RECOMBINANT TECHNOLOGY IN HEMOSTASIS AND THROMBOSIS

Transcription

1 RECOMBINANT TECHNOLOGY IN HEMOSTASIS AND THROMBOSIS

2 RECOMBINANT TECHNOLOGYIN HEMOST ASIS AND THROMBOSIS Edited hy Leon W. Hoyer and William N. Drohan Jerome H. Holland Laboratory American Red Cross B100d Services Rockville, Maryland SPRINGER SCIENCE+BUSINESS MEDIA, LLC

3 Llbrary of Congress Cataloglng-ln-Publlcatlon Data American Red Cross Scientific Symposium (21st D.C. ) 1990 Washington, Recombinant technology in hemostasis and thrombosis I edited by Leon W. Hoyer.nd William N. Drohan. p. cm. "Proceedlngs of the American Red Cross Twenty-first Annual Scientific Symposium, impact of recombinant technalogy in hemostasis and thrombosis, held May 15-16, 1990, in Washington, DC"--T.p. verso. Includes bibliographical references and index. ISBN ISBN (ebook) DOI / i. Blooa--Coagulation, Dlsorders of--congresses. 2. Recombinant proteins--congresses. 3. Blood--Coagulation--Congresses. 4. Blood coagulatlon factors--biotechnology--congresses. 1. Hoyer, Leon W. II. Drohan, Wi 11 iam. III. T1tle. [DNLM, 1. Blood Coagulation Disorders--diagnosis--congresses. 2. Blood Coagulation Disorders--drug therapy--congresses. 3. Biood Coagulat ion Factors--congresses. 4. Recombinant Proteins- -congresses. 5. Thrombosis--drug therapy--congresses. WH 322 A215r RC647.C55A '57--dc20 DNLM/DLC for Llbrary of Congress CIP Proceedings of the American Red Cross Twenty-first AnnuaJ Scientific Symposium: Impact of Recombinant Technology in Hemostasis and Thrombosis, held May 15-16, 1990, in Washington, D.C. ISBN Springer Science+Business Media New York OriginaJly published by Plenum Press, New York in 1991 Softcover reprint ofthe hardcover 1 st edition 1991 Ali rights reserved No part of this book may be reproduced, stored in a retrieval system, Of transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

4 PREFACE Recent progress in molecular biology has led to a rapid expansion of our understanding of the proteins that are essential for hemostasis and thrombosis. The goal of the XXI Annual Scientific Symposium of the American Red Cross was to provide a forum to explore and document the impact of recombinant DNA technology in this field. The speakers described the essential features of the genes responsible for key plasma proteins important in hemostasis, including procoagulant Factors VIII and IX and anticoagulant proteins, Antithrombin III and Protein C. They emphasized the advances in recombinant DNA technology that have led to the cloning of these genes. Careful examination of the gene sequence has then provided a clearer understanding of the structure of the encoded proteins, and has given additional insight into their functional domains and their interactions in hemostasis. At the same time, these advances have made it possible to better characterize hemostatic disorders. A large number of published studies have shown that the mutations affecting biological activity are clustered in areas that define functional domains. They have led to fundamental advances in our understanding of specific diseases and they have made it possible to develop more accurate and sensitive diagnostic tests for the detection of the disease states. v

5 Recombinant DNA technology is also beginning to be used to produce coagulation proteins for clinical use. The first example of this is the outstanding technical accomplishment of producing human coagulation Factor VIII in mammalian tissue culture cells, and the subsequent evaluation of the recombinant-produced protein in clinical trials. During this symposium, the advantages and limitations of protein production by recombinant technology were carefully examined by the participants. The rapid progress during the past decade provides strong support for the view that even more remarkable advances will soon be available to improve the treatment of diseases affecting hemostasis and thrombosis. The success of the symposium was due to the efforts of the Program Committee that planned and chaired the scientific sessions: Morris A. Blajchman, M.D., William N. Drohan, Ph.D., Leon W. Hoyer, M.D., Kenneth G. Mann, Ph.D., and Frederick J. Walker, Ph.D. The rapid publication of these proceedings has been facilitated by the excellent editorial assistance of Debbie Wilder. Leon W. Hoyer, M.D. William N. Drohan, Ph.D. vi

6 CONTENTS CHARACTERIZATION OF GENE AND PROTEIN STRUCTURE Biosynthesis and Assembly of the Factor VIII-von Willebrand Factor Complex Jan A. van Mourik, Anja Leyte, Harm B. van Schijndel, Martin Ph. Verbeet, Jan Voorberg, Ruud D. Fonteijn, Hans Pannekoek, and Koen Mertens Factor IX: Gene Structure and Protein Synthesis D.B.C. Ritchie, D.L. Robertson, and R.T.A. MacGillivray Antithrombin III Genetics, Structure and Function Susan Clark Bock Interactions Between the Functional Domains of Antithrombin III Paula R. Boerger, Robert M. Wolcott, Morgan Lorio, and Michael N. Blackburn Protein C: Gene Structure and Protein Synthesis George L. Long Structural and Functional Properties of Protein C Frederick J. Walker MOLECULAR DEFECTS AFFECTING HEMOSTASIS Molecular Defects in Hemophilia A Leon W. Hoyer Molecular Defects in Hemophilia B Arthur R. Thompson Molecular Defects in Human Antithrombin III Deficiency W.P. Sheffield, F. Fernandez-Rachubinski, R.C. Austin, and M.A. Blajchman The Biologic Impact of Hereditary Defects that Cause Thrombosis Kenneth A. Bauer

7 PROTEIN PRODUCTION BY RECOMBINANT TECHNOLOGY Factors Limiting Expression of Secreted Proteins in Mammalian Cells Randal J. Kaufman, Robert J. Wise, Louise C. Wasley, and Andrew J. Dorner Synthesis of Biologically Active Vitamin K-Dependent Coagulation Factors Barbara C. Furie and Bruce Furie The Expression of Therapeutic Proteins in Transgenic Animals Rekha Pa1eyanda, Janet Young, William Ve1ander, and William Drohan CLINICAL USE OF PROTEINS PRODUCED BY RECOMBINANT TECHNOLOGY The Use of Animal Models to Evaluate Proteins Produced by Recombinant Technology Alan R. Giles Experiences with Recombinant Factor VIla in Hemophiliacs Ulla Hedner Clinical Trials of Factor VIII Produced by Recombinant Technology Richard S. Schwartz Clinical Trials of Recombinant Factor VIII Gilbert C. White, II, and Clinical Study Group CONCLUDING OVERVIEW The Impact of Recombinant Technologies in Understanding Plasma Proteins Important for Hemostasis and Thrombosis Kenneth G. Mann Contributors Index viii