christine Lee Emeritus Professor of Haemophilia University of London London, UK

Stefan Lethagen Center for Hemostasis & Thrombosis Copenhagen University Hospital Copenhagen, Denmark

Darla Liles Craig Kessler Comprehensive Treatment Center for Hemophilia and Thrombosis Georgetown University Medical Center Washington, DC, USA

Division of Hematology/Oncology East Carolina University School of Medicine Greenville, NC, USA

David Lillicrap Seiji Kinoshita Department of Clinical Chemistry and Laboratory Medicine Kyushu University Hospital Fukuoka, Japan

Carl Kirchmaier Deutsche Klinik fuer Diagnostik Wiesbaden, Germany

R.A. Kobelt President of the Medical Board Swiss Hemophilia Society Wabern, Switzerland

Marion Koerper Department of Pediatrics University of California San Francisco San Francisco, CA, USA

Barbara A. Konkle Professor of Medicine, Hematology/Oncology Penn Comprehensive Hemophilia & Thrombosis Program

Department of Pathology Queens University Kingston, Ontario, Canada

John Lloyd Division of Haematology IMVS Adelaide, Australia

Christopher Ludlam Department of Clinical & Laboratory Haematology Royal Inﬁrmary of Edinburgh Edinburgh, UK

Alice Ma Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

B. Gail Macik University of Virginia Charlottesville, VA, USA

List of Haemostasis Forum Editors xiii

German A. Marbet

Laszlo Muszbek

Hemostasis Laboratory University Hospital Basel Basel, Switzerland

University Debrecen Medical Health Science Center Debrecen, Hungary

Guglielmo Mariani

Thomas L. Ortel

Department of Internal Medicine and Public Health University of L’Aquila L’Aquila – Coppito, Italy

Division of Hematology/Oncology Duke University Medical Center Durham, NC, USA

Bjarne Østerud André Marinato Department of Hematology Medical Clinic College of Medicine of Ribeirão Preto Sao Paulo, Brazil

Department of Biochemistry Institute of Medical Biology Faculty of Medicine University of Tromso Tromso, Norway

Uri Martinowitz

K. John Pasi

Director, The National Hemophilia Center Ministry of Health The Chaim Sheba Medical Center Tel Hashomer, Israel

Professor of Haemostasis and Thrombosis Centre for Haematology Institute of Cell and Molecular Science Barts and The London, Queen Mary’s School of Medicine and Dentistry London, UK

EP Mauser-Bunschoten Department of Internal Medicine University Medical Center Utrecht Utrecht, The Netherlands

Jean McPherson University of Newcastle New South Wales, Australia

Miguel de Tezanos Pinto Instituto de Hematologia, Academia Nacional de Medicina Buenos Aires, Argentina

Man-Chiu Poon Massimo Morﬁni Hemophilia Center Ospedale di Careggi Florence, Italy

Foothills Hospital University of Calgary Calgary, Alberta, Canada

Kevin Rickard Michael Mosesson Blood Center Wisconsin Milwaukee, WI, USA

Institute of Haematology Royal Prince Alfred Hospital Sydney, Australia

Wolfgang Muntean

Chantal Rothschild

Department of Pediatrics University of Graz Graz, Austria

Centre Hemophilie F Josso Hopital Necker Paris, France

xiv

List of Haemostasis Forum Editors

Hussain Saba

Yvette Sultan

University South Florida Medical College/VA Hospital Tampa, FL, USA

Professor at the Faculty of Medecine Chief of the Haematology Service at the Hospital Cochin Paris, France

Geoffrey Savidge Haemophilia Centre St Thomas’ Hospital London, UK

Wolfgang Schramm Department of Hemostasis University Munich Munich, Germany

Edward Tuddenham Haemophilia Centre and Haemostasis Unit Royal Free Hospital London, UK

Herbert Watzke Medical University of Vienna Vienna, Austria

Sam Schulman Hamilton Health Sciences – General Hospital Hamilton, Ontario, Canada

Amy Shapiro Indiana Hemophilia and Thrombosis Center Indianapolis, IN, USA

Midori Shima Department of Pediatrics Nara Medical College Kashihara City, Japan

Jeffrey I. Weitz Henderson Research Center Henderson General Hospital Hamilton, Ontario, Canada

Brian Wicklund Children’s Mercy Hospital Kansas City, MO, USA

Wing-Yen Wong Childrens Hospital of Los Angeles Los Angeles, CA, USA

Guy Young Steen Sindet-Pedersen Eastman Dental Hospital and Institute London, UK

Pediatric Subspecialty Faculty Orange, CA, USA

Bülent Zülﬁkar Mark Smith Consultant Haematologist Canterbury District Health Board Christchurch, New Zealand

Alison Street Hematology Department Alfred Hospital Prahan, Australia

Department of Pediatric Hematology/ Oncology President of Hemophilia Society of Turkey Istanbul, Turkey

List of Contributors

Tom Abshire, MD

Erik Berntorp, MD, PhD

Department of Pediatric Hematology Emory University School of Medicine Atlanta, GA, USA

Malmo University Hospital; and Department for Coagulation Disorders Lund University Malmo, Sweden

Louis M. Aledort, MD Mt Sinai School of Medicine New York, NY, USA

Maureen Andrew, MD (deceased) Hospital for Sick Children Toronto, Ontario, Canada

Paula Bolton-Maggs, MD University of Manchester Manchester, UK

Henri Bounameaux, MD Department of Medicine University Hospital of Geneva Geneva, Switzerland

Pantep Angchaisuksiri, MD Divison of Hematology Department of Medicine Ramathibodi Hospital Bangkok, Thailand

Morio Arai, MD, PhD Tokyo Medical University Tokyo, Japan

Brigit Brand, MD Haemophilia Center University Hospital Zurich, Switzerland

Ernest Briet, PhD Sanquin Blood Supply Foundation Amsterdam, The Netherlands

Pilar Arranz, PhD Technical Director The Institute of Counselling, Antäe Madrid, Spain

Alice J. Cohen, MD Division of Oncology/Hematology Newark Beth Israel Medical Center Newark, NJ, USA

Karen Beeton Department of Physiotherapy University of Hertfordshire Hatﬁeld, Hertfordshire UK

Philip G. de Groot, PhD Department of Haematology University Medical Center Utrecht, The Netherlands

xv

xvi

List of Contributors

Donna M. DiMichele, MD

Robert L. Janco, MD

Pediatric Hematology/Oncology New York Presbyterian-Weill Cornell Center New York, NY, USA

Hematology Clinical Affairs Wyeth Pharmaceuticals Collegeville, PA, USA

Kaan Kavakli, MD Miguel A. Escobar, MD Assistant Professor of Medicine and Pediatrics University of Texas Health Science Center at Houston; and Associate Medical Director Gulf States Hemophilia & Thrombophilia Center Houston, TX, USA

Department of Pediatric Hematology Ege University Hospital Izmir, Turkey

Christine Kempton, MD Emory University/CHOA Comprehensive Hemophilia Program Atlanta, GA, USA

Augusto B. Federici, MD

Gili Kenet, MD

Associate Professor of Hematology Angelo Bianchi Bonomi Hemophilia Thrombosis Center Department of Internal Medicine University of Milan Milan, Italy

The National Hemophilia Center Sheba Medical Center Tel Hashomer, Israel

Craig Kessler, MD

OrthoCarolina Charlotte, NC, USA

Comprehensive Treatment Center for Hemophilia and Thrombosis Georgetown University Medical Center Washington, DC, USA

Ulla Hedner, MD, PhD

Nigel S. Key, MD

Professor, University of Lund Malmo, Sweden; and Research & Development Novo Nordisk A/S, Denmark

Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

Keith Hoots, MD

Barbara A. Konkle, MD

Gulf States Hemophilia & Thrombosis Center University of Texas Houston Health Houston, TX, USA

Professor of Medicine, Hematology/ Oncology Penn Comprehensive Hemophilia & Thrombosis Program University of Pennsylvania Philadelphia, PA, USA

Walter B. Greene, MD

Jørgen Ingerslev, MD Haemophilia Center Department of Clinical Immunology University Hospital Skejby Aarhus, Denmark

Maria Koopman, MD Sanquin Blood Supply Foundation Amsterdam, The Netherlands

List of Contributors xvii

Roshni Kulkarni, MD

Uri Martinowitz, MD

Director, Division of Hereditary Blood Disorders (DHBD) National Centers for Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, GA, USA; and Professor, Pediatric and Adolescent Hematology/Oncology Michigan State University East Lansing, MI, USA

Director, The National Hemophilia Center Ministry of Health The Chaim Sheba Medical Center Tel Hashomer, Israel

David Lillicrap, MD

K. John Pasi, MD, PhD

Department of Pathology Queens University Kingston, Ontario, Canada

Professor of Haemostasis and Thrombosis Centre for Haematology Institute of Cell and Molecular Science Barts and The London, Queen Mary’s School of Medicine and Dentistry London, UK

Ton Lisman, PhD Department of Haematology University Medical Center Utrecht, The Netherlands

Jeanne Lusher, MD Wayne State University School of Medicine Detroit, MI, USA

B. Gail Macik, MD University of Virginia Charlottesville, VA, USA

German A. Marbet, MD Hemostasis Laboratory University Hospital Basel Basel, Switzerland

Victor Marder, MD

Johannes Oldenburg, MD, PhD Institute of Experimental Haematology and Transfusion Medicine University Clinic Bonn Bonn, Germany

Man-Chui Poon, MD University of Calgary, Foothills Hospital Calgary, Alberta, Canada

Francis E. Preston, MD University Department of Haematology Royal Hallamshire Hospital Shefﬁeld, UK

Margaret Ragni, MD Division of Hematology/Oncology University of Pittsburgh Physicians Pittsburgh, PA, USA

Kevin Rickard, MD

School of Medicine at UCLA Los Angeles, CA, USA

Royal Prince Alfred Hospital Sydney, Australia

Guglielmo Mariani, MD

Harold Ross Roberts, MD

Department of Internal Medicine and Public Health University of L’Aquila L’Aquila – Coppito, Italy

Division of Hematology/Oncology University of North Carolina Medical School Chapel Hill, NC, USA

xviii

List of Contributors

E. Carlos Rodriguez-Merchan,

Edward Tuddenham, MD

MD, PhD

Haemophilia Centre and Haemostasis Unit Royal Free Hospital London, UK

Consultant Orthopaedic Surgeon Department of Orthopaedics and Hemophilia Unit La Paz University Hospital and Associate Professor of Orthopaedics Autonoma University Madrid, Spain

Ophira Salomon, MD Amalia Biron Research Institute of Thrombosis and Hemostasis Tel Hashomer and Sackler Faculty of Medicine Tel-Aviv University Tel Aviv, Israel

Inge Scharrer, PhD Department of Haematology University of Mainz Mainz, Germany

Sam Schulman, MD, PhD Hamilton Health Sciences – General Hospital Hamilton, Ontario, Canada

Jos Vermylen, MD Center for Molecular & Vascular Research University of Leuven Leuven, Belgium

Herbert Watzke, MD Medical University of Vienna Vienna, Austria

Harvey J. Weiss, MD Columbia University College of Physicians & Surgeons New York, NY, USA

Jeffrey I. Weitz, MD Henderson Research Center Henderson General Hospital Hamilton, Ontario, Canada

Preface

In 1996, in response to a need for practical advice on management of patients with bleeding disorders, Haemophilia Forum was established with an unrestricted grant from Novo Nordisk. The Editor-in-Chief and the Associate Editors as well as the Editorial Board are listed on the preceding pages. The name Haemophilia Forum was changed to Haemostasis Forum in 2003 in view of the interest of most coagulationists in thrombosis as well as haemorrhagic conditions. Following the name change from Haemophilia Forum to Haemostasis Forum, the Editorial Board was enlarged to include individuals whose main interest was in thromboembolic complications. No members of the Editorial Board or members of the editorial staff receive compensation for this contribution; rather, Novo Nordisk has offered to support the World Federation of Hemophilia in lieu of an honorarium to the editorial staff. Since its inception, hundreds of practitioners without access to on-site experts in coagulation have written into the forum and have received practical, hands-on answers to perplexing, complicated management questions. Because many discussion topics and questions to the panel of the Haemostasis Forum are not found in textbooks, it occurred to the editorial staff that the questions and answers found on the Forum might be compiled in book form. After consultation with members of the editorial board, selected discussion topics and questions have been edited and arranged by subject matter into a book that Blackwell has agreed to publish. We hope the information found in this book will be of value to physicians interested in coagulation problems related to acquired and congenital haemorrhagic and thrombotic problems. As a disclaimer, the answers in this book represent the opinions of the individual authors at the time that the question was written. We generally agree with the advice provided within, but wish to caution the readers that this advice is not meant to supplant good medical judgement and current medical literature. Additionally, the answers are meant to be general and not pertain to any individual patient.

xix

xx

Preface

The editorial staff wishes to thank Dr Mads Valentin, Dr Klaus Højbjerg-Hansen, and Dr Stefan Bosbach, all of Novo Nordisk, for their continued support and encouragement with unrestricted funds that have been used to maintain the Haemostasis Forum website and to subsidize the publication of selected material. We also wish to thank Mr Cary Clark, who has acted as an administrative assistant and has managed the web pages for the editorial staff for the past several years. Daniel Carrizosa, MD, Associate Editor Alice Ma, MD, Associate Editor Harold Ross Roberts, MD, Editor-in-Chief

1 Haemophilia A and Haemophilia B

General Overview Haemophilia and Immune Tolerance Therapy, 3 The Haemophilic Ankle: An Update, 5 The Haemophilic Knee: An Update, 15

Issues with Complicated Diagnoses Combined Haemophilia A and B Carrier, 23 A Complex Case of Haemophilia with HIV and Hepatitis C, 25 A Case of Haemophilia B, Mild VWD, and a Factor IX Inhibitor, 29 Premature Infant with Haemophilia B, 33

Haemophilic Carriers Haemophilic Carriers and Delivery, 35 Mild Haemophilia in Women, 37 Treatment of the Pregnant Haemophiliac, 41

Anticoagulation and Haemophilia Anticoagulation for Atrial Fibrillation in a Haemophiliac, 43 Anticoagulation for a Cardiac Valve in a Haemophiliac, 47 Cardiac Catheterization in a Haemophiliac, 49 Anticoagulation for a DVT in a Haemophiliac, 51

Treatment of Haemophiliacs DDAVP for Treatment of Mild Haemophilia during Surgery, 55 Haemophilia and Haemodialysis, 57 Haemophilia and Hepatitis C Treatment, 59 Haemophilia and Physical Therapy, 63 Haemophilia and Renal Bleeds, 65 Haemophilia and Scuba Diving, 67 Haemophilia and Ventricular Septal Defect Repair, 69 Haemophilia with Hepatitis C and Recurrent Bleeding, 73

1

2 Haemophilia A and Haemophilia B

Isotretinoin in Haemophilia, 75 Laser Eye Surgery in a Haemophiliac, 77 Managing Haemophilic Pseudotumours, 79 Continuous NovoSeven: Pros and Cons, 81

Complications of Treatment Haemophilia B and Immune Tolerance with Anaphylaxis, 85 rFVIIa (NovoSeven), 87 Thrombosis in PCCs vs. APCCs, 91

Haemophilia and Immune Tolerance Therapy

Question/ Case

A 2.5-year-old boy has severe haemophilia A diagnosed at 11 months of age and no family history. An inhibitor was detected at 22 months after 25 exposures to FVIII lacking the B domain, Refacto™. The inhibitor titre never rose above 17 BU. The genetic defect was due to a large FVIII deletion of exons 7–10. He was started on low-dose immune tolerance for 8 months with no response. Should we consider change of regimen or any additional therapies? He receives 25 U/kg per infusion three times a week and bleeds are treated with rVIIa. The inhibitor titres have been 5.1, 5.1, 11.6, 10, 17.5, 17.5, and 18 BU.

Response from Keith Hoots, MD

Gulf States Hemophilia & Thrombosis Center, University of Texas Houston Health, Houston, Texas, USA This is, unfortunately, not a unique situation since 25–30% of attempts at immune tolerance induction (ITI) fail. This may be even higher for patients with large deletions, although data are still not sufficient to firmly draw that conclusion. At this stage of ITI after approximately 8 months of poor response, I typically consider altering the regimen by escalating the dosage and frequency when a low-dose regimen has been employed. You did not say whether the inhibitor has stayed at a plateau around 20 BU or if there has been a significant anamnesis that leaves the child with a much higher titre now. The latter scenario may lessen the likelihood of successful ITI even after increasing the dose and the frequency. Also, I would recommend a high-dose regimen for immune tolerance, that is 100–200 U/kg FVIII per dose daily. There is some suggestion in the literature that an intermediate-purity product may be successful when ultra-high-purity products have failed to induce IT; this is still far from proven but it is an option to offer the

3

4 Haemophilia A and Haemophilia B

parents. If they prefer to continue the recombinant route, I still think there is a real, as-yet-undefined possibility that a high-dose regimen could work – even after initial ITI failure. I do not think that immune suppression therapy should be a component of the ITI at this stage of the process.

The Haemophilic Ankle: An Update

Question

What is the latest information regarding the treatment of the haemophilic arthropathy in the ankle?

Response from E. Carlos Rodriguez-Merchan, MD, PhD La Paz University Hospital; and Autonoma University, Madrid, Spain

Introduction It is well known that in haemophilia the ankles tend to bleed beginning at an early age of 2–5 years. The synovium is only able to reabsorb a small amount of intra-articular blood; if the amount of blood is excessive, the synovium will hypertrophy as a compensating mechanism, so that eventually the affected joint will show an increase in size of the synovium, leading to hypertrophic chronic haemophilic synovitis. The hypertrophic synovium is very richly vascularized, so that small injuries will easily make the joint rebleed. The final result will be the vicious cycle of haemarthrosis–synovitis–haemarthrosis, which eventually will result in haemophilic arthropathy (Figure 1.1a and b).

Pathogenesis of Synovitis and Cartilage Damage in Haemophilia: Experimental Studies There are three articles on the pathogenesis of synovitis and cartilage alterations in haemophilic joints. In the first article, Hooiveld et al. investigated the effect of a limited number of joint bleedings, combined with loading of the affected joint, in the development of progressive degenerative joint damage [1]. They concluded that experimental joint bleedings, when combined with loading (weight bearing) of the involved joint, result in features of progressive degenerative joint damage, whereas similar joint haemorrhages without joint loading do not. The authors suggest that this might reflect a possible mechanism of joint damage in haemophilia. In two other articles, haemophilic arthropathy was studied in animal models [2,3]. Despite these three

5

6 Haemophilia A and Haemophilia B

(a)

(b)

Figure 1.1 Haemophilic arthropathy of the ankle in a young boy: (a) A/P view and (b) lateral view.

The Haemophilic Ankle: An Update 7

interesting articles, the pathogenesis of haemophilic arthropathy is poorly understood. The best way to protect against haemophilic arthropathy (cartilage damage) is primary prophylaxis beginning at a very early age. Starting prophylaxis gradually with once-weekly injections has the presumed advantage of avoiding use of a central venous access device, such as a PortaCath, which is often necessary for frequent injections in very young boys. The decision to institute early full prophylaxis by means of a port has to be balanced against the child’s bleeding tendency, the family’s social situation, and the experience of the specific haemophilia centre. The reported complication rates for infection and thrombosis have varied considerably from centre to centre. Risk of infection can be reduced by repeated education of patients and staff, effective surveillance routines, and limitations on the number of individuals allowed to use the device. In discussing options for early therapy, the risks and benefits should be thoroughly discussed with the parents. For children with inhibitors needing daily infusions for immune tolerance induction, a central venous line is often unavoidable and is associated with an increased incidence of infections. From a practical point of view, radioactive synoviorthesis, together with primary prophylaxis to avoid joint bleeding, can help halt haemophilic synovitis. Ideally, however, synoviorthesis should be performed before the articular cartilage has eroded. Radioactive synoviorthesis is a relatively simple, virtually painless, and inexpensive treatment for chronic haemophilic synovitis, even in patients with inhibitors, and is the best choice for patients with persistent synovitis.

Synoviorthesis Radiation synovectomy consists of destruction of synovial tissue by intra-articular injection of a radioactive agent. Radioactive substances have been used for the treatment of chronic haemophilic synovitis for many years (Figures 1.2 and 1.3). Radiation causes fibrosis within the subsynovial connective tissue of the joint capsule and synovium. It also affects the complex vascular system, in that some vessels become obstructed; however, articular cartilage is not affected by radiation. The indication for medical synovectomy is chronic haemophilic synovitis causing recurrent haemarthroses, unresponsive to treatment. Synoviorthesis is the intra-articular injection of a certain material to diminish the degree of synovial hypertrophy, and decrease the number

8 Haemophilia A and Haemophilia B

Figure 1.2 Lateral view of an MRI of the ankle showing an intense degree of haemophilic synovitis. Radiosynoviorthesis should then be indicated early.

Figure 1.3 MRI anteroposterior views of the two ankles of the same child. On the left (right ankle) the distal tibial physis and the talus are severely affected in comparison with the same structures of the left ankle. Although radiosynoviorthesis could be indicated in both ankles, it will be much better in the left ankle.

The Haemophilic Ankle: An Update 9

and frequency of haemarthroses. There are two basic types of synoviortheses: chemical synoviorthesis and radiation synoviorthesis. On average, the efficacy of the procedure ranges from 76% to 80% and can be performed at any age. The procedure slows the cartilaginous damage, which intra-articular blood tends to produce in the long term. Synoviorthesis can be repeated up to 3 times at 3-month intervals if radioactive materials are used (yttrium-90, phosphorus-32, and rhenium-186), or weekly up to 10–15 times if rifampicin (chemical synovectomy) is used. After 30 years of using radiation synovectomy worldwide, no damage has been reported in relation to the radioactive materials. Radiation synovectomy is currently the preferred procedure when radioactive materials are available; however, rifampicin is an effective alternative method if radioactive materials are not available. Several joints can be injected in a single session, but it is best to limit injections to two joints at the same time. There are two interesting articles that focus on the treatment of chronic haemophilic synovitis. Corrigan et al. have used oral D-penicillamine for the treatment of 16 patients [4]. The drug was given as a single dose in the morning before breakfast. The dose was 5–10 mg/kg body weight, not to exceed 10 mg/kg in children or 750 mg/day in adults. The duration of treatment was 2 months to 1 year (median 3 months). Ten patients had an unequivocal response, three had a reduction in palpable synovium, and three had no response. Minor reversible drug side effects occurred in two patients (proteinuria in one and a rash in the second). Radossi et al. have used intra-articular injections of rifamycin [5]. Among a large cohort of nearly 500 patients, they treated 28 patients during a 2-year period. The patients followed an on-demand replacement therapy programme and developed single or multiple joint chronic synovitis. The indications for synoviorthesis were symptoms of chronic synovitis referred by patients reported in a questionnaire. In Radossi’s series there were five patients with inhibitors to factor VIII [5]. Their average age was 34 years. Rifamycin (250 mg) was diluted in 10 ml of saline solution and 1–5 ml was then injected into the joint. The follow-up ranged from 6 to 24 months. Thirty-five joints were treated with 169 infiltrations in total. Rifamycin was injected once a week for 5 weeks, that is the patient had to come to hospital at weekly intervals. Twenty-four procedures were considered effective in 19 patients according to the evaluation scale, while six

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Haemophilia A and Haemophilia B

treatments were considered fair to poor. Five patients (six joints) with anti-factor VIII inhibitors were treated. In four joints the results were good, while in the two remaining joints the results were poor. There are two main limitations for the use of antibiotics in synoviorthesis: the procedure is painful, and it should be repeated weekly for many weeks to be effective. In fact, Radossi’s schedule included injection of rifamycin into the joints once a week for 5 weeks [5]. However, the authors make no mention of the pain associated with the injections. They also state that rifamycin may be indicated when radiosynoviorthesis is not available, contraindicated for medical reasons, or not accepted by patients. To the best of my knowledge, I do not know of any medical contraindications to radiosynoviorthesis, or why patients should reject such an efficient and safe procedure. The Italian authors state that, to date, they cannot say if their programme is able to delay long-term functional impairment because of the lack of a longer follow-up. However, according to their preliminary experience, they consider that rifamycin synoviorthesis appears to be effective in reducing joint pain and improving the range of motion. The study of Corrigan et al. who used D-penicillamine has two main limitations: the small number of patients, and the lack of use of ultrasound and/or magnetic resonance imaging (MRI) for diagnostic purposes. It is also important to emphasize two potential side effects of D-penicillamine: aplastic anaemia and renal disease. To minimize the possibility of side effects, Corrigan and co-workers have suggested that the drug be used on a short-term basis (i.e. 3–6 months) and the amount restricted (see reference for dosing) [4]. I agree with the authors’ statement that synoviorthesis (radiosynovectomy) using intra-articular yttrium-90 or phosphorus-32 has been reported to be effective. However, I disagree with the authors’ comment that this is an invasive procedure whose long-term safety has not been established. In fact, the long-term safety has been established after 30 years of using radiation synovectomy worldwide, with no damage reported in relation to the radioactive materials [2]. It is important to emphasize that controversy exists regarding which type of synoviorthesis is better. Most authors in developed countries use radiosynoviorthesis (yttrium-90 and phosphorus-32), while others utilize chemical synoviorthesis mainly because of the lack of availability of radioactive materials. My view is that further studies with an adequate number of patients and an appropriate follow-up are needed to confirm the efficacy of oral penicillamine and rifamycin synoviorthesis for chronic haemophilic synovitis. In other words, the aforementioned

The Haemophilic Ankle: An Update 11

articles are preliminary studies requiring confirmation. Meanwhile, the general recommendation is to use yttrium-90 or phosphorus-32 synoviorthesis, because these agents have proved to be efficient for the treatment of chronic haemophilic synovitis, even in patients with inhibitors. Moreover, no complications related to the use of radioactive materials have been reported after 30 years of being used worldwide.

Editors’ Note In 2005 after the initial publication of this monograph, a report of pain of patients treated with P32 radioactive synovectomies was published. These 2 boys developed ALL, one T-cell ALL & one precursor B-cell ALL, within one year of radioactive synovectomy. Dunn AL, et al., J Thromb Haemost 2005;3: 1541–2.

Haemophilic Arthropathy of the Ankle and Subtalar Joints Chang et al. have made an analysis of podiatric surgery in haemophilic arthropathy of the ankle and subtalar joints [6]. This condition often results in severe pain and physical limitations. Conservative treatment (splints, braces, wedge insoles, and calipers) should always be attempted prior to surgery. The most common surgical approaches are synovectomy, joint debridement, arthroplasty, and arthrodesis. Finally, the authors describe an interesting case of avascular necrosis of the talus, ankle/joint degeneration with periarticular osseous fragmentation, a cyst in the medial aspect of the talar dome, and a fracture of the os trigonum with resultant hypertrophy of soft tissues. The most common deformities affecting the ankle and subtalar joints are fixed plantar flexion due to degeneration of the anterior part of the ankle, varus hindfoot due to malalignment of the subtalar joint, and valgus rotation of the ankle due to differential overgrowth of the distal tibial epiphysis during adolescence or progressive arthropathy during maturity. The process always starts with a single or a recurrent haemarthrosis, which is extremely painful, and results in an equinus or a plantar flexion position of the ankle. This deformity, initially correctable, eventually becomes fixed. Probably the first treatment to be considered for recurrent ankle haemarthroses is radiosynoviorthesis. Another common procedure to prevent fixed equinus deformity is lengthening the Achilles tendon.

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Sometimes a large osteophyte develops on the anterior part of the ankle, which can cause severe pain. Surgical removal of the osteophyte (queilectomy) is sometimes indicated. When the ankle joint shows an important degree of malalignment, a supramalleolar valgus or varus osteotomy is indicated. In advanced haemophilic arthropathy, an ankle arthrodesis or arthroplasty should be considered. The main indications for these are intractable pain not relieved by alternative treatments and severe deformity. Regular prophylactic transfusions of clotting factor may prevent recurrent bleeds and further development of haemarthrosis. Ankle arthrodesis has been associated with better long-term results than ankle arthroplasty (rarely performed in haemophilia today). [For more detailed description of ankle haemarthropathy, the reader is referred to the original submission by Dr Rodriguez-Merchan, www.haemostasis-forum.org.]

Rehabilitation The importance of preoperative and postoperative rehabilitation of the ankle joint in haemophilia must be emphasized. Children must utilize the resources available and seek early consultation with their centre’s rehabilitation physician and physiotherapist. Using the techniques

Figure 1.4 Ankle arthrodesis with two crossed screws in a haemophilia patient with severe haemophilic arthropathy of the ankle.

The Haemophilic Ankle: An Update 13

available, rehabilitation has been shown to speed recovery, reduce pain, and prevent contractures. Physiotherapy is important to ankle rehabilitation of patients following surgical procedures, and the physical therapist must work closely with the orthopaedic surgeon.

Conclusions Radiation synoviorthesis is a very effective procedure that decreases both the frequency and the intensity of recurrent intra-articular bleeds related to joint synovitis. The procedure should be performed as soon as possible to minimize the degree of articular cartilage damage. It can also be used in patients with inhibitors with minimal risk of complications. Radioactive synoviorthesis is the best choice for patients with persistent synovitis. Personal experience and the general recommendation among orthopaedic surgeons and haematologists are that when three early consecutive synoviortheses (repeated every 3 months) fail to halt synovitis, a surgical synovectomy (open or by arthroscopic) should be immediately considered. For advanced haemophilic arthropathy of the ankle, the best solution is an ankle arthrodesis (Figure 1.4) [7].

References 1 Hooiveld MJ, Roosendaal G, Jacobs KM, Vianen ME, van den Berg HM, Bijlsma JW, et al. Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: a possible mechanism of hemophilic arthropathy. Arthritis Rheum 2004;50(6):2024–31. 2 Hakobyan N, Kazarian T, Jabbar AA, Jabbar KJ, Valentino LA. Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene. Blood 2004;104(7): 2060–4. 3 Valentino LA, Hakobyan N, Kazarian T, Jabbar KJ, Jabbar AA. Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiency. Haemophilia 2004;10(3):280–7. 4 Corrigan Jr JJ, Damiano ML, Leissinger C, Wulff K. Treatment of chronic haemophilic synovitis in humans with D-penicillamine. Haemophilia 2003;9(1): 64–8. 5 Radossi P, Baggio R, Petris U, De Biasi E, Risato R, Davoli PG, et al. Intra-articular rifamycin in haemophilic arthropathy. Haemophilia 2003;9(1):60–3. 6 Chang TJ, Mohamed S, Hambleton J. Hemophilic arthropathy: considerations in management. J Am Podiatr Med Assoc 2001;91(8):406–14. 7 Rodriguez-Merchan E. The Haemophilic Joints: New Perspectives. Oxford: Blackwell, 2003.

The Haemophilic Knee: An Update

Question

What is the latest information on the treatment of haemophilic arthropathy in the knee?

Response from E. Carlos Rodriguez-Merchan, MD, PhD La Paz University Hospital; and Autonoma University, Madrid, Spain Figure 1.5 shows hypertrophic haemophilic synovitis in the knee. Synovectomy of the knee is similar to that in the ankle (see The Haemophilic Ankle: An Update). Surgical synovectomy may be done through an open technique or by arthroscopic means. At the knee, arthroscopic synovectomy is preferred and the open procedure is reserved for when the arthroscopic technique fails to control the synovitis. Open synovectomy should be performed through a medial parapatellar approach, and a synovectomy as complete as possible should be carried out (Figure 1.6). Arthroscopic synovectomy should be done through three portals (anterolateral, anteromedial, and lateral or medial suprapatellar

Figure 1.5 Clinical view of a haemophilic knee with intense synovitis (take the contralateral side for comparison).

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(a)

(b)

Figure 1.6 Open surgical synovectomy sometimes is needed for the treatment of chronic haemophilic synovitis: (a) intraoperative view of the synovium and (b) macroscopic view of the resected synovial tissue.

portals). In other words, at least three portals are needed to perform a “complete” synovectomy. The synovectomy should be performed with a motorized resector. After surgical synovectomy, the knee should be immobilized in a Robert Jones dressing for 3 days and active movement encouraged. Holmium:Yag laser would appear to be superior to conventional arthroscopic synovectomy, which utilizes mechanical devices, because laser therapy might improve the quality of local haemostasis and the rapidity of postoperative recovery.

Knee Flexion Contractures The management of an articular contracture in a patient with haemophilia represents a major challenge (Figure 1.7). The treatments available are physiotherapy, orthotics and corrective devices, and surgical

The Haemophilic Knee: An Update 17

Figure 1.7 Clinical view of a knee joint with fixed flexion contracture.

procedures. End-stage arthropathy of the knee is the most frequent cause of severe pain and disability in haemophiliacs. Some patients have such severe arthropathy that a total joint arthroplasty is required.

Severe Haemophilic Arthropathy There are a number of orthopaedic procedures that can be carried out in the haemophilic knee when a severe degree of arthropathy is reached (Figure 1.8).

Joint Debridement A joint debridement is commonly performed in young patients suffering from severe haemophilic arthropathy, who are too young for a total joint replacement. In other words, debridement is a procedure that can alleviate articular pain and bleeding for a number of years, delaying the need for a total joint arthroplasty. A joint debridement consists of the opening of the joint to remove the existing osteophytes, and resect the synovium. Some authors do not believe in the efficacy of debridement, and therefore when facing a severe degree of arthropathy in a young patient, they recommend a total joint replacement. It should be emphasized that if debridement fails, a joint arthroplasty can be performed by the same approach. Some authors perform joint debridement by arthroscopic means with results similar to those obtained by open surgery. In many occasions, a synovectomy

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Haemophilia A and Haemophilia B

Figure 1.8 Severe haemophilic arthropathy.

and a debridement are performed together, because haemophilic synovitis and early arthropathy commonly coexist. Again, postoperative rehabilitation is paramount to avoid loss of range of motion and, therefore, adequate control of rebleeding is essential.

Alignment Osteotomy Sometimes, during childhood, adolescence, or early adulthood, some haemophilic joints suffer from an alteration of the normal axis. It is common that haemophilic ankles and knees show varus, valgus, and flexion deformities. When the misaligned joint is painful, the patient will need an alignment osteotomy. The most common osteotomies performed in haemophiliacs are proximal tibial valgus osteotomy (Figure 1.9), supracondylar femoral varus osteotomy, ankle alignment osteotomy, and knee extension osteotomy. In all of them, the rationale is to produce a fracture at an adequate area to re-align the joint to a normal axis. After the osteotomy, it would be necessary to get an adequate bone fixation by any kind of internal fixation device. It is interesting to note that sometimes I have corrected a flexion contracture of the knee at the same time as a spontaneous supracondylar fracture of the femur. Curettage of Subchondral Bone Cysts Some haemophilic patients present great subchondral cysts on the proximal tibia. When such cysts are symptomatic, curettage and filling with fibrin glue and/or cancellous bone graft should be recommended (Figure 1.10).

The Haemophilic Knee: An Update 19

Figure 1.9 Valgus osteotomy for the correction of a varus deformity fixed by means of two staples.

Figure 1.10 Subchondral cyst in the proximal tibia.

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(a)

(c)

Haemophilia A and Haemophilia B

(b)

(d)

(e)

(f)

Figure 1.11 TKA in a young haemophilic patient: (a) preoperative AP radiograph; (b) lateral preoperative view; (c) intense synovitis can be noted; (d) severe arthropathy is seen; (e) prosthetic components; (f) TKA implanted.

The Haemophilic Knee: An Update 21

(g)

(h)

Figure 1.11 (continued) (g) postoperative AP radiograph; and (h) postoperative lateral view.

Total Knee Arthroplasty Between the second and the fourth decades, many haemophilic patients develop severe articular destruct ion. For the knee, the best solution is a total knee arthroplasty (TKA) (Figure 1.11). The role of total knee replacement in persons with haemophilia is very important. Haemophilic patients infected by human immunodeficiency virus are at risk of bacterial and opportunistic infections because of immunosuppression. In these patients, the risk of infection after orthopaedic surgery is of considerable concern. Arthroplasty appeared to have seven times the risk of infection than other procedures. Total knee replacement for advanced haemophilic arthropathy has good or excellent results in about 85% of cases. The principal risk is late infection that can occur regardless of HIV status. However, this risk appears increased in patients with CD4 counts under 200/l. Although the message of this article may seem conservative, it should not be inferred that a total knee replacement should be avoided in an HIV-positive haemophilic patient today, but that the orthopaedic surgeon, treatment team, and the patient should weigh the risks and benefits carefully.

