Table Of ContentTHE NEW DIMENSIONS
OF WARFARIN
PROPHYLAXIS
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
EPHRAIM KA TCHALSKI-KA TZIR, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
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THE NEW DIMENSIONS
OF WARFARIN
PROPHYLAXIS
Edited by
Stanford Wessler
New York University School of Medicine
New York, New York
Carl G. Becker
Cornell University Medical College
New York, New York
and
Yale N emerson
Mt. Sinai School of Medicine of the City University of New York
New York, New York
Springer Science+Business Media, LLC
Library of Congress Cataloging in Publication Data
International Symposium on the New Dimensions of Warfarin Prophylaxis (1986:
New York University Medical Center)
The new dimensions of warfarin prophylaxis.
"Proceedings of the International Symposium on the New Dimensions of Warfarin
Prophylaxis, held October 16-18, 1986, at the New York University Medical Center in
New York"-T.p. verso.
Includes bibliographies and index.
1. Warfarin - Therapeutic use - Congresses. 2. Thrombosis - Chemotherapy - Con
gresses. 3. Thrombosis-Prevention-Congresses. I. Wessler, Stanford, 1917-
II. Becker, Carl G. III. Nemerson, Yale. IV. Title. [DNLM: 1. Thromboembolism
prevention & control-congresses. 2. Warfarin-pharmacodynamics-congresses. 3.
Warfarin-therapeutic use-congresses. QV 193 I613n 1986)
RC694.3.I575 1986 616.1'35061 87-20260
ISBN 978-1-4757-5987-7 ISBN 978-1-4757-5985-3 (eBook)
DOI 10.1007/978-1-4757-5985-3
Proceedings of the International Symposium on the New Dimensions of
Warfarin Prophylaxis, held October 16-18, 1986, at the New York University
Medical Center in New York
© 1987 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1987.
Softcover reprint of the hardcover 1st edition 1987
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
The International Symposium on The New Dimensions of Warfarin
Prophylaxis held on October 16-18, 1986 in New York City was conceived as
a forum to bring together physicians and other scientists knowledgeable
about the pharmacological effects of warfarin on the hemostatic mechanism
and the clinical usefulness of this compound in the prevention of
thromboembolic phenomena.
The coumarin compounds have commanded a striking breadth of interest
among members of the biomedical research community for almost one-half
century. Aspects of its effects on the vitamin K-dependent proteins, on
the laboratory recognition of the drug's pharmacologic action and its use
as a therapeutic agent in a variety of disease states have been actively
studied with increasing intensity in the past several decades. Thus, the
present state of these studies seemed to be a timely subject for
discussion, not only to gather together in one place representative
samples of the myriad of data on warfarin, but also to underscore the
ever increasing necessity for communication between basic research and
clinical practice.
The content and organization of this monograph reflect the scope and
importance of warfarin prophylaxis. One of the unique aspects of this
publication is that it spells out in one place the warfarin story from
molecular biology through clinical trials to future directions of
research and patient care.
The editors wish to thank DuPont Pharmaceuticals for a generous
educational grant in support of the symposium. Without their financial
backing this symposium would not have become a reality. We wish also to
thank both the American Heart Association, New York City Affiliate and
the National Heart, Lung and Blood Institute, National Institutes of
Health for their co-sponsorship.
Car 1 G. Becker
Yale Nemerson
Stanford Wessler
New York, NY
October 1986
v
CONTENTS
The Scope of Thromboembolism 1
S. Wessler
VITAMIN K-DEPENDENT PROTEINS
The Biochemical Basis of Warfarin Therapy 3
J.W. Suttie
Warfarin and the Biochemistry of the Vitamin K Dependent
Proteins •••.• • • • • • • • 17
E.G. Bovill and K.G. Mann
Anticoagulation Proteins C and S • • • • • • • • • • • • • • • • 47
C.T. Esmon, S. Vigano-D'Angelo, A. D'Angelo, and P.C. Comp
Warfarin and Bone: Implications for Rational Strategies to
Selectively Antagonize the Action of Vitamin K in
Target Tissues • • • • • • •.••• 55
P.A. Price
Human Genes for Factor IX and Other Vitamin K Dependent
Blood Protiens • • •••••• 67
K. Kurachi and S.H. Chen
THE PROTHROMBIN TIME
Tissue Factor. • • • • • • • • • • • • 83
Y. Nemerson
INR - Calibration of the Therapeutic Range • • • • • • • • • . • • • • 95
L. Poller
Cold-Promoted Activation of Factor VII and Shortening
of the Prothrombin Time • • • • • • • • • • • • • .113
H.R. Gralnick and O.J. Wilson
Immunologic Aspects of Vessel Injury and Thrombosis ••••.•••• 131
C.G. Becker
What's The Dose? • • • • • • • • • • • • • • • • • • • • • • • . • . .149
