New Therapeutic Agents in Thrombosis and Thrombolysis, Second Edition, (Fundamental and Clinical Cardiology, V. 46)

705 Pages·2002·5.26 MB·English

by  Arthur Sasahara

New Therapeutic Agents
in Thrombosis
and Thrombolysis
Second Edition, Revised and Expanded
edited by
Arthur A. Sasahara
Brigham and Women’s Hospital and
Harvard Medical School
Boston,Massachusetts,U.S.A.
Joseph Loscalzo
Boston University Medical Center,
Whitaker Cardiovascular Institute,and
Boston University School of Medicine
Boston,Massachusetts,U.S.A.
Marcel Dekker, Inc. New York Basel
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Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
ISBN: 0-8247-0795-8
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Series Introduction
Marcel Dekker, Inc., has focused on the development of various series of beautifully produced
books in different branches of medicine. These series have facilitated the integration of rapidly
advancing information for both the clinical specialist and the researcher.
My goal as editor-in-chief of the Fundamental and Clinical Cardiology series is to
assemble the talents of world-renowned authorities to discuss virtually every area of cardiovas-
cular medicine. In this second edition of New Therapeutic Agents in Thrombosis and
Thrombolysis, Arthur A. Sasahara and Joseph Loscalzo have edited a much-needed and
timely book. Future contributions to this series will include books on molecular biology,
interventionalcardiology,andclinical managementofsuchproblemsascoronaryarterydisease
and ventricular arrhythmias.
Samuel Z. Goldhaber
iii
FUNDAMENTALANDCLINICALCARDIOLOGY
Editor-in-Chief
SamuelZ.Goldhaber,M.D.
HarvardMedicalSchool
andBrighamandWomen'sHospital
Boston,Massachusetts
AssociateEditor,Europe
HenriBounameaux,M.D.
UniversityHospitalofGeneva
Geneva,Switzerland
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ADDITIONALVOLUMESINPREPARATION

Preface
Since the publication of the first edition of New Therapeutic Agents in Thrombosis and
Thrombolysis book five years ago, our understanding of the determinants of the hemostatic
cascadehasevolvedconsiderably.Wecontinuetolearnmoreabouttheintricaciesoftheprimary
andsecondaryhemostaticandfibrinolyticpathways,andtobesurprisedatordisappointedwith
the results of the clinical applications of different agents targeted to these pathways. Recently,
there has been a flurry of activity in developing new pharmaceutical agents that target both
conventional and newly characterized pathways of hemostasis. These agents, which generally
impair coagulation, include low-molecular-weight heparins, direct thrombin inhibitors, tissue
factor pathway inhibitors, and an oral form of unfractionated heparin. New agents have been
produced to minimize the prothrombotic activity of activated platelets, such as thienopyridines
and the glycoprotein IIb/IIIa receptor antagonists. New thrombolytic agents are also being
developedandtestedtoachievegreaterefficacyofthrombolysisandtodosowithfewerbleeding
complications, especially intracranial hemorrhage.
Thebookisdividedintofourparts.Thefirstbeginswithanoverviewofnewdevelopments
inhemostasisandthrombolysis,followedbytwoother usefuloverviews.The‘‘DesignIssuesin
Clinical Trials’’ overview reflects the current thinking of the FDA on the development of these
new agents. Parts II and III focus on new heparins, thrombin inhibitors, and other new agents.
Chapters on low-molecular-weight heparins havebeen updated based on newer clinical studies,
for example, on hirudin, bivalirudin, and protein C. Notably, new chapters have been added on
pentasaccharide, TFP1, and soluble thrombomodulin.
In the last part, on thrombolytic agents, additional clinical studies have been included on
variantsoft-PA,aswellasonstaphylokinaseandprourokinase.Alfimepraseisanewandnovel
thrombolyticagentthatisnotaplasminogenactivator.Thelastchapterdiscussesrecentworkon
thrombolysis enhancement with ultrasound.
We are grateful to our distinguished section editors who remained with us from the first
edition:JeffreyWeitz,JackHirsh,JamesWillerson,andMarcVerstraete.Wearealsogratefulto
ournewsectioneditors:RobertGiugliano,ShakerMousa,andSamuelGoldhaber.Wealsowish
v
vi Preface
to thank Stephanie Tribuna, editorial assistant to Dr. Loscalzo. Special thanks to Sandra
Beberman, Vice President, Marcel Dekker, Inc., who convinced us to undertake this second
edition, and to Richard Johnson, Production Editor, whogave us continued support throughout
the process.
Arthur A. Sasahara
Joseph Loscalzo
Contents
Series Introduction Samuel Z. Goldhaber iii
Preface v
Contributors xi
PART I. Overview
1. Overviewof Hemostasis and Fibrinolysis 1
Joseph Loscalzo and Andrew I. Schafer
2. A Survey of Animal Models to Develop Novel Antithrombotic Agents 9
Walter P. Jeske, Omer Iqbal, Jawed Fareed, and Brigitte Kaiser
3. Design Issues in Clinical Trials of Thrombolytic and Antithrombotic Agents 33
Dina S. Stolman, Marc K. Walton, Dwaine Rieves, Victor F. C. Raczkowski,
and Jay P. Siegel
PART II. New Heparins, Thrombin Inhibitors, and Other New Agents
4. Overviewof New Anticoagulant Drugs 61
Jeffrey I. Weitz and Jack Hirsh
5. Low-Molecular-Weight Heparins in Acute Coronary Syndromes 75
David A. Morrow and Elliott M. Antman
6. Low-Molecular-Weight Heparin Use in Pregnancy 91
Wee Shian Chan and Jeffrey S. Ginsberg
vii