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Conclusions Radiation synoviorthesis is a very effective procedure that decreases both the frequency and the intensity of recurrent intra-articular bleeds related to joint synovitis. The procedure should be performed as soon as possible to minimize the degree of articular cartilage damage. It can also be used in patients with inhibitors with minimal risk of complications. Radioactive synoviorthesis is the best choice for patients with persistent synovitis. Personal experience and the general recommendation among orthopaedic surgeons and haematologists are that when three early consecutive synoviortheses (repeated every 3 months) fail to halt synovitis, a surgical synovectomy (open or by arthroscopy) should be immediately considered. For advanced haemophilic arthropathy of the knee, the best solution is a total knee replacement. In polyarthritic conditions the repair of a single joint may not improve functional ability, and the aim should be to create a functional limb. Some authors have reported the use of multiple joint procedures on haemophilic patients in a single operative session (double knee arthroplasty). This succeeded in achieving a functional limb. The complication rate was less than expected and the rehabilitation period was relatively short [1]. [For a more detailed discussion, please see the original submission by Dr. Rodriguez-Merchan at www.haemostasis-forum.org.]

Editors’ Note Please see the note on the two cases of ALL following radioactive synovectomies in the chapter on the hemophilic ankle.

Reference 1 Rodriguez-Merchan E. The Haemophilic Joints: New Perspectives. Oxford: Blackwell, 2003.

Combined Haemophilia A and B Carrier

Question/ Case

I am a genetic counselling student. A 35-year-old man with haemophilia A presented recently. His partner is a confirmed carrier of haemophilia B. In evaluating the pattern of X-linked recessive inheritance with an affected male and a carrier female, the question arose as to whether a female carrier of both haemophilias A and B would be more severely affected than would a carrier of either one alone.

Response from Edward Tuddenham, MD Royal Free Hospital, London, UK I find this a very interesting question, particularly as I have been working on combined factor V and VIII deficiency for the last 4 years. In that particular combined deficiency the levels of factors V and VIII range from 5% to 20%, but even individuals with the lowest levels did not bleed more than one would expect with a single factor deficiency. The best explanation I can give for this is that the rate-limiting step for one factor does not affect the rate limitation set by the other factor. The speed of an army is that of the slowest soldier, but if there are two equally slow soldiers that does not slow things up any more. Now, in the case of factors VIII and IX one is a cofactor for the other and they actually form a binary complex, which activates factor X. I think the slowest soldier argument applies to this and, therefore, would advise that a carrier of factors VIII and IX would not have a greater bleeding risk than a carrier of either deficiency alone. However, an additional consideration is that the couple in question, should they have a double-carrier daughter, will have transmitted the defects on different X chromosomes. Therefore, in the process of X inactivation (Lyonisation), the levels of the factors will be reciprocally affected so that their sum is 100%. In the worst case of extreme Lyonisation, one factor would be normal and the other zero. The net effect of all this is that the bleeding chances of a double-carrier daughter are exactly the same as those of a single-carrier daughter, neither better nor worse.

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Haemophilia A and Haemophilia B

Things get a bit more complicated when the double-carrier daughter has offspring. Due to meiotic crossover, her children can be of eight different types: normal males/normal females; double-carrier females/doubly affected males; haemophilia A carriers/haemophilia A males; haemophilia B carriers/haemophilia B males. I leave it to the questioner (who is a student of human genetics) to work out the expected proportions based on the fact that the loci F8C and F9 are about 30 centiMorgans apart on Xq (2.8 and 2.6). Obviously, the worst-case scenario is a doubly affected male. However, that just means that he would have to use a mixture of factors VIII and IX for therapy.

Editors’ Note Professor Tuddenham’s answer is supported by experiments in haemophilic dogs. It has been shown that combined haemophilias A and B in male or female dogs bleed no more than dogs with either defect alone. As stated by Professor Tuddenham, they require replacement with both factors VIII and IX.

A Complex Case of Haemophilia with HIV and Hepatitis C

Question/ Case

A 17-year-old male with severe haemophilia A is on prophylaxis with recombinant FVIII. He is on his high-school varsity team and, so far, has had no problems with bleeds. He was found to be HIV positive by ELISA and western blot tests. Ten years later, his HIV viral load was found to be 400 copies/ml by PCR analysis. The most recent HIV-1 PCR RNA quantitative test was 25 (normal 0–25) copies/ml. His CD4 count has varied between 518 and 910 cells/l. He has not required anti-retroviral therapy. His most recent HCV RNA is approximately 450,000 copies/ml. His ALT and AST are normal. The patient does not know about his HIV or HCV status, and the parents have steadfastly refused permission for the health team to discuss this with him. They have, however, allowed discussions of universal precautions. The university lawyers have upheld the parents’ rights. My questions are as follows: (1) Would you treat this asymptomatic patient for HIV or HCV or both? (2) If, in view of the low HIV viral load and normal liver function, treatment is not yet required, then what arguments can one make about telling the patient his status (both the parents and the patient swear that he is not sexually active)? (3) In a co-infected patient, does HIV viral load or HCV RNA load have any prognostic implications in the face of normal liver function? (Note: The parents do not want a liver biopsy.)

Response from Margaret Ragni, MD University of Pittsburgh Physicians, Pittsburgh, Pennsylvania, USA The case presented is of interest from both a scientific and an ethical perspective. It is very likely, in view of both the patient’s age and immune function “after at least 13 years of HIV infection he maintains a CD4 count of 520 cells/l and undetectable HIV viral load”, that he is a slow progressor. Medically, the experts are not in agreement

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Haemophilia A and Hemophilia B

about how to approach such a patient. Some advise treatment, while others suggest waiting for the CD4 to fall below 500 cells/l. Ethically, given the importance of informed consent in initiating drug treatment and in explaining why treatment is given and considering the potential side effects, it would be very difficult to treat a patient who does not know his diagnosis. If there is a convincing argument for treatment now, then I would strongly suggest persuading the parents that, to receive treatment, the patient must be informed. On the other hand, if you wait just one more year, he will be 18 and legally able to decide for himself. Your institutional review board and your Ethics Committee might be able to assist in discussing this with the parents. Parents want the best for their children, in general, and if it becomes medically clear that the patient needs treatment and that you cannot do so without discussing this with him, then my guess is that they will agree with your plan. With regard to hepatitis C, the hepatology literature suggests that the HCV viral load is not directly related to the pathology or severity of chronic liver disease, and despite all the molecular techniques available, the liver biopsy remains the gold standard for diagnosis. As discussed earlier, it would be difficult to initiate treatment without informed consent. Finally, certainly, given the patient’s age and current or potential sexual activity (no matter what the parents think is the case), it is crucial that the patient be informed of his HIV status so that he can take appropriate precautions to prevent sexual transmission or transmission to others through exposure to his blood (e.g. with cuts or bleeds or with potential trauma). This is a societal issue, and unknowing HIV transmission would be inexcusable! One last word: from the ethical literature, the majority of patients who have not been informed of a “bad diagnosis” often suspect it and may hold resentment and anger towards those who withhold information important to their future. This boy deserves to know his diagnosis and the potential benefits of antiviral treatment for HIV and HCV in planning his future life. My guess is that involving the parents in a discussion with you and other hospital personnel or other haemophilia providers would help them see the significant benefits in disclosing this information. The longer they wait, the greater the likelihood that potential medical disaster may occur (sexual transmission), and the greater the potential for anger, hard feelings, and psychological difficulties in their teenager.

A Complex Case of Haemophilia with HIV and Hepatitis C 27

Editors’ Note Professor Ragni wishes to remind the audience that HIV/AIDS is a continuously changing disease. Treatment patterns for this disease were current at the time of above response. Since 1999, new guidelines have been published and can be found in Hammer SM, Saag MS, Schechter M, et al., Treatment for Adult HIV Infection: 2006 Recommendations of the International AIDS Society – USA Panel. J Am Med Assoc 2006;296:827–43.

A Case of Haemophilia B, Mild VWD, and a Factor IX Inhibitor

Question/ Case

I have a 7-year-old patient with severe hemophilia B and mild von Willebrand disease (VWD) type 1. The patient has a low titre inhibitor to factor IX and has developed an anaphylactic reaction to plasma-derived FIX concentrates. We have treated haemorrhagic episodes with recombinant FVIIa (rFVIIa). Last year he suffered from repeated haemarthroses. He did not report trauma or possible bleeding early enough, so that his ankle was swollen when he arrived at our centre. Our problem is: how, and for how long should we treat this patient? We have used rFVIIa at 180 g/kg as the first dose followed by 90 g/kg after 2 h. We have also used oral tranexamic acid and intravenous desmopressin acetate. The manufacturer’s recommendation is to continue rFVIIa treatment as long as the bleeding continues, but it is difficult to assess whether the bleeding has stopped when the ankle is swollen. What protocols are recommended? Do other practitioners have recommendations for the length of treatment for articular bleeds?

Response from Ulla Hedner, MD, PhD University of Lund, Malmo, Sweden; Novo Nordisk A/S, Denmark This patient is a complicated haemophilia B patient. He has anti-factor FIX antibodies and experiences anaphylactic reactions to FIX concentrates [1,2]. To achieve optimal efficacy of rFVIIa in the treatment of bleeds, the drug should preferably be administered very soon after the start of bleeding, and it is clear that one of the problems is that this patient tends to delay his visit to the centre when he experiences a bleed. Would it be possible to administer rFVIIa in a home treatment setting? It was shown in the Home Treatment Study in the USA that an

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Haemophilia A and Haemophilia B

average of 2.2 doses was needed to achieve haemostasis in the moderate-to-mild bleeds treated in that study [3]. Many centres do apply home treatment, teaching the parents and the patient himself how to inject the rFVIIa to allow immediate initiation of treatment as soon as the patient experiences any signs of a bleed. The pharmacokinetics of rFVIIa exhibit a shorter half-life and higher clearance in haemophiliacs below the age of 15 years compared with adults [4]. However, if you did not perform a pharmacokinetic study in the patient, a dose of 180 g/kg is most probably high enough. It seems unlikely that this dose would not give him a satisfactorily high peak level of FVII:C right after the injection. It may, however, be a good idea to use this dose for the next injection(s) given at 2 h intervals. The questions of how long the treatment should be continued and how to decide when to stop are difficult in a patient with a joint that is already swollen. The best marker of the cessation of bleeding would be relief of pain. Most haemophilic patients can accurately assess when the bleeding has stopped. There is no firm protocol for how long to continue rFVIIa in joint bleeds. One has to rely on the patient’s assessment or until the swelling diminishes. As already mentioned, pain is a good marker. If the patient is experiencing repeated bleeds in the same joint, he may develop a target joint characterized by chronic swelling, which makes it even more difficult to tell whether the discomfort is due to an acute bleeding episode or to inflammatory changes in the joint. To prevent the development of a target joint, I would recommend that such patients be given 2–4 injections of rFVIIa using the high-dose regimen (180 g/kg/dose) at 2 h intervals to make sure full haemostasis is achieved. Ideally the first dose should be given at home. The use of tranexamic acid is recommended as an adjunct therapy, although its effect in joint bleeds may not be as effective as for mucocutaneous bleeds and surgery. If DDAVP is being used, tranexamic acid should be given, since DDAVP releases not only FVIII, but also fibrinolytic activators.

References 1 Warrier I, Ewenstein BM, Koerper MA, Shapiro A, Key N, DiMichele D, et al. Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol 1997;19(1):23–7.

A Case of Haemophilia B, Mild VWD, and a Factor IX Inhibitor 31

2 Warrier I. Management of haemophilia B patients with inhibitors and anaphylaxis. Haemophilia 1998;4(4):574–6. 3 Lusher JM. Recombinant activated factor VII for treatment of intramuscular haemorrhages: a comparison of early versus late treatment. Blood Coagul Fibrinolysis 1998;9(Suppl 1):S111–14. 4 Hedner U, Kristensen H, Berntorp E, Ljung J, Petrini P, Tengborn L. Pharmacokinetics of rFVIIa in children. Haemophilia 1998;4(3):244 (Abstract 355).

Premature Infant with Haemophilia B

Question/ Case

We recently discovered severe haemophilia B in a neonate born prematurely after 27 weeks of gestation. He had a patent ductus arteriosus that needed surgical closure. Factor IX was 1% and his family history was negative. The patient was diagnosed with an intraventricular haemorrhage. He was treated with FIX prior to surgery. Now he needs large amounts of factor IX to maintain an adequate level. Does anybody have experience with a premature infant with severe haemophilia B? What are the pitfalls one could expect? What is a safe level of factor IX for a patient in severe respiratory distress on the ventilator, who may receive corticosteroids?

Response from Donna M. DiMichele, MD New York Presbyterian-Weill Cornell Center, New York, USA The management of a sick newborn with haemophilia is indeed challenging. Prematurity adds further to its complexity. The major challenges include (1) uncertainty about true factor recovery and survival in neonates; (2) concerns about inhibitor development with longterm high-dose exposure to factor in this age group (although somewhat less of a concern with haemophilia B); (3) venous access difficulties; (4) the need for frequent invasive procedures associated with concurrent illnesses; and (5) the difficulties in educating and supporting the emotional needs of the family when the diagnosis is made under such stressful circumstances. Unfortunately, there are no published evidence-based guidelines for managing haemophilia in a premature or a full-term infant. Considering the issues at hand, some recommendations for the management of babies of this type would include the following. Given the extraordinarily large extracellular volume of the premature infant (80–90% of weight) and the presumably higher factor IX clearance rate in the young infant, it is not surprising that high doses of FIX were required to achieve haemostatic levels for both the PDA

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repair and subsequent prophylaxis. This is especially the case if recombinant FIX is used. If the baby is undergoing frequent invasive procedures, it might be safer to maintain a minimum haemostatic FIX level of 15–20% and use intermittent bolus dosing to achieve FIX levels of 50–70% to cover the baby for major interventions (surgery, venous access placement, etc.). This could be accomplished on a daily dosing schedule, or if central venous access is available, by continuous FIX concentrate infusion. The latter will reduce the total daily FIX requirement, maintain constant target FIX levels, and simplify FIX plasma monitoring. Alternatively, if the baby is stable and not undergoing frequent invasive procedures such as arterial punctures, etc., the infant may not need a persistent haemostatic FIX level. In that case, haemostasis could be maintained using a more “routine prophylaxis” regimen. However, I suspect that this regimen would have to be augmented both with respect to bolus dose and frequency of administration, based on the FIX recovery and half-life data that you will be able to collect. Given the above recommendations, permanent central venous access is highly recommended. Although inhibitor development is less likely in haemophilia B, the risk for this complication remains high in individuals with large or complete gene deletions. In patients like these from the FIX Inhibitor Registry, inhibitor development can occur after as few as 2 or as many as 180 FIX exposures and can be accompanied by mild-to-severe allergic manifestations. For these reasons, I would strongly recommend early gene-based diagnosis for this infant. In the meantime, regular monitoring of FIX plasma levels is recommended for inhibitor surveillance. Lastly, I recommend intensive ongoing reassurance, support, and education for the family.

Haemophilic Carriers and Delivery

Question/ Case

I would very much like to ask the panel of how best to deal with a pregnant woman who is an asymptomatic carrier of severe haemophilia A and expects a male baby. No prenatal diagnosis has been done. Would you recommend caesarean section over spontaneous delivery? Is the newborn, who may well be a haemophiliac, at risk? Is the mother at risk? I am aware that bleeds are very rare in newborns with severe haemophilia and that carriers usually do not bleed, but is the risk actually zero? Would you recommend delivery in an obstetric department associated with a haemophilia centre or is it appropriate for the mother to deliver in a local hospital?

Response from Jeanne Lusher, MD Wayne State University School of Medicine, Detroit, Michigan, USA In response to the query concerning delivery, if the newborn is affected (i.e. has severe haemophilia), the most severe potential risk is intracranial haemorrhage (ICH). While the risk is not great, it is a definite risk of which all concerned should be aware. Assuming that there is no cephalopelvic disproportion, most clinicians would recommend vaginal delivery. However, vacuum suction and forceps should be avoided, as should prolonged labour. Since it is not known whether the foetus in question has haemophilia or not, all these recommendations should apply. In addition, a cord blood sample should be obtained at birth (from a vessel on the foetal side of the placenta) for a FVIII assay. If there is any question about a possible ICH in the neonate, imaging studies should be carried out, and FVIII should be given. While all efforts should be made to avoid an unusually difficult, precipitous, or otherwise traumatic delivery, should this occur, I would recommend imaging studies to rule out ICH. Otherwise, ICH may go unrecognized for several days and become much more extensive before obvious symptoms develop.

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While the exact incidence of ICH in haemophilic neonates is not known, most surveys indicate an incidence of around 1%. However, most surveys have been relatively small and data appear “soft”. With regard to the place of delivery, I would definitely recommend that delivery take place in an obstetric department associated with a haemophilia centre. There should be close cooperation between haemophilia centre personnel and the obstetrician. The risk of unusual maternal haemorrhage is uncommon. However, it would be helpful to know what the woman’s baseline FVIII level is. If she has a very low level, there may be a risk of vaginal bleeding several days post delivery (levels generally rise during the third trimester of pregnancy, so bleeding at delivery related to low FVIII levels would be unusual). If bleeding occurs a few to several days postpartum, and the mother’s FVIII level has fallen to 20% or less, desmopressin (DDAVP) could be given.

Mild Haemophilia in Women

Question

Can women have mild haemophilia A?

Case

I am a middle-aged woman with a diagnosis of mild haemophilia, although I am constantly told by physicians that only males are haemophiliacs. My medical history is rather confusing since I am the only one in my family with a history of haemophilia. I have a factor VIII level of 22%. Over a period of several years, I have experienced postsurgical haemorrhage, postpartum haemorrhage, haemarthroses, and bleeding after tooth extraction. Some haemorrhages were sufficiently severe to require transfusions with blood and/or cryoprecipitate. I have been diagnosed with hepatitis and mild haemophilia. I am to undergo further surgery and I would value your explanation of my diagnosis of mild haemophilia without any family history. Would you consider the surgery to be relatively safe provided there is meticulous and adequate (to 100% of normal) replacement of factor Vlll for a period of about 10 days after surgery?

Response from Barbara Konkle, MD University of Pennsylvania, Philadelphia, Pennsylvania, USA Mild haemophilia is characterized by trauma-induced bleeding and the symptoms described would be compatible with the diagnosis of mild haemophilia. To confirm that diagnosis requires additional laboratory data to rule out von Willebrand disease (VWD). In all patients with a low factor VIII level, VWD should be ruled out. FVIII binds to, and is stabilized by, von Willebrand factor. Thus when von Willebrand factor is decreased, so is factor VIII. While both mild haemophilia and VWD usually respond to treatment with desmopressin (DDAVP), the approach may be different for treatment of severe bleeding or for

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major surgery. Furthermore, the inheritance of VWD differs from classic haemophilia and correct diagnosis is important for genetic counselling and family studies. Rarely, patients can have a low factor VIII level due to a subtype of VWD, resulting from a mutation(s) in the factor VIII binding region of (VWD 2N, Normandy); this would not respond to DDAVP therapy. Also described are combined factor VIII and V deficiencies. In addition, one would want to rule out a factor VIII inhibitor by clinical history and laboratory analysis. Carriers of haemophilia have widely varying factor VIII levels and often have levels low enough to result in symptoms compatible with haemophilia. In women, in cells expressing genes carried on the X chromosome, only one copy of each gene is expressed (the Lyon hypothesis). Within each cell, which gene is expressed is a random event. Thus the levels of factor VIII in women with one functioning and one non-functioning gene reflect the sum of these events and may vary. Women with sufficiently low levels to produce symptoms of mild haemophilia are often called symptomatic carriers. Both haemophilias A and B are frequently due to new mutations. This happens more commonly in the germline of the mother, particularly with haemophilia due to the factor VIII inversion mutation that occurs, almost exclusively during gamete production in the carrier’s father as described by Rossiter et al. [1]. In most new carriers, it will not be manifest until the woman has a son with haemophilia. The most famous carrier of haemophilia, without a family history of such, was Queen Victoria. She was not known to have bleeding symptoms. However, it is very possible that a new carrier of haemophilia would have levels that would produce symptoms compatible with mild haemophilia. For further information on bleeding in carriers of haemophilia, the reader is referred to Greer and Walker’s chapter, “Bleeding in the Hemophilia Carrier,” in Hemophilia, Forbes, Aledort, and Madhok (eds.), Chapman and Hall, 1997 [2]. In patients with mild haemophilia without inhibitors who respond well to factor VIII therapy, surgery can be safely performed with factor VIII replacement pre- and postoperatively. Major surgery on patients with haemophilia should always be performed under the supervision of a physician with experience in haemophilia care and at an institution where factor VIII levels can be followed and can be obtained on an emergency basis, if needed.

Mild Haemophilia in Women 39

References 1 Rossiter JP, Young M, Kimberland ML, Hutter P, Ketterling RP, Gitschier J, et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum Mol Genet 1994;3(7):1035–9. 2 Greer IA, Walker ID. Bleeding in the Hemophilia Carrier. In: Forbes CD, Aledort LM, Madhot R (eds.), Hemophilia. London: Chapman and Hall, 1997.

Treatment of the Pregnant Haemophiliac

Question

I understand haemophilia is rare in women. Is there any current literature on the treatment of the pregnant haemophiliac: antepartum, intrapartum, and postpartum?

Response from Keith Hoots, MD Gulf States Hemophilia & Thrombosis Center, University of Texas Houston Health, Houston, Texas, USA Two recent studies have been published concerning the management of pregnancy in the two most common clinical situations that result in phenotypic haemophilia among women of child-bearing age: a Lyonized carrier of haemophilia A or B; and the onset of a Type I or Type II factor (F)VIII inhibitor arising prior to the third trimester of pregnancy and extending well into the postpartum period [1,2]. Kadir et al. followed 82 pregnancies among 24 carriers of haemophilia A and 8 carriers of haemophilia B [1]. Thirty-two of the 82 pregnancies were spontaneously or electively aborted. Thirty-five per cent of the women opted for prenatal diagnosis, with five male foetuses being diagnosed; three of these women opted for termination. Foetal blood sampling on four occasions was without incident. However, a ventouse delivery resulted in a huge cephalohaematoma in one foetus. Eight caesarean sections were performed that might have been avoided had gender been determined. Most importantly, 22% of the deliveries resulted in primary postpartum haemorrhage and 11% had secondary bleeding; this despite all deliveries having occurred in a hospital with a large comprehensive haemophilia centre. This experience strongly supports aggressive factor replacement and other haemostatic support for women with low or moderately low FVIII or FIX levels prior to, during, and following delivery. Ultra-highpurity factor concentrates should be chosen for viral safety. Michaels et al. report four women with acquired haemophilia in association with pregnancy and delivery [2]. Three had Type II FVIII inhibitors (typical of acquired inhibitors) and one had a Type I (more typically seen in individuals with haemophilia). High-dose FVIII was

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effective in the two of three Type II patients who experienced postpartum bleeding, but not in the woman with the Type I antibody. Immunosuppression was unsuccessful in significantly reducing the inhibitor in any of the women. Management of obstetrical events in women with acquired haemophilia continues to be fraught with peril. Advice from only the most experienced coagulationists should be sought to assist with ante-, intra-, and postpartum inhibitor therapy.

References 1 Kadir RA, Economides DL, Braithwaite J, Goldman E, Lee CA. The obstetric experience of carriers of haemophilia. Br J Obstet Gynaecol 1997;104(7):803–10. 2 Michiels JJ, Hamulyak K, Nieuwenhuis HK, Novakova I, van Vliet HH. Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of the factor VIII inhibitor. Eur J Haematol 1997; 59(2):105–9.

Anticoagulation for Atrial Fibrillation in a Haemophiliac

Question/ Case

When a 23-year-old patient with haemophilia A (factor VIII of 4%) has atrial fibrillation (AF), what do you choose to prevent thromboembolism: anticoagulation or antiplatelet therapy?

Response from Brigit Brand, MD University Hospital, Zurich, Switzerland Venous and arterial thromboses are rare occurrences in patients with haemophilia, but this subject has gained considerable attention in recent years. Recently, all reported cases of non-catheter associated venous thrombosis in haemophilia have been carefully evaluated by Girolami et al. [1]. They found the most frequent risk factor to be the administration of FEIBA or rFVIIa. The same authors published an evaluation of all 42 reported cases of myocardial infarction and other arterial thromboses [2]. Neither article offers general recommendations on antithrombotic prophylaxis. There is little experience in this field, and treatment must be individualized. Strong data have emerged to support anticoagulation with warfarin to prevent stroke in non-haemophilic patients with AF [3,4]. When warfarin is contraindicated, aspirin or other antiplatelet agents are also efficacious, but less than warfarin. Haemophiliacs have been reported to be treated safely with anticoagulation in conjunction with factor replacement, usually for short periods of time. With these points in mind, I suggest, for a haemophilic patient, that the first aim must be to convert the AF back to sinus rhythm for prevention of thromboembolism. I personally prefer aspirin rather than anticoagulation with warfarin or with direct thrombin inhibitors. Vitamin K antagonists have too many variables in predicting a safe, but efficient dose. Due to lack of data from the literature, the treatment has to be individualized and closely watched.

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Response from Miguel A. Escobar, MD University of Texas Health Science Center at Houston; Gulf States Hemophilia & Thrombophilia Center, Houston, Texas, USA AF is uncommon among individuals less than 50 years old. Prospective studies show that the rate of ischaemic strokes is about 4.5% per year in untreated patients. Certainly most of the individuals included in the studies are more than 50 years old. Stroke in individuals with AF appears to be as a result of cardiogenic embolism. When it is decided to treat a patient with AF, one has to take into account the age and risk factors for stroke (prior ischaemic stroke, transient ischaemic attack, systemic embolism, impaired left ventricular function and/or congestive heart failure, hypertension, or diabetes). Management with anticoagulants is usually indicated in the older patient with any of the above risk factors or valvular heart disease. For individuals younger than 65 years with no other risk factors, the recommendation is to use aspirin 325 mg/day only (Grade 1B). More specifically in this young individual with moderate haemophilia A, I suggest the following: 1 Find the underlying cause of the AF given his age. 2 Cardioversion will be my first treatment option if there is no contraindication. First, I suggest doing a transesophageal echocardiogram to rule out a thrombus in the heart. If the echo is normal then cardioversion without the use of anticoagulation should be considered, as the patient could be considered “already anticoagulated” due to his haemophilia. 3 If cardioversion is not an option, my second choice would be the use of an aspirin 325 mg/day. 4 I would not recommend anticoagulation with vitamin K antagonists given the increased risks for bleeding. For more details you can read the recently published recommendations from the ACCP (The Eighth American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Evidence-based guidelines. Northbrook, IL: ACCP, 2006). These are only guidelines taken from clinical studies and should be used as such. These guidelines may not apply to cases like the one described here.

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References 1 Girolami A, Scandellari R, Zanon E, Sartori R, Girolami B. Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases. J Thromb Thrombolysis 2006;21(3):279–84. 2 Girolami A, Ruzzon E, Fabris F, Varvarikis C, Sartori R, Girolami B. Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature. Acta Haematol 2006;116(2):120–5. 3 Chong JY, Mohr JP. Anticoagulation and platelet antiaggregation therapy in stroke prevention. Curr Opin Neurol 2005;18(1):53–7. 4 MacKinlay N, Taper J, Renisson F, Rickard K. Cardiac surgery and catheterization in patients with haemophilia. Haemophilia 2000;6(2):84–8.

Anticoagulation for a Cardiac Valve in a Haemophiliac

Question/ Case

We are treating a 42-year-old patient with mild haemophilia A (factor VIII level 20%) with a bicuspid aortic valve and severe aortic regurgitation. We are planning an aortic valve replacement operation. Our question is: should we use a prosthetic or a mechanical valve? Considering the age of the patient, a prosthetic valve would require future replacement; however, with a mechanical heart valve, life-long anticoagulation will be required in a patient who already suffers from a congenital bleeding tendency. If we did use a mechanical valve, what international normalized ratio (INR) range would you recommend?

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark The question raised is very difficult to answer. Since I have no personal experience with artificial valves in patients with haemophilia, a literature search helped me to identify two cases. One case report concerned a patient with severe haemophilia A who had a double (aortic and mitral) valve replacement [1]. The abstract did not report on the subsequent use of oral anticoagulants. The second report concerned a patient with moderate haemophilia who underwent an aortic valve replacement [2]. In this case, doctors deferred coumarin therapy postoperatively “due to the prolonged partial thromboplastin time time.” Though these two reports do not answer the question, they do signify that, with the availability of modern replacement therapy (factor VIII), major surgery of this kind can be successfully accomplished in patients with haemophilia. For intraoperative thromboprophylaxis, it is advisable to use heparin as in other patients, and monitoring can follow the same principles. It is important to note that, to achieve the activated thrombin time or other unactivated clotting measures, the requirements for heparin dosage during extracorporeal circulation will be lower than in non-haemophilic patients. The choice of valve

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prosthesis is not easy. In my hospital, we would probably focus on the postoperative thromboembolic/bleeding balancing problem and select a biological valve. Since experience in this field is so extremely limited, the choice of a postoperative INR level cannot be based on solid evidence, but rather subjective criteria. Patients with mild haemophilia can die from an acute myocardial infarction, and there is no reason to believe a mild haemophiliac could not produce other kinds of thrombi. Hence, postoperative anticoagulation is advisable, but the best therapeutic level is not known. The judgement should clearly consider the risk of untoward excessive bleeding, including central nervous system and other serious bleeds. I would be in favour of an initial INR level of around 2.0, but lower levels should be chosen if bleeding poses problems.

References 1 Meagher PD, Rickard KA, Richards JG, Baird DK. Aortic and mitral valve replacement in a patient with severe haemophilia A. Aust N Z J Med 1981; 11(1):76–9. 2 Krawietz W, Loracher C, Struck E, Schlimok G, Falk H. Surgical aortic valve replacement for acute Streptococcus viridans endocarditis with simultaneous moderate hemophilia A. Z Kardiol 1988;77(7):470–3.

Cardiac Catheterization in a Haemophiliac

Question/ Case

A 45-year-old haemophiliac with factor VIII levels of 5% has unstable angina with a 90% proximal left-anterior-descending artery occlusion. He needs angioplasty with stent placement, and he will need heparinization and may require an antiplatelet agent like abciximab (ReoPro®) postprocedure. Does he need factor VIII infusion during the procedure? Can he be heparinized and which type is better, unfractionated heparin or low-molecular-weight heparin? Should he need factor VIII at the time of femoral sheath removal?

Response from Craig M. Kessler, MD Georgetown University Medical Center, Washington, DC, USA This is not an uncommon problem in individuals with haemophilia and coronary artery disease. I believe that these patients need to have factor replacement therapy, initially up to 100% of normal, when the angioplasty and stent placement are performed and the abciximab and heparin are given. This way, this patient’s risk of bleeding is equivalent to any other individual with normal coagulation. I would also ensure the patient has factor replacement to 50% of normal when the femoral artery sheath is pulled. Thereafter, I would not think the patient would need replacement, unless bleeding occurs. As for the type of heparin to be used in this situation, I would opt for the low-molecular-weight heparins since they have been shown to be associated with better patency rates post angioplasty. I would treat the patient just like anyone else, as long as the factor VIII level is adequate to sustain normal blood coagulation.

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Anticoagulation for a DVT in a Haemophiliac

Question

How do you manage a deep venous thrombosis (DVT) in the presence of haemophilia?

Case 1

We have an elderly patient with moderate haemophilia B (factor IX level of 2%) with a history of DVT. Is there an indication for oral anticoagulation? If yes, what is the level of INR recommended?

Case 2

This question is regarding a patient with severe haemophilia A who developed pulmonary embolism during the perioperative period (surgery was for abdominal trauma sustained in a motor vehicle accident). His FVIII level did get up to 150% on one occasion. The patient was also found to be heterozygous for FV Leiden. No other sites of DVT were detected. Would you send the patient home on anticoagulation and how long would anticoagulation be continued? How aggressively would you address the FVIII deficiency while the chronic anticoagulation is ongoing?

Response from German A. Marbet, MD University Hospital Basel, Basel, Switzerland Venous thromboembolism is a rare event in haemophiliacs. It may occur if several risk factors accumulate. A special condition is central venous catheter-associated thrombosis, mainly in children receiving coagulation factor concentrates. A recent review of the literature showed an average prevalence of 11% – 45 catheter-related thromboses in 419 catheters placed [1]. Interestingly, deep vein thrombosis is quite rare in haemophiliacs undergoing orthopaedic surgery despite vigorous replacement of the deficient coagulation factor. However, the DVT risk may be substantial in haemophilia B patients receiving prothrombin complex concentrates as a source of factor IX instead of highly purified plasma-derived or recombinant factor IX.

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We do not know which risk factors had favoured DVT in the elderly patient with moderate haemophilia B. Anyway, I would not use vitamin K antagonists in a haemophilia B patient. The bleeding risk appears excessive as factor IX activity would drop to values below 1% accompanied by the reduction of other vitamin-K-dependent factors to 20–30%. Therefore, I would treat acute venous thromboembolism with therapeutic doses of unfractionated or low-molecular-weight heparin. In the presence of a bleeding lesion (e.g. postoperatively), treatment with factor IX replacement would continue. After 10–14 days, it may be possible to reduce heparin in parallel with decreasing factor IX replacement. If possible, other thrombogenic risk factors (e.g. stasis, venous compression) should be removed. Low-molecularweight heparin could then be administered in prophylactic doses for about 6 weeks. Later, the low factor IX level could be expected to prevent recurrence of DVT. Response from Sam Schulman, MD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada The second case is an obvious challenge where you have two potentially life-threatening conditions, but in opposite ways. One would theoretically think that by just stopping the FVIII substitution, the effect of severe haemophilia will be sufficient to prevent extension or progression of the venous thromboembolism, so that the body can take care of the fibrinolytic issue. This may be the case, but it is impossible to know how well the two diseases can balance each other. In addition, the patient is in the postoperative period after both trauma and major surgery. Thus, it would be too risky to leave him without factor replacement therapy. I had a patient with von Willebrand disease and bilateral total knee replacement, complicated by sub-massive pulmonary embolism. This patient was managed by continuing factor replacement therapy (bolus injections of FVIII-von Willebrand factor concentrate) and treating with anticoagulants. The factor replacement was kept at the minimum dose required to control bleeding. Postoperatively a level of 50–60% of FVIII is sufficient, and every 3 days this can be lowered by 10 percentage points. However, with anticoagulant therapy on board, you have to be more careful and perhaps double the interval between lowering the FVIII dose. When you reach a maintenance level of 20%, you may switch to prophylaxis by intravenous injections with

Anticoagulation for a DVT in a Haemophiliac 53

20 IU/kg every 2 days, at least until anticoagulation therapy is completed. I would give full heparinization by intravenous infusion of unfractionated heparin, aiming at an APTT of 1.5–2 times prolongation of the upper limit of normal (thus a bit conservative) for 5 days. For secondary prophylaxis, I would not give warfarin but rather lowmolecular-weight heparin for 3 months at a dose of 40 mg or 5000 units once daily. Another alternative is to give the secondary prophylaxis only for 1 month and at that point also reduce the FVIII substitution. A third alternative is to insert a vena cava filter to reduce the need for secondary prophylaxis, but the initial treatment of pulmonary embolism is necessary.

Reference 1 Franchini M. Thrombotic complications in patients with hereditary bleeding disorders. Thromb Haemost 2004;92(2):298–304.

DDAVP for Treatment of Mild Haemophilia during Surgery

Question

Can we use desmopressin acetate (DDAVP) for treatment during and after a total hip replacement in a patient with mild haemophilia A?

Case

A mild haemophilia A (19%) patient is scheduled to undergo a total hip replacement for osteoarthritis. A post-IV DDAVP peak level recently was 61% peak. His past bleeding history has been mild, consistent with his FVIII level. There is no family history of thrombophilia. Should we treat with DDAVP or with FVIII replacement?