S. Wessler
VENOUS THROMBOEMBOLISM - PRIMARY PROPHYLAXIS
Venous Thromboembolism in
Moderate Risk Patients •••••••••••••••.••••• 153
E. Genton
vii
Two-St8P warfarin Therapy for the Prophylaxis of
Venous Thrombosis after Elective Surgery •.••...••.•. 159
V.J. Marder and C.W. Francis
Prevention of Venous Thromboembolism in High-Risk Patients
by Prophylactic Administration of Oral Anticoagulants .•.•• 165
E.W. Salzman
Genetic Coagulation Defects ••••..•.••..•..•.•..• 175
E. Marciniak
VENOUS THROMBOEMBOLISM - SECONDARY PROPHYLAXIS
Treatment of First Episode of Venous Thrombosis . . • . .187
J. Hirsh, M. Levine, and R. Hull
Management of Recurrent VEnous Thromboembolism ••..•..•...• 195
K.M. Moser
SPECIAL ISSUES
Warfarin Metabolism and Drug-Drug Interactions .•.•...••..• 205
R.A. O'Reilly
Improving the Benefit/Risk Ratio • . • • . • . . . • . • . • . . . .213
S. Wessler
Oral Anticoagulant Therapy and Skin Necrosis: Speculations
on Pathogenesis .•.•.....••.•..•.••• 217
C.G. Becker
CARDIOVASCULAR - ARTERIAL THROMBOEMBOLISM
Clinical Trials in Myocardial Infarction and
Coronary Heart Disease. • • . .. • .•....•.•..• 223
L.H. Kuller
Anticoagulants in Acute Myocardial Infarction ..••••...•.•. 231
D. Deykin
Long-Term Anticoagulant Treatment after Acute Myocardial
Infarction ...•...••.......••.•••.•... 243
A.W. Broekmans and E.A. Loeliger
Following Coronary Thrombolysis .•.••.•.•...•.....•. 255
S. Sherry
Arterial Thromboembolism: Valvular Heart Disease
and Prosthetic Heart Valves. . . . . • . . . . . .265
J.E. Dalen
NEUROVASCULAR - ARTERIAL THROMBOEMBOLISM
Clinical Trial Dilemmas and Cerebrovascular Disease • • . . . • .271
L.H. Kuller
Atrial Fibrillation and Stroke: The View from Cardiology •...•. 279
J.E. Dalen
viii
Atrial Fibrillation and Stroke: The View from Neurology .•...•.• 283
D.G. Sherman
Cardiac Embolic Stroke: Anticoagulating the Elderly ....•..••. 291
S. wessler
Anticoagulants for the Treatment of Transient
Ischemic Attacks • . . • . . . . . • . . • . . . . . • . • . • .299
F.H. McDowell
Epilogue. . .317
Contributors .325
Index. . . . .327
ix
THE SCOPE OF THROMBOEMBOLISM
Stanford Wessler
Department of Medicine
New York University School of Medicine
550 First Avenue, New York, NY
Why, the question may be appropriately asked, should there be, in 1986,
a 3-day symposium on warfarin prophy1axis--a drug, after all, that was
introduced into clinical medicine 45 years ago?
It is because new knowledge concerning the pathophysiology of
hemostasis, the effect of warfarin on an increasing number of vitamin
K-dependent proteins and the results of recent clinical trials, have
dramatically enhanced the usefulness of oral anticoagulants in both the
primary and secondary prevention of thromboembolic episodes in an ever
broader range of clinical conditions prone to intravascular coagulation.
The impact of thromboembolism unchecked, on mortality and morbidity in
the U.S. is impressive. Thrombosis is a pathologic process that complicates
the course and contributes to the lethal nature of several major killers in
American society. Arterial thrombosis plays a role in the initiation,
growth, and terminal occlusion of the atherosclerotic lesion and is a major
contributor to mortality in acute myocardial infarction and stroke, the
number 1 and 3 causes of death in the United States. In addition,
thromboembolic events are frequently associated with cardiac arrhythmias,
congestive failure, shock, valvular heart disease and intimal damage to
arteries in the cerebral, cervical, aortoiliac, visceral, and peripheral
areas of the circulation. Some inborn errors of metabolism, infections,
blood dyscrasias, trauma, drugs, and certain diseases of unknown etiology
are also associated with arterial as well as venous thrombosis.
Venous thromboembolism itself causes approximately 300,000 patients
annually to be hospitalized in the United States, of whom more than 50,000
die, primarily in hospitals, rehabilitation centers, and nursing homes where
prophylaxis would be feasible. Pulmonary embolism is a major threat to life
in the postoperative state. It is the most frequent nonsurgical cause of
death among patients hospitalized for hip fractures and major orthopedic
reconstructive surgery; a co~on cause of mortality following neurosurgical
procedures; the most frequent nonobstetrical cause of postpartum death; a
major factor in mortality among the extensive population of patients with
chronic cardiac and pulmonary disease, and among an equally large group who
are subjected to prolonged immobilization because of a variety of medical
and surgical conditions. Indeed, in hospitalized adult patients who die,
careful autopsy examinations disclose evidence of antemortem pulmonary
embolism in more than 60% of cases.
