Table Of ContentHEMOPHILIA CARE IN
THE NEW MILLENNIUM
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK. State University of New York at Buffalo
IRUN R. COHEN. The Weizmann Institute of Science
DAVID KRITCHEVSKY. Wistar Institute
ABEL LA1THA. N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
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TAURINE 4: Taurine and Excitable Tissues
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HEADS PACE ANALYSIS OF FOODS AND FLAVORS: Theory and Practice
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HEMOPHILIA CARE IN THE NEW MILLENNIUM
Edited by Dougald M. Monroe, Ulia Hedner, Maureane R. Hoffman, Claude Negrier,
Geoffrey F. Savidge, and Gilbert C. White II
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HEMOPHILIA CARE IN
THE NEW MILLENNIUM
Edited by
Dougald M. Monroe
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Ulla Hedner
Novo Nordisk AIS, Malov, Denmark and
University of Lund, Lund, Sweden
Maureane R. Hoffman
Duke University and Durham VA Medical Centers
Durham, North Carolina
Claude N egrier
H6pital Edouard Herriot
Lyon, France
Geoffrey F. Savidge
Guys' and St. Thomas's Trust
London, United Kingdom
and
Gilbert C. White II
University of North Carolina School of Medicine
Chapel Hill, North Carolina
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging-in-Publication Data
Hemophilia care in the new millennium 1 edited by Dougald M. Monroe ... [et al.].
p. cm. -- (Advances in experimental medicine and biology; 489)
Includes bibliographical references and index.
ISBN 978-1-4613-5474-1 ISBN 978-1-4615-1277-6 (eBook)
DOl 10.1007/978-1-4615-1277-6
1. Hemophilia--Congresses. I. Monroe, Dougald McDougald. n. Series.
RC642 .H453 2001
616.1'572--dc21
00-054579
ISBN 978-1-4613-5474-1
©200l Springer Science+Business Media New York
Originally published by Kluwer AcademiclPlenum Publishers in 2001
Softcover reprint ofthe hardcover 1s t edition 2001
http://www.wkap.nll
10 9 8 7 6 5 4 3 2
A c.I.P. record for this book is available from the Library of Congress
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or
by any means, electronic, mechanical. photocopying, microfilming, recording, or otherwise, without
written permission from the Publisher
PREFACE
There should be, and in the best of cases there is, a synergy between basic research
and patient care. However, this synergy is hard to develop because the techniques
required to be a successful researcher are so different from the skills required to be
an outstanding physician. Harold R. Roberts, M.D., of the University of North
Carolina at Chapel Hill, is an example of a physician-researcher who has benefited
from having his feet in both the world of patient care and the world of the
laboratory: he has let clinical problems direct his basic research effort and
conversely has adopted research advances in his care of patients.
Dr. Roberts's long and continuing career has included many research and
clinical advances. He was part of the first group to determine the amino acid
sequence of the important thrombin inhibitor hirudin and part of the group that
prepared the first cryoprecipitates which were the first alternative to plasma as
therapy in hemophilia A. Dr. Roberts has made significant advances in
understanding the protein chemistry behind hemophilia B; he was among the first
researchers to identify some patients as not being completely deficient but instead as
having measurable levels of protein and subsequently demonstrated that this protein
was dysfunctional. This important advance led him to a classification scheme for
patients into Cross Reacting Material (CRM) positive, negative, and reduced. Dr.
Roberts was the first to identify the molecular defect in a hemophilia B patient
(factor IX Chapel Hill). He was the first to identify defects in factor IX activation
and his group was one of the first to develop recombinant factor IX molecules with
significantly enhanced activity. His contributions as a physician are also numerous.
He was one of the first to argue for strong viral inactivation procedures in the
product supply. He was one of the first to treat patients with high purity factor
concentrates, recombinant factor concentrates (both hemophilia A and B) and with
high-dose recombinant factor VIla. He also conducted important research studies
on the mechanism behind the action of high dose factor VIla.
He has encouraged the exchange of information between scientists
internationally as the executive director of the International Society for Thrombosis
and Hemostasis and in 1978 he established the UNC-CH Center for Thrombosis and
v
vi Preface
Hemostasis to encourage collaborations among scientists at the University of North
Carolina at Chapel Hill.
Advances in both patient care and research have been rapid in the twentieth
century. Planners of the "Hemophilia Care in the New Millennium" symposium,
held in Chapel Hill on April 8-10, 1999, felt that on the eve of a new century it was
urgent to bring together physicians and researchers to look at four important areas
which are at the crossroads between patient care and research.
The symposium and this book are dedicated to Dr. Roberts in honor of his
many and continuing contributions to the field.
In this book, part I explores transmissible agents, especially viral agents, as
a risk to the blood supply. The chapter in this section describes the major viruses
that are transmitted as a consequence of transfusion. The chapter describes the
incidence of these viruses and presents information about the screening tests that are
available. This summary shows that current methods of viral inactivation have so
far proven quite effective and should, with due diligence, prove effective in the
future. However, the question of how to prevent transmission of infectious agents
hidden in cells has arisen. This chapter touches on current research into ways of
inactivating such transmissible agents. These studies may ultimately be brought to
the clinical setting to provide a safer blood supply.
In part II, Unexplained Aspects of Hemophilia and Hemostasis, the two
chapters look at clinical problems that present puzzles to researchers. These types
of problems provide some of the strongest rational for interaction between clinicians
and researchers. For example, protein S deficiency is clearly associated with
thrombotic complications in patients, yet assays commonly used in the research
laboratories have not unambiguously identified a mechanism for the action of
protein S. In this book, Dr. Nurden and colleagues form a clinical question by
combining two observations: 1) platelet aggregation appears to be important in the
development of atherosclerotic lesions and 2) some patients have platelet defects
such that their platelets do not aggregate. The investigators then pose the question:
do these defects protect patients from atherosclerosis? Also in this section, Dr.