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark If I understand the question right, your patient suffers from mild haemophilia, and the consideration is the use of DDAVP to raise and maintain a safe level of factor VIII. In my numerous years of experience with DDAVP in my patients, I have never attempted to use DDAVP for a truly major surgery like this. There are several reasons here. Importantly, you cannot rely on a response like the one seen previously (60%) when DDAVP is used on a daily basis, and the half-life of FVIII released from patient’s own stores may be shorter compared to exogenous factor VIII. If DDAVP is used once daily, the trough level of factor VIII will be close to patient’s residual F VIII level of 19%, and there will be a significant risk of excessive bleeding. Further, there is the important issue of tachyphylaxis, that is the gradual or abrupt exhaustion of FVIII stores. This is very unpredictable. Even with dual or multiple daily recordings of the FVIII level, I would fear bleeding problems. So, if this were my patient, I would prefer factor VIII replacement therapy. If the patient’s response to a factor VIII concentrate (in vivo recovery) has been tested some time during previous 1–2 years, I would trust this as a basis for calculating the correct dose for surgery

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itself, so as to raise the level to 100%. I would certainly check the factor VIII level 15 min after the first infusion. In the postoperative setting, I would raise the factor VIII level by infusions, according to local preferences, to maintain a factor VIII level that should not go below 50% at any time for the first 3–5 days. From day 5 onwards, I would still suggest a level of factor VIII kept above 40% at all times for 2–3 days with a gradual decrease in the dose until day 10. From that time on, I would give a dose of factor VIII every morning prior to rehabilitation training.

Editors’ Note An alternative approach would be the continuous infusion of factor VIII maintaining the levels suggested by Dr Ingerslev.

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Haemophilia and Haemodialysis

Questions/ Cases

Case 1: A 50-year-old patient with severe haemophilia B and no inhibitors has suffered from diabetes mellitus for 25 years. He now has renal insufficiency and will soon require chronic dialysis. Does anyone have any experience in the management of chronic dialysis in haemophilia patients? Case 2: Would you recommend antithrombotic prophylaxis with heparin during haemodialysis in severe haemophilia patients?

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark The first patient illustrates that, in severe haemophilia, vascular complications due to diabetes can develop with quite dramatic results. Peritoneal dialysis might be a good solution because this procedure does not require heparin, and there is absolutely no need for replacement therapy during dialysis sessions. Should haemodialysis be preferred in this case, the critical issue to address is the requirement for heparin. Adequate vascular access can be achieved through a shunt or an arterio-venous fistula. The surgical establishment of the latter will require replacement with factor IX concentrate. Since this patient has clinical evidence of a vascular disorder, the factor IX concentrate should be carefully selected to avoid thrombogenic complications. Prothrombin complex concentrates should be avoided. Haemodialysis in itself may require heparin to avoid formation of platelet aggregates in the artificial kidney, but the requirements must be established empirically. For the first session, priming with a very small dose of heparin, such as 500 IU, may be sufficient. Theoretically, there may be no need for heparin at all, but it should be remembered that this patient may have quite dramatically increased levels of von Willebrand factor. To avoid oozing from puncture sites and prevent haematomas on the arterial side, prolonged compression and replacement with factor IX at the end of dialysis may be required.

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Response from Victor Marder, MD School of Medicine at UCLA, Los Angeles, California, USA Would I recommend anticoagulation during dialysis? The short answer is “yes”, for the simple reason that I would normalize patients with prophylactic factor prior to accessing the arterio-venous shunt or fistula with a large gauge needle. This being the case, the haemophilic patient is essentially the same as a non-haemophilic in regard to the need to anticoagulate the dialysis machine.

Haemophilia and Hepatitis C Treatment

Question/ Case

Should the patient with mild haemophilia A (12% FVIII) and hepatitis C be treated with interferon therapy? For more than 15 years, the patient has had elevated transaminases, without symptoms. He has not received FVIII for more than 10 years. We have recently done virus screening and we have found HCV positivity.

Response from German A. Marbet, MD University Hospital Basel, Basel, Switzerland I think that the patient with mild haemophilia A and laboratory evidence of chronic hepatitis C (increased transaminases, anti-HCV positive by immunoenzymatic assay and positive with a qualitative PCR-based HCV RNA assay) should be further evaluated for combined treatment with one of the two available pegylated alpha-interferons and ribavirin. A quantitative HCV RNA assay and HCV genotyping will provide information about the chance of a durable response and are required for the follow-up of therapy. In most patients with chronic hepatitis C, liver biopsy is required for appropriate therapeutic decisions. Liver histology will show the degree of inflammatory activity and of fibrosis and may also detect stigmata of surreptitious alcohol abuse and other pathologic conditions. Because of the higher bleeding risk, there is much reluctance to perform liver biopsy in haemophiliacs. However, a recent article by Stieltjes et al. in the British Journal of Hematology 2004 reports successful transjugular liver biopsy (88 transjugular liver biopsies in 69 individuals) in adult patients with haemophilia or other congenital bleeding disorders infected with hepatitis C virus [1]. Earlier positive reports about liver biopsies in smaller numbers of haemophiliacs are also quoted by the authors. Before and after biopsy, the patients require appropriate replacement of coagulation factors. Stieltjes et al. gave about 40 IU/kg in severe haemophilia A and 60 IU/kg in severe haemophilia B patients, respectively, before biopsy and followed by appropriate doses for 24–48 h. There is also a regimen in the guidelines on hepatitis by Makris et al. in Hemophilia 2001 [2].

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In this mild haemophilia A patient, I would first exclude the presence of a factor VIII inhibitor and then test the effect of an infusion of 0.3 g/kg desmopressin. If there were an increase of factor VIII to 80%, desmopressin could be administered before biopsy and then at 12 and 24 h post-biopsy. If the increase were smaller, factor VIII concentrates would be required before biopsy to reach 80–100% factor VIII. Desmopressin or factor VIII concentrates (20 IU/kg) would be given at 12 and 24 h post-biopsy. After biopsy, the patient should remain in the hospital for at least 24 h for clinical monitoring and factor VIII control. Ultimately, the decision to treat with pegylated alpha-interferon and ribavirin will depend on: (a) treatment indication based on histology (inflammatory activity, fibrosis) (b) absence of contraindications (c) informed consent (d) capability of adherence to the treatment regimen and to the required controls (clinical and blood tests). It may be worth noticing that 37% of all assessable biopsies in the series of Stieltjes et al. showed only minor or no histological alterations. In these patients, no treatment was started and regular clinical follow-up was recommended. Response from Sam Schulman, MD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada On one hand, many of the patients with hepatitis C will live with their chronic infection for decades without any complications. On the other hand, we have already had several patients who developed liver cirrhosis, and some unfortunately also developed hepatocellular carcinoma. The latter is rarely curable. Policies may vary from country to country, depending on resources, but if affordable, I think the patient should be offered the possibility to eliminate the chronic infection. The first step is to verify that the elevated aminotransferases really are caused by hepatitis C. Thus, a PCR analysis of hepatitis C RNA should be performed and must be positive to justify therapy. In addition, it is very useful to perform genotyping of the virus. Patients

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with genotype 2 or 3 only need 6 months of combination therapy, while the other genotypes will need 12 months. Other liver disorders like haemochromatosis, Wilson’s disease, diabetes, or autoimmune hepatitis should be excluded. It is a matter of taste whether Pegasys® or PEG-Intron® should be chosen. It should be combined with ribavirin 1000 mg/day or more if body weight is 100 kg. If the repeat PCR is still positive at 6 months, continuing antiviral therapy is futile. Patients with bleeding disorders may suffer increased bleeding from mucous membranes during this treatment. We do not perform liver biopsies in these patients unless a malignancy is suspected.

References 1 Stieltjes N, Ounnoughene N, Sava E, Paugy P, Roussel-Robert V, Rosenberg AR, et al. Interest of transjugular liver biopsy in adult patients with haemophilia or other congenital bleeding disorders infected with hepatitis C virus. Br J Haematol 2004;125(6):769–76. 2 Makris M, Baglin T, Dusheiko G, Giangrande PL, Lee CA, Ludlam CA, et al. Guidelines on the diagnosis, management and prevention of hepatitis in haemophilia. Haemophilia 2001;7(4):339–45.

Haemophilia and Physical Therapy

Question

I am a physiotherapist attending a haemophilia clinic. I would like to know more about safe exercises to teach our patients for strengthening their muscles. What is safe practice when there are already contractures present? Also, which electrical apparatus, for example ultrasound, is safe to use for pain when patients are not bleeding?

Response from Sam Schulman, MD, PhD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada In any exercise, the basic rule is to start carefully and increase the load gradually and even more so when contractures are present. It is generally better to keep the exercise periods short and repeat it several times per day. A simple tool to assist the patient in exercise is a rubber band, such as the Thera-band® (The Hygienic Corporation, USA). They can easily be used for both leg and arm exercises. Weight cuffs can also be used if one needs to change the load, but these are more expensive. The electrical instrument we have found most useful against pain is transcutaneous electrical nerve stimulation (TENS). We know that in some countries ultrasound or short wave is also being used for this purpose. However, we only use ultrasound to enhance reabsorption of large muscle haematomas. For acute pain cold packs are helpful, whereas in chronic pain heat may be better. This is particularly true when the patient starts exercising a contracted extremity. Ideally, this is started in a warm swimming pool (up to 37ºC) so that the load on the joint is minimal and the tissues become more flexible. Response from E. Carlos Rodriguez-Merchan, MD and Karen Beeton La Paz University Hospital; and Autonoma University, Madrid, Spain All the information needed for the practical treatment of the musculoskeletal complications of haemophilia can be found in a single volume [1].

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Safe Exercises To Teach Patients for Strengthening Their Muscles This is difficult to say without more information. Basically, all patients should be fully assessed by both a subjective and a physical examination prior to treatment to establish if there are any precautions to treatment or contraindications. Chapter 1 in Physiotherapy Management of Hemophilia provides an overview of the assessment process [2]. Following this, a suitable treatment programme can be determined. Generally, weight-bearing exercises should be started with caution, particularly if patients have arthropathy. All treatments should be tailored to the individual.

Safe Practice If There Are Contractures Again, a careful and thorough assessment is the key to management. It is important to determine the severity of the contracture, availability of factor replacement therapy for physiotherapy, and whether there is a soft tissue or bony end feel. A bony or hard end feel is less likely to respond to physiotherapy, and other means will have to be considered. The Haemophilia supplement on articular contractures may be useful further reading [3].

Electrical Apparatus Physiotherapists often use ultrasound pulsed short wave, interferential or TENS for patients with haemophilia. The physiotherapy book has a good chapter on electrotherapy use in haemophilia [2].

References 1 Rodriguez-Merchan EC, Goddard NJ, Lee CA. Musculoskeletal Aspects of Hemophilia. Oxford: Blackwell Science Ltd, 2000. 2 Buzzard B, Beeton K. Physiotherapy Management of Haemophilia. Oxford: Blackwell Science Ltd, 2000. 3 Rodriguez-Merchan EC. Therapeutic options in the management of articular contractures in haemophiliacs. Haemophilia 1999;5(Suppl 1):5–9.

Haemophilia and Renal Bleeds

Question

Is it possible to use inhibitors of fibrinolysis when treating renal bleeding?

Response from Tom Abshire, MD1 with Roshni Kulkarni, MD2 Emory University School of Medicine, Atlanta, Georgia, USA 2 Centers for Disease Control and Prevention, Atlanta, Georgia; and Michigan State University, East Lansing, Michigan, USA

1

It turns out that the overall incidence of renal disease in haemophilia is approximately 35%, so haematuria and other renal abnormalities may be more common than we think [1]. For mild renal bleeding, inhibitor or not, fluids and rest are probably adequate. In more severe bleeding, defined by pain, drop in haemoglobin, or persistent bleeding despite hydration and rest, the following treatment should be considered: renal imaging (ultrasound) to define an anatomic problem, factor replacement for non-inhibitor patients and by-passing agents for inhibitor patients, and consideration of steroids for 3–5 days. The issue of anti-fibrinolytic therapy is tricky: the maxim is not to use them in renal bleeding because of the possibility of a clot within the collecting system.

Reference 1 Small S, Rose PE, McMillan N, Belch JJ, Rolfe EB, Forbes CD, et al. Haemophilia and the kidney: assessment after 11-year follow-up. Br Med J (Clin Res Ed) 1982;285(6355):1609–11.

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Haemophilia and Scuba Diving

Question

Should we worry about scuba diving in our haemophilia population?

Case

I have several patients with haemophilia who participate in scuba diving. Currently, I recommend that they perform prophylaxis prior to a dive. Should I be more worried?

Response from Craig M. Kessler, MD Georgetown University Medical Center, Washington, DC, USA There are no data regarding the safety of scuba diving in individuals with a propensity to bleed; however, recent articles suggest that individuals with iatrogenic qualitative platelet dysfunction may be at increased risk of developing spontaneous bleeding and death with scuba diving. I believe that these findings could be extrapolated to individuals with haemophilia. Essentially, spontaneous intrapulmonary bleeds can occur in divers [1]. Also, there is an anecdotal report of spontaneous spinal haemorrhage [2]. Along with the above, there is a report of massive variceal bleeding caused by scuba diving that illustrates the bleeding propensity in otherwise normal individuals who have taken aspirin [3]. The aetiology of the spontaneous bleeds is thought to be due to pressure changes that are proportional to the depth of diving. Intrathoracic pressures become equal to ambient pressure and force more blood flow to these areas of the body, thus inducing spontaneous bleeds. If the haemorrhagic potential appears increased with aspirin use alone, I believe that haemophiliacs and other coagulopathic individuals may be at increased risk of spontaneous bleeding. I concur with your decision to provide haemophiliacs with prophylactic replacement therapy if they choose to dive; however, the data suggest that they may remain at increased risk if they are taking anti-inflammatory medications that could affect platelet function. Haemophiliacs should be educated about the increased risks of spontaneous bleeding proportional to depth of diving. All these risks are certainly compounded by the inherent

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physical risks to bleeding with trauma during diving (e.g. cuts from coral reefs).

References 1 Boussuges A, Pinet C, Thomas P, Bergmann E, Sainty JM, Vervloet D. Haemoptysis after breath-hold diving. Eur Respir J 1999;13(3):697–9. 2 Hida K, Iwasaki Y, Akino M. Spontaneous spinal hemorrhage during scuba diving. Case illustration. J Neurosurg 2002;96(Suppl 3):351. 3 Nguyen MH, Ernsting KS, Proctor DD. Massive variceal bleeding caused by scuba diving. Am J Gastroenterol 2000;95(12):3677–8.

Haemophilia and Ventricular Septal Defect Repair

Question

What is the standard protocol in a patient with severe haemophilia A and an elective cardiac surgery such as a ventricular septal defect (VSD) repair?

Response from Margaret Ragni, MD University of Pittsburgh Physicians, Pittsburgh, Pennsylvania, USA There is probably no “standard protocol” for VSD repair in a patient with severe haemophilia A. A review of the literature adds little to this notion [1–7]. However, there are probably a few points worth noting. These might be grouped into three categories: (1) the surgical approach (extracorporeal bypass or not), (2) the surgical procedure (valve repair also involved or not), and (3) postoperative procedures (drains removed or not). A couple of general points: Preoperatively, it would be important to check a peak factor VIII level aiming for 100%. It would also be important to discontinue non-steroidal anti-inflammatory drugs (NSAIDs), which the patient might be using for painful haemophilic arthropathy. Perioperatively, standard perioperative factor VIII dosing might be initiated, that is, dosing to 100% FVIII level prior to sternotomy, 50% just after the procedure, every 8 h for the next 24 h, then every 12 h for 14 days, and then daily for 7 days, for a total 3 weeks of coverage. Monitoring activated partial thromboplastin time (APTT), and FVIII levels, nadir (just before the next dose) if available, may also be helpful in avoiding preventable bleeding.

Surgical Approach It is important to establish whether the VSD repair will be done by minimally invasive techniques with skin incisions and robotically assisted repair vs. use of extracorporeal bypass with heparin. If the latter is planned, some recommend antifibrinolytic agents, such as aprotinin, amicar, or tranexamic acid, be maintained during the surgical

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procedure. Whether antifibrinolytic agents are necessary is not established as there have been no controlled trials in haemophilia. However, at least five separate randomized, double-blind clinical trials have shown that antifibrinolytic agents reduce blood loss in individuals without haemophilia. It is important to note, however, that a small number of case reports in patients with haemophilia, including some with severe disease, find factor coverage alone sufficient to cover VSD repair.

Surgical Procedure If valve repair will be part of the surgery planned, it is important to be sure tissue valves rather than prosthetic valves, which require anticoagulation, be used. The risk with the latter is that anticoagulation in the setting of an underlying bleeding disorder is not standardized. Although the target INR in a patient without haemophilia is 3 or higher, whether in a haemophilic patient, a level of 1.5–2 is sufficient to prevent thrombosis, but not high enough to precipitate bleeding, remains unknown.

Postoperative Procedures Although seemingly less important in the realm of septal defect or valvular repair procedures, it is important to ensure factor coverage for removal of drains and chest tubes, or placement of drains, should haematomas form. This is particularly important for those individuals in which new problems arise in an outpatient setting. Raising the factor level to 50–100% dose would be appropriate for drain removal.

References 1 MacKinlay N, Taper J, Renisson F, Rickard K. Cardiac surgery and catheterization in patients with haemophilia. Haemophilia 2000;6(2):84–8. 2 Ghosh K, Madkaikar M, Jijina F, Gandhi S, Shetty S, Mohanty D. Open heart surgery with mitral valve replacement–ordeal of an undiagnosed haemophilia patient. Clin Lab Haematol 2003;25(2):131–3. 3 Ghosh K, Shetty S. Anticoagulation in haemophilia patients with prosthetic valve replacement. Haemophilia 2004;10(6):743.

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4 Nomura K, Nakamura Y, Yamagishi M, Yamamoto K, Hanada R. Perioperative management of ventricular septal defect and right coronary cusp prolapse in a patient with hemophilia A. Kyobu Geka 1994;47(13):1071–4. 5 Boilletot A, De Geeter B, Wiesel ML, Kieny MT, Bopp P, Hemmendinger S, et al. Surgical correction of interventricular communication with pulmonary stenosis in a hemophiliac. Arch Fr Pediatr 1983;40(7):571–3. 6 Moritz A, Ozaslan F, Dogan S, Abdel-Rahman U, Aybek T, Wimmer-Greinecker G. Closure of atrial and ventricular septal defects should be performed by the surgeon. J Interv Cardiol 2005;18(6):523–7. 7 Aris A, Pisciotta AV, Hussey CV, Gale H, Lepley D. Open-heart surgery in von Willebrand’s disease. J Thorac Cardiovasc Surg 1975;69(2):183–7.

Haemophilia with Hepatitis C and Recurrent Bleeding

Question/ Case

Two haemophilic patients who develop chronic hepatitis C were found to bleed more frequently. Despite repeated injections of FVIII, it seems that FVIII products are not as efficacious in treating this recurrent bleeding (haemarthroses), as they were prior to the development of hepatitis. The platelet count is about 60K/l. Neither a FVIII inhibitor nor other coagulation abnormalities have been detected. Has someone on the panel experienced such cases? How can we manage these patients?

Response from Margaret Ragni, MD University of Pittsburgh Physicians, Pittsburgh, Pennsylvania, USA Potential causes of bleeding in patients with end-stage liver disease and bleeding disorders include the other coagulopathies that occur. As the case points out, thrombocytopaenia is very commonly the problem. Normally, most individuals would not experience bleeding problems at a platelet count of 60,000 but the likely bleeding tendency could be multifactorial (platelet dysfunction, other medications, and/ or anatomic lesions (e.g. varices)). We generally begin factor treatment on a daily basis if the patient has a bleed. One could also consider prophylactic therapy in the absence of a bleed. Occasionally, revising the medication list or avoiding penicillin or other antibiotics that inhibit platelet function may be helpful. DDAVP may also be helpful in improving platelet function. Response from Sam Schulman, MD, PhD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada Thrombocytopaenia could indicate liver cirrhosis with hypersplenism. This is often associated with acquired platelet function defects. This should be registered as a prolonged bleeding time, whereas the PFA100 instrument (Dade Behring) is not always sufficiently sensitive to

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pick up such abnormalities. One reason for the acquired defect is reduced clearance of fibrin split products (D-dimers, etc.), which may coat platelets and thereby impair their function. Desmopressin (DDAVP) is often effective in shortening a prolonged bleeding time, irrespective of the acquired risk factor, and even if the patients had haemophilia and no increment of the factor VIII level is expected, the effect on the bleeding time remains. Another possibility is reduced clearance of fibrinolytic factors due to decreased liver function, and in that case it would be important to use tranexamic acid in combination with any other treatment given. Response from Francis E. Preston, MD Royal Hallamshire Hospital, Sheffield, UK Is there any evidence of impaired hepatic synthetic function (i.e. low serum albumin and/or prolonged prothrombin time)? We have observed surprisingly low factor IX levels in some patients with haemophilia A and chronic hepatitis C. When bleeding has occurred, this has necessitated the use of both factor IX and VIII concentrates.

Isotretinoin in Haemophilia

Question/ Case

A 17-year-old patient with mild haemophilia (FVIII 6%) has to be treated with isotretinoin because of severe acne, resistant to previous therapy. Increased bleeding risk due to isotretinoin has been described, which could be related to enhancement of tissue plasminogen activator (t-PA) levels. Has someone experienced increased bleeding episodes in haemophilic patients during treatment with isotretinoin as described in case reported by Dootson? [1]

Response from Kaan Kavakli, MD Ege University Hospital, Izmir, Turkey I have just investigated the topic using the Internet and I have spoken with my colleagues about this subject. Unfortunately, neither my dermatologist friends nor I have any clinical experience about this vitamin A metabolite (isotretinoin) in acne treatment and increased bleeding risk in haemophilic patients. However, as far as I learned from related references, this drug causes t-PA (tissue plasminogen activator) secretion from human endothelial cells. So this drug may accelerate fibrinolysis. Hence, there is a theoretical possibility that haemophilic boys may experience increased bleeding. The patient mentioned is a mild haemophiliac. Therefore, in my opinion, I don’t think that he will have any problem with this drug. Perhaps, tranexamic acid capsules may be recommended for this patient to inhibit fibrinolysis. Response from Erik Berntorp, MD, PhD Lund University, Malmo, Sweden It is true that retinoic acid can promote fibrinolysis, at least in experimental systems, and probably also cause vessel growth and skin fragility. Going through the literature this does not seem to be an obvious clinical problem in ordinary acne patients. I am not aware of any reports, written or verbal, other than that by Dootson et al., saying that haemophilia patients treated this way may experience an increased bleeding tendency. However, the changed bleeding pattern

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reported by Dootson et al. may indicate increased fibrinolysis in their patient. In cases such as this, with a basal factor VIII level of 6%, I would not hesitate to treat with isotretinoin. If the patient experiences increased bleeding symptoms, tranexamic acid may be given to inhibit fibrinolysis. This can also be given as a long-term treatment.

Editors’ Note If the simple addition of tranexamic acid does not prevent bleeding, infusion of Factor VIII concentrate to levels of 30–50% could be considered.

Reference 1 Dootson GM, Keidan J, Anderson JA. Exacerbation of bleeding tendency in a patient with haemophilia A during treatment with isotretinoin. Br J Dermatol 1992;127(2):186–7.

Laser Eye Surgery in a Haemophiliac

Question

Should we cover a patient with severe Haemophilia A who is undergoing laser eye surgery for the correction of short-sightedness?

Response from Walter B. Greene, MD OrthoCarolina, Charlotte, North Carolina, USA Based on my discussion with a local Chairman of Ophthalmology, there are two techniques of refractory surgery using a laser. The older photorefractive keratectomy (PRK) technique is suitable for milder cases of myopia and should not cause bleeding. With the newer technique, a small cut is made in the cornea and a suction cup is used. This would entail a small risk of corneal bleeding and/or a “black eye”. If the latter technique is used, then a single transfusion of factor VIII would advisable.

Editors’ Note To be on the “safe” side, some clinicians would administer FVIII concentrate to levels close to 100% of normal. The eye could be considered a vital organ, and unexpected surgical complications might jeopardise the patient’s vision if the patient is left untreated.

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Managing Haemophilic Pseudotumours

Question

How do you manage haemophilic pseudotumours?

Case

A patient with haemophilia B and a low inhibitor titre (1 BU) presented with a painless, slow-growing mass over his upper inner right thigh, which disturbed his gait. An X-ray of his right femur showed a calcific mass compatible with a pseudotumour. I would like to hear the panel’s experiences regarding management of haemophilic pseudotumours.

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark Recently we had to solve a problem of the same nature: The patient with a known inhibitor developed a haemophilic pseudotumour of the thigh after surgery to fix a fracture of the femoral bone by osteosynthesis. This tumour was removed under the cover of tranexamic acid 25 mg/kg every 6 h and rFVIIa (NovoSeven®) at 100 g/kg every 2 h for 36 h. This was followed by the same dosing regimen of rFVIIa every 3 h for another 3 days, after which the injection intervals were shifted to every 4 h. We kept the patient’s wound well packed with very careful haemostasis. He subsequently underwent rehabilitation training from day 8 onwards. The final outcome was excellent. This approach is probably the one that you should use too. Since the inhibitor level is quite low at this time, you even have the chance to dose the patient with a highly purified factor IX concentrate (if bleeding occurs while the patient is on rFVIIa). It is not advisable to simultaneously use rFVIIa together with any older type of factor IX concentrate because such concentrates contain various other coagulation factors and there is a risk of thrombosis.

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Continuous NovoSeven: Pros and Cons

Question

Could someone on the panel tell me what the current opinion is with respect to using factor VIIa as a continuous infusion (CI)? Is this better than intermittent dosing given the fact that a lot of people now think that higher bolus doses are needed? Is continuous dosing safer and less expensive?

Response from Ulla Hedner, MD, PhD University of Lund, Malmo, Sweden and Novo Nordisk A/S, Denmark

Continuous infusion of rFVIIa The mechanism of action of rFVIIa is, according to current understanding, to enhance the thrombin generation on thrombin-activated platelets. By doing so, the fibrin structure of the haemostatic plug will be tighter and more resistant against premature lysis. It has been shown that the amount of thrombin as well as the rate of thrombin generation is important for fibrin structure [1]. To obtain this effect, bolus dosing seems to be most adequate. A high bolus dose will give a peak of thrombin generation, which should be optimal in creating a firm and stabile fibrin plug. Using CI of rFVIIa has been tried to save product [2,3]. This concept was based upon the experience of using CIs of FVIII and FIX in the treatment of haemophilias A and B, respectively. However, the concept of using rFVIIa in treatment of bleeding is totally different, since rFVIIa is not used as substitution therapy. As pointed out earlier, the effect of rFVIIa most probably is to enhance thrombin generation independent of the presence of FVIII or FIX. Therefore, the most adequate dosing schedule of rFVIIa would be bolus dosing. Two studies of CI of rFVIIa in patients undergoing surgery, including major surgery, have been performed in the UK. The first one, using the originally recommended dosing (one bolus of 90 g/kg initially followed by 16.5 g/kg/h in a CI), was published [3]. This study showed several failures with increased bleeding in association with

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major surgery in haemophilia patients. The conclusion therefore must be that this regimen does not represent adequate dosing for surgery in haemophilia. The second study used a bolus of 90 g/kg followed by 50 g/kg/h in a CI. This study showed an effect comparable to previous studies of rFVIIa therapy in surgery [4,5]. However, the regimen in this study used more drug than the bolus dosing schedule recommended previously. The conclusion regarding the use of CI of rFVIIa in the treatment of bleeding episodes would be that in cases where it is going to be used, one has to use: (1) doses of up to 50 g/kg/h in the CI or (2) a dose that has to be adjusted carefully in each patient with respect to pharmacokinetics performed repeatedly in each patient during each treatment. The pharmacokinetics has been reported to vary in some patients during treatment [2]. The dose has to be adjusted and extra bolus doses have to be administered in case of breakthrough bleeds. Based on the above information, CI is not recommended for rFVIIa treatment. Rather, bolus dosing with high initial doses is recommended. Response from Sam Schulman, MD, PhD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada CI with recombinant factor VIIa (rFVIIa) is not endorsed by the manufacturer and is an off-label use. However, there are several publications on case series, where there has been a mixture of successes and failures in the treatment peri- and postoperatively or for a major haemorrhage [6,7]. The failures have to a large extent been associated with the omission of antifibrinolytic therapy (tranexamic acid), sometimes with pump failures, subcutaneous infusion, or surgical bleeding. The clearance of rFVIIa is very variable, partly age dependent. It is therefore advisable to perform a single-dose pharmacokinetic study before a treatment course. There is software available to calculate the clearance. A bolus dose must always be given intravenously at the start of the treatment, typically with 90 g/kg. For major surgery with extensive muscle trauma, a repeat bolus dose after 2 h seems beneficial and should be given for total hip replacement. Some centres give bolus doses for a couple of days before switching to CI. CI follows the last bolus dose with an infusion rate that is based on the clearance and desired factor VII level. When the latter has been kept at 10 IU/ml together with a well-functioning pump and tranexamic acid, most cases

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using CI have been a success. The main exception is total hip replacement, where the level should be 20 IU/ml for the first 2–3 days. In patients with factor XI deficiency much lower levels are needed, probably around 3 IU/ml and in FVII deficiency, where the treatment is pure substitution, a level of 0.5–0.8 IU/ml suffices. Monitoring is done with a factor VII one-stage clot assay, but some reagents have a thromboplastin that is not as sensitive as required. A shortening of the prothrombin time should also occur, but this test alone is not useful for the monitoring. To avoid local thrombophlebitis, a parallel infusion with saline 20 ml/h is given in the same peripheral vein. Unfractionated heparin should not be mixed in the factor concentrate, since it affects the activity. Low-molecular-weight heparin causes agglutination in the factor concentrate and, therefore, should also be avoided. The CADD pump is very reliable, but other minipumps can be used, provided that they have alarm functions for end of infusion, occlusion, low battery, and pump failure. Substantial savings can be achieved with CI, but only if the surgical outcome is successful. The chance for this increases with the experience of the staff with constant infusion of rFVIIa. CI is not safer than bolus doses, but the latter are inconvenient (every 2 h dosing initially). Bolus dosing can also be unsafe, if a dose is missed, especially shortly after surgery. This may well happen at night if the staff suddenly gets occupied with another big problem. There are some centres that have been using rFVII in CI for several surgical procedures with repeated success, and they would not consider reverting to bolus injections on this occasion.

References 1 Blomback B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994;75(5):521–38. 2 Schulman S, Bech Jensen M, Varon D, Keller N, Gitel S, Horoszowski H, et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 1996;75(3):432–6. 3 Smith MP, Ludlam CA, Collins PW, Hay CR, Wilde JT, Grigeri A, et al. Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding. Thromb Haemost 2001; 86(4):949–53.

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4 Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998;80(5):773–8. 5 Ingerslev J, Freidman D, Gastineau D, Gilchrist G, Johnsson H, Lucas G, et al. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis 1996;26(Suppl 1):118–23. 6 Schulman S. Safety, efficacy and lessons from continuous infusion with rFVIIa. rFVIIa-CI Group. Haemophilia 1998;4(4):564–7. 7 Schulman S, d’Oiron R, Martinowitz U, Pasi J, Briquel ME, MauserBunschoten E, et al. Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinolysis 1998;9(Suppl 1):S97–101.

Haemophilia B and Immune Tolerance with Anaphylaxis

Question/ Case

I have a question about immune tolerance (IT) in haemophilia B. I was concerned about the low reported response rate and the possible development of the nephrotic syndrome or anaphylaxis. The patient has experienced an anaphylactic reaction. I would like advice on how to proceed. Should desensitization be attempted and if so how? Should Rituximab be considered? The child (age 1 year) has significant bleeding and requires frequent treatment with rFVIIa.

Response from Erik Berntorp, MD, PhD Lund University, Malmo, Sweden It is true that the reported response rate to IT induction is low in haemophilia B. It is important to consider that IT induction in haemophilia B is not as well documented as for haemophilia A. This is due to the rarity of the disorder and the fear of inducing thromboembolic complications with older factor IX products. In Malmö, we have used the Malmö protocol in eight high-responding haemophilia B patients and have been successful in six of these [1]. One conclusion from our experience is that the Malmö protocol gives a high response rate in the treatment of high-responding factor IX inhibitor patients and, given the short treatment time compared to other protocols, could be an option to reduce treatment complications such as the development of the nephrotic syndrome. Thus, I think the Malmö protocol really should be considered as a first-line IT therapy in patients with haemophilia B, and we have never seen any anaphylactic or nephrotic complications in our patients. The problem then comes up about what to do in a patient who already has an anaphylactic reaction. Rituximab could be considered, but the documentation for using Rituximab in that situation is lacking. The use of Rituximab in other inhibitor situations is also lacking. Another alternative is to try to desensitize the patient and then try IT induction. Desensitization could be achieved by giving slow intravenous

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injections or by step-wise infusions of factor IX concentrates under cover of hydrocortisone therapy [2,3]. The use of plasmapheresis and antigen exposure has also been reported [4]. We have our own experience with one patient who was successfully desensitized by giving very low doses of a high-purity factor IX concentrate: 30 units subcutaneously three times per week during one week; 40 units subcutaneously three times per week the following week; and then 50 units subcutaneously three times per week for about 3 months. After desensitization, the patient could be treated with regular factor IX doses although we never achieved IT to the factor IX inhibitor. The management of haemophilia B inhibitor patients, who have developed allergic reactions, is thus very difficult and no established guidelines have been developed as far as I know. However, the chance to desensitize the patient is quite good and my recommendation is to follow up by trying the Malmö protocol (cyclophosphamide intravenous gammaglobulin factor IX concentrate with hydrocortisone administration the first two days). If applying this protocol, the inhibitor titre should be below 10 Bethesda units at the start of treatment. Extracorporeal adsorption of the inhibitor can be used if the titre is above 10 BU, but in a young child this can be technically difficult. If the patient is a high responder, the desensitization procedure may boost the inhibitor to very high level. Therefore, the patient should be treated with recombinant factor VIIa for a long period of time, allowing the inhibitor titre to decline to a level below 10 BU.

References 1 Berntorp E. The Malmö immune tolerance experience in hemophilia B. Haematologica 2003;88(Suppl 12):71–4. 2 Tengborn L, Hansson S, Fasth A, Lubeck PO, Berg A, Ljung R. Anaphylactoid reactions and nephrotic syndrome – a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers. Haemophilia 1998;4(6):854–9. 3 Shibata M, Shima M, Misu H, Okimoto Y, Giddings JC, Yoshioka A. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates. Haemophilia 2003;9(3):269–71. 4 Barnes C, Brewin T, Ekert H. Induction of immune tolerance and suppression of anaphylaxis in a child with haemophilia B by simple plasmapheresis and antigen exposure: progress report. Haemophilia 2001;7(4):439–40.

rFVIIa (NovoSeven)

Question/ Case

The patient is a middle-aged woman who underwent a caesarean section. Postoperatively, she became hypotensive and suffered from continued bleeding. Laboratory investigation revealed a marked shift to the left in the white blood cell differential, with many immature granulocytes. Hypoalbuminaemia and thrombocytopaenia were also present. The patient developed the fulminate syndrome known as streptococcal toxic shock syndrome. Group B streptococci were isolated from surgical wound cultures, and the patient subsequently developed diffuse intravascular coagulation (DIC) as evidenced by prolonged clotting times, decreased fibrinogen levels, and the presence of fibrin degradation products. She was given supportive care in the form of fluid resuscitation, vasopressors, and mechanical ventilation, in addition to antimicrobial therapy, and transfusions of blood combined with fresh-frozen plasma and platelets. Presently, her platelet count is 25,000–40,000/l and she has no bleeding. Standard treatment for severe thrombocytopaenia consists of platelet transfusions. However, a considerable proportion of recipients of multiple transfusions of platelet concentrates from random donors become allo-immunized to HLA antigens. Is recombinant factor VIIa (rFVIIa) recommended as alternative therapy when a patient becomes “refractory” to platelet transfusions or when a life-threatening bleed occurs? Promising results have been reported with rFVIIa in thrombocytopaenic patients with overt bleeding [1]. However, no controlled clinical trials of rFVIIa in thrombocytopaenic patients have yet been reported. Recombinant FVIIa is currently only licensed for use in haemophiliacs with inhibitors. It may also be possible for significant amounts of

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tissue factor to be present in circulating blood in situations such as sepsis and DIC, and for this to cause thrombotic complications. However, we are not aware of any published reports of such complications. Do others have experience with rFVIIa in patients with thrombocytopaenia, sepsis, DIC, and bleeding? Would other users administer rFVIIa under these circumstances?

