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Phospholipid-Binding Antibodies Editors E. Nigel Harris Associate Professor Division of Rheumatology University of Louisville Louisville, Kentucky Thomas Exner Department of Hematology Westmead Hospital Westmead, Sydney, Australia Graham R. V. Hughes Consultant Rheumatologist Head Lupus Arthritis Research Unit The Rayne Institute St. Thomas' Hospital London, England Ronald A. Asherson Director of Clinical Research The Lupus Arthritis Research Unit The Rayne Institute St. Thomas' Hospital London, England Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW. Suite 300 Boca Raton, FL 33487-2742 Reissued 2019 by CRC Press © 1991 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-0-367-23036-4 (hbk) ISBN 13: 978-0-429-27812-9 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com PREFACE The current explosion of literature on phospholipid-binding antibodies must be attributed in part to the diverse clinical and biomedical backgrounds of investigators interested in the subject. Such diversity has the potential for providing much broader insight into this subject and the possibility of obtaining significant new information. On the other hand, individual investigators in this field are often limited by their specialty interests and may find it difficult to appreciate the full breadth of information available about phospholipid-binding antibodies. This book was designed primarily to establish dialogue between the various specialty interests working on phospholipid-binding antibodies. The book is divided into six sections, each section dealing with a different aspect of phospholipid-binding antibodies. Each section is introduced by one or more chapters giving a broad overview of the particular subject. The first section has only two chapters and provides (we believe) necessary background information on the “Biochemistry of Phos- pholipids” and on “Phospholipids and Clotting”. The second section deals with the “Im- munology of Phospholipid Binding Autoantibodies” , but for readers who are not immunologists, the section is introduced by an overview on “Autoantibodies”, followed by an overview of “Lipid Antibodies”. In like manner, we introduce the section on “Phos- pholipid Binding Antibodies and Thrombosis” with chapters on “The Diagnosis and Man- agement of Arterial Thrombosis”. Chapters on “Habitual Abortion” and on “Pregnancy in SLE” introduce the section on “Phospholipid Binding and Pregnancy Loss”. The last section of the book deals with the clinical entity that is coming to be known as the “Anti- Phospholipid Syndrome”. This section begins with a short introductory chapter that tries to place the subsequent discussion in perspective. It was inevitable that in a book with so many contributors, there would be areas that overlap in some of the discussions. This was particularly evident in the section on “Throm- bosis”, where mechanisms of action of phospholipid-binding antibodies were discussed. Despite some overlap in discussions of this subject, it was intriguing how various groups of investigators interpreted the same set of data differently, or differed in their choices of information to highlight. Since there is no “truth” about phospholipid-binding antibodies (as yet), these differences in points of view and interpretation are exactly what are required for new ideas and research findings to emerge. There are a number of contributors to the study of phospholipid-binding antibodies who have not written chapters in this text, but whose work I feel merit special consideration (this list is very far from complete). To name a few: Sandor Shapiro (crucial work on specificities of antibodies responsible for the lupus anticoagulant phenomenon); Takao Koike (specificities of monoclonal and polyclonal anti-phospholipid antibodies); Pier Luigi Meroni (anti-mito- chondrial and anti-endothelial antibodies); Guido Valesini (anti-idiotype anti-cardiolipin an- tibodies); Donato Alarcon-Segovia (introduction of useful concepts on the Anti-Phospholipid Syndrome); Renee Norberg and Wendell Wilson (both of whom explored several clinical aspects of these antibodies, including their relationship to complement); Steven Levine and Robin Brey (work