Inhibitors to Coagulation Factors PDF
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INHIBITORS TO COAGULATION FACTORS ADV ANCES 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 LAJTHA, N. S: Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 378 DENDRITIC CELLS IN FUNDAMENTAL AND CLINICAL IMMUNOLOGY, Volume 2 Edited by Jacques Banchereau and Daniel Schmitt Volume 379 SUBTILISIN ENZYMES: Practical Protein Engineering Edited by Richard Bott and Christian Betzel Volume 380 CORONA-AND RELATED VIRUSES: Current Concepts in Molecular Biology and Pathogenesis Edited by Pierre J. Talbot and Gary A. Levy Volume 381 CONTROL OF THE CARDIOVASCULAR AND RESPIRATORY SYSTEMS IN HEALTH AND DISEASE Edited by C. Tissa Kappagoda and Marc P. Kaufman Volume 382 MOLECULAR AND SUBCELLULAR CARDIOLOGY: Effects of Structure and Function Edited by Samuel Sideman and Rafael Beyar Volume 383 IMMUNOBIOLOGY OF PROTEINS AND PEPTIDES VIII: Manipulation or Modulation of the Immune Response Edited by M. Zouhair Atassi and Garvin S. Bixler, Jr. Volume 384 FATIGUE: Neural and Muscular Mechanisms Edited by Simon C. Gandevia, Roger M. Enoka, Alan J. McComas, Douglas G. Stuart, and Christine K. Thomas Volume 385 MUSCLE, MATRIX, AND BLADDER FUNCTION Edited by Stephen A. Zderic Volume 386 INHIBITORS TO COAGULATION FACTORS Edited by Louis M. Aledort, Leon W. Hoyer, Jeanne M. Lusher, Howard M. Reisner, and Gilbert C. White II A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. INHIBITORS TO COAGULATION FACTORS Edited by Louis M. Aledort Mount Sinai Medical School New York, New York Leon W. Hoyer American Red Cross Biomedical Services Rockville, Maryland Jeanne M. Lusher Wayne State University School of Medicine and The Children's Hospital of Michigan Detroit, Michigan Howard M. Reisner University of North Carolina at Chapel Hill Chapel Hill, North Carolina and Gilbert C. White II University of North Carolina at Chapel Hill Chapel Hill, North Carolina PLENUM PRESS • NEW YORK AND LONDON Library of Congress Cataloging-in-Publication Data On file Proceedings of the Second International Symposium on Inhibitors to Coagulation Factors, held November 3-5, 1993, in Chapel Hill, North Carolina ISBN-13: 978-1-4613-8001-6 e-ISBN-13: 978-1-4613-0331-2 DOl: 10.1007/978-1-4613-0331-2 © 1995 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1995 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N. Y. 10013 10987654321 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 Contributors Louis M. Aledort, Mt. Sinai Medical Center, New York, NY Jeff Alexander, Cytel Corporation, San Diego, CA M. Algiman, Centre des Hemophiles, H6pital Cochin, Paris, France Stylianos E. Antonarakis, Division of Medical Genetics, University of Geneva Medical School, and Cantonal Hospital, Geneva, SWitzerland; and Center for Medical Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD William R. Bell, Johns Hopkins University School of Medicine, Division of Hematology, Baltimore, MD R. Bellocco, Instituto Superiore di Sanita, Rome, Italy David C. Benjamin, Department of Microbiology and the Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Genter, Charlottesville, VA H. H. Brackmann, Institut Fur Exp Hiimatologie Und Transfusionmedizin -Der Universitiit Bonn, Bonn, Germany Ernest Briet, Hemostasis and Thrombosis Center, Department of Hema tology, University Hospital, Leiden, The Netherlands J. Donald Capra, Department of Microbiology, UT Southwestern Medical Center, Dallas, TX AdelIa Clark, Department of Pathology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Suzanne Courter, Baxter/Hyland, Glendale, CA Philippe de Moerloose, Hemostasis Unit, Cantonal Hospital, Geneva, Switzerland G. Dietrich, Unite INSERM 28, H6pital Broussais, Paris, France Pamela Esmon, Miles Inc., Berkeley, CA Jorn F. Falch, Novo Nordisk A/S, Biopharmaceuticals Division, Gentofte, Denmark A. B. Federici, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Institute of Internal Medicine and IRCCS Maggiore Hospital, University of Milano, Milan, Italy Matthew Felch, Holland