Response from Harold Ross Roberts, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA This case raises interesting questions based on thrombocytopaenia occurring in a patient with DIC and toxic shock syndrome. Firstly, the question/case asks whether rFVIIa is recommended as alternative therapy when a patient becomes refractory to platelet transfusions. Recombinant FVIIa has been used in patients with mildto-moderate thrombocytopaenia (platelet counts not lower than 20,000–30,000/l) [1]. Bleeding times were improved in about 50% of the patients and haemostasis should also be improved. Most of these patients had haematological malignancies with thrombocytopaenia due to the malignancy itself or to concomitant chemotherapy. In a series of eight patients with haemorrhage due to thrombocytopaenia, rFVIIa was administered in doses of 50–100 g/kg body weight and in six patients bleeding stopped. One patient with Glanzmann’s thrombasthenia also responded to infusions of rFVIIa. Whether rFVIIa would be of benefit in acquired platelet disorders is not clear, although there is an anecdotal report of benefit in a patient with renal disease. The rationale for using rFVIIa in thrombocytopaenia and platelet qualitative disorders is that the tissue factor (TF)-FVIIa pathway is necessary for the initial platelet activation. It has also been shown in vitro that, at the doses of rFVIIa mentioned above, FVIIa binds to activated platelets with low affinity, but sufficient to support activation of factor X on the platelet surface [2,3]. These data suggest that rFVIIa might represent useful adjunctive therapy for haemostasis in thrombocytopaenic patients but, as yet, there are not sufficient data to make this an official recommendation.

rFVIIa (NovoSeven) 89

With respect to the possibility of rFVIIa inducing DIC, one should remember that in any disease in which there is active tissue factor circulating, DIC will occur whether or not the patient receives rFVIIa. Tissue factor will result in activation of endogenous zymogen factor VII with the result that in vivo coagulation will be triggered if the stimulus is sufficient. It has been clearly shown that even haemophilic animals given infusions of TF will experience DIC. In patients such as the one described here, it is possible that infusion of rFVIIa will enhance DIC. Recombinant FVIIa has been given to many patients with chronic persistent and chronic active hepatitis without inducing DIC. It has also been given to patients with sepsis without complications but, in these patients, there was no evidence of pre-existing DIC. DIC has been reported, following the use of rFVIIa in one haemophilic patient with an inhibitor who had an extensive haemorrhage into the lower extremity that became necrotic and infected [4]. When surgically manipulated this patient developed DIC. The DIC seemed to be as much related to the surgical manipulation as to the infusion of rFVIIa. This is to be expected since the patient presumably had normal levels of zymogen FVII circulating. The patient received rFVIIa again before surgery, and DIC, which had been corrected, occurred again after surgical manipulation of the wound. The patient died with extensive haemorrhage. Other reports of DIC are less convincing and have occurred under circumstances where one would expect DIC or have been reported as DIC on the basis of elevated fibrin degradation products or other markers of thrombosis. In many of these patients, the increased levels of such markers were of a degree that would be compatible with uncomplicated surgery, rather than actual DIC. All in all, rFVIIa has proven to be remarkably safe. This is not surprising since in most cases of haemorrhage, there is in fact a separation between the initiation of coagulation and the subsequent propagation of thrombin generation. Would the administration of rFVIIa be recommended in this specific patient? It would not be recommended in the acute phase of her illness since there is no rationale for use of rFVIIa as treatment for DIC. Replacement therapy is indicated for this condition and some physicians would even use heparin therapy in selected patients. From the description, the cause of thrombocytopaenia in this patient was DIC, so correction of DIC by usual means should represent therapy for the secondary thrombocytopaenia. Recombinant FVIIa would not be recommended in a thrombocytopaenic patient who is not bleeding.

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Although not stated in the case report, the patient has apparently responded to replacement therapy and presumably her streptococcal infection has been eradicated. If so, one would expect the thrombocytopaenia to gradually disappear as the patient recovers. Recombinant FVIIa has been shown to be of benefit in patients with mild-to-moderate thrombocytopaenia due to decreased production; increased sequestration; and selected conditions of increased destruction, such as auto-immune thrombocytopaenia. Further clinical trials of rFVIIa for thrombocytopaenia are indicated.

References 1 Kristensen J, Killander A, Hippe E, Helleberg C, Ellegard J, Holm M, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996;26(Suppl 1):159–64. 2 Monroe DM, Hoffman M, Oliver J, Roberts HR. High dose factor VIIa activates factor X on activated platelets in the absence of tissue factor. Thromb Haemost 1997;(Suppl 168):(Abstract SC681). 3 Rao LV, Rapaport SI. Factor VIIa-catalyzed activation of factor X independent of tissue factor: its possible significance for control of hemophilic bleeding by infused factor VIIa. Blood 1990;75(5):1069–73. 4 Stein SF, Duncan A, Cutler D, Glazer S. Disseminated intravascular coagulation in a hemophiliac treated with recombinant factor VIIa. Blood 1990;76:438a.

Thrombosis in PCCs vs. APCCs

Question

Is the risk of thrombosis greater with Prothrombin Complex Concentrates (PCCs) or activated Prothrombin Complex Concentrates (APCCs – FEIBA)?

Response from Jeanne Lusher, MD Wayne State University School of Medicine, Detroit, Michigan, USA In general, I do not think that PCCs are more thrombogenic than APCCs when used in persons with haemophilia complicated by an inhibitor. The greatest risk of the thrombogenicity is when persons with haemophilia B receive repeated doses of PCCs at frequent intervals. In fact, shortly after the introduction of factor IX complex concentrates (so-called PCCs) in the late 1960s, reports of thrombotic complications began to appear. Deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation (DIC) occurred most often in persons with haemophilia B who were undergoing orthopaedic (or other) surgical procedures or who had crush injuries or extensive intramuscular haemorrhages – situations in which thromboplastic substances entered the circulation. Persons with significant hepatocellular disease were also at risk, as they often had low levels of antithrombin and could not clear clotting intermediates from the circulation. It was speculated that partially activated clotting factors (FIXa, FXa), and/or platelet-active phospholipids might be responsible for the thrombotic complications. In surveys conducted on behalf of the International Society of Thrombosis and Hemostasis’ Scientific and Standardization Committee (SSC), factor VIII/factor IX Subcommittee, it was apparent that such complications were still occurring in persons with haemophilia B in the early 1990s. However, throughout the 1980s and 1990s, their incidence declined – no doubt due to greater awareness of this potential complication and more judicious use of PCCs. Since inhibitor patients receive considerably more PCCs per bleeding episode than non-inhibitor patients, one might have expected that more thrombotic episodes would have occurred in inhibitor patients. However, this was not the case. Possible explanations for the lower

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incidence in inhibitor patients include the fact that, unlike the situation in haemophilia B, PCCs given to inhibitor patients do not correct the underlying haemostatic defect. Additionally, far fewer elective orthopaedic surgical procedures were being performed in inhibitor patients because of the unpredictability of maintaining haemostasis with either “standard” or activated PCCs (APCCs). From a theoretical stand-point, one might expect to see a higher incidence of thrombotic complications in inhibitor patients being treated with PCCs than with APCCs, as the latter are more effective than PCCs and thus fewer doses would be used. On the other hand, APCCs contain more activated clotting factors, and thus might be expected to be more thrombogenic, even in inhibitor patients. However, since some inhibitor patients do develop thrombotic complications when treated with PCCs or APCCs, one should consider an alternative therapy (e.g. rFVIIa, or porcine FVIII, if available) for patients with situations known to predispose to venous thrombosis and/or DIC.

2 Von Willebrand Disease

Epidurals and VWD, 95 Anticoagulation for a Cardiac Valve in a Patient with VWD Type 1, 97 VWD Type 2A and Pregnancy, 99 VWD Type 2B and Pregnancy, 101 VWD Type 2B vs. Platelet Type, 103 Prophylaxis in VWD Type 3, 105 Platelet Type VWD, 107

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Epidurals and VWD

Question

When is it safe to use epidural anaesthesia as obstetric pain relief in women with von Willebrand disease (VWD)?

Response from K. John Pasi, MD, PhD Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, UK The level of von Willebrand factor (VWF) increases 3- to 5-fold during pregnancy in women without VWD, and in most but not all women with VWD type 1 [1,2]. Although published data most frequently compare baseline and the third trimester, the level of VWF is often raised earlier in pregnancy and may rise as early as the sixth week [3,4]. Consequently, by the third trimester, many women with type 1 VWD achieve VWF levels in the normal range. The changes in VWD type 2A, 2B, and 2M are variable with increases in VWF:Ag and VIII:C not necessarily paralleled by useful increases in VWF:RCo [5]. Women with type 3 VWD will inevitably require haemostatic coverage for the delivery. For all women with VWD, a delivery plan is clearly important and should be drawn up jointly between the obstetrician and haemophilia centre. All women will wish to be closely informed of the plans for the management of their pregnancy, risk of bleeding, and risk to the foetus. One very frequent question that is asked at the time of writing a delivery plan for women with all types of VWD is the safety of epidural anaesthesia. For women without a bleeding disorder, epidural anaesthesia is a common and often preferred method of pain relief. In all women with normal coagulation, it should not be undertaken lightly and without due consideration. However, in any woman with a history of a bleeding disorder, before an epidural is used, consideration must be given to the additional haemostatic concerns such as the degree of pregnancy-associated correction of the plasma FVIII:C and VWF levels, possible degree of residual platelet impairment, possible rate of postpartum decline of VWF/FVIII, treatment or not for delivery, and consequent risks of bleeding such as a spinal haematoma.

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Ideally, these issues need to be considered and balanced against the potential obstetric indications for epidural anaesthesia in discussions with the obstetrician and the anaesthetist in advance of the delivery. One further very important consideration is use of an epidural or spinal anaesthetic for caesarean section, both elective and emergency, and the relative risk of an alternative general anaesthetic. There appears little, if any, clear guidance in the literature about use of epidural anaesthesia in VWD. Divergent views are often expressed by anaesthetists experienced in epidural anaesthesia, obstetricians, and haematologists.

Editors’ Note In general, patients with VWD who require epidural anaesthesia should be treated with appropriate replacement therapy using FVIII/VWF-rich concentrates.

References 1 Bennett B, Ratnoff OD. Changes in antihemophilic factor (AHF, factor 8) procoagulant activity and AHF-like antigen in normal pregnancy, and following exercise and pneumoencephalography. J Lab Clin Med 1972;80(2):256–63. 2 Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost 1984;52(2):176–82. 3 Kadir RA, Lee CA, Sabin CA, Pollard D, Economides DL. Pregnancy in women with von Willebrand’s disease or factor XI deficiency. Br J Obstet Gynaecol 1998;105(3):314–21. 4 Ramsahoye BH, Davies SV, Dasani H, Pearson JF. Pregnancy in von Willebrand’s disease. J Clin Pathol 1994;47(6):569–70. 5 Greer IA, Lowe GD, Walker JJ, Forbes CD. Haemorrhagic problems in obstetrics and gynaecology in patients with congenital coagulopathies. Br J Obstet Gynaecol 1991;98(9):909–18.

Anticoagulation for a Cardiac Valve in a Patient with VWD Type 1

Question

Is there any experience or advice about anticoagulation in the context of type I von Willebrand disease (VWD)?

Case

We have a young girl with a history of surgical bleeding who now needs a mechanical mitral valve. Ordinarily we would anticoagulate with coumadin keeping PT/INR (prothrombin time/international normalized ratio at 2.5–3.5. Her laboratory results are: ristocetin cofactor level 3% of normal; von Willebrand factor (VWF):Ag level 35% of normal; FVIII 63% of normal; bleeding time (BT): 14.5 min; 1 h post desmopressin (DDAVP) BT: 13 min.

Response from Tom Abshire, MD Emory University School of Medicine, Atlanta, Georgia, USA Assuming the diagnosis of type 1 VWD is correct, I would recommend anticoagulation to an INR as you do routinely. If you notice excessive mucosal bleeding symptoms, I would back down on the INR to 2–3. You will also have to give coverage for the surgery, and I would suggest you to use a VWF/FVIII containing concentrate. Response from Alice J. Cohen, MD Newark Beth Israel Medical Center, Newark, New Jersey, USA We have followed a woman with type 1 VWD and a mechanical heart valve for more than 5 years. She developed endocarditis and required valve replacement. We utilized Humate-P for the procedure and have maintained her on coumadin with an INR 2–2.5 (lower than we would have done if she did not have a bleeding disorder). To date, there have been no major bleeding or embolic events. She only utilizes DDAVP prior to dental work or other procedures.

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VWD Type 2A and Pregnancy

Question/ Case

A pregnant 19-year-old woman with severe von Willebrand disease (VWD) type 2A was recently referred to us for management of her VWD during delivery. She has a history of severe epistaxis and bleeding during surgical procedures. Past treatments for bleeding episodes include cryoprecipitate and packed red blood cells (PRBCs). She has not been connected with a haemophilia treatment centre in recent years. Current results for assays performed in the third trimester include RCo factor: 10%, VWF Ag. 63%, FVIII activity 72%. Baseline levels (first trimester) were RCofactor: 10%, VWF Ag. 38%, FVIII activity 35%. The patient is scheduled to be delivered by induction. Is prophylaxis at delivery appropriate as opposed to observation and treatment on demand? What is the treatment of choice: DDAVP (response unknown) vs. Humate-P/Alphanate?

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark Management of labour in VWD type 2A is a delicate problem, and there is no consensus opinion expressed on how to do it. However, just a few months ago, a young nulliparous patient with a type 2A VWD went into labour, and so perhaps our procedure in this case may be of some help. In my country, the only concentrate available for management of severely deficient patients with types 2A, 2B, 2N, and 3 VWD is called Haemate, which is, assumedly, an equivalent of Humate-P. Although not a high-tech concentrate, for over 15 years Haemate has safely served our VWD patients. Our patient has a profound deficiency in normal VWF, and she has an established history of bleeding episodes, in particular mucosal bleeds. Both the platelet count and her extrinsic coagulation function are normal. There was inertia following induced labour and delivery was accomplished by caesarean section. Our substitution programme for this patient consisted of tranexamic acid (2 g every 6 h orally or 1 g every 6 h intravenously) for the first

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2 weeks. Haemate was dosed at 40 IU/kg immediately before the caesarean and this dose was repeated 12 h later. For the next 6 days, 20 IU/kg was given twice daily, the dose being reduced to 10 IU/kg daily from day 7 to 14 followed by discontinuation. Slight oozing was observed from the wound site on days 1–2, but no other bleeding problems occurred. There was apparently some accumulation of VWF and factor VIII during the first days of treatment. However, there were no signs of thrombotic complications. We did not adopt heparin prophylaxis in this case since no controlled clinical trials have been performed in VWD. Below, however, I have referenced a few retrospective collections of data that may serve as additional information [1–3]. Here you can find reports on other deliveries, and some general advice on the use of continuous infusion during and after delivery. At around 14 h, the in vivo half-life of VWF is very similar to that of factor VIII. One may be curious as to why our case did not display a pregnancy-induced (acute-phase reaction pattern) increase in VWF:Ag. The explanation is probably that this type 2A belongs to the class where the intracellular transportation of VWF is compromised.

References 1 Berntorp E, Nilsson IM. Use of a high-purity factor VIII concentrate (Hemate P) in von Willebrand’s disease. Vox Sang 1989;56(4):212–17. 2 Scharrer I, Vigh T, Aygoren-Pursun E. Experience with Haemate P in von Willebrand’s disease in adults. Haemostasis 1994;24(5):298–303. 3 Lubetsky A, Schulman S, Varon D, Martinowitz U, Kenet G, Gitel S, et al. Safety and efficacy of continuous infusion of a combined factor VIII – von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease. Thromb Haemost 1999;81(2):229–33.

VWD Type 2B and Pregnancy

Question/ Case

I have a woman with type 2B von Willebrand disease (VWD) who is in her first pregnancy. She is becoming progressively thrombocytopaenic as she approaches term. There is spontaneous aggregation of platelets in platelet-rich plasma (PRP). In sisters from another family with this disorder, their deliveries have been associated with unexpectedly severe bleeding, despite the use of seemingly adequate Humate-P and platelet transfusions. Does anybody have the same adverse experience? Is it possible that the patient’s own platelet GP1b receptors are so saturated that platelets cannot adhere to subendothelial von Willebrand factor (VWF) at the time of delivery?

Response from Barbara A. Konkle, MD University of Pennsylvania, Philadelphia, Pennsylvania, USA The limited experience reported in the literature and my own is as you describe. Patients become progressively thrombocytopaenic during pregnancy, presumably due to the pregnancy-associated increased VWF synthesis. This VWF binds circulating platelets, and the aggregates are then cleared. With labour, the platelet count can decrease even further. We had a patient whose platelet count was 5000/l at the time of labour. Pareti et al. reported a patient with 2B VWD with spontaneous platelet aggregation at 37 weeks of pregnancy [1]. Using her PRP, they found that they could inhibit aggregation with either of two monoclonal antibodies raised against VWF that block ristocetin-induced binding of normal VWF to platelets, but they could not inhibit aggregation by an antibody that blocked VWF–GpIIb/IIIa interaction. You are right that there is likely significant adhesion dysfunction in the remaining circulating platelets. The reported treatment includes a combination of VWF containing concentrate and platelet transfusions. It is conceivable that plasmapheresis could be helpful by decreasing the abnormal VWF, but this practice is unproven and is, at best, experimental.

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Reference 1 Pareti FI, Federici AB, Cattaneo M, Mannucci PM. Spontaneous platelet aggregation during pregnancy in a patient with von Willebrand disease type IIB can be blocked by monoclonal antibodies to both platelet glycoproteins Ib and IIb/ IIIa. Br J Haematol 1990;75(1):86–91.

VWD Type 2B vs. Platelet Type

Question

How can we differentiate von Willebrand disease (VWD) type 2B and platelet type?

Response from David Lillicrap, MD Queens University, Kingston, Ontario, Canada Type 2B VWD and platelet-type VWD (pseudo-VWD) present with very similar clinical and laboratory phenotype. Type 2B VWD is the result of gain-of-function missense mutations in the A1 domain of von Willebrand factor (VWF), while platelet-type VWD is due to missense mutations in the platelet glycoprotein Ib alpha receptor gene. Both conditions can show chronic mild thrombocytopaenia, normal to low levels of VWF:Ag and VWF:RCo, a VWF:RCo to VWF:Ag ratio that is usually 0.6, and a loss of high-molecular-weight VWF multimers. In both conditions there is an enhanced ristocetin-induced platelet agglutination (RIPA) at ristocetin concentrations of 0.6 mg/ml. There are two options for differentiating between these conditions. The first involves studying washed patient platelets mixed with normal plasma and performing a RIPA test. Only platelets with a platelet-type VWD mutation should show enhanced response in this RIPA assay. A more definitive solution to this question involves testing for type 2B missense mutations in exon 28 of the VWF gene. This latter approach of a targeted mutation analysis must take into account the potential of amplifying and sequencing the chromosome 22 VWF pseudogene. Response from Harvey J. Weiss, MD Columbia University College of Physicians and Surgeons, New York, USA While the two methods described by Dr Lillicrap would certainly differentiate the two disorders, a much simpler method is based on our original article of pseudo-VWD in which we reported that the addition of VWF (cryoprecipitate was used in the original study) to platelet-rich plasma resulted in platelet aggregation without the necessity of adding

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ristocetin [1]. In performing the test, care must be taken to take into account any spontaneous platelet aggregation that might introduce a problem in interpreting the results in patients with type 2B VWD.

Reference 1 Weiss HJ, Meyer D, Rabinowitz R, Pietu G, Girma JP, Vicic WJ, et al. Pseudovon Willebrand’s disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med 1982;306(6):326–33.

Prophylaxis in VWD Type 3

Question

Should patients with type 3 von Willebrand disease (VWD) be considered for prophylaxis?

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark The question concerns prophylaxis in patients with type 3 VWD. Reproductive health in VWD, in general, appears to be affected by a higher proportion of spontaneous miscarriage and intermittent bleeding. Therefore, the idea of a prophylactic regimen seems highly appropriate. Were I to manage a pregnant VWD type III patient, I would probably begin prophylaxis right away. I would not only look at the amount of factor VIII, because factor VIII synthesis in the patient will ensure a normal level of factor VIII once you have corrected the deficiency in von Willebrand factor (VWF), but also at the level of VWF as determined by VWF:Ag. The ristocetin cofactor level may be lower than the Ag in post-infusion measurements. I would probably infuse VWF-rich concentrates every 2–3 days, aiming at a trough level of VWF at or above 40% of normal. During the course of pregnancy, the plasma volume increases and more concentrate may be required to maintain the same level of VWF. During labour, I would adopt a strategy to lift the level of VWF to close to 100% of normal. Response from Augusto B. Federici, MD University of Milan, Milan, Italy As you may know from the literature, there are a few reports of venous thromboembolic events in type 3 VWD treated with FVIII/VWF concentrates for major surgery. However, there is no experience until now for prophylaxis in these cases. In case of orthopaedic surgery in adult type 3 VWD, we treat the patient with FVIII/VWF doses high enough to keep daily FVIII levels between 70 and 150 U/dl. Since there is a sustained rise in FVIII (due to the stabilizing effect of exogenous VWF on endogenous FVIII)

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lasting up to 24 h, in case of concentrates containing FVIII/VWF (Humate-P) we suggest the following schedule to avoid accumulation of FVIII (exogenous from the concentrate and endogenous from the patient): 1 Day of surgery: give 50–80 U/kg of Humate-P measured as VWF: RCo before surgery. 2 Post surgery day 1: measure FVIII before and after Humate-P 50–80 U/kg. 3 Post surgery day 2: measure FVIII before and after Humate-P 50–80 U/kg. 4 Post surgery day 3: measure FVIII, if more than 150 U/dl – NO THERAPY: low dose (25–40 U/kg) concentrate infusion required only in case of bleeding and/or levels of FVIII below 70 U/dl. 5 We proceed with every other day injections until wound healing occurs (7–10 days). By using the Humate-P regimen described earlier, we have not used low-molecular-weight heparins requiring orthopaedic surgery and despite the lack of heparin prophylaxis, we have had no thrombotic events. In cases of very complicated surgery in elderly patients at high thrombotic risk (type 3 VWD, atrial fibrillation, mitral valve replacement in extracorporeal circulation), replacement therapy can be organized during surgery to reduce the bleeding. After surgery, type 3 VWD patients should also be considered for antithrombotic prophylaxis with doses of drugs to be adjusted according to the clinical situation. I do not exclude the use of heparin or warfarin in such extreme cases.

Platelet Type VWD

Question/ Case

I have a young patient who needs a caesarean section. Her platelet count is 20,000/µl. She is refractory to platelet transfusion. She was diagnosed as having pseudo-von Willebrand as a child. Any thoughts on treatment? I am giving her Humate-P and will use NovoSeven® if she has uncontrollable bleeding. Her baseline platelet count is 10,000–20,000/µl.

Response from Tom Abshire, MD Emory University School of Medicine, Atlanta, Georgia, USA This is an unusual case of platelet type of von Willebrand disease (VWD) due to the unusually low platelet count. Platelet-type VWD often looks exactly like type 2B VWD with loss of high-molecularweight multimers but must be treated with platelets. It is important to remember that the platelet count may not rise, but haemostatic efficacy is still achieved. von Willebrand factor containing products are not as effective. I would make sure that there is no other cause for the thrombocytopaenia (immune related, myelodysplasia, familial, etc.) and then give platelet transfusions prior to the caesarean section and with less concern about the platelet count. If there is still bleeding around the wound site despite the platelet transfusion, I would consider giving rFVIIa (NovoSeven®).

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3 Factor Deficiencies

Combined Factor V and VIII Deficiency, 111 DVT Prophylaxis in FVII Deficiency, 113 Menorrhagia in Factor VII Deficiency, 115 Anticoagulation for Atrial Fibrillation in FX Deficiency, 119 Management of Factor X Deficiency, 121 Anticoagulation for Atrial Fibrillation in a Patient with Factor XI Deficiency, 123 Factor XI Deficiency and Surgery, 125 Prophylaxis for Patients with Factor XIII Deficiency and Intracranial Bleeding, 127

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Combined Factor V and VIII Deficiency

Question/ Case

A middle-aged patient with combined FVIII (12% activity) and FV (14% activity) deficiency has to undergo cardiac surgery (cardiopulmonary bypass for mitral valve replacement). He has a mild bleeding tendency and has experienced bleeding during minor surgical procedures.

1

Which type of prosthetic heart valve should be used? If mechanical, is the long-term administration of oral anticoagulants acceptable in a patient with a bleeding tendency? Or is a tissue heart valve, requiring only short-term antithrombotic therapy (several weeks), preferable?

2

Does this patient, who is in a spontaneous hypocoagulable state (prothrombin time, PT 21.7 (normal 13) s; activated partial thromboplastin time, APTT 75 (normal 37) s), require oral anticoagulants?

3

If oral anticoagulants are to be used, how should the treatment be monitored (spontaneous INR 1.8)?

4

What haemostatic level of FV should be maintained during cardio-pulmonary bypass and postoperatively? How should the patient’s coagulopathy be corrected (fresh-frozen plasma (FFP), with or without platelet concentrates)? assuming that FVIII deficiency will be easily corrected by FVIII concentrates?

Response from Harold R. Roberts, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA In our experience of cardiovascular surgery on patients with combined factor V/factor VIII deficiency, patients should be prepared for surgery by plasma exchange sufficient to raise the factor V level to almost normal. Surgery should be carried out immediately after exchange and

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factor V and VIII levels monitored intra- and postoperatively. Factor V and VIII levels during the intra- and postoperative periods can be maintained by infusions of factor VIII products and by plasma infusions as a source of factor V. We would prefer to use a tissue valve instead of a mechanical valve, so as to avoid the use of postoperative anticoagulant therapy. Subsequently, we treated the patient differently as he developed severe allergic reactions post-exchange therapy. She corrected the FVIII using FVIII concentrates and substituted normal platelet infusions as a source of FV. Twenty per cent of the circulating pool of FV is located in platelets.

DVT Prophylaxis in FVII Deficiency

Question

Should we use deep venous thrombosis prophylaxis in a patient with FVII deficiency?

Case

We plan to carry out a total hip replacement on an elderly woman with factor VII deficiency. We intend to treat this patient with French factor VII concentrates.

Response from Guglielmo Mariani, MD University of L’Aquila, L’Aquila – Coppito, Italy There is no definitive answer to this question, but considering the age of the patient, the possibility of a long-term immobilization and the possible presence of supranormal factor FVII levels, I would recommend prophylaxis with standard dosing of heparin for non-high-risk patients. Response from Harold R. Roberts, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA It is my practice to treat patients with hereditary deficiency of a clotting factor as a “normal” individual once the clotting factor deficiency is corrected by replacement therapy. Thus, once the factor FVII deficiency is corrected in a patient such as this, I would administer the usual thromboprophylaxis during hip surgery. Thromboprophylaxis should cease when FVII replacement is discontinued.

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Menorrhagia in Factor VII Deficiency

Question

How do you manage menorrhagia in the presence of factor VII deficiency?

Case 1

A young woman with severe factor VII deficiency (activity 2%) wants to become pregnant and has stopped using oral contraceptives (OCPs). After stopping OCPs, she has had severe menorrhagia without any other bleeding problems such as haematomas or epistaxis. The patient refuses to take hormones again because of her desire to conceive. Do you have any suggestions as to how to manage menorrhagia and yet avoid FVII substitution every 4 weeks?

Case 2

An 11-year-old girl with a factor VII deficiency, who rarely bleeds except for severe menorrhagia, has received the following treatment without success: medroxyprogesterone acetate injection (150 mg) to which oestrogen was added in an attempt to stop bleeding. She was also put on a norgestrel/oestrogen combination tablet without success. Plasma infusions have not been tried as the bleeding does not occur regularly and may occur a few times every month. Factor VIIa is not available to this patient.

Response from Herbert Watzke, MD Medical University of Vienna, Vienna, Austria Menorrhagia is a common symptom of congenital factor VII deficiency. It appears to be predominantly associated with the severe form (factor VII levels 3 U/dl) or the moderate form (factor VII levels of 3–5 U/dl) of the disease but may also occur in less affected patients. Patients with moderate disease (and of course those with severe disease) may also suffer from bleeding into the joints (haemarthrosis). Although some controversy exists about the correlation of factor VII levels with clinical severity, it is generally assumed that bleeding due to factor VII deficiency is unlikely when factor VII clotting activity is

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greater than 10%. Menorrhagia is also a frequent finding in otherwise healthy women. In the second case, it is essential to know the patient’s baseline factor VII level. Only with levels of 10% or lower would it be likely that the menorrhagia is associated with factor VII deficiency. Other defects of haemostasis, which can cause menorrhagia, such as von Willebrand disease (VWD) should be excluded if factor VII levels are well above 10%. Secondly, it is stated that the second patient, aside from her menorrhagia, rarely bleeds. It would be a sign of a severe factor VII deficiency if these rare events are bleedings in the joints. It may be a sign of less severe factor VII deficiency if the bleeding is into the gums or skin only. If the bleeding that has occurred was severe and/or haemophilic arthropathy exists, a prophylactic regimen with factor VII needs to be considered irrespective of the problem of menorrhagia. Thirdly, the intensity of bleeding during menstruation, which is generally overestimated, needs to be defined more precisely (e.g. by determination of the iron status and by red blood cell count). Factor VII replacement therapy needs to be considered if severe anaemia persists despite iron supplementation in severe factor VII deficiency. Finally, a thorough gynaecologic investigation must be performed to rule out intrauterine or hormonal abnormalities that could account for the menorrhagia. This is particularly important when bleedings occur irregularly and several times within a month, as is the case in this patient. If the frequent bleedings in the young patient are simply due to a recent onset of menstruation, it can be expected that symptoms will improve over time. In this case, factor VII replacement therapy should be withheld if possible. If necessary, there are several alternatives for prophylactic factor VII replacement in severe factor VII deficiency. Plasma has long been used but has the limitation of low factor VII concentration. Thus, rather large amounts of plasma are necessary to achieve adequate haemostasis. Prothrombin complex concentrates are plasma-derived products with a high concentration of factor VII. In addition, a plasma-derived factor VII concentrate is available in some European countries. Finally, recombinant factor VIIa has been successfully used in factor-VIIdeficient patients. The optimal level of factor VII and the optimal frequency of factor VII replacement in the prophylaxis of menorrhagia are not known. Levels of 5–10% are probably sufficient to stop spontaneous haemorrhage. Administration every 12 h is necessary due to the short half-life of factor VII. Preliminary reports on infusions of desamino-D-arginine vasopressin show increase of factor VII levels.

Menorrhagia in Factor VII Deficiency 117

However, this treatment has not been investigated with respect to its clinical effect in women with factor VII deficiency and menorrhagia. Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark This clinical problem is very delicate. A well-known hallmark of severe factor VII (FVII) deficiency is the tendency to mucocutaneous bleeding, of which menorrhagia is a classic manifestation. Hormonal substitution is also known to be quite effective in control of uterine bleeds in practically all patients with haemostatic defects. Both case histories give the reader the impression that menorrhagia poses problems in these patients only during their menstrual periods. Should this be the case, a patient of mine would be advised to use tranexamic acid, probably beginning with a smaller dose of 1 g three times daily administered during days 2–4 of menstruation. The reason for this particular scheme is that tranexamic acid appears to be quite effective in reducing blood loss, though larger doses may provoke formation of clots, causing contractions and pain. The dose of tranexamic acid can be increased (up to 25 mg/kg body weight every 6 h) if the lower dosage regimen is ineffective. Since tranexamic acid is quickly cleared from circulation, toxicity problems to a foetus should not be expected.

Editors’ note We have used rVIIa for prophylaxis in a woman with severe FVII deficiency. Her FVII level was 1%, and she was having weekly hemarthroses. We used 120mcg/kg thrice weekly with excellent results.

Anticoagulation for Atrial Fibrillation in FX Deficiency

Question

Should a patient with factor X deficiency be anticoagulated for atrial fibrillation?

Case

We have a middle-aged patient with congenital factor X deficiency. He has a FX level of 7% and an international normalized ratio (INR) of 2.33. He has had minimal haemorrhagic problems and as a boy he had spontaneous joint bleeds. In the last years, he has not had spontaneous bleeding episodes. At the moment, he has been diagnosed with atrial fibrillation with indication to undergo anticoagulation. Is there any indication to do the oral anticoagulant therapy, especially in a patient with an INR of 2.33?

Response from Craig Kessler, MD Georgetown University Medical Center, Washington, DC, USA This case presents several very interesting and complex problems. While we cannot write specifically about the patient in question, a general response to this type of patient is described later. Without seeing the patient, we cannot make specific recommendations. First of all, how accurate is the INR in an individual with moderately to mildly severe factor X deficiency? An INR of 2–3 is quite likely an underestimate of antithrombotic potential for warfarin in this patient. On the other hand, are such patients naturally anticoagulated because of the coagulation deficiency? I suspect that such patients are and, therefore, in view of a prior history of bleeding, it might be wise to avoid oral anticoagulation. Other potential approaches could be instituted, however, which might be beneficial to such patients for atrial fibrillation and yet not raise risks of life-threatening bleeding. Acetylsalicyclic acid (ASA) 81 mg/day might be a reasonable alternative.

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The degree of aggressiveness for antiplatelet treatment in my mind would be based on whether the atrial fibrillation is stable or whether there are runs of other dysrhythmias. I do not think such patients would need anything as aggressive as low-molecular-weight heparin, but I think that is another alternative. The anti-Xa level can be measured despite his factor X deficiency, as long as factor X is added back to the plasma for the assay.

Management of Factor X Deficiency

Question

What is the management of factor X deficiency?

Case

This concerns a 4-year-old girl with a diagnosis of factor X deficiency who was referred by her physician for further advice. At a young age, she had gastroenteritis associated with a lower gastrointestinal (GI) bleed requiring blood transfusion. She had a markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) with undetectable FX. The rest of her factor levels were normal. She was then managed with fresh-frozen plasma (FFP), which gave good control of her bleeding. Since the GI bleed, she has had no major events. Recently, she developed a similar episode of gastroenteritis with a GI bleed and had a non-recordable clotting time for both the PT and APTT. She was managed at another hospital with FFP until the bleeding stopped. On presentation (a week after the event) her PT and APTT were markedly prolonged. One hour post FFP, her PT was 22 s (control 15 s), APTT was 39 s (control 29 s), and factor X was 22%. Her mother and father had FX levels of about 50%, compatible with carrier status. Some questions are: How do I manage her during her acute bleeds? Does she require prophylactic FFP? If so how often, given that despite a very prolonged PT, APTT, and a factor X of 0%, she has had only two events so far? What advice and management should be given before her menstrual cycle starts and before pregnancy? What about family counselling and future pregnancies?

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Response from Erik Berntorp, MD, PhD Lund University, Malmo, Sweden This girl is probably homozygous for factor X deficiency. A molecular genetic diagnosis should be searched for. I understand that the bleeding episodes are very rare, something that makes regular prophylactic treatment somewhat difficult to recommend. The laboratory check up should be supplemented with a bleeding time to see whether the platelets are affected in their function. If so, I would suggest that desmopressin could be valuable as a complementary treatment not only during acute bleeds, but also when she starts to menstruate. My response to the other questions are as follows: Give FFP or a prothrombin complex concentrate containing factor X. Desmopressin and antifibrinolytics should be given as well, at least if FFP is chosen. A potential risk of thrombosis should be considered, however, if combined with prothrombin complex concentrate. A factor X level 20% should be enough for most bleeds. The half-life of factor X is 1–3 days and therefore dosing every 12–24 h should be enough for most events. Products like factor VIIa would probably not help very much as factor X is lacking in the patient. Due to the rarity of bleeding, I would not recommend prophylaxis. If she develops severe bleeds in the future, with the risk of complications (such as joint bleeds), prophylaxis should be started. Give FFP, and see what preventative effect it has. A higher dose, and if possible, a concentrate could be more beneficial. Try antifibrinolytics and/or desmopressin if menstrual bleeding is heavy. I am not sure any treatment is needed during pregnancy. However, for delivery, FFP or concentrate should be given. The children will be heterozygous, provided the father is not a carrier of the trait. Prenatal diagnosis is thus not needed as I see it. This opinion is based upon my understanding that the patients’ parents do not have any clinical symptoms.

Anticoagulation for Atrial Fibrillation in a Patient with Factor XI Deficiency

Question

Should a patient with Factor XI deficiency and atrial fibrillation be anticoagulated with warfarin?

