HANDBOOK OF PLATELET PHYSIOLOGY AND PHARMACOLOGY Edited by Gundu H. R. Rao University of Minnesota KLUWER ACADEMIC PUBLISHERS Boston / Dordrecht / London Distributors for North, Central and South America: Kluwer Academic Publishers 101 Philip Drive Assinippi Park Norwell, Massachusetts 02061 USA Telephone (781) 871-6600 Fax (781) 871-6528 E-Mail <kluwer@wkap.com> Distributors for all other countries: Kluwer Academic Publishers Group Distribution Centre Post Office Box 322 3300 AH Dordrecht, THE NETHERLANDS Telephone 3178 6392 392 Fax 3178 6546 474 E-Mail <services@wkap.nl> Electronic Services <http://www.wkap.nl> Library of Congress Cataloging-in-Publication Data Handbook of platelet physiology and pharmacology / edited by Gundu H.R. Rao. p. cm. Includes bibliographical references and index. ISBN 0-7923-8538-1 (alk. paper) 1. Blood platelets Handbooks, manuals, etc. I. Rao, Gundu H.R 1938- . QP97.H36 1999 612.ri7-dc21 99-27962 CIP Copyright © 1999 by Kluwer Academic Publishers All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo- copying, recording, or otherwise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, Massachusetts 02061 Printed on acid-free paper. Printed in the United States of America List of Contributors 1 . Kailash C. Agarwal, Ph. D. Department of Molecular Pharmacology, Brown University Providence, RI 02912,USA 2. Colin N. Baigent, Ph. D. ATT Collaboration CTSU Harkness Building Radcliffe Infirmary Woodstock Road Oxford 0X2 6HE United Kingdom 3. Rodger L. Bick, M. D., Ph. D. Departments of Pathology & Pharmacology Loyola University Med. Center 21260 South First Ave. Maywood, IL 60153,USA 4. David C. Calverley, M. D. USC School of Medicine 1441EastlakeAve NOR MS 34 Los Angeles, CA 90033, USA 5. Thomas Chandy, Ph. D. Chemical Engineering and Material Sciences University of Minnesota Minneapolis, MN 55455, USA 6. Kenneth J. Clemetson, Ph. D. Theodor Kocher Institut Der Universitat Bern Freiestrasse 1, Ch-3012 Berne Switzerland 7. Robert W. Colman, M. D. Thrombosis Research Center Temple Univ. Sch. of Medicine 3400 N. Broad Street Philadelphia, PA 19140,USA 8. Maribel Diaz-Ricart, Ph. D. Servicio de Hemoterapia Hospital Clinico Provincial Villarroel 170, Barcelona 08036, Spain 9. Gines Escolar, M. D. Ph. D. Servicio de Hemoterapia Hospital Clinico Provincial Villarroel 170, Barcelona 08036, Spain. 10. Daniel Fareed, B.Sc. Departments of Pathology & Pharmacology Loyola University Med. Center 2 1260 South First Ave. Maywood, IL 60153,USA 1 1 . Jawed Fareed, Ph. D. Departments of Pathology & Pharmacology Loyola University Med. Center 2 1 260 South First Ave. Maywood, IL 60153,USA 12. Deborah French, M. D. Department of Medicine Mount Sinai Hospital & Medical School One Gustave L. Levy Place New York, NY 10029-6574,USA 1 3. Mony M. Frojmovic, Ph. D. Mclntyre Medical Science Building McGiIl University 3655 Drummond Street Montreal, QB Canada, H3GIY6 14. Nicholas J.Greco, Ph. D. Platelet Biology Laboratory American Red cross 1 5601 Crabbs Branch Way Rockville, MD 20855,USA 15. HolmHolmsen,Ph.D. Department of Biochemistry and Molecular Biology University of Bergen Astradveien 19, Bergen N5009, Norway 1 6. Debra Hoppensteadt, Ph. D. Departments of Pathology & Pharmacology Loyola University Med. Center 2 1260 South First Ave. Maywood, IL 60153,USA 17. Huzoor-Akbar, Ph. D. Molecular and Cellular Biology Department of Biological Sciences, Irvine Hall Athens, OH 45701,USA 1 8. G. A. Jamieson, Ph. D, D. Sc. Platelet Biology Laboratory American Red Cross 15601 Crabbs Branch Way Rockville, MD 20855,USA 1 9. Gerhard J. Johnson, M. D. Veterans Affairs Medical Center One Veterans Way Minneapolis, MN 55417,USA 20. BeateKehrel,Ph.D. Experimental and Clinical Haemostaseology Department of Anaesthesiology and Intensive Care Medicine University of Muenster D-48149 Muenster, Germany 2 1 . Bruce R.Lester, Ph. D,. Knowledge