on phospholipid-binding antibodies and stroke). As our knowledge grows, it is likely that future books on this subject will assume quite a different character and the list of contributors will become longer. This is only a beginning. Given the rarity with which I am able to acknowledge (in print) the people who most support the work I do, I shall seize this opportunity to say thanks to my wife (Yvette), to my children (Zaman, Tamia, and Sandhya), to Sheila Thorpe, to Alexis, Denise and Michael Harris, and to Jan Carew and Wilson Harris. What contributions I have made in this book are dedicated to the memory of my mother, Cicely Harris. E. Nigel Harris, M.D., DM. EDITORS E. Nigel Harris, B.S., MPhil., M.D., D.M., is an associate professor in the Department of Medicine at the University of Louisville, Louisville, KY. Dr. Harris received his B.S. degree in chemistry from Howard University in 1968. He received a Master of Philosophy degree in Biochemistry from Yale University in 1973. Dr. Harris studied medicine at the University of Pennsylvania and received an M.D. degree in 1977. He specialized in internal medicine at the University of the West Indies in Jamaica and received a doctor of medicine (D.M.) degree in internal medicine in 1982. He joined Dr. Graham Hughes as a research fellow in rheumatology at the Hammersmith Hospital (London, England) during the period 1983 to 1985. In 1985, with Doctors Graham Hughes and Azzudin Gharavi, he founded the Lupus Research Unit at St. Thomas’ Hospital. Doctor Harris returned to the United States in 1987, where he joined the faculty of medicine at the University of Louisville. Dr. Harris has published over 80 papers on anti-phospholipid antibodies. Along with Doctors Graham Hughes and Azzudin Gharavi, he has organized four international symposia on this subject. He has established an anti-phospholipid standardization laboratory at the University of Louisville and in addition to ongoing work on standardization of anti-phos- pholipid antibody tests, this laboratory is investigating specificities and mechanisms of action of these antibodies. Thomas Exner, Ph.D., is Principal Scientific Officer in the Hematology Department, Westmead Hospital, Westmead, Sydney, Australia. Dr. Exner graduated in 1965 from Sydney University with an M.Sc. degree in inorganic chemistry and subsequently obtained his Ph.D. degree in biochemistry from the University of Waterloo, Ontario, Canada in 1972. Dr. Exner is a member of Haematology Society of Australia, the International Society of Thrombosis and Haemostasis (ISTH), the New York Academy of Sciences, Australian Society for Medical Research and the Sydney Protein Group. He is currently chairman of the subcommittee on Lupus Anticoagulant Standardization of the ISTH Scientific and Stand- ardization Committee and is a consultant for the Australian Coagulation Quality Assurance Program and the Hemostasis Reference Laboratory at Westmead. Dr. Exner has been the recipient of research grants from the National Health and Medical Research Council and the National Heart Foundation. He has made over 50 presentations at various national and international meetings and has published approximately 70 research papers. His current major research interests include the study of circulating anticoagulants, surface binding phenomena and enzymes from snake venoms. Graham R. V. Hughes, M.D., F.R.C.P., is head of the Lupus Arthritis Research Laboratory, Rayne Institute, St. Thomas’ Hospital and Consultant Rheumatologist at St. Thomas’ Hospital, London. Dr. Hughes qualified at the London Hospital in 1964 and his post-graduate experience included two years in New York (Columbia Presbyterian and Cornell Universities). He succeeded Professor Bywaters as head of Rheumatology in the Hammersmith Hospital and took up his present post at St. Thomas’ Hospital in 1985. Dr. Hughes is a member of the American College of Rheumatology, The British Society of Rheumatology, The Association of Physicians, and is an honorary member of the Aus- tralian and New Zealand Rheumatology Society, Greek Rheumatology Society, Scandana- vian Rheumatology Society and Hong Kong Rheumatism Association. He is Honorary Consultant Rheumatologist to the Royal Air