Case

The patient is a middle-aged man of Ashkenazi Jewish descent who has had no history of bleeding whatsoever, though he has not had very many haemostatic challenges. He did not bleed with circumcision. He does not have easy bruising, nosebleeds, or gum bleeding. He has had no other surgical interventions, including tooth extractions. His parents and his two sons have had surgeries, all without abnormal bleeding, but we have no information on factor XI levels in these individuals. The patient has a factor XI level of 5%. He has had two episodes of paroxysmal atrial fibrillation in the past year. His cardiologist wishes to put him on warfarin. He is currently in normal sinus rhythm.

Response from Ophira Salomon, MD1 and Uri Martinowitz, MD2 Tel-Aviv University, Tel Aviv, Israel 2 The Chaim Sheba Medical Center, Tel Hashomer, Israel

1

Most likely the patient is a compound heterozygote to type II/III mutations (based on his FXI level). According to our experience, patients with severe FXI deficiency with atrial fibrillation can be safely treated with warfarin with an international normalized ratio not exceeding 2.5 [1].

Reference 1 Salomon O, Seligsohn U. New observations on factor XI deficiency. Haemophilia 2004;10(Suppl 4):184–7.

123

Factor XI Deficiency and Surgery

Question/ Case

We have in our charge a patient with FXI deficiency (plasma level: 11 U/dl), which is potentially of acquired origin. Within the next few days, the patient will need to undergo major surgery to repair a thighbone. According to your current experience, could you give me information about what plasma levels of factor XI should be achieved for this type of surgery?

Response from Paula Bolton-Maggs, MD1 and Jørgen Ingerslev, MD2 1 University of Manchester, Manchester, UK 2 University Hospital Skejby, Aarhus, Denmark The patient described has a factor XI level of 11% who requires “thighbone” repair. From this, I understand that the patient perhaps has a fractured femur that requires surgery. It is asked what level the factor XI should be raised to for surgery, but also comments that this may be acquired factor XI deficiency, that is associated with an inhibitor to factor XI. 1 The level of factor XI required for surgery: The following comments relate to people with congenital deficiency only [1]. This is controversial because while some patients with congenital factor XI deficiency do not bleed if the factor XI is raised to 30–40%, other partially deficient individuals have presented with bleeding after surgery with baseline levels of 30–40% and higher. Because of this, it seems logical to aim at the lower end of the “normal” range if therapy is given (i.e. 60–70%) to be safest, while accepting that a lower level may suffice. In patients without inhibitors, it would be difficult to achieve this level with fresh-frozen plasma (FFP) alone – a dose of at least 20 ml/kg is probably needed, and may be more. With FFP one could probably achieve the lower suggested levels of 35–40%. Factor XI concentrate could be used, but it has been associated with thrombotic

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problems in elderly patients with pre-existing cardiovascular diseases, so the risks would have to be carefully balanced. If factor XI concentrate is used, and the patient is elderly, it would be wise to accompany this with prophylactic heparin. An option would be to use FFP and FXI concentrate for use in case of excessive bleeding. 2 A patient with inherited factor XI deficiency, who has developed antibodies to factor XI: Some of these individuals have measurable residual factor XI as in this case and may respond to plasma products – the response would have to be carefully monitored. Others do not respond and have to be managed in the same way as patients with high-titre inhibitors to factor VIII or IX, that is with prothrombin complex concentrates or recombinant factor VIIa. 3 Autoimmune antibodies to factor XI: Individuals are described with antibodies to factor XI, discovered because of a prolonged activated partial thromboplastin time, who have not presented with bleeding. These are most often found in patients with systemic lupus erythematosis, and according to the literature are not associated with a bleeding tendency, although not all have been challenged [2]. Some cases have been associated with thrombosis. Many of these are said to have a low level of factor XII as well. In such a case, one could proceed to surgery without any special measures to raise the factor XI level. Further characterization of the individual and his/her factor XI problem would be necessary to decide which of the above would be most appropriate.

Editors’ Note Some clinicians would recommend rFVIIa in patients with hereditary FXI deficiency, if such patients experienced excessive bleeding. Additionally, FXI concentrates are not available in the US.

References 1 Bolton-Maggs PH. The management of factor XI deficiency. Haemophilia 1998; 4(4):683–8. 2 Scott-Timperley LJ, Haire WD. Autoimmune coagulation disorders. Rheum Dis Clin North Am 1997;23(2):411–23.

Prophylaxis for Patients with Factor XIII Deficiency and Intracranial Bleeding

Question

Should we use some sort of prophylaxis for patients with intracerebral bleeding from factor XIII deficiency?

Case

The patient is a middle-aged female with severe factor XIII deficiency who recently developed a spontaneous intracerebral haemorrhage (ICH). She previously had intracerebral bleeds at earlier ages without permanent neurological deficits. Her brother died as a child from a similar problem. Her episodes of joint bleeding respond well to fresh-frozen plasma (FFP) infusions. Should she receive fibrinolytic inhibitors and regular FFP infusions prophylactically? Blood pressure and MRI angiography of the intracranial arteries are normal.

Response from Morio Arai, MD Tokyo Medical University, Tokyo, Japan ICH is one of the characteristic manifestations in patients with factor XIII deficiency. Thirty per cent of the patients suffer from ICH after minor trauma or spontaneously without any antecedent episodes. Lifelong prophylaxis is indeed required in such patients using factor XIII concentrates or FFP. We are treating four patients with factor XIII deficiency with regular administration of factor XIII concentrate (Fibrogammin-P®) every 4 weeks for 10–19 years. After starting the prophylaxis, the bleeding episodes were remarkably decreased from 4.2 1.5/year to 0.2 0.2/year with no life-threatening haemorrhage. The trough plasma factor XIII activity is about 10% of normal, which allows in vitro fibrin γ-dimer formation. If the factor XIII concentrate is not available, I would use FFP every 2–3 weeks. Dose and interval of FFP transfusion should be adjusted in a way that the trough plasma factor XIII activity remains 5% or more. Note that the clearance of factor XIII is quite long (T1/2; 10 days).

Editors’ Note Another possible alternative is the use of cryoprecipitate as a source of FXIII. 127

4 Rare Platelet and Coagulation Disorders

Coagulation Disorders Afibrinogenaemia, 131 Dysfibrinogenaemia, 135 Hypofibrinogenaemia, 139 Gardner–Diamond Syndrome, 141 Hereditary Haemorrhagic Telangiectasia, 145 Hereditary Vitamin-K-Dependent Coagulation Factors Deficiency and Pregnancy, 151

Platelet Disorders Glanzmann’s Thrombasthaenia and Gastrointestinal Angiodysplasia, 153 Glanzmann’s Thrombasthaenia and Pregnancy, 157 rVIIa (NovoSeven®) and the Wiskott–Aldrich Syndrome, 159

129

Afibrinogenaemia

Question

What experience do we have with afibrinogenaemia in the neonate and in the pregnant patient?

Case 1

We have recently diagnosed a neonate with congenital afibrinogenaemia. He presented on day 2 with bilateral cephalohaematomas and, in initial testing, his blood was found to be incoagulable due to an absence of fibrinogen. Subsequent analysis demonstrated afibrinogenaemia. Other factors are normal and the patient is otherwise well. I am currently treating him with prophylactic infusions of fibrinogen concentrate. Has anyone had experience in this condition over a long period of time? Will this patient need continuous replacement therapy? What is the outlook? Is it ever possible to leave such children untreated, or is there an unacceptable risk of bleeding complications? The literature does not seem very clear about this rare condition.

Case 2

We have a 5-year-old boy in our practice, diagnosed postpartum as having afibrinogenaemia. He was born at home and subsequently developed neonatal jaundice, requiring exchange transfusions. During this procedure, his bleeding tendency became apparent but responded well to fresh-frozen plasma. The diagnosis was made on blood removed during the exchange transfusion and was confirmed 3 months later. Other clotting factors are normal and besides bleeding from venapuncture sites and the occasional bruise secondary to minor trauma, he has remained symptom free. Is there any advantage in testing him again? What, if any, are the indications for starting prophylactic therapy in this child? The parents and two male siblings are unaffected. What advice should we give regarding possible transmission to the next generation?

Case 3

I have a young woman who came to me pregnant with a history of afibrinogenaemia. What do I do?

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Response from Erik Berntorp, MD, PhD Lund University, Malmo, Sweden Afibrinogenaemia is a very rare disorder and subsequently the clinical experience of how to handle these patients is limited. In the first two cases, it is important to really establish whether the patients have true afibrinogenaemia, or dysfibrinogenaemia with a potential risk of thrombosis. From the descriptions, however, I understand that the diagnoses have been well documented. The plasma level of fibrinogen is somewhat lower in infants than in adults, so a repeat test can be of some value. The bleeding symptoms in afibrinogenaemia are usually less pronounced than in severe haemophilia and are usually related to trauma, surgery, etc. Therefore, the issue of prophylaxis has to be judged taking the clinical picture into consideration. Prophylaxis with fibrinogen concentrate is easy to do as the half-life is long (4–5 days) and a plasma level of 0.5–1 g/l is enough to obtain good haemostasis. In cases such as these, where the patients seem to be almost symptom free, I would advise delay in prophylaxis and only give prophylaxis in special situations such as before surgery or if the child wishes to play sports in the future. Thus, the patient’s future symptoms and lifestyle will influence the decision of prophylaxis. The children are probably homozygous for this trait and, thus, their future offspring would be heterozygous with no clinical symptoms. This is provided that the future mothers do not have the trait, something that is very unlikely unless they are a blood relative of the patient. Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark Congenital afibrinogenaemia is a rare disorder and only 250–300 cases have been reported in the literature. This condition is assumed to be homozygous (or double heterozygous), and it has a higher prevalence in ethnic cultures with a tradition of consanguineous marriages. While several less severe variant fibrinogen phenotypes, including those causing spontaneous thrombosis, have been investigated and assigned various names covering practically all major cities of the world, until recently we had no information on the underlying genetic abnormalities in total afibrinogenaemia. However, a report on the causative mutations in a Swiss family has been published in January 1999 [1].

Afibrinogenaemia 133

Patients suffering from afibrinogenaemia have incoagulable blood using the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). The cephalohaematomas, which occurred in the first patient, are not atypical, but fortunately were not associated with intracranial bleeding. I fully agree that it is not easy to collect a lot of useful information in the available literature. The literature does, however, have a lot of single-case data on the benefit of fibrinogen for both substitution and prophylactic therapy in afibrinogenaemic patients. I agree on the use of a purified and virally inactivated concentrate of fibrinogen especially when bleeding is present. The in vivo half-life of fibrinogen is presumably around 2–3 days, but this has been difficult to prove. We do not know whether the lack of fibrinogen is due to a loss of synthesis; a lack of assembly in, or release of fibrinogen from, hepatocytes; or the rapid degradation of the synthesized fibrinogen molecule. Fibrinogen may also be rapidly cleared from the circulation for other reasons. For prophylaxis, the level of fibrinogen required need not be higher than 0.8–1.0 g/l. In addition, I would consider the use of antifibrinolytic therapy in the management of bleeds, as well as in prophylaxis. Response from Harold R. Roberts, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA In pregnant patients with afibrinogenaemia like case 3, prophylactic therapy with fibrinogen is indicated. In the USA, cryoprecipitate is the most commonly used replacement as we do not have purified fibrinogen. In general, one bag of cryoprecipitate contains about 300 mg of fibrinogen, and in a patient with a plasma volume of about 3000 ml it would require about 10–12 bags of cryoprecipitate to raise the fibrinogen level to 1 mg/ml. Given the half-life of fibrinogen, one would need to give about four bags of cryoprecipitate daily to keep the fibrinogen at this level. Some investigators would allow the fibrinogen to be between 0.5 and 1 mg/ml during the pregnancy. It should be pointed out that adverse reactions to fibrinogen therapy, especially in afibrinogenaemic patients, have been reported and these are in addition to the usual allergic and febrile reactions. One is that afibrinogenaemic patients may develop antifibrinogen antibodies. Another is that thrombotic events have been reported in some

134 Rare Platelet and Coagulation Disorders

patients following replacement therapy. Finally, one must remember that even though well-screened cryoprecipitate is very unlikely to transmit infectious diseases, when large amounts of cryoprecipitate are given the risk of transmitting viral diseases increases. This could be decreased if the cryoprecipitate were prepared from solventdetergent-treated plasma.

Editors’ Note Afibrinogenaemias due to the lack of all three chains have been reported [2]. Additionally, solvent-detergent-treated plasma is no longer available in the USA.

References 1 Neerman-Arbez M, Honsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen (correction of fibrogen) alpha-chain gene (FGA) causes congenital afibrogenemia. J Clin Invest 1999;103(2):215–18. 2 Neerman-Arbez M. The molecular basis of inherited afibrinogenaemia. Thromb Haemost 2001;86(1):154–63.

Dysfibrinogenaemia

Question/ Case

A middle-aged woman has a history of at least 10 recurrent abortions. Laboratory data showed a prolonged prothrombin time (PT) and partial thromboplastin time (PTT) and a fibrinogen level of 20 mg/dl. The patient has five sisters with a similar disorder. Both parents have normal fibrinogen levels. What does the patient have?

Response from Christine Kempton, MD Emory University/CHOA Comprehensive Hemophilia Program, Atlanta, Georgia, USA The notable features in this patient include: (1) recurrent foetal loss, (2) prolongation of both the PT and PTT, and (3) low fibrinogen. The differential diagnosis for each of these abnormalities is as follows: 1 Recurrent foetal loss: Antiphospholipid antibodies, protein C deficiency, protein S deficiency, dysfibrinogenaemia, and factor V Leiden. Other non-haematological causes of recurrent foetal loss would include chromosomal and uterine abnormalities and autoimmune disorders. 2 Prolongation of both the PT and PTT (a) Deficiency of functional factors V, X, prothrombin, and fibrinogen. (b) Inhibitors specifically directed against factors V, X, prothrombin, or fibrinogen. (c) Non-specific inhibitors: lupus anticoagulant. 3 Low fibrinogen (a) Congenital: (i) Quantitative defects: hypofibrinogenaemia. (ii) Qualitative defects: dysfibrinogenaemia. (b) Acquired quantitative and/or qualitative defects: (i) Disseminated intravascular coagulation, liver disease, antifibrinogen antibodies, and malignancy.

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It is notable that dysfibrinogenaemia is part of the differential diagnosis for each abnormality. Dysfibrinogenaemias are a heterogeneous group of disorders and can be both acquired and congenital and are characterized by an abnormally functioning fibrinogen molecule. Inheritance of a dysfibrinogenaemia can be either autosomal recessive or dominant. Of 250 cases of dysfibrinogenaemia, 55% were reported to be asymptomatic, 25% had a tendency towards bleeding, and 20% developed thrombosis. Some of the patients with thrombosis also developed abnormal bleeding [1]. The thrombotic manifestations can include venous and/or arterial clots and recurrent foetal loss. Despite the association between dysfibrinogenaemia and thrombosis, only 0.8% of patients with venous thrombosis have dysfibrinogenaemia. Thus, routine screening in patients with a history of venous thrombosis is not warranted. The mechanism of thrombosis in patients with dysfibrinogenaemia remains unclear. Currently, two mechanisms are hypothesized to be responsible for thrombosis associated with dysfibrinogenaemia. The first mechanism is that the abnormal fibrinogen is unable to bind thrombin. This results in increased circulating thrombin that can lead to platelet activation and clot formation. The proposed second mechanism is impaired fibrinolysis as a result of resistance to plasmin or abnormal binding of tissuetype plasminogen activator [2,3]. To evaluate patients for dysfibrinogenaemia, one should perform a reptilase time, a thrombin time (TT), and a measurement of fibrinogen. The reptilase time can be performed in the presence of heparin. The TT is performed by adding human or bovine thrombin to recalcified citrated plasma and recording the time to clot formation in seconds. Since the test is performed by the addition of thrombin, the final step of coagulation, conversion of fibrinogen to fibrin monomers followed by fibrin polymerization, is measured. In addition to dysfibrinogenaemia as a cause of a prolonged TT, other considerations include heparin contamination and the presence of a direct thrombin inhibitor, fibrin or fibrinogen degradation products, antibodies to thrombin, or high concentrations of serum proteins as occurs in multiple myeloma or amyloidosis. To measure fibrinogen, most laboratories use the Clauss method. The Clauss method utilizes high thrombin concentrations in diluted recalcified citrated plasma. Under normal conditions, the clot time is inversely proportional to the amount of fibrinogen present. Thus, the total amount of fibrinogen is estimated based on the rate of fibrin formation.

Dysfibrinogenaemia 137

The fibrinogen level based on a functional assay should be compared to a fibrinogen antigen level using immunological methods. Fibrinogen antigen and activity should be assayed on the same day. Most dysfibrinogenaemias will have discordance between fibrinogen activity and antigen level giving a ratio of 1:2. Further evidence for the presence of an abnormal fibrinogen can be obtained by detecting an abnormal fibrinogen protein in a one- or two-dimensional electrophoresis compared to a known fibrinogen standard. The gold standard for the diagnosis of dysfibrinogenaemia is the identification of a molecular defect [3,4]. In this case, the presence of similar abnormal laboratory findings in other family members is consistent with the presence of a congenital defect. However, in isolated cases without additional affected family members, one should exclude acquired causes of dysfibrinogenaemia, including liver disease, autoantibodies to fibrinogen, and elevated fibrinogen degradation products. Dysfibrinogenaemia may also coexist with other inherited hypercoagulable states, and thus other causes of thrombosis and recurrent foetal loss should be investigated in this patient. Particularly, these include antiphospholipid antibodies, protein C, protein S, antithrombin, and factor V Leiden. Treatment of dysfibrinogenaemia is based on the clinical presentation. Patients who are asymptomatic do not require intervention. Patients who are bleeding need replacement of fibrinogen using freshfrozen plasma, cryoprecipitate, or fibrinogen concentrates. Patients with thrombotic complications require anticoagulation. Patients with a history of recurrent foetal loss have a successful pregnancy with the use of fibrinogen replacement. Fibrinogen should be given weekly during pregnancy to maintain through fibrinogen levels 60–100 mg/dl starting as early as week 4–5 of gestation. Fibrinogen requirements may increase as gestation progresses. At the time of delivery, fibrinogen levels should be maintained at 100–200 mg/dl by continuous infusion [5].

References 1 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995;73(1):151–61. 2 Hayes T. Dysfibrinogenemia and thrombosis. Arch Pathol Lab Med 2002; 126(11):1387–90.

138 Rare Platelet and Coagulation Disorders

3 Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol 2001;114(2):249–57. 4 Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002;126(4):499–505. 5 Yamanaka Y, Takeuchi K, Sugimoto M, Sato A, Nakago S, Maruo T. Dysfibrinogenemia during pregnancy treated successfully with fibrinogen. Acta Obstet Gynecol Scand 2003;82(10):972–3.

Hypofibrinogenaemia

Question/ Case

I have recently seen an infant with fibrinogen levels of 30 mg/dl (normal range 150–430) and fibrinogen antigen levels 45 mg/dl (normal 149–353). He was found to have a large intracranial haemorrhage (ICH) and ocular haemorrhages at 4 days of age. There was no evidence of trauma. He was born to a mother who had a caesarean section because of lack of progression of labour and signs of foetal distress. Apgar score at birth was 9. The parents are blood relatives. Both have normal fibrinogen levels (285 and 306). The infant has had no bruising, mucosal bleeding, or soft tissue bleeding. However, as soon as the diagnosis was made, he was started on cryoprecipitate twice weekly. Following cryoprecipitate, his fibrinogen values fell back to the baseline by 3 or 4 days. My questions for the panel are: (1) What do you think is the cause of this infant’s large ICH and intraocular haemorrhages: prolonged labour, hypofibrinogenaemia, or both? (2) How long would you continue him on twice weekly cryoprecipitate? (3) What would you advise the parents about future pregnancies? In view of the parents’ normal fibrinogen values, can we exclude them from being “carriers”? They would like to have another child but would like to know if there is a risk of having another child with severe hypofibrinogenaemia.

Response from Gail Macik, MD University of Virginia, Charlottesville, Virginia, USA I think the haemorrhage is a complication of labour due to congenital hypofibrinogenaemia, but spontaneous/coagulopathic haemorrhage at this age is also possible. If this couple wishes additional children, they should know that there is a real risk of another hypofibrinogenaemic

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child. As the parents are most likely carriers, genotyping of both parents is indicated. Life-long prophylaxis will depend on the frequency of future bleeding episodes in this patient, as fibrinogen levels may improve as the liver matures. A protocol that I used in one patient was weekly/biweekly infusions of cryoprecipitate, with daily infusions at the time of haemorrhages. Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark In my understanding, your child suffers from a quite severe deficiency in fibrinogen that, at least in part, has been responsible for lifethreatening haemorrhage. Professor Samama once summarized the picture of afibrinogenaemia and dysfibrinogenaemia by stating that 50% are symptomless, 25% have bleeding symptoms, and 25% have thrombosis. Expression of fibrinogen depends on the normal function of no less than three separate genes, and so cases are not easily genotyped. Parents may be asymptomatic carriers.

Gardner–Diamond Syndrome

Question

What experience do we have with the rare disorder autoerythrocytic sensitization (AS) syndrome?

Case 1

I have a young female patient who presented with unexplained bruising and knee pain. All standard tests for haemostasis were normal. All inflammatory and autoimmune markers were normal. Orthopaedic evaluation of the knee was normal. An MRI scan raised the possibility of “bruising” of the medial femoral condyle. There were some clinical features of AS and a subcutaneous injection of autologous blood induced an enormous bruise. The literature suggests that this condition is usually self-limiting in months or years. There is a suggestion that it may be “stress” related. My patient has undergone a psychiatric evaluation, which was negative. Some investigators have reported abnormalities of fibrinolysis. Currently, she continues to experience regular painful bruises and has given up all sporting activity due to the knee problem. My management approach has been based on strong reassurance that the symptoms will eventually improve, and I have been reluctant to embark on any treatment but she is becoming increasingly keen to “try something”. Various treatment approaches are reported in the literature (steroids; chloroquine; other immunosuppression; immunoglobulin infusions; plasma exchange), but there is not much evidence that any such treatment is worthwhile. My questions for the panel are: (1) What is the underlying disease process in this condition? (2) Should I undertake any further investigations? (3) Should treatment be considered and, if so, what would be the best approach?

Case 2

I have seen quite a few cases of AS syndrome (also known as Gardner–Diamond syndrome or psychogenic purpura). All of them are women who are not older than 40 years. The treatment we tried in one of them was interesting: a

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young woman with spontaneous painful ecchymosis in arms, thighs, and legs, not related to menstrual periods. She accepted hypnosis instead of drug treatment and after two sessions in 1 week the ecchymoses stopped. She continued well, and after 2 months we decided to learn more about this disease and with her consent, she was hypnotized again and induced to “produce” ecchymoses. Next day she showed ecchymoses on arms, thighs, and legs. We had no valid explanation.

Response from Harold R. Roberts, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA The syndrome of AS is an anathema to most physicians who see patients who fit the original description as described by Gardner and Diamond. We have recently seen two such patients and have not been able to find any effective treatment. Follow-up of similar patients has been difficult, so that we have not been able to confirm or deny whether the symptoms expressed by these patients gradually disappear or not. While emotional problems are often described in such patients, especially clinical depression, a cause-and-effect relationship between emotional problems and the signs and symptoms of AS has not been clearly established. A factitious pathogenesis has been suggested by some, but this seems to be unlikely in my own experience. We have used plasma exchange on patients who experience improvement in symptoms, but whether the exchange transfusion was clearly the cause of improvement is not known. Unfortunately, we do not know the pathogenesis of this disorder and we cannot offer any meaningful suggestions for further treatment of such patients. Response from Nigel S. Key, MD University of North Carolina Medical School, Chapel Hill, North Carolina, USA If ever there was an example of a failure of “evidence-based medicine”, this must be it! My own experience in this unusual and perplexing disorder is limited to two patients, both of whom were similar

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to the patients described. The only large series in the literature is still the one from Dr Ratnoff and his group in Cleveland. This and subsequent publications have emphasized the link to an underlying psychiatric disorder, although in my limited experience, this is not always detectable, even after a detailed evaluation. I do not think the literature allows a clear conclusion as to the pathophysiology of this uncommon condition, and the sensitivity and the specificity of the skin tests to detect hypersensitivity to autologous erythrocytes, red cell stroma, and/or DNA are unknown. To my knowledge, the diagnosis is primarily based on the history and, in particular, the painful prodrome that occurs before the onset of bruising. Once again, the literature is probably of limited value in selecting therapy in this situation, and it could be argued that especially in a disorder of this type, it has to be considered whether the placebo effect accounts for any described benefit. For this reason, I would favour avoiding any of the potentially more harmful therapies, including immunosuppressive agents, but one might be tempted to try an antifibrinolytic agent, beginning with a relatively low dose. Response from Pilar Arranz, PhD The Institute of Counselling, Antäe, Madrid, Spain Gardner–Diamond syndrome is very unusual. It is associated with an AS. The subsequent extravasation of blood during unrecognized trivial injuries seems to induce purpuric lesions. We have had only one case and we tried hypnosis without maintained results. Although the stereotypic description of patients with AS is remarkable, it does not explain their propensity for bruising. Perhaps a clue may be found by an examination of the specific psychosocial stresses to which these persons have been subjected. A psychological approach to these patients might help them cope with their difficulties. Some empirical data have been published by David Agle and Oscar Ratnoff [1–3].

References 1 Ratnoff OD. The psychogenic purpuras: a review of autoerythrocyte sensitization, autosensitization to DNA, “hysterical” and factitial bleeding, and the religious stigmata. Semin Hematol 1980;17(3):192–213.

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2 Ratnoff OD, Agle DP. Psychogenic purpura: a re-evaluation of the syndrome of autoerythrocyte sensitization. Medicine (Baltimore) 1968;47(6):475–500. 3 Agle DP, Ratnoff OD, Wasman M. Studies in autoerythrocyte sensitization. The induction of purpuric lesions by hypnotic suggestion. Psychosom Med 1967;29(5):491–503.

Hereditary Haemorrhagic Telangiectasia

Question

What is the management for Osler–Weber–Rendu syndrome (hereditary haemorrhagic telangiectasia, HHT)?

Case 1

We have an elderly female patient severely affected by Rendu–Osler syndrome. She bleeds continuously with severe gingival bleeding associated with recurrent acute anaemia. We plan to use desmopressin (DDAVP) in combination with tranexamic acid and are also considering embolization. What experience do other users have of DDAVP treatment in this particular condition, and would you recommend any other therapeutic options?

Case 2

I have in my care a teenage patient with Rendu–Osler syndrome. He has already been treated by laser vaporization for severe laryngopharyngeal bleeding. Laser therapy cannot be applied over extended periods without adverse effects. The only alternatives would be a pharynx and a larynx transplantation. Does anybody have any experience of a similar situation? What could be the effect of oestrogen– progesterone therapy, which is sometimes proposed for the treatment of gastrointestinal (GI) angiodysplasia?

Response from Kevin Rickard, MD Royal Prince Alfred Hospital, Sydney, Australia Rendu–Osler syndrome/HHT is a rare bleeding disorder with haemorrhage occurring from superficial telangiectasia that is seen most frequently in the nose and mouth but which can occur throughout the GI tract and elsewhere. The condition was first described by Rendu in Paris in 1896. The clinical spectrum of the disease has now broadened to include vascular abnormalities in several viscera and also arteriovenous (AV) malformations that can occur in the pulmonary and the hepatic circulation [1]. AV malformation in the pulmonary circuit can lead to hypoxaemia and paradoxical embolism, while hepatic manifestations may result in congestive cardiac failure.

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HHT is inherited as an autosomal dominant trait and displays agerelated penetrance, with manifestations developing throughout life. Affected individuals in families may display widely differing patterns of disease. It now appears that there are at least three HHT genetic loci on chromosomes 9, 12, and elsewhere. The mutated genes have been identified: endoglin on chromosome 9 and activin receptor kinase 1 (ARK1) on chromosome 12, which encodes for a transmembrane protein expressed on endothelial cells.

Clinical Management The condition may be extremely difficult to manage; it is often only possible to manage bleeding in a symptomatic manner. The following observations may be relevant in relation to this patient. It is important to exclude any associated and underlying bleeding disorder or predisposing condition for excessive bleeding in HHT, such as underlying von Willebrand disease (VWD), or abnormal platelet function, for example secondary to analgesic or aspirin ingestion. If either of the above is present, then corrective action needs to be taken (factor VIII concentrate for VWD and platelet infusions for abnormal reversible platelet malfunction). Blood transfusion will probably be necessary to correct anaemia, and there is probably also a need for prolonged oral iron supplementation to correct iron deficiency secondary to blood loss. Antifibrinolytic agents administered systemically by oral therapy or by local application together with topical thrombin in solution may be advantageous in this woman, particularly as she has gingival bleeding. The local application of a thrombin antifibrinolytic mixture (e.g. gauze swabs soaked in a solution of saline–thrombin and epsilon aminocaproic acid (EACA)) may be valuable. Oestrogen therapy, although advocated in most haematology textbooks, has not been successful in the cases that we have seen in this hospital over the past 30 years, so I would certainly not advocate its use. We have not had any experience with the use of DDAVP in this condition, but I doubt that it will be very effective, since bleeding is due to a physical defect in aberrant blood vessels. However, DDAVP would be worth trying, bearing in mind the problem of tachyphylaxis with DDAVP. If severe local bleeding occurs, local embolization of the nutrient artery to the area in question may be possible, with the assistance of a

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very skilled interventional radiologist. Certainly, for AV malformations in the pulmonary and hepatic circulation, embolism is often a very effective procedure.

Response from Ernest Briet, PhD and Maria Koopman, MD Sanquin Blood Supply Foundation, Amsterdam, The Netherlands The management of bleeding in patients with Rendu–Osler–Weber syndrome is often difficult, and several therapeutic options have been suggested. Local treatments such as arterial ligation, irradiation, local pressure, topical vasoconstrictors, or cryosurgery offer temporary, but never permanent relief. Systemic treatment with haemostatic drugs such as DDAVP, tranexamic acid, or aminocaproic acid could be a good alternative, theoretically. A MedLine search, however, revealed no data on the efficacy of DDAVP in the management of these patients, except for those who have decreased von Willebrand factor levels. The use of oral tranexamic acid has been studied in the management of epistaxis in patients without Rendu–Osler–Weber syndrome [2]. In these patients, there was no difference in the occurrence of severe rebleeding between the placebo and the treatment groups. Patients treated with tranexamic acid had fewer minor or moderate rebleeds. Local application of tranexamic acid gel was no more effective in controlling either the initial bleeding or rebleeding than placebo gel. Some more data are available on the use of oestrogens or the combination of oestrogens and progesterone for this indication. The exact mechanism of action of hormonal therapy is unknown. But there is evidence that hormonal therapy causes thickening of the squamous epithelium in the nostrils of patients and improves the integrity of the endothelium. Several uncontrolled trials have reported effective control of recurrent epistaxis in patients with Rendu–Osler–Weber syndrome using systemic oestrogen or oestrogen–progesterone therapy. Also, the results of a randomized placebo-controlled study have shown a significantly decreased need for packed red cell transfusion in patients with bleeding from GI vascular malformations [3]. In conclusion, there is little evidence about the efficacy of DDAVP and tranexamic acid and rather more evidence about the efficacy of oestrogen–progesterone therapy for the treatment of bleeding

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problems in patients with Rendu–Osler syndrome. In these particular patients, however, it may be worthwhile to try DDAVP in combination with tranexamic acid. As a second-line treatment, hormonal therapy should be considered. Whatever treatment you choose, it is advisable to have the patient keep a diary before and during treatment to document the effect, if any. Our own experience with oestrogen and progesterone in a single patient has been disappointing. Response from Miguel A. Escobar, MD1 and Harold R. Roberts, MD2 1 University of Texas Health Science Center at Houston and Gulf States Hemophilia and Thrombophilia Center, Houston, Texas, USA 2 University of North Carolina Medical School, Chapel Hill, North Carolina, USA The treatment of patients with HHT is cumbersome and frustrating. The use of local pressure, topical vasoconstrictors, chemical cautery, and electrocautery is usually only of temporary effectiveness. Experience with the use of aminocaproic acid (EACA) in HHT is limited. Saba et al. reported a successful, rapid, and sustained response with a low dose of EACA (2 g) in two patients with epistaxis and GI bleeding [4]. However, Korzenick et al. reported no response to EACA when the treatment was administered to three different patients [5]. Treatment with oestrogen alone is controversial. The only randomized placebo-controlled study involved 17 patients, who were treated with oral estradiol valerate 4 mg daily. After a period of 3 months, there was no significant reduction in the frequency or the intensity of bleeding compared to the placebo group (14 patients) [6,7]. Harrison probably has most experience with the use of high-dose oestrogen [8]. Over a 25-year period, he has successfully treated 67 patients with HHT and epistaxis. His recommendation is to start with oral ethinyl estradiol 0.25 mg/day and increase it to 0.5 mg/day after 2 weeks if symptoms are not controlled. Once the bleeding is under control, he recommends adjusting the dose to meet individual requirements. This can vary between 0.25 and 1.0 mg/week. Doses lower than 0.25 mg/week are usually insufficient. At these doses, side effects are a major concern, especially in men [8]. McCaffrey et al. treated 16 patients with oral oestrogen. Use of conjugated oestrogens (premarin) 1.25 mg/day was recommended as a

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starting dose [9]. There was a 69% overall response rate, and in 50% of patients the response continued for more than 6 months. Abnormal uterine bleeding was seen in 50% of treated women. No information is available from this study on the most effective oestrogen preparation or minimal dosage required to control the bleeding [9]. The exact mechanism by which hormones work is not well understood, but some reports have shown that high-dose oestrogen can produce metaplasia of the normal nasal mucosa to form thick layers of keratinizing squamous epithelium [8]. Electron microscopy studies of the vascular lesions of patients with HHT before and after hormonal therapy have shown improvement using a combination of norethynodrel 5 mg with mestranol 0.75 mg [10]. The combination of oestrogen–progesterone treatment in patients with HHT seems more effective than oestrogens alone, as shown in some uncontrolled trials. This combination therapy also gives rise to fewer side effects. Van Cutsem et al. carried out a prospective, doubleblind, crossover study in patients with GI vascular malformations (six patients had HHT). A combination of daily oral oestrogen–progesterone (0.05 mg ethinyl estradiol/1 mg norethisterone) was compared to placebo over a 6-month period. The combination hormonal treatment arm significantly decreased the requirement for transfusion when compared to placebo [3,11]. Other more invasive treatments, such as pulsed dye laser and Nd: YAG laser, have produced some temporary improvement of symptoms, but more studies are needed as well as long-term results. The role of embolization is not yet clear. As you can see, the treatment of patients with HHT is difficult since, in addition to the telangestasic changes, other factors may contribute to bleeding. The use of oestrogen alone, either at regular or high doses, usually has frequent secondary side effects. We think it is reasonable to give patients a trial of oestrogen–progesterone combination therapy, but overall the responses of any given treatment seem to be based on the individual [12].

References 1 Peery WH. Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler– Weber–Rendu disease). Am J Med 1987;82(5):989–97. 2 White A, O’Reilly BF. Oral tranexamic acid in the management of epistaxis. Clin Otolaryngol Allied Sci 1988;13(1):11–16.

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3 Van Cutsem E, Rutgeerts P, Vantrappen G. Treatment of bleeding gastrointestinal vascular malformations with oestrogen–progesterone. Lancet 1990; 335(8695):953–5. 4 Saba HI, Morelli GA, Logrono LA. Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 1994; 330(25):1789–90. 5 Korzenik JR, Topazian MD, White R. Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 1994;331(18):1236. 6 Vase P. Estrogen treatment of hereditary hemorrhagic telangiectasia. A double-blind controlled clinical trial. Acta Med Scand 1981;209(5):393–6. 7 Vase P, Lorentzen M. Histological findings following oestrogen treatment of hereditary haemorrhagic telangiectasia. A controlled double-blind investigation. J Laryngol Otol 1983;97(5):427–9. 8 Harrison DF. Use of estrogen in treatment of familial hemorrhagic telangiectasia. Laryngoscope 1982;92(3):314–20. 9 McCaffrey TV, Kern EB, Lake CF. Management of epistaxis in hereditary hemorrhagic telangiectasia. Review of 80 cases. Arch Otolaryngol 1977; 103(11):627–30. 10 Menefee MG, Flessa HC, Glueck HI, Hogg SP. Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease). An electron microscopic study of the vascular lesions before and after therapy with hormones. Arch Otolaryngol 1975;101(4):246–51. 11 Van Cutsem E, Rutgeerts P, Geboes K, Van Gompel F, Vantrappen G. Estrogen–progesterone treatment of Osler–Weber–Rendu disease. J Clin Gastroenterol 1988;10(6):676–9. 12 Haitjema T, Westermann CJ, Overtoom TT, Timmer R, Disch F, Mauser H, et al. Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease): new insights in pathogenesis, complications, and treatment. Arch Intern Med 1996;156(7):714–19.