Kalafatis and Dr. Mann give an overview of the function of factor V. Since
mutation of a specific residue of factor V, residue 506, leads to a common mutation
called factor V Leiden, and since activated protein C cleaves factor V at this
residue, it seems clear what is the cause of thrombosis in patient with the factor V
Leiden defect. However, this chapter explores many aspects of factor V behavior
and shows that, under some assay conditions, cleavage at residue 506 does not
appear all that important. So, both of these chapter illustrate the difficulty that
researchers often have in assigning a mechanism to clinical observations.
Preface vii
Part III, Novel Approaches to Therapy, describes ongoing research to
overcome the current limitations of replacement therapy. Currently, the standard of
care for hemophilia is replacement of the missing factor by injection of purified
protein. One chapter describes the use of high dose factor VIla to stimulate
thrombin generation by a mechanism independent of the usual physiology of blood
coagulation. Another chapter describes construction of factor VIII molecules that
are hybrids between human factor VIII and porcine factor VIII (which is also used
as a therapy in humans). These chimeric factor VIII molecules show promise to
avoid the inhibitor development that plagues the use of both products. Dr.
Mannucci and colleagues describe how a different method of administering the
currently used human product can possibly improve patient care. Also, part III
include a chapter on gene therapy, which provides the hope for curing, as opposed
to treating, hemophilia by supplying a patient with the gene for the missing protein.
Finally, in Part IV, Inhibitor Development in Hemophilia Patients,
chapters examine ways to overcome the serious problems that arise when
neutralizing antibodies develop in hemophilia patients. These chapters look at how
exciting research into basic immunology is leading to therapies that may go beyond
overcoming the effect of inhibitors and actually block or reverse the formation of
inhibitors in patients. The chapters look at B-cell, T-cell, and costimulatory
mediated mechanisms of blocking inhibitors. The mechanisms proposed in these
chapters may be the basis for new design of therapies.
A synergy between basic research and medical care has resulted in a
number of improvements in the care of people with hemophilia. It is hoped that this
book will become a resource for the ongoing dialogue between basic researchers,
who can attack problems that are of ongoing concern to physicians, and physicians,
who understand from patient interactions what the important problems are that need
to be solved.
My thanks to the members of my lab who assisted me with the final
preparation of the book for pUblication: Jennifer Browning, Alexis Henry, Eva
Olson, Diane Palmieri, Jay Shelton, and Jennifer Wemhoff.
Dougald M. Monroe, Ph.D.
School of Medicine
The University of North Carolina at Chapel Hill
ACKNOWLEDGMENTS
The editors wish to thank the following sources for their generous educational
grants in support of the symposium.
AHF, Inc.
American Red Cross
Baxter Hyland Immuno
Bayer Corporation, Pharmaceutical Division
Biogen, Inc.
Centeon LLC
Cerus Corporation
Chiron Corp.
The Coalition for Hemophilia B, Inc.
COBE BCT, Inc.
Genetics Institute
Green Mountain Antibodies, Inc.
Hemophilia Health Services
NabiT"
National Heart, Lung, and Blood Institute*
Novo Nordisk A/S
Speywood Pharmaceuticals, Inc.
Transkaryotic Therapies
* This publication was made possible by Grant Number 1 R13 HL62346-01 from the National Heart.
Lung. and Blood Institute. Its contents are solely the responsibility of the authors and do not necessarily
reflect the official views of the NHLBI.
ix
SPONSORS
Hemophilia Care: An International Symposium in Honor of Harold R. Roberts,
M.D., was presented by the UNC-CH Center for Thrombosis and Hemostasis, the
Harold R. Roberts, M.D., Comprehensive Hemophilia Diagnostic and Treatment
Center and the Hemophilia Treatment Centers in Region IV North. It was
sponsored by the School of Medicine of the University of North Carolina at Chapel
Hill.
xi
Contents
I. Infectious Disease Risk
1. The Transfusion-Transmitted Viruses in Blood Transfusion..................... 1
Naomi L.c. Luban and Rima F. Jubran
II. Unexplained Aspects of Hemophilia and Hemostasis
2. Are Patients with Glanzmann Thrombasthenia and the Bernard-
Soulier Syndrome Protected Against Atherosclerosis? ................... 13
Alan T. Nurden, Paquita Nurden and James N. George
3. Factor V: Dr. Jeckyll and Mr. Hyde.......................................................... 31
Michael Kalafatis and Kenneth G. Mann
III. Novel Approaches to Therapy
4. Gene Therapy for Hemophilia B: AA V-Mediated Transfer of the
Gene for Coagulation Factor IX to Human Muscle......................... 45
Peter J. Larson and Katherine A. High
5. Use of Prophylaxis to Prevent Complications of Hemophilia.................... 59
Pier M. Mannucci, L. Mendolicchio and A. Gringeri
6. Factor VIII Inhibitors ............................................................................... 65
Pete Lollar, John F. Healey, Rachel T. Barrow, Ernest T. Parker
7. Use of High Dose Factor VIla in Hemophilia Patients.............................. 75
Ulla Hedner
IV. Inhibitor Development in Hemophilia Patients
8. The Incidence of Inhibitors in Hemophilia A and the Induction of
Immune Tolerance ......................................................................... 89
Ernest Briet and MaIjolein Peters
xiii