Force. Dr. Hughes is the author of more than 500 papers and author or co-author of seven books. Ronald Asherson, M.D., F.A.C.P., F.C.P., graduated from the University of Cape Town School of Medicine, South Africa in 1957. He received a Fellowship of the South African College of Physicians in 1964 and from then to 1975, apart from a private practice commitment, he served as a Clinical Tutor in the Department of Medicine of the Groote Schuur Hospital, Cape Town. From 1976 to 1980 he was an Assistant Clinical Professor of Medicine at the New York Hospital—Cornell Medical Center under the late Prof. Henry Heinemann. He joined Dr. Graham R. V. Hughes, Head of the Rheumatology Unit at the Royal Postgraduate Medical School of London in 1981 and moved with him to St. Thomas’ Hospital, London in 1986. He was appointed as Honorary Consultant Physician at St. Thomas’ Hospital in 1988 and is Senior Research Fellow at the Rayne Institute and Director of Clinical Research of the Lupus Arthritis Research Unit. Dr. Asherson is the author of more than 150 papers and abstracts on systemic lupus erythematosus and other rheumatological topics, particularly in the field of anti-phospholipid antibodies. His current interests still include clinical relationships and associations of the anti-phospholipid antibodies, the “Primary” Anti-phospholipid Syndrome, hormonal influ- ences in the connective tissue diseases and coagulopathies associated with these disorders. CONTRIBUTORS Carl R. Alving Christine L. Cook Department of Membrane Biochemistry Associate Professor Walter Reed Army Institute of Research Department of Obstetrics and Gynecology Washington, D.C. University of Louisville School of Medicine Ronald A. Asherson Louisville, Kentucky Director of Clinical Research The Lupus Arthritis Research Unit F. Susan Cowchock The Rayne Institute Professor St. Thomas’ Hospital Department of Medicine London, England Thomas Jefferson University Hospital Philadelphia, Pennsylvania Genesio Balestrieri Ph.G. de Groot Deputy Director Department of Hematology Servizio Immunologia Clinica University Hospital Spedali Civili Utrecht, The Netherlands Brescia, Italy R. H. W. M. Derksen Edouard M. Bevers Department of Internal Medicine Department of Biochemistry Division of Immunopathology University of Limburg University Hospital Maastricht, The Netherlands Utrecht, The Netherlands D. Ware Branch Murdo G. Elder Assistant Professor Professor Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology University of Utah RPMS Institute of Obstetrics and Salt Lake City, Utah Gynecology London, England Luis O. Carreras Head of Thrombosis and Hemostasis Keith B. Elkon Division of Hematology Associate Professor University of Buenos Aires Department of Rheumatic Disease Buenos Aires, Argentina Cornell University Medical Center New York, New York Jean-Pierre Cazenave Department of Hemostasis and Thomas Exner Thrombosis, U.311 INSERM Department of Hematology Centre Régional de Transfusion Sanguine Westmead Hospital Strasbourg, France Westmead, Sydney, Australia Colin N. Chesterman Jean-Marie Freyssinet Professor Department of Hemostasis and Department of Hematology Thrombosis, U.311 INSERM Prince of Wales Hospital Centre Régional de Transfusion Sanguine Randwick, New South Wales, Australia Strasbourg, France Azzudin E. Gharavi Munther A. Khamashta Department of Medicine Deputy Director Cornell University Medical Center Lupus Research Unit New York, New York The Rayne Institute St. Thomas’ Hospital David Green London, England Professor Department of Medicine Steven A. Krilis Northwestern University Medical School Senior Lecturer Chicago, Illinois University of New South Wales School of Medicine Délia Grunebaum Kogarah, New South Wales, Australia Department of Hemostasis and Thrombosis, U.311 INSERM Michael D. Lockshin Centre Régional de Transfusion Sanguine Director, Extramural Program Strasbourg, France National Institute of Arthritis and Musculoskeletal and Skin Diseases E. Nigel Harris National Institutes of Health Associate Professor Bethesda, MD Division of Rheumatology University of Louisville Wilhelm F. Lubbe Louisville, Kentucky Professor Paula Hasselaar Department of Medicine University of Auckland Departments of Internal Medicine