Hereditary Vitamin-K-Dependent Coagulation Factors Deficiency and Pregnancy

Question/ Case

We have a young girl with hereditary deficiency of vitamin-Kdependent coagulation factors, who is 13 weeks pregnant. In her childhood, she had multiple bruises and haematomas without actual haemorrhagic symptoms. I would like to ask the experts how to deal with this situation: Are prophylactic antithrombotic drugs recommended during pregnancy? Fresh-frozen plasma (FFP) should be given throughout the pregnancy or just at delivery? Should delivery be planned at 38 weeks or at full term? Which should be recommended: caesarean or normal delivery?

Response from Miguel A. Escobar, MD University of Texas Health Science Center at Houston and Gulf States Hemophilia and Thrombophilia Center, Houston, Texas, USA This is certainly an interesting and rare case. To my knowledge, there is no literature in patients with hereditary vitamin K deficiency and pregnancy. I will give my opinion and raise a few other questions. Does this patient respond to vitamin K? I think this is important to know since some patients can have a partial response to high doses of vitamin K (up to 100 mg/day) and may avoid the use of plasma replacement therapy. What are the baseline levels of the vitamin-K-dependent factors? It would be ideal to check her vitamin-K-dependent factor levels, and if

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they are below 30% I think her risk of bleeding could be increased. In this case, you might consider using FFP during pregnancy maybe once or twice a week if her levels are very low. On the other hand, if proteins C and S are also low, her risk of thrombosis could be also high and again I will suggest the use of FFP. I would not use thromboprophylaxis. During delivery, if her levels can be maintained above 50%, I think it might be safe. If caesarean section is needed, the use of partial plasma exchange to raise her levels to ~50% may be necessary. The other option is the use of a prothrombin complex concentrate (PCC) at a low dose. Remember, thrombosis can occur with PCCs. Certainly all plasma-derived products should be screened for possible pathogens. I would also explain to the patient all the pros and cons of the treatment and have her sign a consent form for the treatment plan. Response from Johannes Oldenburg, MD University Clinic Bonn, Bonn, Germany I would like to add another aspect to the very helpful comments of Miguel Escobar: There is evidence that vitamin K coagulation factor deficiency (VKCFD) affected newborns who are at high risk of bleeding during the perinatal time. Because of their natural vitamin-K-deficient status, the condition is diagnosed because of perinatal bleeding. Since during pregnancy the demand of vitamin K may increase, the activity of the vitamin-K-dependent coagulation factors may drop with a subsequent increased risk of bleeding. We have some data that in such patients the vitamin-K-dependent coagulation factor activities are especially sensitive to the vitamin K levels. Therefore, it might be important to closely monitor vitamin-K-dependent factors during pregnancy. Most of the patients (almost all with a defect in the vitamin K epoxide reductase complex and some with mutations in the carboxylase gene) respond at least partially to oral substitution with vitamin K. In case the patient responds to vitamin K, which probably is known from the bleeding experiences in childhood, I would recommend a low dose of oral vitamin K substitution during pregnancy, if the coagulation factor levels fall below 30–40%. In this case, the risk of bleeding at time of delivery could be controlled by vitamin K substitution.

Glanzmann’s Thrombasthaenia and Gastrointestinal Angiodysplasia

Question/ Case

There is a patient with severe Glanzmann’s thrombasthaenia who does not have antibodies to platelets. This patient is a middle-aged male with gastrointestinal (GI) angiodysplasia. Is there an association between angiodysplasia and severe bleeding disorders, particularly disorders of primary haemostasis? What is the optimal management of angiodysplasia in patients with severe hereditary bleeding disorders? What would be the optimal treatment regimen for massive haemorrhage in this patient?

Response from Man-Chiu Poon, MD University of Calgary, Foothills Hospital, Calgary, Alberta, Canada Angiodysplasia is a submucosal vascular malformation found commonly in the GI tract and is likely a degenerative process of aging. It is common in the elderly population and may be a cause of acute and/ or chronic bleeding. In the population without a bleeding disorder, clinical presentation varies from an incidental finding in an otherwise asymptomatic individual to occult bleeding or an acute massive haemorrhage. Angiodysplasia with severe bleeding has been frequently reported in patients with bleeding disorders of primary haemostasis, as reported by Fressinaud et al. in congenital or acquired deficiency of high-molecular-weight (MW) multimers of von Willebrand factor (VWF) (e.g. type 2 and type 3 VWD (von Willebrand disease)), including that associated with aortic stenosis reported by Vincentelli et al., and as reported by Okamura et al. in severe congenital platelet functional disorders like Glanzmann’s thrombasthaenia and Bernard– Soulier syndrome [1–3]. Both high MW VWF multimers and platelets are important in preventing bleeding in angiodysplasia as the angiodysplasia produces a very high local shear rate condition, in which the largest VWF multimers are required for platelet–subendothelium interaction to prevent bleeding. Thus, in the presence of angiodysplasia,

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primary haemostatic abnormalities predispose the patients to serious haemorrhage (hence frequent association and reporting), but do not necessarily play a pathogenic role in the development of angiodysplasia. The literature and experience suggest that no treatment modality has been successful in all cases of GI angiodysplasia, irrespective of whether a bleeding disorder is also present or not. In a patient with a severe primary haemostatic disorder and angiodysplasia, it is reasonable to try hormonal therapy to prevent bleeding. There are also anecdotal reports suggesting success in preventing angiodysplastic bleeding with a combination of octreotide, ethinylestrial and norethisterone in Glanzmann’s thrombasthaenia patients and with hormonal therapy or octreotide in VWD patients [4–6]. While hormonal therapy has also been used successfully in patients without a bleeding disorder, two clinical trials suggest hormonal therapy does not prevent rebleeding in these patients [7,8]. In Glanzmann’s thrombasthaenia with bleeding from acute angiodysplasia, if the patient is not refractory to platelets, the first-line treatments should include platelet transfusion, antifibrinolytics, local coagulation measures (where possible), and red cell transfusions to keep haematocrit over 30%. rFVIIa could be used when the patient is refractory to platelets. In the International Registry on Congenital Platelet Disorders and rFVIIa, the success rate with rFVIIa appears lower in GI bleeds compared to bleeds at other sites, but rFVIIa treatment is defined as not evaluable if platelets are used concurrently. We do not have enough data to indicate whether rFVIIa used together with platelets is more effective than either agent alone.

References 1 Fressinaud E, Meyer D. International survey of patients with von Willebrand disease and angiodysplasia. Thromb Haemost 1993;70(3):546. 2 Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349(4):343–9. 3 Okamura T, Kanaji T, Osaki K, Kuroiwa M, Yamashita S, Niho Y. Gastrointestinal angiodysplasia in congenital platelet dysfunction. Int J Hematol 1996;65(1):79–84. 4 Coppola A, De Stefano V, Tufano A, Nardone G, Amoriello A, Cerbone AM, et al. Long-lasting intestinal bleeding in an old patient with multiple mucosal vascular abnormalities and Glanzmann’s thrombasthenia: 3-year pharmacological management. J Intern Med 2002;252(3):271–5.

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5 Bowers M, McNulty O, Mayne E. Octreotide in the treatment of gastrointestinal bleeding caused by angiodysplasia in two patients with von Willebrand’s disease. Br J Haematol 2000;108(3):524–7. 6 Chey WD, Hasler WL, Bockenstedt PL. Angiodysplasia and von Willebrand’s disease type IIB treated with estrogen/progesterone therapy. Am J Hematol 1992;41(4):276–9. 7 Lewis BS, Salomon P, Rivera-MacMurray S, Kornbluth AA, Wenger J, Waye JD. Does hormonal therapy have any benefit for bleeding angiodysplasia? J Clin Gastroenterol 1992;15(2):99–103. 8 Junquera F, Feu F, Papo M, Videla S, Armengol JR, Bordas JM, et al. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology 2001; 121(5):1073–9.

Glanzmann’s Thrombasthaenia and Pregnancy

Question

How would you manage a patient with Glanzmann’s thrombasthaenia who is pregnant?

Case

We have a young Glanzmann’s thrombasthaenia patient, 26 weeks pregnant, treated in the past with blood and platelets. Until now, no haemorrhagic problems have occurred. We would appreciate an opinion on the management of the patient’s delivery and postpartum period. Should the delivery be planned and done at 38 weeks? Which will be the best prophylactic/therapeutic option, if she has anti-HLA/platelet antibodies? When should platelets be given – before or after delivery induction? Should we use antifibrinolytic agents?

Response from Man-Chiu Poon, MD University of Calgary, Foothills Hospital, Calgary, Alberta, Canada There is really no evidence-based guidelines for the management of pregnant women with Glanzmann’s thrombasthaenia. Bleeding is usually not a problem during pregnancy except under abnormal circumstances such as abruption, eclampsia, etc. However, there is a risk of bleeding during and after delivery. For the management of bleeding, platelet transfusion remains the standard of treatment. The downside is the development of platelet allo-antibodies to HLA and/or GPIIb/IIIa rendering future platelet transfusions ineffective. GPIIb/IIIa antibodies may also enter from the maternal circulation to the foetus, resulting in neonatal thrombocytopaenia and haemorrhage, including intracranial haemorrhage. For this reason, in patients who have previously been given platelet transfusions or in multiparous women with Glanzmann’s thrombasthaenia, platelet antibodies should be monitored throughout pregnancy to assess the risk of thrombocytopaenia in the foetus and the available treatment options.

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The alternative agent for treatment of bleeding in Glanzmann’s patients is recombinant factor VIIa, particularly in patients already resistant to platelet transfusion because of prior allo-immunization, but experience in using it in pregnancy is limited. If this treatment fails, I would consider methods for reducing platelet antibodies that include immunoadsorption – to allow the use of platelet concentrates for haemostasis. Recombinant factor VIIa should preferably be given by bolus infusions, particularly in pregnant woman. Whether to plan the delivery at 38 weeks or leave the pregnancy to term is a judgement call, but I would favour leaving the pregnancy to term. As indicated earlier, rFVIIa would be the agent of choice for pregnant women with Glanzmann’s thrombasthaenia who have antiHLA/platelet antibodies. Whether to give this agent just before delivery or only when postpartum bleeding develops is also a judgement call, but I would favour giving rFVIIa prophylactically just before delivery to prevent bleeding. I would also avoid using antifibrinolytics at delivery and in the postpartum period.

rVIIa (NovoSeven®) and the Wiskott– Aldrich Syndrome Question/ Case

We have been presented with an infant boy with severe thrombocytopaenia, immune deficiency, and eczema (variant Wiskott–Aldrich syndrome without sialoglycoprotein deficiency on thrombocytes and lymphocytes). The patient experienced a large subcutaneous, subperiosteal bleed the size of a plum on his forehead. The platelet count at that time was 10,000/l. The bleed was treated with four doses of rFVIIa (30 g/kg) at 3-hourly intervals. Treatment was effective in stopping bleeding and the platelet count 24 h later was 33,000/l. Is treatment with rFVIIa advisable for this type of patient?

Response from Ulla Hedner, MD, PhD University of Lund, Malmo, Sweden and Novo Nordisk A/S, Denmark Recombinant FVIIa has been used to a limited extent in patients with platelet defects, including thrombocytopaenia. It has been reported to induce haemostasis in a number of patients with Glanzmann’s thrombasthaenia, in a few patients with Bernard–Soulier’s syndrome and in a few patients with thrombocytopaenia [1–4]. There are also some patients with defects like storage pool diseases in whom rFVIIa has been found to induce haemostasis. However, some failures have also been reported. Reported dose levels have varied substantially from 90 to 270 g/kg, administered as a bolus. In those cases where several doses have been given, they have been administered with a dose interval of 2–4 h. There may be a tendency towards the need for fewer doses provided that initial higher doses are used. With regard to Wiscott–Aldrich syndrome, I am only aware of one patient who has received rFVIIa for bleeding. In summary, your patient may very well benefit from rFVIIa in case of bleeding. You may be able to try doses of 90–180 g/kg and examine the clinical effect on bleeding. If the first dose is ineffective, you may increase the dose. If there is a partial response, you may add a second dose with a dose interval of 2–3 h.

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References 1 Tengborn L, Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa. Thromb Haemost 1996;75(6):981–2. 2 Poon MC, Demers C, Jobin F, Wu JW. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood 1999;94(11):3951–3. 3 Peters M, Heijboer H. Treatment of a patient with Bernard–Soulier syndrome and recurrent nosebleeds with recombinant factor VIIa. Thromb Haemost 1998;80(2):352. 4 Kristensen J, Killander A, Hippe E, Helleberg C, Ellegard J, Holm M, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996;26(Suppl 1):159–64.

5 Acquired Bleeding Diatheses

Acquired Haemophilia and Second Pregnancy, 163 Developing a Factor IX Inhibitor, 165 End-Stage Liver Disease and Surgery, 167 Treatment for Acute DIC, 169

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Acquired Haemophilia and Second Pregnancy

Question

How would you counsel a women with a history of postpartum-acquired haemophilia with regard to risk of recurrence with a second pregnancy?

Case 1

A middle-aged patient in our centre has developed a postpartum anti-factor VIII inhibitor after in vitro fertilization (IVF). The peak titre was 4 BU, and, due to the absence of life-threatening haemorrhage, she was treated with corticosteroid only for 5 months. Seventeen months after the onset of the inhibitor, the level of FVIII was 38% and the inhibitor titre was 0.6 BU and has been stable for the past 9 months.

Case 2

A 32-year-old woman experienced a limb-threatening bleed 6 weeks postpartum. She was treated with emergent fasciotomy and subsequently experienced intractable bleeding. Four days after surgery, she was diagnosed with antibodies to factor VIII. Treatment involved infusion of recombinant FVIIa, tranexamic acid, prednisone, cyclophosphamide, and intravenous immunoglobulin. Maximum Bethesda titre was 14.4 BU, 20 weeks after therapy the titre was 0.4 BU.

Response from Inge Scharrer, MD University of Mainz, Mainz, Germany The first description of postpartum antibodies to FVIII was published in 1946 [1]. However, it is still unknown at which stage in the pregnancy or postpartum period antibodies are acquired. Michiels and coworkers have shown that FVIII autoantibodies may appear as late as 2–5 months after delivery [2]. Margolius et al. reported that they may also recur in a subsequent pregnancy [3]. Autoantibodies to FVIII associated with pregnancy can lead to very severe uterine bleeding, often requiring a hysterectomy. The foetus may also be affected. For instance, we observed a patient with

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extreme postpartum haemorrhage, and the occurrence of cerebral haemorrhage in the neonate, which resolved spontaneously. The prognosis of untreated bleeding episodes in patients with acquired haemophilia is very poor. Spontaneous remission has been reported in postpartum FVIII inhibitor formation, but only after a long delay [4]. Up to now the risk of recurrence with a second pregnancy cannot be predicted. Response from Jos Vermylen, MD University of Leuven, Leuven, Belgium At our centre, we have no data on the risk of a postpartum inhibitor occurring during a subsequent pregnancy and puerperium. In an abstract presented at the XXIII Congress of the World Federation of Hemophilia in May 1998, Yee et al. mentioned that two postpartum FVIII inhibitor patients continued on to uneventful second pregnancies [5].

References 1 Fantl P, Nance M. Med J Aust 1946;2:125. 2 Michiels JJ, Bosch LJ, van der Plas PM, Abels J. Factor VIII inhibitor postpartum. Scand J Haematol 1978;20(2):97–107. 3 Margolius Jr A, Jackson DP, Ratnoff OD. Circulating anticoagulants: a study of 40 cases and a review of the literature. Medicine (Baltimore) 1961;40:145–202. 4 Hauser I, Gisslinger H, Locker G, Elbl W, Kyrle PA, Pabinger I, et al. Postpartum factor VIII inhibitors. Report of two cases with special reference to the efficacy of various treatments. Wien Klin Wochenschr 1993;105(12):355–8. 5 Yee et al. Haemophilia 1998 (Abstract 376).

Developing a Factor IX Inhibitor

Question

Can factor IX inhibitors develop in conditions other than those following treatment of haemophilia B, for example, following transfusion of non-haemophiliacs, those with haemophilia A or other diseases? How are circulating factor IX inhibitors in haemophilic patients managed?

Response from Jeanne Lusher, MD Wayne State University School of Medicine, Detroit, Michigan, USA In response to the queries regarding factor IX inhibitors, they are rarely seen except in persons with haemophilia B who have received FIX-containing preparations. Almost all the inhibitors that develop in non-haemophilic individuals are directed against FVIII. While abnormally low levels of FIX can be seen in a variety of acquired conditions (such as hepatocellular disease and nephrotic syndrome) and in early infancy, the low levels in these situations are mediated by other mechanisms. FIX inhibitors occur in 1–3% of persons with haemophilia B; they usually occur in those individuals with severe haemophilia B resulting from large gene deletions, stop codons, and frameshift mutations. As to management of persons with haemophilia B and FIX inhibitors, one should keep in mind the following: FIX inhibitors usually develop quite early in life, after a median of 9–12 exposure days to FIX. In 40– 50% of cases, inhibitor development is associated with anaphylaxis or severe allergic reactions. While these severe allergic reactions are temporally associated with FIX inhibitor development, they may occur before or after inhibitor detection. Thus, it has been recommended that young children with severe haemophilia B be given their first 20 or so infusions of FIX in a medical facility equipped to handle such emergencies. While one can attempt to eradicate FIX inhibitors with an immune tolerance induction (ITI) regimen employing frequent large doses of FIX, the likelihood of this being successful is less than it is with FVIII inhibitors (~50% vs. 80–85% success rate with haemophilia A and

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FVIII inhibitors). The success rate with ITI appears to be even less in those patients who have had severe allergic reactions to FIX, and there have been 10 or so reports of the development of nephrotic syndrome in such patients who have been on an ITI regimen for 7–9 months. For treatment of bleeding episodes in persons with FIX inhibitors who are “high responders”, one can use an activated prothrombin complex concentrate (APCC) or recombinant (r) FVIIa (NovoSeven). There are advantages and disadvantages with each. APCCs have been used for approximately 25 years and thus most physicians are familiar with their use (both in-hospital and at home). Their effectiveness is independent of the patient’s FIX inhibitor titre. However, there is no readily available laboratory test for monitoring effectiveness in the recipient. The APCCs are not always effective in controlling bleeding; thus, many physicians have been reluctant to rely on APCCs for surgical coverage in patients with FIX (or FVIII) inhibitors. The other therapeutic option, rFVIIa, is a recombinant product, unlike the APCCs, which are plasma derived. The active agent, rFVIIa, is known, and the amount of rFVIIa is listed on the vial label. It has been used in a wide variety of settings, including major surgery, home treatment, and for compassionate use in rather desperate situations where all else has failed. Like the APCCs, efficacy of rFVIIa is independent of the patient’s inhibitor titre. However, rFVIIa has a short half-life (approximately 2.5 h), and thus for surgical situations or serious bleeding episodes, repeat bolus dosing must be given at frequent intervals. Like the APCCs, there is no readily available laboratory test for monitoring efficacy, and the product is not universally effective. However, haemostasis following infusion of rFVIIa appears to be localized to the site(s) of injury. For each of the small number of cases of disseminated intravascular coagulation, thromboembolism, or myocardial infarction seen in association with the use of rFVIIa, there appeared to be other predisposing factors. These include gramnegative sepsis, prior history of angina or atherosclerotic cardiovascular disease. As with all therapeutic agents for treating bleeding episodes, early treatment with rFVIIa is extremely important. Acute haemarthroses or other bleeding episodes, treated as soon as possible after the onset, can often be managed with one or two doses of rFVIIa. For the subset of haemophilia B patients with inhibitors and anaphylactic reactions to any FIX-containing product, rFVIIa is clearly the treatment of choice, as opposed to APCCs, since rFVIIa contains no FIX.

End-Stage Liver Disease and Surgery

Question/ Case

I have a patient who is to undergo elective neurosurgery for treatment of a herniated disc. He has hepatitis C, haemochromatosis, and acute intermittent porphyria. His platelet count is 60–70K/µl but does rise with transfusion of platelets. His baseline prothrombin is 33% of normal but rises only to 44% with 2 units of plasma. His factor VII level is 42% of normal and rises to 49% with 2 units of plasma. Other factors are approximately 50% and show little response to plasma. His prothrombin time (PT) is 14.6 s (normal to 13.2). His activated partial thromboplastin time (APTT) is 34.7 s (normal to 33.0). His fibrinogen levels are normal. Would the panel: (a) clear him for surgery, (b) clear him but treat with plasma perioperatively, (c) use recombinant VIIa preoperatively, or (d) defer surgery given the elective nature of the neurosurgery?

Response from Barbara A. Konkle, MD University of Pennsylvania, Philadelphia, Pennsylvania, USA Procedures in patients with liver disease and an associated coagulopathy are at a variable risk of bleeding. This is due to a combination of decreased synthesis of multiple clotting factors, increased fibrinolysis due to impaired clearance of fibrinolytic enzymes, acquired dysfibrinogenaemia, and thrombocytopaenia due to hypersplenism and/or decreased synthesis of thrombopoeitin. They may also have evidence of low-grade disseminated intravascular coagulation. Commonly used screening laboratory testing, including the PT, APTT, and platelet count, may not reflect the bleeding risk or lack thereof. Particularly, the PT may not be a good predictor of underlying factor levels. In a study by Chowdhury et al., it was found that many individuals with modestly elevated INRs had factor levels greater than 0.30 U/ml, which they considered haemostatic [1]. They also found that infusing 15 U/kg of fresh-frozen plasma (FFP) had minimal effectiveness in increasing low factor levels to a therapeutic level. In patients who

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received 30 U/kg of FFP, the patients who had low factor levels (as low as 10% for factor V), the factor levels all increased to above 0.30 U/ml [2]. The increases in factor levels in response to FFP infusion in the patient presented are consistent with the findings in this paper. How much the combined deficiency of multiple factors in liver disease increases the risk of bleeding is not known. However, it is likely to be greater than that seen when one has only one factor decreased. Thus, we do not know that using a cut off of 0.30 U/ml applies to patients with liver disease. By the patient’s history and physical exam, one can get an idea as to the bleeding risk and approach a patient with bleeding symptoms more cautiously than one without. Global assays of haemostasis, particularly ones that also assess fibrinolysis, may be helpful in this setting but have not been assessed in a prospective manner. Acute intermittent porphyria adds additional medical risks, particularly as related to anaesthesia. In complex patients with a probable increased risk of bleeding, elective surgeries should be carefully considered, particularly when bleeding, if it occurs, could be devastating. In patients with relatively mild coagulopathies, such as that in the patient presented, if surgery is undertaken, there are no data to suggest that rFVIIa would be more effective than FFP at doses adequate to correct the coagulopathy, and if needed, platelet transfusions.

Editors’ Note Some physicians would consider giving rFVIIa instead of FFP, simply to avoid overloading the circulation with large volumes of plasma. We concur with Dr Konkle on the use of caution before subjecting a complex patient with severe liver disease to an elective surgery with a significant risk of bleeding.

References 1 Chowdhury P, Saayman AG, Paulus U, Findlay GP, Collins PW. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004; 125(1):69–73. 2 Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol 2003;98(6):1391–4.

Treatment for Acute DIC

Question

What is the modern treatment for acute disseminated intravascular coagulation (DIC) in adults, children, and newborns, in sepsis and not in sepsis?

Response from Sam Schulman, MD, PhD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada When acute DIC is suspected, treatment of the patient should begin immediately. There is usually a triggering cause, such as sepsis, obstetric complication, trauma, malignancy, etc. and symptoms of disseminated microthrombi or haemorrhage due to depletion of consumable clotting factors. Once screening of haemostasis has been undertaken, treatment can begin with the infusion of at least 3–4 units of freshfrozen plasma (FFP). At the same time, measures should be taken to remove the stimuli activating the coagulation cascade. This includes administration of antibiotics in the case of septicaemia, stabilization of fractures, proper oxygenation, efficient analgesia, and so on. If the patient deteriorates while still in the ischaemic phase with the formation of disseminated thrombi, there may be a benefit in adding small amounts of heparin to the FFP therapy. Start with a bolus dose of 30 IU/kg and then an intravenous infusion of 100 IU/kg per 24 h. Heparin should not be added if the patient has bleeding symptoms or leukaemia with a risk of intracranial bleeding. If the patient deteriorates and is bleeding, I would add antithrombin concentrate, but at this point it would be helpful to have a measurement of antithrombin levels available. If, from the beginning, the DIC state is superacute (e.g. a patient with obstetric complications, massive bleeding from the uterus and other sites, who has already received several infusions of packed cells and plasma by the time you are consulted), you may lose the patient if you just continue with FFP. Assume a very low antithrombin level (20–30%) and give an initial dose of antithrombin accordingly, but always continue with FFP. Do not give heparin when antithrombin concentrate is added to ongoing therapy.

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Avoid transfusions of platelet concentrates – some of the platelets are in poor condition and release vasoactive factors. These may cause the DIC to deteriorate still further. Avoid inhibitors of fibrinolysis, such as tranexamic acid. Such agents will inhibit removal of the disseminated thrombi with subsequent multiorgan damage. Response from Robert L. Janco, MD Wyeth Pharmaceuticals, Collegeville, Pennsylvania, USA Disseminated intravascular coagulopathy represents an acquired dysregulation of haemostasis characterized by the pathologic production and deposition of fibrin with concomitant depletion of coagulant and regulatory proteins as well as platelets. It is a pathologic process, rather than a true disease, that is associated most often with sepsis or septic shock, malignancy, obstetrical complications, massive trauma, toxins or venoms, and immune disorders. Among infections, meningococcal sepsis, gram-negative sepsis, fungaemia, and varicella may be associated with the severe form of DIC referred to as purpura fulminans. There are no universally accepted criteria currently published for the clinical or laboratory diagnosis of DIC; however, most haematologists would suggest that there should be evidence of consumption coagulopathy and fibrinolysis, manifest by low levels of fibrinogen, elevated prothrombin time (PT) and partial thromboplastin time (PTT), low or declining platelet count, and fibrin (ogen) split products or elevated D-dimer levels. Many patients with DIC are also found to have low levels of antithrombin and impairment of the protein C pathway as well. There are new tools emerging such as transmission waveform analysis for biphasic activated partial thromboplastin time (APTT) waveform that may have enhanced sensitivity or specificity for non-overt (subclinical or asymptomatic) DIC. This and other newly devised tests of the haemostatic system may better predict the onset, severity, and ultimately the therapy of DIC; however, such information must come from controlled clinical trials. Management of DIC historically has relied upon the correction of the underlying or inciting event or disorder. Additionally, some patients whose major problem is haemorrhage will benefit from replacement of deficient plasma factors and platelets. Theoretically, and possibly in some patients whose major problem is microvascular

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deposition of fibrin, anticoagulation might interrupt the cycle of fibrin deposition and consumption; however, there are few controlled trials supporting this approach. In contrast, the recent multi-institutional, controlled, double-blind trial by Bernard et al. showed a significant improvement in D-dimer levels, reduced levels of cytokines, and most importantly, survival among adults with sepsis and organ dysfunction in the intensive care unit setting treated with recombinant human activated protein C [1]. While this latter study represents the most recent advance in management of adults with severe sepsis, its applicability to other triggers or clinical settings of DIC remains to be demonstrated. In fact, this study excluded patients with very low platelet counts or who had conditions that increased the risk of bleeding. Indeed, some increase in bleeding was observed during the infusion in those receiving the study drug. However, there are no completed trials supporting this strategy in infants or children. Future approaches for study would include modulation of the tissue-factor pathway with inhibiting pharmacologic substances or tissue pathway factor inhibitor (TFPI). Response from Tom Abshire, MD Emory University School of Medicine, Atlanta, Georgia, USA The key to the treatment of DIC is an understanding that it is a pathologic process of generalized activation of coagulation leading to excessive thrombin production. Usually, the generalized fibrin formation and secondary breakdown of fibrin can lead to depletion of clotting factors, platelets, excessive fibrinolysis and bleeding. But occasionally, fibrin formation and rapid depletion of the natural inhibitors to clotting and inhibition of fibrinolysis can lead to organ dysfunction, purpura fulminans, and clinical thrombosis. There are many causes of DIC, one of which is sepsis. In most cases of sepsis with DIC, the patient presents with thrombocytopaenia. The most useful screening laboratory tests to help guide the diagnosis and treatment of DIC include PT, APTT, fibrinogen, D-dimer, and CBC. It is important to remember, however, that other conditions may modify the screening tests (e.g. inflammation) and that chronic or compensated DIC may have normal screening tests and therefore it may be difficult to render a diagnosis in this situation. Additionally, even though elevated D-dimer is an important laboratory hallmark of DIC, it should not be the only laboratory parameter utilized in the

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diagnosis, as resolving DIC may have a lingering elevated D-dimer due to reabsorption of fibrin degradation products from the extravascular space. Accordingly, no screening test is specific for DIC. Sometimes more sensitive testing includes thrombin activation such as assays for fragment 1.2 and thrombin–antithrombin complexes, low antithrombin or protein C levels, and other assays for consumable clotting factors. Management of DIC should always be directed towards recognition and removal of the underlying cause. If there is a predominant haemorrhage, the screening tests should be utilized for replacement therapy (platelet transfusion for thrombocytopaenia and platelet dysfunction, FFP for increased PT/APTT, cryoprecipitate for decreased fibrinogen, etc.). If there is clinical evidence of large vessel thrombosis or organ dysfunction, then low dose heparin (5–10 U/kg/h) and/or ATIII or protein C concentrates can be utilized, after checking appropriate levels. In the case of anticoagulation therapy with heparin, the risk of further aggravating the bleeding should always be kept in mind. Use of antifibrinolytic therapy (e.g. aminocaproic acid), if used at all, must be used with extreme caution and only when a primary fibrinolytic syndrome such as seen in certain malignancies, including acute promyelocytic leukaemia and prostate cancer. Even then, primary fibrinolysis must be confirmed with tests such as the euglobulin lysis time. An excellent review of DIC can be found in Scott H. Goodnight Jr and William E. Hathaway’s “Disorders of Hemostasis and Thrombosis: A Clinical Guide”, McGraw-Hill, New York, 2001.

Editors’ Note Criteria for the diagnosis of DIC can be found on the website of the International Society of Thrombosis and Hemostasis: http://www.med.unc. edu/isth/welcome and the diagnostic criteria would be under the subcommittee for DIC.

Reference 1 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344(10):699–709.

6 Miscellaneous Questions

Bleeding Time vs. PFA-100, 175 Cocaine and DDAVP, 177 Hyponatraemia and DDAVP, 179 The Use of the INR, 181 Selective Serotonin Reuptake Inhibitors and Clotting Disturbances, 185 Work-up for Children with Intracranial Bleeding, 189

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Bleeding Time vs. PFA-100

Question

Does the bleeding time still have a role in the work-up of patients with bleeding disorders? For work-up of patients with von Willebrand disease (VWD), there is ample evidence that Platelet Function Analyser (PFA-100) closure times are sensitive and are better than the bleeding time. The bleeding time also is exceedingly difficult for young children and infants. Management in many clinical laboratories now consider discontinuing bleeding time tests altogether and using PFA-100 closure times exclusively for the work-up of all bleeding disorders both in children and adults. My questions to the expert panel in the field are: (1) Is the move considered acceptable to the haemostasis community in general? (2) Are there situations where closure times are misleading (i.e. false positive or false negative)? (3) What role does bleeding time still have in the work-up of patients with bleeding disorders?

Response from Jos Vermylen, MD University of Leuven, Leuven, Belgium In contrast to a few years ago, I rarely perform bleeding times in the initial work-up of patients with suspected haemorrhagic problems. As reported by Favaloro, all studies evaluating the PFA-100 against the classic skin bleeding time as a screening assay for detecting VWD concur on the superior sensitivity of the PFA-100 [1]. The PFA-100 uses whole blood flow through a capillary device to create high shear stress, a situation in which von Willebrand factor function is essential for platelet plug formation. Defective adhesion/ aggregation results in prolonged closure times. On the other hand, being a global test system, the PFA-100 is not specific for VWD; patients with thrombasthaenia for instance also have prolonged closure times. Additional tests are required for a final diagnosis. The cartridges contain a membrane coated with collagen and either epinephrine or adenosine diphosphate (ADP). The presence of

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added ADP may mask a storage pool defect. However, the selective prolongation with the collagen/epinephrine membrane usually indicates recent aspirin intake. Some patients exist who are exquisitely sensitive to vessel wall prostacyclin because of Gs hyperfunction [2,3]. Such patients usually have a prolonged bleeding time despite normal platelet aggregation studies in plasma and normal PFA-100 closure times. In conclusion, the PFA-100 has largely replaced the skin bleeding time as initial screening test for disorders of primary haemostasis, but it does have its limitations that need to be recognized. The bleeding time remains essential when a strong suspicion of a primary haemostatic defect persists despite a normal PFA-100.

References 1 Favaloro EJ. Utility of the PFA-100 for assessing bleeding disorders and monitoring therapy: a review of analytical variables, benefits and limitations. Haemophilia 2001;7(2):170–9. 2 Freson K, Hoylaerts MF, Jaeken J, Eyssen M, Arnout J, Vermylen J, et al. Genetic variation of the extra-large stimulatory G protein alpha-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding. Thromb Haemost 2001;86(3):733–8. 3 Freson K, Jaeken J, Van Helvoirt M, de Zegher F, Wittevrongel C, Thys C, et al. Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 2003;12(10):1121–30.

Cocaine and DDAVP

Question

How long after cocaine use can desmopressin (DDAVP) be given?

Case

There is a young female patient with type 1 von Willebrand disease (VWD) who unfortunately uses cocaine. We understand that cocaine use can be associated with acute myocardial infarction (MI) particularly in the first 60 min after use, presumably due to vasospasm as an acute adverse effect. DDAVP has been reported to be associated with MI in some elderly individuals with atherosclerotic heart disease. Putting aside that chronic cocaine use can increase atherosclerosis, how long after acute cocaine use can DDAVP be safely given in a young person – or should DDAVP not be used at all in cocaine users? Obviously, we have discouraged the patient from using cocaine, but unfortunately, our advice may not be followed.

Response from Barbara A. Konkle, MD University of Pennsylvania, Philadelphia, Pennsylvania, USA Cocaine use increases the risk of myocardial ischaemia and infarction [1,2]. This is thought to be due to a combination of: (1) increased myocardial oxygen demand in the setting of a limited or fixed oxygen supply, (2) marked coronary arterial vasoconstriction, and (3) enhanced platelet aggregation. The major risk is early after cocaine use due to its short half-life. The risk of MI is increased 24-fold in the first 60 min after use in subjects considered at low risk for infarction. However, effects have been reported as late as 5–15 h after use, possibly due to the effects of cocaine metabolites. Since DDAVP may increase the risk of MI, it would seem prudent to delay its use at least until 15 h after cocaine use. A good reference on VWD can be found in Blood [3].

References 1 Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE. Triggering of myocardial infarction by cocaine. Circulation 1999;99(21):2737–41.

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2 Brogan III WC, Lange RA, Glamann DB, Hillis LD. Recurrent coronary vasoconstriction caused by intranasal cocaine: possible role for metabolites. Ann Intern Med 1992;116(7):556–61. 3 Mannucci PM. How I treat patients with von Willebrand disease. Blood 2001; 97(7):1915–19.

