Table Of ContentPhospholipid-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
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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