Laboratory, American Red Cross, Rockville, MD Alessandra Franco, Cytel Corporation, San Diego, CA Christian Freiburghaus, Excorim AB, Lund, Sweden A. Ghirardini, Instituto Superiore di Sanita, Rome, Italy Jane Gitschier, Howard Hughes Medical Institute and University of v California, San Francisco, CA Contributors Steven Glazer, Novo Nordisk AlS, Biopharmaceuticals Division, Gentofte, Denmark Edward Gomperts, Baxter/Hyland, Glendale, CA Christopher Goodnow, Stanford University Medical Center, Stanford, CA Howard M. Grey, Cytel Corporation, San Diego, CA Charles Hay, Liverpool University Department of Haematology, Royal Liverpool University Hospital, Liverpool, England Ulla Hedner, Novo Nordisk AlS, Biopharmaceuticals Division, Gentofte, Denmark Stephen M. Hedrick, Department of Biology and the Cancer Center, University of California, San Diego, La Jolla, CA Katherine A. High, Children's Hospital of Phil~delphia, Philadelphia, PA . M. W. Hilgartner, Division of Pediatric Hematology, New York Hospital, New York, NY Leon W. Hoyer, Holland Laboratory, American Red Cross, Rockville, MD Deborah Hurst, Miles Inc., Berkeley, CA Pierre Hutter, Division of Medical Genetics, University of Geneva Medical School and Cantonal Hospital, Geneva, Switzerland Glenn Y. Ishioka, Cytel Corporation, San Diego, CA Srinivas S. Kaveri, Service d'Immunologie and INSERM U28, H6pital Broussais, Paris, France Mark A. Kay, Markey Molecular Medicine Center, Division of Medical Genetics, University of Washington, Seattle, WA M. D. Kazatchkine, Service d'Immunologie and INSERM U28, H6pital Broussais, Paris, France Haig H. Kazazian, Center for Medical Genetics, The Johns Hopkins University School of MediCine, Baltimore, MD Craig Kessler, George Washington University School of Medicine, Washington, DC Linda Levin, Department of Pathology, School of Medicine, and Depart ment of Endodontics, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC Pete Lollar, Division of Hematology-Oncology, Department of Medicine, Emory University, Atlanta, GA Jay N. Lozier, University of North Carolina School of Medicine, Depart ment of MediCine, Division of Hematology, Chapel Hill, NC Jeanne M. Lusher, Children's Hospital of Michigan, Wayne State Univer sity School of Medicine, Detroit, MI VI M. J. Manco-Johnson, University of Colorado Health-Science Center, Denver, CO Contributors P. M. Mannucci, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Institute of Internal Medicine and IRCCS Maggiore Hospital, University of Milano, Milan, Italy G. Mariani, University of Rome, Ematologia, Rome, Italy Alison Moliterno, Johns Hopkins University School of Medicine, Division of Hematology, Baltimore, MD Michael A. Morris, University of Geneva Medical School and Cantonal Hospital, Geneva, Switzerland Yale Nemerson, Mt. Sinai School of Medicine of the City University of New York, New York, NY Inga Marie Nilsson, Department for Coagulation Disorders, University of Lund, Malmo General Hospital, Malmo, Sweden Urs E. Nydegger, Center for Blood Transfusion, Inselspital, Bern, Switzer land L)awne M. Page, Department of Biology and the Cancer Center, Univer sity of California, San Diego, La Jolla, CA Virginia Pascual, Department of Microbiology, UT Southwestern Medical Center, Dallas, TX Richard Prescott, Holland Laboratory, American Red Cross, Rockville, MD Howard M. Reisner, Department of Pathology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Harold R. Roberts, Center for Thrombosis and Hemostasis, School of Medicine, University of North Carolina at Chapel Hill, NC M. A. Robinson, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD F. Rossi, Unite INSERM 28, H6pital Broussais, Paris, France Jorg Ruppert, Cytel Corporation, San Diego, CA Dorothea Scandella, Holland Laboratory, American Red Cross, Rockville, MD David W. Scott, University of Rochester Cancer Center and Department of Microbiology and Immunology, School of Medicine and Dentistry, Rochester, NY Alessandro Sette, Cytel Corporation, San Diego, CA Y. Sultan, Centre des Hemophiles, H6pital Cochin, Paris, France