Hyponatraemia and DDAVP

Question/ Case

It is well known that young children are at risk of hyponatraemia following deamino-D-arginine vasopressin (DDAVP/ desmopressin) treatment. Recently, I treated two older patients who developed hyponatraemia and concomitant symptoms after DDAVP. Both patients were female haemophilia A carriers with a history of postoperative haemorrhage. The first, who underwent haemorroidectomy, was given 0.3 µg/kg DDAVP intraoperatively and discharged soon after. She then received 0.3 µg/kg every 12 h for 6 doses as an outpatient. After 5 doses, the patient developed nausea and headache and presented to the emergency clinic. No further DDAVP was given. She was given 1 l saline intravenously and discharged. Twenty-four hours later, she returned to the hospital and was admitted when her serum sodium was measured at 126 and 123 mmol/l. A gradual recovery was achieved by fluid restriction and bed rest. Her routine medications included an angiotensin-converting enzyme (ACE) inhibitor. The second patient underwent a partial colectomy for stage I carcinoma of the colon and was given a similar regimen in hospital. After 4 doses, she became drowsy and breathless and was admitted to the critical care unit. The patient was diagnosed with acute pulmonary oedema, secondary to hypertensive cardiomyopathy. She made a gradual recovery with standard care but her serum sodium dropped to 132 mmol/l. She had received 1.5 l crystalloid intravenously and was in positive fluid balance. She also was on an ACE inhibitor for hypertension. Although, in this case, other factors appear to be involved, the DDAVP clearly added to the problem. Are these severe reactions more frequent than I have previously been aware? Are the elderly more at risk? Are either ACE inhibitors or non-steroidal anti-inflammatory likely to increase risk?

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Response from Louis M. Aledort, MD Mt Sinai School of Medicine, New York, USA Hyponatraemia is an omnipresent threat for adults and the elderly who receive DDAVP. This varies from patient to patient, especially when DDAVP is administered more than once a day. Fluid restriction is critical and water diuresis is more important than sodium replacement. Whether it is for inpatients or outpatients, I insist on the monitoring of sodium every other day and discontinue DDAVP when their levels fall below 130 mmol/l. Yes, adverse reactions occur commonly enough to require regular monitoring. Response from Erik Berntorp, MD, PhD Lund University, Malmo, Sweden Serious side effects of DDAVP are very uncommon. If desmopressin is avoided in small children (2 years) and in patients with congestive heart failure, this drug can be considered very safe. However, it has been shown from our centre that repeated doses (4) at 12-h intervals have a tendency to decrease serum sodium [1]. The authors recommend restrictions in fluid intake after repeated doses. The cases described are probably very rare and special medical circumstances may prevail. They also received several doses of desmopressin, even if the number of doses was by no means excessive. The cases obviously demonstrate that one should be careful in treating patients repeatedly at 12-h intervals or shorter. In many cases, 1 or 2 doses of desmopressin should be enough, at least when combined with tranexamic acid, a treatment that can be extended to about a week. Another option is to prolong dose intervals.

Reference 1 Lethagen S, Frick K, Sterner G. Antidiuretic effect of desmopressin given in hemostatic dosages to healthy volunteers. Am J Hematol 1998;57(2):153–9.

The Use of the INR

Question

We have been using the international normalized ratio (INR) exclusively for patients on that is warfarin/coumadin. However, it seems that many are using the INR value to assess patients who are not on coumadin. Is this an appropriate use of the INR?

Response from B. Gail Macik, MD University of Virginia, Charlottesville, Virginia, USA The INR was developed and standardized for patients on vitamin K antagonists (VKA) and all studies were done in this population. Therefore, strictly speaking evidence-based research only supports use of the INR for patients on warfarin or like drugs. The INR standardizes prothrombin time (PT) measurement based upon characteristics of the thromboplastin reagent used in the laboratory. This helps to eliminate variability between measurements in which different thromboplastin reagents are used and assure a stable level of anticoagulation. Increasingly, the INR has become the unofficial unit of reporting for all PTs with some laboratories no longer reporting the result in seconds, irrespective of whether the patient is on a VKA. However, use of the INR may not be directly applicable to patients with liver disease. In contrast to its use in patients on VKA, the INR may not be the best expression of coagulation derangement in patients with liver failure, unless the same thromboplastin reagent is consistently used for measurement. Furthermore, comparison of the degree of synthetic dysfunction using the INR in patients who underwent testing at centres using different thromboplastin reagents may not be valid. This may be particularly relevant when prioritizing patients for liver transplantation. An INR of 1.8 for a patient on a VKA does not necessarily convey the same information regarding haemostatic potential as an INR of 1.8 in a liver disease patient. Finally, patients with deficiencies of factor VII, X, V, prothrombin, or fibrinogen will have prolonged PTs but primary deficiencies of these factors are rare. The effect on the INR may not be the same for

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single factor deficiencies as for the combined deficiencies seen with VKA; therefore, the INR should not be used to assess haemostatic potential in these patients. In conclusion, the INR is only validated for use in monitoring anticoagulation with VKA. Within a single institution, the INR may be used as a sequential measure of improvement or worsening of liver synthetic function if the thromboplastin and the method of testing remain the same. The INR is not a valid standard of measure for single clotting factor. Response from Sam Schulman, MD Hamilton Health Sciences – General Hospital, Hamilton, Ontario, Canada It is true that the INR system is intended for use in patients on anticoagulant therapy with VKA. Thus, it is not calibrated for and may not have the same reproducibility for either the initiation phase of anticoagulation or for pure liver function. However, in my experience from several years of using the INR in Sweden for evaluating patients with hepatitis C, it seemed quite possible to use it for that purpose as well as part of the assessment of liver function and staging for the need of transplantation. Response from Ton Lisman, PhD and Philip G. de Groot, PhD University Medical Center, Utrecht, The Netherlands One important aspect of the interpretation of the INR is rarely mentioned in the literature. Two different methodologies are used to measure the INR. The Quick assay is the most widely used, whereas the Owren assay is used almost exclusively in northern Europe (specifically the Nordic countries and the Benelux) and in Japan. The Quick assay is performed using a 33% volume of test plasma in the final reaction mixture and is sensitive for factors VII, X, V, prothrombin, and fibrinogen. The Owren assay is performed in diluted plasma (5% volume of test plasma in the final reaction mixture), and the Owren reagent contains fibrinogen and factor V, often derived from absorbed bovine plasma. The Owren assay is thus only sensitive for factors VII, X, and prothrombin and is less sensitive for pre-analytical factors such as sample citrate concentration compared to the Quick assay. Thus, despite the fact that the INR was developed to enable comparison of

The Use of the INR 183

PT values of patients receiving oral anticoagulation, satisfactory harmonization of INR values between different laboratories has not yet been reached. Although we generally discourage the use of the INR to assess patients who are not taking anticoagulants, the use of the INR using the Owren assay for patients not on oral anticoagulants is especially discouraged. The Owren assay performed in patients not on oral anticoagulants can give false negative results as a result of the supplementation of fibrinogen and factor V. Although deficiencies or inhibitors of fibrinogen and factor V are rare, it is advisable to screen all patients who require a measurement of the PT for reasons different from the monitoring of anticoagulant therapy with reagents devised to measure a PT, and not with reagents manufactured for determination of the INR. Finally, as a remark to Dr Macik’s comment on the use of the INR in liver disease patients, we feel that it is fair to say that an INR of 1.8 in a patient on oral anticoagulants conveys almost per definition different information on the haemostatic potential as an INR of 1.8 in a liver disease patient. In a patient taking oral anticoagulants, low levels of the vitamin-K-dependent factors and normal levels of all other haemostatic proteins are present. In a liver disease patient, there are low levels of FV and the intrinsic factors (except factor VIII), low levels of the non-vitamin-K-dependent anticoagulants (such as antithrombin), and complex disturbances of primary haemostasis and the fibrinolytic system. This leads to a different disturbance in the haemostatic balance and requires a different interpretation of a PT or an INR. Moreover, as the PT or the INR is insensitive for the anticoagulants, and does not measure the intrinsic system, the translation of a PT or an INR in a liver disease patient to the in vivo haemostatic potential is not justified, whereas this generally is the case in patients taking oral anticoagulants.

Selective Serotonin Reuptake Inhibitors and Clotting Disturbances

Question

I would like to ask the panel the following question. Prozac and other selective serotonin reuptake inhibitors (SSRIs) use is becoming increasingly utilized for the management of affective disorders in Western society. Is the panel aware of any significant clotting disturbances with their use?

Response from Craig Kessler, MD Georgetown University Medical Center, Washington, DC, USA SSRIs have become a common and an effective first-line treatment modality for depressive illnesses, anxiety, and obsessive–compulsive disorders since they have demonstrated a favourable risk-to-benefit ratio and side-effect profile. As suggested by their class designation, their antidepressant effect is derived from their ability to selectively inhibit neuronal reuptake of serotonin (5-hydroxytryptamine, 5-HT). An occasional adverse haematologic effect of this class of medication is easy bruising, associated at times in the literature with prolonged prothrombin times, partial thromboplastin times, and bleeding times. The aetiology of the platelet function abnormalities also has been attributed to the prevention by these agents of serotonin-induced amplification of platelet aggregation by virtue of their observed in vitro blockade of 5-HT uptake in the platelets. This leads to reduced or depleted serotonin stores in the dense bodies of platelets, thereby producing a “spent platelet” thrombocytopathy. Thus, there is a theoretical possibility that bleeding symptoms could increase the bleeding tendency of patients using SSRIs. Alderman et al. examined the effects of SSRIs on platelet aggregation in patients at baseline, 2, and 4 weeks after the initiation of treatment with an SSRI (fluoxetine or paroxetine) [1]. No abnormalities in platelet aggregation or coagulation were noted and no patient developed clinical signs of abnormal haemostasis. This suggests that although the SSRIs may cause abnormal haemostasis, this is probably rare and may be more likely to occur when high doses of SSRIs are administered.

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Similarly, the in vitro effects of escalating concentrations of another SSRI, sertraline, and its major inactive liver metabolite were assessed on human platelet function [2]. These agents produced a dosedependent inhibition of platelet-rich plasma and whole blood platelet aggregation induced by adenosine diphosphate (ADP) (P 0.002), collagen (P 0.008), and thrombin (P 0.026). Surface expression of major surface receptors with flow cytometry revealed reduced expression of CD9 (P 0.004), GP Ib (P 0.0001), GP IIb/IIIa (P 0.007), VLA-2 (P 0.01), P-selectin (P 0.02), and PECAM-1 (P 0.01), but not the vitronectin receptor. Closure times in the PFA-100 were delayed for the collagen-ADP cartridge (P 0.009) and for the collagen-epinephrine cartridge (P 0.01), indicating platelet inhibition in whole blood under high shear conditions. Also to be considered when SSRIs are used in combination with warfarin is the influence of SSRIs on the cytochrome-P450 system and the metabolism of that oral anticoagulant and the ability of the SSRIs to displace warfarin from circulating plasma proteins. These effects will produce changes in the plasma concentration of warfarin and potentiate anticoagulant effects, potentially leading to clinical bleeding. SSRIs and newer generation antidepressants and antipsychotics, such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and amisulpride, are extensively metabolized in the liver by cytochrome-P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with warfarin or other medications that also interact with warfarin. These new antidepressants differ in their potential for metabolic drug interactions [3]. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. Sertraline, citalopram, venlafaxine, mirtazapine, and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. These interactions should be applied when prescribing these medications for individuals on warfarin. In the future, pharmacogenomics, particularly involving the gene polymorphisms within the serotonin transporter and cytochrome-P450 drug-metabolizing enzymes, may be a useful tool to individualize therapy with SSRIs and/or warfarin [4]. In spite of these theoretical and potentially important effects of the SSRIs on haemostasis, it is surprising how uncommonly any clinically significant bleeding events are reported in the literature. One retrospective analysis of 30 patients on SSRIs described bruising, haematoma,

Selective Serotonin Reuptake Inhibitors and Clotting Disturbances 187

petechiae or purpura, epistaxis, and rarely intestinal haemorrhage, ocular bleeding, or cerebral haemorrhage [5]. Symptoms were sometimes associated with prolonged bleeding time and platelet aggregation disorders. These usually resolved within 2 days to 4 months after treatment discontinuation. Nevertheless, it is prudent for the patient who is using antiplatelet medications or anticoagulants to be aware of these possible problems and for the prescribing physician to consider the impact of these drug interactions. Finally, an interesting twist on the theme of antiplatelet effects of the SSRIs deals with the hypothesis that the depleted platelet may delay or prevent the progression of atherosclerosis and coronary artery disease. Unfortunately, clinical studies of patients on SSRIs do not confirm that this benefit exists despite in vitro evidence of platelet dysfunction. There have been several reports that SSRIs might increase bleeding tendency in some patients by affecting platelet function. However, to our knowledge, there have been no reports about their relation to thrombosis. In a brief report, we present a case of venous thromboembolism associated with escitalopram in a patient with psychotic depression without any major risk factors for thrombosis. SSRIs might have a dual effect on platelet function [6]. The immediate and early effect of SSRI use on platelets might be an increase in tendency for thrombosis, whereas the late effect after repeated dosing might be an increase in tendency to bleed. Response from Gili Kenet, MD The National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel With regard to the discussion topic of SSRI and coagulation, I would like to provide some further information together with a viewpoint of a pediatric haematologist. Many neonatology specialists are currently concerned about the potential impact of maternal SSRI, given during pregnancy, upon neonatal platelet function and the potential risk of bleeding in such neonates. This issue was recently approached by a single-centre study comparing platelet function, as tested by the cone-and-platelet analyser (CPA), in neonates born to mothers treated with SSRI and their mothers as compared to non-treated controls. In our study, 27 SSRIexposed full-term neonates and their 23 mothers were compared to 27 controls. No correlation was found between SSRI exposure among

188 Miscellaneous Questions

either neonates or mothers and parameters of surface coverage (SC) and average size (AS), manifesting platelet function as tested by CPA. SC was similar among SSRI-exposed babies as compared to those in the control group, whereas the size of platelet aggregates (AS) was higher among controls. Neither maternal diseases nor SSRI intake was associated with impaired platelet function and lower SC values, nor were any perinatal conditions. None of the babies suffered bleeding. This study shows that maternal SSRI therapy does not impair whole blood CPA-tested platelet function of healthy full-term neonates [7].

References 1 Alderman CP, Seshadri P, Ben-Tovim DI. Effects of serotonin reuptake inhibitors on hemostasis. Ann Pharmacother 1996;30(11):1232–4. 2 Serebruany VL, Gurbel PA, O’Connor CM. Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharmacol Res 2001;43(5):453–62. 3 Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol 2003;17(5):517–38. 4 Mancama D, Kerwin RW. Role of pharmacogenomics in individualising treatment with SSRIs. CNS Drugs 2003;17(3):143–51. 5 Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, et al. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature. Rev Med Interne 2000;21(2):152–60. 6 Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57(4):507–33. 7 Maayan-Metzger A, Kuint J, Lubetsky A, Shenkman B, Mazkereth R, Kenet G. Maternal selective serotonin reuptake inhibitor intake does not seem to affect neonatal platelet function tests. Acta Haematol 2006;115(3–4):157–61.

Work-up for Children with Intracranial Bleeding

Question

What does the panel feel would be an appropriate work-up for battered children with evidence of intracranial bleeding? Our current protocol would divide patients into two groups: those with personal or family history of bleeding and those without. For those without a history of bleeding, we obtain prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, thrombin time (TT), and a complete blood count. For those with a suggestive history we add a von Willebrand profile, plasminogen activator inhibitor type 1, antiplasmin and factor XIII levels, and platelet function assay (platelet aggregation if the patient is anaemic). Are there any other suggestions?

Response from Edward Tuddenham, MD Royal Free Hospital, London, UK It is quite possible for a child with a coagulopathy to be battered. Personally, I would do a very full work-up on all such children since, inevitably, the defence in any subsequent litigation will bring up the possibility of an underlying coagulopathy. Of course, one also needs to know from the point of view of future management. I think that a PT and an APTT are quite inadequate to rule out mild haemophilia. Response from Roshni Kulkarni, MD Centers for Disease Control and Prevention, Atlanta, Georgia; and Michigan State University, East Lansing, Michigan, USA The work-up for paediatric abusive head trauma suggested by Dr Dunn appears adequate, although I would like to add some recommendations and make some comments.

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In all cases of child abuse, to avoid repeated needle punctures, we recommend obtaining an extra tube of citrated plasma at the time of initial screening tests. The plasma can be frozen in several aliquots for future testing. Although a family history of bleeding is important in considering congenital coagulation disorders, it may be absent in 30% of patients with sporadic haemophilia. Furthermore, mild haemophilia patients with coagulation factor levels of ~30% may have normal screening tests and yet be at risk for bleeding. Hence, it may be important to consider factor VIII and IX assays in male children with intracranial haemorrhage (ICH) such that appropriate and timely treatment with factor concentrates can be instituted. Rare bleeding disorders (factors X, VII, II, V, and fibrinogen deficiencies) can also present with ICH. In a recent report from Europe, of 102 patients with factor X deficiency, ICH was noted in 21% of 42 symptomatic patients [1]. Coagulopathy, often secondary to parenchymal brain damage, can occur in abusive head trauma in children. Disseminated intravascular coagulation has been reported in 22.2% of children with severe head injury [2]. Hymel et al. reported mild PT and APTT prolongation in 54% and 24% of child abuse patients (n 101), respectively, with parenchymal brain damage [3]. In children with head trauma but without parenchymal brain damage (n 46), 20% had a prolonged PT and 27% had a prolonged APTT. Factor assays were not reported in these patients. Another cause of coagulopathy in infants is late vitamin-K-deficiency bleeding that manifests between 2 and 6 months of age and may be mistaken for child abuse [4]. We recommend that any abnormal tests in paediatric abusive trauma be repeated in 3–6 months to confirm an inherited bleeding disorder. Finally, patients with inherited disorders of coagulation can also be victims of child abuse. Therefore, any suspicious bruising in such patients should be assessed thoroughly.

References 1 Herrmann FH, Auerswald G, Ruiz-Saez A, Navarrete M, Pollmann H, Lopaciuk S, et al. Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene. Haemophilia 2006;12(5): 479–89. 2 Chiaretti A, Pezzotti P, Mestrovic J, Piastra M, Polidori G, Storti S, et al. The influence of hemocoagulative disorders on the outcome of children with head injury. Pediatr Neurosurg 2001;34(3):131–7.

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3 Hymel KP, Abshire TC, Luckey DW, Jenny C. Coagulopathy in pediatric abusive head trauma. Pediatrics 1997;99(3):371–5. 4 Vora A, Makris M. Personal practice: an approach to investigation of easy bruising. Arch Dis Child 2001;84(6):488–91.

7 Thrombotic Disorders

Are Asians Genetically Different from Westerners When it Comes to VTE?, 195 Treatment of Antithrombin Deficiency, 201 Anticardiolipin Antibody Questions, 203 Paediatric Antiphospholipid Syndrome and Recurrent Thrombosis, 205 Anticoagulation for Deep Venous Thrombosis in the Presence of an Intracranial Haemorrhage, 209 Clinical Probability Assessment for Thromboembolic Disease, 213 D-dimer

in Thromboembolic Disease, 215

Progestins and Thrombosis, 217 Unknown Thrombophilia and Surgery, 221

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Are Asians Genetically Different from Westerners When it Comes to VTE?

Question

Are Asians genetically different from Westerners when it comes to venous thromboembolism (VTE)?

Response from Pantep Angchaisuksiri, MD Ramathibodi Hospital, Bangkok, Thailand VTE is a multifactorial disease with a number of genetic and environmental risk factors. It is suggested that the incidence of VTE is lower in Asians than in Westerners partly because of genetic differences between the two populations. The major heritable risk factors for thrombophilia are factor V Leiden, prothrombin gene mutation; and deficiencies in protein C, protein S, and antithrombin. The presence of one or more of these factors will result in predisposition to venous thrombosis. Asian literature shows contrasting evidence for the prevalence of genetic thrombophilic risk factors in the Asian population. Several studies have shown a low prevalence of factor V Leiden and prothrombin G20210A mutation, particularly in Chinese, Japanese, and Thai populations [1–9]. Studies in Thailand, Taiwan, and Japan have suggested that the prevalence of protein C, protein S, and antithrombin deficiencies is 26–34% in patients with VTE, which is higher than in Western countries, but there were no patients with factor V Leiden [10–12].

Factor V Leiden Factor V Leiden has been found to be the most common cause of familial venous thrombosis in the European population. Factor V Leiden is a single point mutation at position 1691 in the factor V gene and is the major cause of “activated protein C resistance” (APCR). Substitution of guanine with adenine results in the loss of one of three APC-cleavage sites and prevents the inactivation of factor V by activated protein C.

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The frequency of factor V Leiden is around 5% in Europeans, but is very rare in other ethnic groups. In a study of world distribution of factor V Leiden, the allele was not present in any of the 1600 chromosomes examined from Southeast Asia, Australasia, Africa, or the Americas [13]. In India the prevalence of factor V Leiden was 1.3%. Epidemiological studies suggest that the factor V Leiden mutation may have originated in central European Caucasians and spread over the world by migration [14].

Prothrombin Gene Mutation Replacement of guanine by adenine at position 20210 of the prothrombin gene is also a common independent risk factor for thrombosis. The mechanism by which the mutation increases the risk of thrombosis is not fully understood, but it has been shown that there is an increase in plasma levels of prothrombin. The G20210A prothrombin gene mutation has also been reported to be common among Caucasians, but rare among Asians [1,2,5–9].

Protein C, Protein S, and Antithrombin It is well established that deficiencies of protein C, protein S, and antithrombin are involved with an increased risk of VTE. Homozygous protein C or S deficiency is extremely rare but can cause purpura fulminans or severe thrombosis in the neonatal period. Tables 7.1 and 7.2 show the frequency of inherited thrombophilias among healthy subjects and among unselected patients with VTE, respectively. The presence of more than one heritable risk factor will further increase the likelihood of developing thrombosis. Use of oral contraceptives and pregnancy will also contribute to a significant increase in the relative risk of VTE in patients with heritable thrombophilia. It is evident that factor V Leiden and prothrombin gene mutation are most common in Caucasians, while protein C, protein S, and antithrombin deficiencies are more common in Asian patients with VTE. Moreover, factor V Cambridge, another mutation associated with resistance to activated protein C, has only been found in Caucasians whereas factor V Hong Kong is more common in Asians [18].

Are Asians Genetically Different from Westerners When it Comes to VTE?

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Table 7.1 Frequency of inherited thrombophilias among healthy subjects.

Inherited thrombophilia

Prevalence in Caucasians (%) [15]

Prevalence in Thais (%) [1]

Prevalence in Chinese (%) [5–7,9,16]

Prevalence in Japanese (%) [4,8,12]

Factor V Leiden Prothrombin G20210A Antithrombin deficiency Protein C deficiency Protein S deficiency

4.8 2.7 0.02 0.2–0.4 0.03–0.13

0.2 0.2 No data No data No data

0 0 2.26 1.06 1.2

0 0 0 0.5 2.02

Table 7.2 Frequency of inherited thrombophilias among unselected patients with VTE.

Inherited Prevalence Prevalence thrombophilia in Western in Thai patients patients with VTE with VTE (%) [15] (%) [10]

Factor V Leiden Prothrombin G20210A Antithrombin deficiency Protein C deficiency Protein S deficiency

18.8 7.1

Prevalence in Chinese patients with VTE (%) [5,7,9,11]

Prevalence in Japanese patients with VTE (%) [4,8,12]

Prevalence in Indian patients with VTE (%) [17]

0 0

0 0

0 0

3 0

1.9

4.7

7.1

1.8

2.6

2.3

8.9

10.7

8.0

9.5

3.7

12.3

10.7

17.8

6.5

References 1 Angchaisuksiri P, Pingsuthiwong S, Aryuchai K, Busabaratana M, Sura T, Atichartakarn V, et al. Prevalence of the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A prothrombin gene mutation in the Thai population. Am J Hematol 2000;65(2):119–22. 2 Lu Y, Zhao Y, Liu G, Wang X, Liu Z, Chen B, et al. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res 2002;106(1):7–12. 3 Ho CH, Chau WK, Hsu HC, Gau JP, Chih CM. Prevalence of factor V Leiden in the Chinese population. Zhonghua Yi Xue Za Zhi (Taipei) 1999;62(12):875–8.

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4 Takamiya O, Ishida F, Kodaira H, Kitano K. APC-resistance and Mnl I genotype (Gln 506) of coagulation factor V are rare in Japanese population. Thromb Haemost 1995;74(3):996. 5 Bai C, Pan J, Li X. Factor V Leiden and PTG20210A gene mutation in patients with venous thrombosis and healthy blood donors. Zhonghua Yi Xue Za Zhi 1999;79(12):900–2. 6 Ho CH. Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol 2000;79(5):239–42. 7 Jun ZJ, Ping T, Lei Y, Li L, Ming SY, Jing W. Prevalence of factor V Leiden and prothrombin G20210A mutations in Chinese patients with deep venous thrombosis and pulmonary embolism. Clin Lab Haematol 2006;28(2):111–16. 8 Miyata T, Kawasaki T, Fujimura H, Uchida K, Tsushima M, Kato H. The prothrombin gene G20210A mutation is not found among Japanese patients with deep vein thrombosis and healthy individuals. Blood Coagul Fibrinolysis 1998;9(5):451–2. 9 Lin JS, Shen MC, Tsay W. The mutation at position 20210 in the 3’-untranslated region of the prothrombin gene is extremely rare in Taiwanese Chinese patients with venous thrombophilia. Thromb Haemost 1998;80(2):343. 10 Angchaisuksiri P, Atichartakarn V, Aryuchai K, Atamasirikul K, Archararit N, Rachakom B, et al. Risk factors of Thai patients with venous thromboembolism. Thromb Haemost 2001; July (Suppl) (Abstract P1535). 11 Chen TY, Su WC, Tsao CJ. Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis. Ann Hematol 2003;82(2):114–17. 12 Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis 2001;12(2):95–9. 13 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346(8983):1133–4. 14 Herrmann FH, Koesling M, Schroder W, Altman R, Jimenez Bonilla R, Lopaciuk S, et al. Prevalence of factor V Leiden mutation in various populations. Genet Epidemiol 1997;14(4):403–11. 15 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344(16):1222–31. 16 Zhao Y, Zhu T, Hua B, Yang R, Wang X, Wang H, et al. Distribution of antithrombin, protein C and protein S activities and prevalence of their deficiencies in the general Chinese healthy population. Abstract Book: The 4th Asian-Pacific Congress on Thrombosis and Hemostasis, 2006, p. 17. 17 Ghosh K, Shetty S, Madkaikar M, Pawar A, Nair S, Khare A, et al. Venous thromboembolism in young patients from western India: a study. Clin Appl Thromb Hemost 2001;7(2):158–65.

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18 Angchaisuksiri P, Inkaew B, Busabaratana M, Aryuchai K, Sura T, Atichartakarn V. The factor V R2 allele (A4070G), factor V gene G1628A mutation, factor V Hong Kong (A1090G), factor V Cambridge (G1091C), the tissue factor pathway inhibitor gene C536T mutation and the risk of venous thrombosis in Thai patients. Thromb Haemost 2003; July (Suppl) (Abstract P0366).

Treatment of Antithrombin Deficiency

Question

I am looking for any comments or suggestions on treatment of a newborn with antithrombin deficiency. How long do you treat with the antithrombin concentrates? How relevant are the levels obtained during treatment?

Case

This is an infant who presented at 7 days of age with a sinus vein thrombosis resulting in a subdural and parietal haemorrhage. The mother has an antithrombin deficiency with levels at 50%. The infant was tested at onset of symptoms and had a level of 40%, partially due to an immature level. The infant is currently in the paediatric intensive care unit, receiving antithrombin infusions and supportive therapy, to which he is responding.

Response from Jørgen Ingerslev, MD University Hospital Skejby, Aarhus, Denmark In our centre, we have experienced two difficult complications related to antithrombin deficiency in newborns, both of whom developed dangerous venous thrombosis in the early neonatal period. Each of these unrelated cases had a parent with a known symptomatic antithrombin deficiency. In case 1, antithrombin deficiency was known in the mother and she had been on permanent warfarin treatment for some time. During pregnancy, her thromboprophylactic regimen of warfarin was shifted to low-molecular-weight heparin and we arranged for antithrombin substitution from the time of ongoing labour until day 8 postpartum. The baby developed severe venous deep vein thromboembolism of both legs immediately after birth. In case 2, antithrombin deficiency was known in the father as well as in other members of his family. A thorough programme was constructed for early detection of antithrombin deficiency in the baby as well as concise advice for treatment, should the child demonstrate biochemical signs of antithrombin deficiency. Unfortunately, the parents

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were lost to follow-up and the parents subsequently brought back a severely sickened child to the hospital. Apart from general malaise, there was haematuria. The inferior vena cava was obstructed by masses of thrombi that also were found in both renal veins. Using recombinant tissue plasminogen activator dissolution of the renal vein obstruction was accomplished and renal function was preserved. Both cases 1 and 2 suffer chronic postphlebitic syndrome. We have no clear evidence concerning the optimal timing and duration of antithrombin therapy in newborns with antithrombin deficiency. In subsequent cases of newborns with antithrombin deficiency, we selected a dose of antithrombin at 50 IU/kg (birth weight) immediately after birth and until day 8 postpartum. The same programme is utilized for mothers with antithrombin deficiency. Antithrombin levels should be monitored peripartum.

Anticardiolipin Antibody Questions

Question/ Case

We have a young female patient who had a transient ischaemic attack (TIA) last year, with involvement of her visual field. Her laboratory results revealed a positive test for anticardiolipin IgG antibody. The patient has now completed a 1-year course of anticoagulant therapy with warfarin. Currently, she is asymptomatic. Does she need to remain on warfarin and, if so, for how long?

Response from Jeffrey I. Weitz, MD Henderson General Hospital, Hamilton, Ontario, Canada Before we can answer this question, we need more information. First, I assume that there was no evidence that the TIA represented a cardioembolic event. This is important because recurrent cardioembolic events are best prevented with warfarin. Second, we need to know whether the patient has any evidence of an underlying connective tissue disease. In addition, it would be useful to repeat the anticardiolipin antibody test and look for a nonspecific inhibitor of coagulation. This information will help us determine whether this patient has primary or secondary antiphospholipid antibody syndrome. Symptoms suggestive of a connective tissue disease or evidence of a nonspecific inhibitor would point towards secondary antiphospholipid syndrome. In this case, long-term warfarin therapy with a target international normalized ratio (INR) of 2–3 may be the best choice. On the other hand, if this patient has primary antiphospholipid antibody syndrome or if the anticardiolipin antibody test is now negative, I would recommend stopping the warfarin and starting the patient on aspirin at a dose of 325 mg daily. This approach is supported by the results of the recent Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study involving 1770 patients enrolled in the larger Warfarin versus Aspirin for Recurrent Stroke Study (WARSS) that randomized 2206 patients with ischaemic stroke to treatment with warfarin (target INR of 1.4–2.8) or aspirin (325 mg/day) [1]. Patients in APASS

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were those who underwent anticardiolipin antibody testing within 90 days of the index event. Of the 1770 patients, 41% had a positive test. The incidence of the primary endpoint, a composite of death, ischaemic stroke, transient ischaemic attack, myocardial infarction, venous thromboembolism, or other systemic thromboembolic event at 2 years, was similar in those with or without a positive anticardiolipin antibody test at baseline, both in patients treated with warfarin and in those given aspirin. Thus, the overall event rate was 22.2% in the anticardiolipin antibody positive group and 21.8% in those who had a negative anticardiolipin antibody test. Based on these results, the presence of a positive anticardiolipin antibody test at baseline in a patient presenting with ischaemic stroke does not predict (a) an increased risk of recurrent vascular occlusive events or (b) a differential response to warfarin vs. aspirin. These findings argue against routine screening for anticardiolipin antibodies in patients presenting with an ischaemic stroke or TIA. The data also suggest that aspirin is a better choice for prevention of recurrence in these patients because the risk of bleeding is lower with aspirin than it is with warfarin.

Reference 1 Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. Jr Am Med Assoc 2004;291(5):576–84.

Paediatric Antiphospholipid Syndrome and Recurrent Thrombosis

Question

What do we know about antiphospholipid syndrome (APS) and its presentation in the paediatric population?

Response from Gili Kenet, MD The National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel APS is a multisystem autoimmune disease, characterized by arterial and venous thromboses; recurrent foetal loss; and persistent circulating antiphospholipid antibodies (APLA), such as lupus anticoagulant (LAC) and anticardiolipin (ACL) antibodies. This syndrome can be either primary or secondary to other autoimmune disease, mainly systemic lupus erythematosus (SLE) [1,2]. Whereas APS in adults has been well characterized, only a few studies, mostly case reports, describe children with this syndrome [3–6]. Paediatric primary APS is very rare, and disease onset occurs before the age of 15 years in only 2.8% of patients from the largest APS cohort [7]. There are very limited data on the influence of age, the prevalence of various clinical manifestations, and the outcome of paediatric APS [4]. The preliminary classification criteria for definite APS require at least one of the laboratory and two of the clinical criteria for actual diagnosis [8]. Of the multiple criteria, obstetric morbidity is generally not applicable in children, and vascular thrombosis is also less common. Nevertheless, the same criteria are used for classification of paediatric APS without validation in children [3]. Recently, a multicentre cohort study of primary APS in paediatric patients was completed in Israel [9]. The Israeli cohort consisted of 28 children (17/28 were females), presenting at a mean age of 11.0 5.8 years. Two patients presented with thrombosis during SLE onset. LAC was detected in 96% of children tested, elevated ACL antibodies in 72%, and anti-β2gp1 in 75%. During the follow-up period of 6.0 4.9 years, CNS involvement appeared in 6 and haematological involvement in 4 children. SLE developed in 3 more females.

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Vascular thromboembolism is the major clinical manifestation of APS; it commonly recurs with significant effects in morbidity [10]. Seven of 22 patients with vascular thrombotic events (venous 13 and arterial 9) had recurrences, all occurring at the same type of blood vessel (either venous or arterial). Recurrence rates were higher in patients with venous thrombosis (5/13, namely 38.5%) as compared to arterial thrombosis (n 2, 18.2%). In general, patients with arterial events were younger, had more CNS manifestations, and less thromboembolic recurrences. Anticoagulants were administered to 14 patients following the initial thrombotic event.

Hereditary thrombophilic defects and paediatric APS Thrombophilic risk factors (apart from APLA) were observed in 10/22 patients with thrombosis in our cohort. Interestingly, hereditary thrombophilia was detected in higher rates (54%) of children with a single episode as compared to only 29% of those with recurrences. This finding stems from the fact that children with APS and other thrombophilic risk factors (including children with combined hereditary thrombophilia) received prolonged anticoagulant therapy after their initial thrombotic manifestation. In a cohort study of 144 patients with SLE-associated deficiencies of antithrombin, protein C, protein S, Factor V Leiden (FVL), prothrombin gene mutation 20210A, and APC resistance, risk of arterial thromboembolism was not affected by a single deficiency or by a deficiency combined with LAC and/or ACLs. On the other hand, FVL and prothrombin gene mutation 20210A were associated with an increased risk of venous thromboembolism (3.5-fold higher than in patients without these mutations) [11]. Other studies showed that FVL is an independent risk factor accounting for a 2.5-fold increased risk for thrombosis in patients with SLE [12,13]. In children with hereditary thrombophilic risk factors, the occurrence of thrombosis is often triggered by a “second hit”. Acquired prothrombotic risk factors common in adults such as smoking, oral contraceptives, and atherosclerotic vascular disease are usually absent in children. Since ACL and LAC may serve as a “second hit” in children with hereditary thrombophilic risk factors, children with APS may benefit from a thorough thrombophilia workup. The presence of inherited thrombophilia may identify the subset of APS patients at highest risk for recurrent thrombosis, and affect intensity and duration of anticoagulant therapy.

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207

Recurrent thrombosis and paediatric APS Campos et al. found a recurrence of 37.5% with a mean interval of 13 months between the events in his small series of secondary paediatric APS [14]. In adults, 61.4% of patients had a recurrence of thrombosis, occurring within 3 years [10]. This long interval suggests that patients are at risk for an extended length of time and long-term anticoagulation should be considered.

Perinatal APS Rare cases of perinatal thrombosis in infants born to mothers with APS or APLAs have been reported [3]. Positive APL tests were observed in 8/13 infants, and as in adults, the clinical presentation consisted of arterial and venous thromboses in multiple localizations. In our cohort, five patients presented with perinatal stroke. Although the clinical and laboratory manifestations of this subgroup are consistent with the diagnostic criteria of APS, their disease behaves differently and does not recur. Thus, perinatal stroke in children with APS deserves special consideration and may not require anticoagulant therapy unless other risk factors prevail.