and Hematology Auckland, New Zealand Division of Immunopathology University Hospital Samuel J. Machin Utrecht, The Netherlands Department of Hematology Middlesex Hospital Ching-hsien Huang London, England Professor Department of Biochemistry Neil A. MacLachlan University of Virginia School of Lecturer Medicine Queen Charlotte’s and Chelsea Hospital Charlottesville, Virginia RPMS Institute of Obstetrics and Gynecology Graham R. V. Hughes London, England Consultant Rheumatologist Head, Lupus Arthritis H. Patrick McNeil Research Unit Department of Medicine The Rayne Institute Harvard Medical School St. Thomas’ Hospital Boston, Massachusetts London, England Neil S. Pattison Andrew S. JanofT Senior Lecturer Executive Director of Research Department of Obstetrics and Gynecology The Liposome Company, Inc. University of Auckland Princeton, New Jersey Auckland, New Zealand Dwight D. Pridham Douglas A. Triplett Instructor Professor Department of Obstetrics and Gynecology Department of Pathology University of Louisville School of Indiana University of Medicine Medicine Muncie, Indiana Louisville, Kentucky Jos G. Vermylen Joyce Rauch Professor Associate Professor Department of Medicine Department of Medicine University of Leuven McGill University Leuven, Belgium Montreal, Quebec, Canada Konrad Wicher Catherine Ravanat Research Physician Department of Hemostasis and Wadsworth Center for Laboratories and Thrombosis, U.311 INSERM Research Centre Régional de Transfusion Sanguine New York State Department of Health Strasbourg, France Albany, New York Jan Rosing Victoria Wicher Department of Biochemistry Senior Research Scientist University of Limburg Wadsworth Center for Laboratories and Maastricht, The Netherlands Research New York State Department of Health James R. Scott Albany, New York Professor and Chairman Department of Obstetrics and Gynecology Marie-Louise Wiesel University of Utah Department of Hemostasis and Salt Lake City, Utah Thrombosis, U.311 INSERM Centre Régional de Transfusion Sanguine Helge Stormorken Strasbourg, France Professor Department of Medicine, Rikshospitalet Robert F. A. Zwaal University of Oslo Professor Oslo, Norway Department of Biochemistry University of Limburg Angela Tincani Maastricht, The Netherlands Deputy Director Servizio Immunologia Clinica Spedali Civili Brescia, Italy TABLE OF CONTENTS SECTION I: PHOSPHOLIPIDS AND CLOTTING Chapter 1 Structures and Properties of Self-Assembled Phospholipids in Excess Water....................3 Ching-hsien Huang Chapter 2 Phospholipids and the Clotting Process...................................................................................31 Robert F. A. Zwaal, Edouard M. Severs, and Jan Rosing SECTION II: THE IMMUNOLOGY OF PHOSPHOLIPID-BINDING AUTOANTIBODIES Chapter 3 Autoantibodies: Their Nature and Significance......................................................................59 Keith B. Elkon Chapter 4 Antibodies to Lipids and Lipid Membranes: Reactions with Phosphatidylcholine, Cholesterol, Liposomes, and Bromelin-Treated Erythrocytes..............................................73 Carl R. Alving Chapter 5 Phospholipid Antibodies in Natural and Experimental Syphilis..........................................97 Konrad Wicher and Victoria Wicher Chapter 6 Role of Monoclonal Antibodies in Understanding the Interactions Between Anti-Phospholipid Antibodies and Phospholipids..................................................................107 Joyce Rauch and Andrew S. Janoff Chapter 7 The Immunology of Phospholipid-Binding Antibodies in the Anti-Phospholipid Syndrome and Related Disorders.............................................................123 E. Nigel Harris, Genesio Balestrieri, Angela Tincani, and Azzudin E. Gharavi SECTION III: MEASUREMENT OF PHOSPHOLIPID-BINDING ANTIBODIES Chapter 8 Lupus Anticoagulants: Characteristics, Methods of Laboratory Detection and Some Clinical Associations...............................................................................................141 Thomas Exner and Douglas A. Triplett Chapter 9 Acquired Circulating Anticoagulants Other than Lupus Anticoagulants...........................159 Thomas Exner and David Green

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