A. R. Thompson, Hemophilia Program, Puget Sound Blood Center, Seattle, WA J. Tusell, Hospital de Traumatologia y Rehabilitacio, Barcelona, Spain Gilbert C. White II, Department of Medicine and Pharmacology, Univer- VII sity of North Carolina at Chapel Hill, Chapel Hill, NC Preface "For the blood is the life .... "(Deut. 12 :23) ". .. because the blood, in its value as life, makes atonement" (Lev. 17: 11) HemoPhilia is a rare disease, severe hemophilia rarer still, yet the written history of hemophilia extends back over a millennium and a half. In the ancient Middle East, blood and life were coupled. Blood was the primary substance necessary for life, given to God in sacrifice and forbidden as a food to mortals by Levitical law. Blood was essential for rites of purification and consecration. But the flow of blood during menstruation or parturition rendered a woman unclean. The circumcision of a male child required 33 days of "blood purification" by the mother.' Circumcision, the visible reminder of the covenant of Abraham lijith Yahweh, was required of newborn Jewish males. It "connote(d) suitability for participation in what God is doing. "2 Hence, free and uncontrolled bleeding of the male child during circumcision, during the ratification of God's covenant, would be noted with awe and concern by those of the Jewish faith. It should not be surprising that the first genetic counseling offered to families with hemophilia is found in the Babylonian Talmud (compilation of Jewish law dated to about the third century AD) and concerns the necessity for circumcision in families with what we would now call hemophilia. It takes no retrodaction of modern genetic concepts into historical texts to demonstrate a sophisticated concept of the inherited basis of bleeding disorders by the 16th century codifier of Jewish law, Rabbi Joseph Karo.3.4 This brief historical introduction reminds us that the social costs and burdens of hemophilia render it far more important than it might be judged if only the limited number of affected patients is considered. Certainly, the availability of replacement therapy has had a dramatic effect on the life of the hemophiliac. The median life expectancy for a severe patient was 11 years in the 19th to early 20th centuries. In the seventh decade of this century (and before the advent of AIDS), median life expectancy approached that of normal males, only to decline drastically in the 1980s.5•6 Technology has removed most or all viral risk factors from currently available coagulation factor preparations but has done nothing to ameliorate the risk of hemophilic patients developing inhibitors (neutralizing antibodies) to F.vlll or EIX with therapy. Indeed, there are those who feel that the risk of inhibitor formation may be increased. If the social cost of hemophilia is high, the cost of caring for hemophiliacs with inhibitors is higher still. Inhibitor patients can no longer rely on well characterized factor replacement therapy but must avail themselves of "bypass" therapy, uncertain in efficacy and as yet poorly understood, or must undergo the time-consuming and extremely costly procedure of high-dose tolerance induction. During November 1983 a symposium organized by Leon Hoyer and Louis Aledort was held on the problem of inhibitors to coagulation factors. In the ten years following that symposium many significant advances have been made in hemophilia research. Pure F.VIII and EIX preparations produced by monoclonal antibody or recombinant DNA technologies IX Preface are available to patients. Improved porcine FVIII preparations, recombinant Vila, and "activated" prothrombin complex concentrates are available to circumvent preformed inhibitors. High-dose tolerance induction has proven effective in many patients, even those having high-titered inhibitors. But as we stand on the threshold of gene therapy for the hemophilias, we still do not know which patient will develop an inhibitor, how to prevent or ameliorate that occurrence, and, having developed an inhibitor, how best to