Anticoagulants and paediatric APS There is general agreement in the literature that long-term anticoagulation is needed in patients who experienced an antiphospholipidrelated thrombosis. However, no consensus exists regarding the duration and intensity of therapy [15]. Among our patients, there were a total of 11 recurrent thrombotic events in 7 patients. Three of these events (2/8 venous, 1/3 arterial) occurred while on anticoagulant therapy, but no data are available regarding whether these events occurred at therapeutic INR levels. It is suggested that longterm anticoagulation is recommended for all paediatric patients with APS to reduce recurrence rate, excluding the perinatal stroke subgroup. To better assess the role of thrombophilic risk factors and anticoagulant therapy as potential predictors of recurrent thrombosis in paediatric APS patients, large prospective multicentre trials are required.

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References 1 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002 Mar 7;346(10):752–63. 2 Shoenfeld Y. Systemic antiphospholipid syndrome. Lupus 2003;12(7):497–8. 3 Boffa MC, Aurousseau MH, Lachassinne E, Dauphin H, Fain O, Le Toumelin P, et al. European register of babies born to mothers with antiphospholipid syndrome. Lupus 2004;13(9):713–17. 4 Gattorno M, Falcini F, Ravelli A, Zulian F, Buoncompagni A, Martini G, et al. Outcome of primary antiphospholipid syndrome in childhood. Lupus 2003;12(6):449–53. 5 von Scheven E, Athreya BH, Rose CD, Goldsmith DP, Morton L. Clinical characteristics of antiphospholipid antibody syndrome in children. J Pediatr 1996;129(3):339–45. 6 Lee T, von Scheven E, Sandborg C. Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents. Curr Opin Rheumatol 2001;13(5):415–21. 7 Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):1019–27. 8 Wilson WA. Classification criteria for antiphospholipid syndrome. Rheum Dis Clin North Am 2001;27(3):499–505. 9 Berkun Y, Padeh S, Barash J, Uziel Y, Harel L, Mukamel M, et al. Antiphospholipid syndrome and recurrent thrombosis in children. Arthritis Rheum 2006;55(6):850–5. 10 Krnic-Barrie S, O’Connor CR, Looney SW, Pierangeli SS, Harris EN. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997;157(18):2101–8. 11 Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der Meer J. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104(1):143–8. 12 Regeczy N, Lakos G, Balogh I, Ajzner E, Kiss E, Szegedi G. The Leiden mutation of coagulation factor V in Hungarian SLE patients. Clin Appl Thromb Hemost 2000;6(1):41–5. 13 Fijnheer R, Horbach DA, Donders RC, Vile H, von Oort E, Nieuwenhuis HK, et al. Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus. Thromb Haemost 1996;76(4):514–17. 14 Campos LM, Kiss MH, D’Amico EA, Silva CA. Antiphospholipid antibodies in 57 children and adolescents with systemic lupus erythematosus. Rev Hosp Clin Fac Med Sao Paulo 2003;58(3):157–62. 15 Khamashta MA, Shoenfeld Y. Antiphospholipid syndrome: a consensus for treatment? Lupus 2003;12(7):495.

Anticoagulation for Deep Venous Thrombosis in the Presence of an Intracranial Haemorrhage

Question/ Case

I would like information on managing deep vein thrombosis (DVT) in a young girl with intracranial bleeding. We saw a patient recently who presented with sudden collapse and left hemiplegia. Intracranial bleeding over the right temporo-parietal region was seen on a computerized tomography scan. An arteriovenous malformation (AVM) was demonstrated in a subsequent arteriogram. Neurosurgical removal was accomplished. Ten days later, while she was recovering from the bleeding and operation, she developed extensive DVT involving the right iliofemoral and popliteal veins. There was no relevant family history. Subsequent investigations revealed that her serum protein S activity was low (10%), while that of protein C and antithrombin was normal. Anticardiolipin antibodies were negative. We were hesitant to administer anticoagulant therapy to the patient. A filter was placed in the inferior vena cava (IVC) above the level of the renal vein via the right internal jugular route because the venous thrombosis progressed. A mechanical removal of the clot was attempted the following day when the clot had extended up to the level of the filter. Once the diagnosis of protein S deficiency was known, we started infusions of fresh-frozen plasma on a daily basis. Thereafter, the clot began to regress. Twenty-one days after the neurosurgical operation, we put the patient on lowmolecular-weight heparin (LMWH). We would like to ask the experts: (1) What is the risk of intracranial bleeding under such circumstances if conventional or LMWH is used? (2) Is there any better or safer treatment?

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Response from Maureen Andrew, MD Hospital for Sick Children, Toronto, Ontario, Canada I would agree with all the steps taken in the care of this child. If the AVM is completely corrected and the central nervous system bleed is gone, the risk of a second bleed is likely to be very small. The options for treatment are either LMWH or oral anticoagulants for at least 3–6 months. Both have problematic issues, which for LMWH include the twice-daily injections and for oral anticoagulants, the difficulty of maintaining international normalized ratio (INR) values in the target range. Oral anticoagulants may be contraindicated in this patient. The issue of life-long anticoagulants is one that depends on whether the protein S level remains at 10%, which would suggest that the child is homozygous with at least one gene that is partially functioning. In this situation, I think that life-long anticoagulants are advised and that oral anticoagulants may be contraindicated because of the risk of decreasing the protein S level to 0% and resultant purpura fulminans. If oral anticoagulants are used, then the INR would need to be kept very high (over 3.5) and the risk of bleeding would be substantial for this child. If the protein S level increases to the usual heterozygote levels of approximately 50%, then oral anticoagulants could be used. However, if there was an inciting event such as a femoral line, then therapy for 3–6 months could be considered and then stopped. Response from Craig Kessler, MD Georgetown University Medical Center, Washington, DC, USA This scenario of hypercoagulability manifested by proximal DVT following neurosurgery is a common one in adult internal medicine. The utilization of extrinsic gradient pneumatic compression stockings has significantly reduced the incidence of thromboembolic complications in this population when applied intra- and postoperatively. Furthermore, in limited studies in adults undergoing neurosurgery, the use of LMWH for DVT prophylaxis suggests that the incidence of bleeding is not increased. Typically, LMWH is initiated approximately 24 h postoperatively, if no untoward haemorrhage is apparent up to that time. This is one of

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the few clinical situations for which the monitoring of anti-factor Xa levels in the plasma might be indicated to increase the safety of LMWH administration. I would aim for anti-Xa levels around 0.6– 0.8 U/ml to maximize safety and efficacy. No DVT prophylaxis was used and no systemic anticoagulation was administered after the IVC umbrella was inserted. If, indeed, the child actually was hypercoagulable by virtue of protein S deficiency, the incidence of subsequent thrombotic complications on the umbrella itself would remain high unless systemic anticoagulation was initiated. A major issue in this case, however, is whether the protein S deficiency in this patient is on a congenital or an acquired basis. Protein S circulates in the plasma in a free form and is complexed to C4b-binding protein. C4-binding protein, a modulator of the complement pathway, is an acute-phase reactant protein, which rises dramatically in postoperative and inflammatory situations. Therefore, the diagnosis of congenital protein S deficiency may be premature in this patient in his convalescence period in the absence of baseline activity levels or positive family or personal history of hypercoagulability. An indirect approach would be to screen his parents and siblings for protein S deficiency. Alternatively, the detection in this patient of concordant levels of low total protein S antigen, low free protein S antigen, and low protein S activity would be suggestive of congenital rather than acquired deficiency. Acquired protein S deficiency usually is characterized by normal total protein S antigen levels, but low protein S activity and low free protein S antigen. Finally, once this patient stabilizes on LMWH, I would be inclined to convert him to oral warfarin therapy, initiated with at least a 5-day overlap with LMWH and continued beyond that if the INR is not therapeutic at 2.0–3.0. Warfarin will interfere with the ability to establish the presence of congenital protein S deficiency since this is also a vitamin-K-dependent protein.

Clinical Probability Assessment for Thromboembolic Disease

Question

Is clinical probability assessment really useful in patients clinically suspected of deep vein thrombosis (DVT) or pulmonary embolism (PE)?

Response from Henri Bounameaux, MD University Hospital of Geneva, Geneva, Switzerland According to the Bayesian approach to the use of diagnostic tests, post-test probability of a disease depends not only upon the test’s characteristics but also upon the a priori (before performing the test) likelihood of the disease. Hereafter, we will call this likelihood, prior clinical probability (pCP). This pCP can be assessed either empirically (or implicitly) or by means of clinical decision rules or scores (explicitly). It has been convincingly shown that both tools are similarly effective and allow the characterization of patients clinically suspected of DVT or PE in groups with low (usual prevalence of the disease 10% or less), intermediate (about 30% prevalence), or high pCP (60% prevalence or more). Even though implicit and explicit assessments have similar performances, the former appears to be more subjective and more difficult to transmit to students or younger colleagues. Explicit rules have the advantage of being more objective and easier to apply. Interestingly, the best performance of a score for PE was obtained if the objective score could be overridden by the clinician’s subjective opinion; such a clinical override was present in about 20% of cases [1]. For DVT, the pCP rule most used is Wells’ score, which combines a few readily available items with the subjective evaluation of the likelihood of an alternative diagnosis (which, if high, reduces the pCP for DVT) [2]. For PE, a similar score by the same authors is available, while a fully objective score has been developed by the Geneva group, which, however, carries the disadvantage of requiring an arterial blood gas analysis [3,4]. Recently, a development of the latter score without arterial blood gas analysis was made available [5].

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The pCP assessment is a prerequisite because, depending upon test sensitivity, venous thromboembolism can be ruled out only in low clinical probability patients (tests with limited sensitivity of 85–95%, e.g. SimpliRed), or in low and intermediate clinical probability patients (tests with a sensitivity of 95%). In high clinical probability patients, the safety of ruling out the disease only with a negative D-dimer test is not established, and exclusive dependence on this test is not recommended [6]. In conclusion, yes, clinical probability assessment is highly useful in the diagnostic approach of clinically suspected venous thromboembolism and available easy-to-use clinical scores should be more widespread.

References 1 Chagnon I, Bounameaux H, Aujesky D, Roy PM, Gourdier AL, Cornuz J, et al. Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med 2002;113(4):269–75. 2 Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350(9094):1795–8. 3 Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83(3):416–20. 4 Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med 2001;161(1):92–7. 5 Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144(3):165–71. 6 Righini M, Aujesky D, Roy PM, Cornuz J, de Moerloose P, Bounameaux H, et al. Clinical usefulness of D-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism. Arch Intern Med 2004;164(22):2483–7.

D-dimer

Question

in Thromboembolic Disease

Is D-dimer measurement really useful in patients clinically suspected of deep vein thrombosis (DVT) or pulmonary embolism (PE)?

Response from Henri Bounameaux, MD University Hospital of Geneva, Geneva, Switzerland The utility of D-dimer measurement is dependent upon several factors, including the particular assay used (with its sensitivity and specificity to the presence of venous thromboembolism), how the assay has been clinically validated, the type of patients (inpatients, outpatients, their ages, and comorbidities), and the prior clinical probability before performing the test. Indeed, there are too many commercial D-dimer tests that do not undergo appropriate clinical validation. In many instances, there are many uncertain diagnostic cut-offs, large 95% confidence intervals for their performance, lack of sensitivity and specificity by comparison with a validated gold standard, and no outcome studies to confirm their safety in daily life. The utility of D-dimer measurement is definitely higher in younger subjects and in those with no co-morbidity attending the emergency rooms with clinically suspected DVT or PE. D-dimer is specific for fibrin, not for thrombus; and inflammatory, infectious, or malignant diseases are likely to increase D-dimer concentration. Thus, specificity is a concern. Increased levels do not mean DVT or PE. False-positive results represent 50–60% of increased levels. The utility of D-dimer measurements resides in its high sensitivity. Every thrombus, at least every significant thrombus, is associated with an increase of the concentration of D-dimer above a cut-off that must be determined for each test. Thus, when below the cut-off, D-dimer measurements allows to rule out DVT or PE, which is particularly important in settings where the prevalence of the disease among suspected patients is low (20% or less) and expensive imaging modalities cannot be afforded in all subjects. Prior clinical probability assessment is a prerequisite because, depending upon test sensitivity, venous thromboembolism can be

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ruled out only in low clinical probability patients (tests with limited sensitivity of 85–95%, e.g. SimpliRed), or in low and intermediate clinical probability patients (tests with a sensitivity of 95%). In high clinical probability patients, the safety of ruling out the disease only with a negative D-dimer test is not established. In conclusion, yes, D-dimer measurement can be useful in the diagnostic approach of clinically suspected venous thromboembolism, but “instructions for use” should be read by the biologists and the clinicians.

Progestins and Thrombosis

Question/ Case

A middle-aged woman required progestin therapy for endometrial hyperplasia. She had two postpartum deep venous thromboses (DVT) and is known to be heterozygous for factor V Leiden. Do you recommend any type of thrombosis prevention during progestin therapy?

Response from Craig Kessler, MD Georgetown University Medical Center, Washington, DC, USA In spite of the absence of data, I do provide prophylactic anticoagulation to women in this situation. I usually recommend low-molecularweight heparin and it is initiated concurrently with the hormonal therapy. Third-generation progestin preparations have been associated with the development of hypercoagulable events, but no prospective, randomized, controlled studies have been conducted to confirm this anecdotal observation or determine if DVT prophylaxis is necessary. Until that information is available, I prefer to err on the side of prophylaxis when third-generation progestins are administered. I suggest this patient undergo a hypercoagulable workup and ascertain whether she has a personal or family history of thrombotic events. Response from Barbara A. Konkle, MD University of Pennsylvania, Philadelphia, Pennsylvania, USA The risk of thrombosis with progesterone use alone in women with thrombophilia is unknown, but there are some data from use in the general female population. In the studies leading to the US FDA approval of medroxyprogesterone acetate (Depo-Provera™), 11,500 women were treated for a total of 208,894 woman-months of use. (1) Fifteen of these women suffered a venous thromboembolic event (VTE). Their mean age was 28.9 years. Five women had superficial thrombophlebitis only. Nine had a DVT (one upper extremity) and one a fatal pulmonary embolism. The latter woman was found to have disseminated lung cancer on autopsy. Three women with DVT

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had a prior history of VTE, one postpartum and one with pregnancy and oral contraceptive preparations (OCP). Another received medroxyprogesterone two days after delivery and developed a DVT seven days later. Taken together, these data do not support a higher risk of DVT after treatment with medroxyprogesterone as used for contraception in the general population. A World Health Organization (WHO) sponsored study evaluated the thrombotic risk of progestins. (2) The study population was a cohort of 74,068 women accessed through a general practice database. They found 59 women who met the criteria for idiopathic VTE (24 PE/35 DVT). Ten cases were excluded from further analysis because they were part of other studies. The 49 remaining cases and 275 matched controls were evaluated using a nested case–control design. They found an overall 2.4 relative risk (RR) associated with progesterone use alone. However, when they separated those using progestins for contraception only, there was no increased risk (RR 1.3), compared to those using progestins for other indications (RR 5.3). The latter likely were treated with higher doses and may have included an older age group. Since the population was largely Caucasian, there should have been significant representation of the common thrombophilias, factor V Leiden, and the prothrombin 20210 mutation. However, the risk of progestin use alone in women with these and other thrombophilias has not been evaluated. The observation of an increased risk of thrombosis in women using third- vs. second-generation combined oral contraceptives has raised the question if the risk with all progestins is the same. The third-generation progestins, norgestimate, gestodene, and desogestrel, when combined with oestrogen as OCP do increase the risk of thrombosis over that seen with combined OCP containing second-generation progestins. While the second-generation progestins, which include norethindrone, levonorgestrel, and norgestrel have not been evaluated individually, no difference in thrombotic risk when used as part of a combined OCP has been reported. Are progestins, when used alone as contraception, safe in women with thrombophilia? The answer to this question is unknown. Based on the WHO study, it seems a reasonable alternative in women with a relatively low risk of thrombosis based on the type of thrombophilia and clinical history. The levonorgestrel-coated intrauterine device (Mirena™) may be a safer alternative although this has not been studied. In thrombophilic women receiving progestins for other indications, an increased risk of DVT should be presumed if alternative

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treatments are not available. The risk vs. benefit of prophylactic anticoagulation should be considered.

References 1 Schwallie PC. Experience with Depo-provera as an injectable contraceptive. J Reprod Med 1974;13(3):113–17. 2 Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999;354(9190):1610–11.

Unknown Thrombophilia and Surgery

Question/ Case

I would value the opinion of the panel on the management of a young male patient who has a thrombotic tendency. Three years ago, he developed a spontaneous right iliofemoral/inferior vena caval thrombosis. Tests for antithrombin, protein C, protein S, factor V Leiden, prothrombin mutation, plasminogen, homocysteine, and lupus anticoagulant were all normal. Moreover, his platelet count was normal. Tests for paroxysmal nocturnal haemoglobinuria were negative. Two years ago, neurological problems appeared and he was diagnosed by magnetic resonance imaging as having an intracranial venous sinus thrombus. One year later, neurological symptoms recurred and a left temporal lobe venous thrombus was diagnosed. The thrombus developed while he was on warfarin anticoagulation therapy, and he now receives daily therapeutic doses of a low-molecular-weight (LMW) heparin. Since starting that treatment he has not had a definite recurrence of thrombosis but continues to have headache and other symptoms suggestive of raised intracranial pressure. His neurologist believes that the intracranial pressure should be measured and, if high, a shunting procedure should be undertaken. The question is: how does the panel recommend the surgery be managed from the point of view of anticoagulant control?

Response from Man-Chiu Poon, MD University of Calgary, Foothills Hospital, Calgary, Alberta, Canada This is quite a case! For the management of the neurological shunting, my suggestion would be to stop the LMW heparin 24 h before the procedure, but restart LMW heparin at 24–48 h after the operation when the neurosurgeon considers it safe to restart. I would also suggest using intermittent pneumatic compression for the legs perioperatively until the patient is back on LMW heparin. One may also

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consider using graduated compression stocking for added protection. All the usual hypercoagulability studies in this patient, including lupus anticoagulant, were normal. I would also suggest testing for anticardiolipin/anti-beta2 glycoprotein 1, as patients with a negative lupus inhibitor test may still have these antibodies.

Index

A Acetylsalicylic acid (ASA), 119–120, see also aspirin Acquired bleeding diatheses acquired haemophilia and second pregnancy, 163–164 acute disseminated intravascular coagulation (DIC), treatment for, 169–172 end-stage liver disease and surgery, 167–168 factor IX inhibitor development, 165–166 Activated protein C resistance (APCR), 195 Activated prothrombin complex concentrates (APCCs) for bleeding episodes in persons with FIX inhibitors, 166 risk of thrombosis, 91–92 Acute DIC, see Disseminated intravascular coagulation Acute intermittent porphyria, 168 Afibrinogenaemia, in neonate and pregnant patient, 131–134 Aminocaproic acid (EACA), in HHT, 148 Anaphylaxis, immune tolerancein haemophilia B with, 85–86 Angiodysplasia, see Gastrointestinal angiodysplasia Angiodysplastic bleeding, 153, 154 Ankle alignment osteotomy, 18, 19 Ankle haemarthroses, see Haemophilic arthropathy Antibodies autoantibodies to FVIII associated with pregnancy, 163 autoimmune antibodies to factor XI, 126 GPIIb/IIIa, 157 Anticardiolipin antibody syndrome, 203–204

Anticoagulants, 210, see also Anticoagulant therapy; Heparin; Warfarin oral, 183, 186 Anticoagulant therapy for atrial fibrillation in factor X deficiency patients, 119–120 for atrial fibrillation in haemophiliacs, 43–44 for cardiac valve in haemophiliacs, 47–48 for children with APS and thrombophilia, 206, 207 with coumadin for cardiac valve in type 1 VWD patient, 97 for DVT in haemophiliacs, 52–53 for DVT in presence of ICH, 209–211 Antidepressants and bleeding, 186 Antifibrinolytic therapy, 65 agents, 145 for DIC, 172 Antiphospholipid antibodies and stroke study (APASS), 203–204 Antiphospholipid syndrome (APS), 205–206 anticoagulants and paediatric, 207 hereditary thrombophilic defects and paediatric, 206 perinatal, 207 recurrent thrombosis and paediatric, 207 Antipsychotics and bleeding, 186 Antithrombin deficiency, treatment of, 201–202 APCC, see Activated prothrombin complex concentrates APS, see Antiphospholipid syndrome Arteriovenous malformation (AVM), 145, 147, 209–211 Arthroscopic synovectomy, 15–16

223

224 Index

Aspirin, 204, see also Acetylsalicylic acid (ASA) Atrial fibrillation (AF) anticoagulation for, in factor X deficiency patients, 119–120 anticoagulation for, in haemophiliac, 43–44 in factor XI deficiency, anticoagulation for, 123 Autoantibodies to FVIII associated with pregnancy, 163 Autoerythrocytic sensitization (AS) syndrome, 141–143 AVM, see Arteriovenous malformation B Bleeding angiodysplasia, 153, 154 in haemophilic patient with chronic hepatitis C, 73–74 in HHT patients, 147 intracranial, in FXIII deficiency patients, see Intracerebral haemorrhage joints, see Haemophilic arthropathy persons with FIX inhibitors, 166 in pregnant women with Glanzmann’s thrombasthaenia, 157–158 Bleeding disorders, see also specific bleeding disorder diseases PFA-100 closure times versus bleeding time for, 175–176 Bleeding time, 175–176 Blood transfusion, 146 Bolus dosing for rFVIIa, 81–83 C Cardiac catheterization, in haemophiliac, 49 Cardiac surgery, and combined FV/FVIII deficiency, 111, see also Surgery Cardiac valves anticoagulation for, in haemophiliacs, 47–48 anticoagulation with coumadin for, in type 1 VWD patient, 97 C4-binding protein, 211 Clauss method, 136 Clinical probability (pCP) assessment, 213–214

Coagulation disorders afibrinogenaemia, 131–134 autoerythrocytic sensitization syndrome, 141–143 dysfibrinogenaemia, 135–137 hereditary haemorrhagic telangiectasia (HHT), 145–149 hereditary vitamin-K-dependent coagulation factors deficiency and pregnancy, 151–152 hypofibrinogenaemia, 139–140 Coagulopathy, in children, 190 Congenital afibrinogenaemia, 131–133 Continuous infusion (CI) of rFVIIa, 91–93 Cryoprecipitate, 127, 133–134 D DDAVP, see Desmopressin D-dimer tests, importance of, 215–216 Deamino-D-arginine vasopressin (DDAVP/ desmopressin), see Desmopressin Deep venous thrombosis (DVT) clinical probability (pCP) assessment for, 213–214 D-dimer tests, 215–216 in haemophiliacs, 51–53 in presence of ICH, LMWH for, 209–211 prophylaxis for factor VII deficiency, 113 Desmopressin (DDAVP) for bleeding in haemophilic patient with chronic hepatitis C, 73–74 for HHT, 146 side effects of treatment with, 179–180 for treatment of mild haemophilia A during surgery, 55–56 use after cocaine intake, risk in, 177 DIC, see Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) rFVIIa in haemophilic patients with, 87–90 treatment for acute, 169–172 D-penicillamine, for haemophilic synovitis, 9, 11 limitations, 10

Index 225

DVT, see Deep venous thrombosis Dysfibrinogenaemia, 135–137 thrombosis and, 135, 136 E EACA, see Epsilon aminocaproic acid Embolism, for HHT, 146–147 End-stage arthropathy, 16–17 End-stage liver diseases, 167–168 Epidural anaesthesia, for VWD patients, 95–96 Epsilon aminocaproic acid (EACA), for HHT, 146, 148 Exchange transfusion, 111 F Factor deficiencies factor V and VIII deficiency, combined, 111–112 factor VII deficiency, DVT prophylaxis in, 113 factor VII deficiency, menorrhagia in, 115–117 factor X deficiency, anticoagulation for atrial fibrillation in, 119–120 factor X deficiency, management of, 121–122 factor XI deficiency, anticoagulation for atrial fibrillation in, 123 factor XI deficiency and surgery, 125–126 factor XIII deficiency and intracerebral haemorrhage, prophylaxis for patients with, 127 Factor V (FV) and factor VIII deficiency, combined, 111–112 Factor V Leiden, for VTE, 195–196 Factor VII (FVII) deficiency, DVT prophylaxis in, 113 deficiency, menorrhagia in, 115–117 replacement therapy, 116 Factor VIII (FVIII) autoantibodies associated to, with pregnancy, 163 and factor V deficiency, combined, 111–112 Factor VIII (FVIII) replacement therapy for deep venous thrombosis in haemophiliacs, 52–53

for mild haemophilia A during surgery, 55–56 Factor IX (FIX) deficiency, 123 infusion for premature infant with haemophilia B, 33–34 Factor IX (FIX) inhibitors case of haemophilia B, mild type 1 VWD, and, 29–30 development, 165–166 Factor X (FX) deficiency, anticoagulation for atrial fibrillation in, 119–120 deficiency and gastrointestinal bleed, management of, 121–122 Factor XI (FXI) deficiency, 125–126 Factor XIII (FXIII) deficiency, 127 FFP, see Fresh-frozen plasma Fibrinogen therapy for afibrinogenaemia, 131–134 for dysfibrinogenaemia, 137 Fibrogammin-P®, 127 Fresh-frozen plasma (FFP) infusion for FX deficiency patient, 122 for FXI deficiency patient undergoing surgery, 125–126 for FXIII deficiency patient with ICH, 127 for patients with liver disease and surgery, 167–168 G Gardner-Diamond syndrome, see Autoerythrocytic sensitization syndrome Gastrointestinal angiodysplasia, 153–154 Gastrointestinal bleeding, 121–122 Glanzmann’s thrombasthaenia and gastrointestinal angiodysplasia, 153–154 and pregnancy, 157–158 GPIIb/IIIa antibodies, 157 H Haemate, for type 2A VWD during labor, 99–100 Haemodialysis, for haemophilia patients, 57–58 Haemophilia, see also Haemophilia treatment

226 Index

Haemophilia (continued) anticoagulation for atrial fibrillation in patient with, 43–44 cardiac catheterization in patient with, 49 isotretinoin risk in patients with, 75–76 laser eye surgery in patients, 77 pathogenesis of synovitis and cartilage damage in, 5–7 physical exercises for patients with, 63–64 postpartum-acquired, and second pregnancy, 163–164 safety of scuba diving for patient with, 67 surgery on patients with, 38 synoviorthesis for haemophilic synovitis, 7–11 treatment of renal bleeding in patient with, 65 Haemophilia A, see also Haemophilia treatment anticoagulation for cardiac valves in patients with, 47–48 case of delivery in patient with carrier of, 35–36 case of HIV infection and hepatitis C with, 25–26 combined carrier of haemophilia B and, 23–24 deep venous thrombosis in patient with, 52–53 and immune tolerance induction (ITI), 3–4 ventricular septal defect repair in, 69–70 in women, 37–38 Haemophilia B, see also Haemophilia treatment case of mild type 1 VWD, factor FIX inhibitor and, 29–30 combined carrier of haemophilia A and, 23–24 deep venous thrombosis in patient with, 51–52 inhibitor patient, management of, 85–86 premature infant with, management of, 33–34 Haemophilia treatment haemodialysis and, 57–58

hepatitis C and, with pegylated alphainterferon and ribavirin, 59–61 with hepatitis C and recurrent bleeding, 73–74 of pregnant women, 41–42 during surgery, DDAVP for mild haemophilia A, 55–56 Haemophilic arthropathy, treatment of in ankle, 5, 6, 7, 11–13 in knee, 15–22 in subtalar joints, 11–12 Haemophilic knee with arthropathy, orthopaedic procedures in alignment osteotomy, 18, 19 curettage of subchondral bone cysts, 18–19 joint debridement, 17–18 total knee arthroplasty (TKA), 20–21 Haemophilic pseudotumours, 79 Haemophilic synovitis, see Synovitis Haemostasis, 116, 166 SSRIs effect on, 185–186 HCV viral load, 26 Heparin, see also Low molecular-weight heparin for deep venous thrombosis in haemophiliacs, 51–53 during haemodialysis in severe haemophilia patient, 57–58 Hepatitis C case of haemophilia A with HIV infection and, 25–26 and haemophilia A treatment, with interferon therapy, 59–61 Hereditary haemorrhagic telangiectasia (HHT), 145–149 HIV infection, case of haemophilia A with hepatitis C and, 25–26 Hormonal substitution, for haemostatis, 117 Hormonal therapy for angiodysplasia, 154 for HHT, 147, 148 Humate-P, see also Haemate for type 3 VWD, 105–106 Hypercoagulation, by DVT, 210–211 Hypofibrinogenaemia, 139–140 Hyponatraemia, in setting of desmopressin, 179–180

Index 227

I ICH, see Intracerebral haemorrhage Immune tolerance (IT) haemophilia A and, 3–4 in haemophilia B with anaphylaxis, 85–86 Immune tolerance induction (ITI), 3, 4, 165–166 and FIX inhibitors, 165–166 Immunoadsorption, 158 Infants antithrombin deficiency, 201–202 FIX infusion for premature infant with haemophilia B, 33–34 International normalized ratio (INR), 167 system, use of, 181–183 Intracerebral haemorrhage (ICH) children with, work-up for, 189–190 and FXIII deficiency, prophylaxis for patients with, 127 in pregnancy with haemophilia A carrier, 35–36 Intracranial bleeding, see Intracerebral haemorrhage Intracranial haemorrhage, see Intracerebral haemorrhage Ischaemic attack, 44 patients with anticardiolipin antibody syndrome and, 203–204 Isotretinoin, risk in haemophilic patients, 75–76 J Joint debridement, 17–18 K Knee flexion contractures, 16–17 L Laser eye surgery, in haemophiliacs, 77 Liver biopsy, in haemophiliacs, 59 Liver disorders, 61 LMWH, see Low molecular-weight heparin Low molecular-weight heparin (LMWH), 83, see also Heparin for DVT, 209–211 for haemophiliac with coronary artery disease, 49 Lyonisation, see X inactivation process

M Malmö protocol, 85–86 Menorrhagia, 115–117 tranexamic acid for, 117 Mild haemophilia, in women, 37–38, see also Haemophilia Missense mutations and von Willebrand disease, 103 N NovoSeven®, see Recombinant factor VIIa O Oestrogen, for HHT, 147, 148–149 Oestrogen-progesterone treatment, for HHT, 149 Oral contraceptives, thrombosis risk of, 217–219 Osler-Weber-Rendu syndrome, see Hereditary haemorrhagic telangiectasia Owren assay, for INR, 182–183 P Paediatric APS and recurrent thrombosis, 207 PCC, see Prothrombin complex concentrates pCP, see Clinical probability Pegylated alpha-interferons, 59–61 Perinatal APS, 207 Photorefractive keratectomy (PRK) technique, 77 Physical exercises, for haemophilic patients, 63–64 Physiotherapy, 12 Platelet aggregation, and SSRIs use, 185–186 transfusion, 101, 107, 154, 157–158, 170 Platelet disorders gastrointestinal angiodysplasia, 153–154 Glanzmann’s thrombasthaenia with pregnancy, 157–158 Wiscott-Aldrich syndrome, 159 Platelet Function Analyser (PFA-100) closure times, 175–176 Platelet-type von Willebrand disease (VWD), 107 type 2B VWD versus, 103–104

228 Index

Porcine valves and combined factor V/factor VIII deficiency, 112 Postphlebitic syndrome, 202 Pregnancy acquired haemophilia and second pregnancy, 163–164 afibrinogenaemia and, 131, 133–134 case of, with carrier of severe haemophilia A, 35–36 Glanzmann’s thrombasthaenia and, 157–158 hereditary vitamin-K-dependent coagulation factors deficiency and, 151–152 management of, in haemophilics, 41–42 type 2A VWD and, 99–100 type 2B VWD and, 101 vitamin K substitution during, 152 von Willebrand factor (VWF) levels and, 95, 101, 105–106 Progestin therapy, thrombotic risk of, 217–219 Prophylaxis DVT, for factor VII deficiency, 113 FX deficiency with gastrointestinal bleeding, 122 for haemophilic arthropathy, 7 for patients with FXIII deficiency and intracerebral haemorrhage, 127 for type 3 VWD, 105–106 Protein C, protein S, and antithrombin, deficiency of, 196–197 Prothrombin complex concentrates (PCCs), 116, 152 with FX, 122 risk of thrombosis, 91–92 Prothrombin gene mutation, 196 Pseudo-VWD, see Platelet-type von Willebrand disease Psychogenic purpura, see Autoerythrocytic sensitization syndrome Pulmonary embolism (PE) clinical probability (pCP) assessment for, 213–214 D-dimer tests, 215–216 Q Quick assay, for INR, 182–183

R Radiation synovectomy, see Radioactive synoviorthesis Radioactive synoviorthesis for haemophilic ankle, 7–11, 12–13 for haemophilic knee, 22 Radiosynoviorthesis, see Radioactive synoviorthesis Recombinant factor VIIa (rFVIIa), 107, 116 for bleeding episodes in persons with FIX inhibitors, 166 continuous infusion (CI) with, advantages and disadvantages of, 81–83 for Glanzmann’s thrombasthaenia in pregnant women, 157–158 for Glanzmann’s thrombasthaenia with GI angiodysplasia, 154 in haemophilic patients with thrombocytopaenia and DIC, 87–90 pharmacokinetics of, in haemophiliacs, 30 for Wiscott-Aldrich syndrome, 159 Rehabilitation, for ankle joints, 12 Renal bleeding, treatment of haemophilics with, 65 Rendu-Osler syndrome, see Hereditary haemorrhagic telangiectasia rFVIIa, see Recombinant factor VIIa Ribavirin, for haemophiliacs with hepatitis C, 59–61 Rifamycin, for joint chronic synovitis, 9–11 RIPA, see Ristocetin-induced platelet agglutination test Ristocetin-induced platelet agglutination (RIPA) test, 103–104 S Scuba diving, and haemophiliac, 67 Selective serotonin reuptake inhibitors (SSRIs), effects of, 185–188 Sertraline, 186 SSRI, see Selective serotonin reuptake inhibitors Streptococcal toxic shock syndrome, 87–90 Subchondral cyston proximal tibia, 18, 19

Index 229

Surgery FXI deficiency and, 125–126 liver diseases and, 167–168 on patients with haemophilia, 38 Surgical synovectomy, 15 Symptomatic carriers, 38 Synoviorthesis, 7, 9–11, 12–13 Synovitis, in haemophilic patients, 5–7 T Thera-band®, for haemophilic patients, 63 Thrombocytopaenia, 73–74, 103 in pregnancy, 101 Thrombophilia(s), inherited children with APS and, 206 frequency of VTE patients with, 196–197 Thromboprophylaxis, see Deep venous thrombosis Thrombosis, see also Deep venous thrombosis and dysfibrinogenaemia, 135, 136 with neurological symptoms, 221–222 paediatric APS and recurrent, 207 perinatal, 207 prevention during progestin therapy, 217–219 risk in APCC and PCC, 91–92 and SSRIs, 187 TKA, see Total knee arthroplasty Total knee arthroplasty (TKA), 20–21 Tranexamic acid, 170 for haemophilic patients, 75–76 for hemophilia B, VWD and factor IX inhibitor, 30 for HHT, oral, 147 for menorrhagia, 117 Tumours, in haemophilic patients, see Haemophilic pseudotumours Type 1 VWD anticoagulation for cardiac valve in patient with, 97 case of haemophilia B, factor FIX inhibitor, and, 29–30

Type 2A VWD, pregnancy and, 99–100 Type 2B VWD platelet type VWD versus, 103–104 pregnancy and, 101 Type 3 VWD, prophylaxis for, 105–106 U Ultrasound, for haemophilic patients, 63, 64 V Venous thromboembolism (VTE), 206 incidence of, in Asians and Westerners, 195–197 Ventricular septal defect (VSD) repair, in severe haemophilia A, 69–70 Vitamin-K coagulation factors deficiency (VKCFD), hereditary, 151–152 VKCFD, see Vitamin-K coagulation factors deficiency von Willebrand disease (VWD) epidural anaesthesia and, 95–96 platelet type, 107 type 1, anticoagulation for cardiac valve in patient with, 97 type 3, prophylaxis for, 105–106 type 2A, pregnancy and, 99–100 type 2B, pregnancy and, 101 type 2B versus platelet type VWD, 103–104 von Willebrand factor (VWF), 95, 101, 103 -rich concentrates, 105–106 VTE, see Venous thromboembolism VWD, see von Willebrand disease W Warfarin for FXI deficiency and atrial fibrillation, anticoagulation with, 123 and SSRIs, use of, 186 Wiscott-Aldrich syndrome, 159 X X inactivation process, 23