deal with it. Considering the advances of the last ten years in the context of future genetic therapies for hemophilia and current unanswered questions, a Second International Symposium on Inhibitors to Coagulation Factors seemed timely and apropos. The Symposium, held in Chapel Hill, North Carolina, November 3-5, 1993, was designed to integrate modern concepts of immunology and hematology toward the design of potential new therapies directed toward the prevention or elimination of antibodies to FVIII and EIX. The reader of the following manuscripts, abstracts, and discussion session transcripts can decide how well that goal has been achieved. I wish to thank my fellow program committee members who generously took time from their pursuits to develop the agenda and plan the meeting: Louis M. Aledort, M.D., Leon W. Hoyer, M.D., Jeanne M. Lusher, M.D., Harold R. Roberts, MD., and Gilbert C. White II, M.D. My thanks as well to the local committee comprised of Herbert Cooper, M.D., Beth Lubahn, Ph.D., and Gail Macik, M.D. Their input in the early going laid a firm foundation for later planning. It was a pleasure to work with both committees. The generous financial grants and contributions by federal and state agencies and by industry allowed us to have both a symposium and this volume, a permanent record of the event. This synoptic acknowledgment should encourage the reader to note each individual contributor on the list. A second element, the human one, was also necessary for success. The Office of Continuing Medical Education at the University of North Carolina at Chapel Hill School of Medicine provided constant guidance and logistical support for all phases of the meeting. To name two individuals is to slight many, but the help of William Easterling, Jr., M.D., and Jane Radford is most gratefully acknowledged. Of course, our most profound thanks to Ms. Jaime Welch-Donahue of the Center for Thrombosis and Hemostasis of the UNC School of Medicine. Without her efforts, there would have been no Symposium, without her persistent efforts, there would have been no symposium volume. Howard M. Reisner, Ph.D. Chapel Hill, North Carolina References 1. Sperling, S.D. Blood in Freedman DN (ed.): The Anchor Bible Dictionary. New York: Doubleday 1992, vol. 1, P 761-763. 2. Hall, R.G. Circumcision in Freedman DN (ed.):The Anchor Bible Dictionary. New York: Doubleday 1992, vol. 1, P 1025-1031. (The quoted phrase is on 1026 column 2.) 3. Rosner, F. Hemophilia in the Talmud and Rabbinic Writings, Ann Int Med 70:833-837, 1969. 4. Rosendaal, F.R., Smit, c., Briet, E. Hemophilia Treatment in Historical Perspective: A Review of Medical and Social Developments, Ann Hematol 62:5-15, 1991. 5. Larsson, S.A. Life Expectancy of Swedish Haemophiliacs, 1831-1980, Brit J Haematol 59:593-602, 1985. 6. Jones, P.K., Ratnoff, O.D. The Changing Prognosis of Classical Hemophilia (Factor VIII x "Deficiency"), Ann Int Med 114:641-648, 1991. Acknowledgments The editors wish to thank the following sources for their generous educational grants in support of the symposium: Alpha Therapeutic Corporation American Diagnostica Inc. American Red Cross Armour Pharmaceutical Company Baxter Healthcare Corporation, Biotech Group, Hyland Division Behringwerke AG Boehringer Mannheim Corporation Cardiovascular Diagnostics, Inc. Centers for Disease Control and Prevention The Coalition for Hemophilia B COBE BCT, Inc. Genetics Institute, Inc. Glaxo Inc. Research Institute ImmunoAG Immuno-U.S., Inc. Miles Inc., Pharmaceutical Division, Biological Products National Heart, Lung, and Blood Institute North Carolina Biotechnology Center' Novo Nordisk AS, Biopharmaceuticals Division Organon Teknika Corporation Ortho Diagnostic Systems Inc. Porton Products Limited Quantum Health Resources 'The proceedings are based upon work supported in whole or in part by the North Carolina Biotechnology Center. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views and policies of the North Carolina Biotechnology Center. XI
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