Frontiers 3989 Central Ave, N. E., # 625 Minneapolis, MN 55421,USA 22. Mahadev Murthy, Ph. D. Division Endocrinolgy, Metabolism & Nutrition Department of Medicine Hennepin County Medical Center 914 South Eighth Street, D-3 Minneapolis, MN 55404. USA 23. Ellinor I. Peerschke, Ph. D. Cornell Medical Center New York University 525 E 68th Street, Rm F51 1 J New York, NY 10021,USA 24. Anna S. Radomski Division of R and D Lacer, S.A. 08025 Barcelona Spain 25. Marek W. Radomski, M.D,D.Sc. Division of R and D Lacer, S.A., 08025 Barcelona Spain 26. Gundu H. R. Rao, Ph. D. Departments of Lab. Med. & Pathol. and Biomed. Engineering P.B. 609 UMHC Academic Health Center University of Minnesota Minneapolis, MN 55455,USA 27. A. Koneti Rao, M. D. Department of Medicine Temple University School of Medicine 3400 N. Broad St Rm 300-OMS Philadelphia, PA 19140,USA 28. Gerald J. Roth, M. D. Division of Hematology V.A. Medical Center 1660 South Columbian Way Seattle, WA 98108,USA 29. Anita Ryningen, Ph. D. Department of Biochemistry and Molecular Biology University of Bergen Astradveien 19 Bergen N-5009 Norway 30. Shivendra D. Shukla, Ph. D. University of Missouri- Columbia 517B Medical Science Building One Hospital Drive Columbia, MO 65212,USA 3 1 . Cathie Sudlow, Ph. D. ATT Collaboration CTSU Harkness Building Radcliffe Infirmary Woodstock Road Oxford OX2 6HE United Kingdom 32. Narendra N. Tandon, Ph. D. Thrombosis & Vascular Biology Otsuka America Pharmaceutical 9900 Medical Center Drive Rockville, Maryland 20850, USA 33. Jeanine M. Walenga, Ph. D. Departments of Pathology & Pharmacology Loyola University Medical Center 2 1260 South First Ave. Maywood, IL 60153,USA 34. Douglas J. Weiss, D. V.M., Ph. D. Department of Pathobiology and Veterinary Sciences University of Minnesota St. Paul, MN 55108,USA 35. Helmut Wolf, M. D, Ph. D. Departments of Pathology & Pharmacology Loyola University Medical Center 2 1260 South First Ave. Maywood, IL 60153,USA PREFACE Despite my many years of research and teaching in platelet physiology and pharmacology at the University of Minnesota, I am often confronted with conflicting opinions as to the relevance of nonnucleated platelets in human health and disease. It is fascinating to think that how cells with no apparent nucleus, have such a towering impact on concepts, dealing with often overlapping physiological (i.e. hemostasis, wound healing, etc.) and pathophysiological (i.e. thrombosis, stroke, atherosclerosis, wound healing, diabetes, inflammation and cancer) components. Although the idea of compiling new frontiers of platelet research in the form of a book was quite simple at the beginning, the project turned out to be a major undertaking from my part. At the end, I am elated that the contributors to this book were gracious enough to write chapters in their area of research expertise despite their pressing and highly valuable time. For me, it has been an humbling experience as the chapters that I have compiled, are written by people with incredible recognition for their relentless contributions over the years to strengthen the understanding of platelet physiology and pharmacology. In my opinion, this has added an immense value to the book. I am proud to have been involved in this undertaking despite several unexpected problems and delays during this project. I am confident that this book would be highly useful to the community of scientists, including graduate students, researchers, academicians, physicians and other health care professionals, and pharmaceutical industry scientists. Circulating platelets which lack nucleus neither adhere to the vessel wall nor aggregate unless they encounter a zone of injury. Upon encountering such a zone of injury, they become almost instantly activated, which leads to their adhesion and aggregation, both reactions are of fundamental importance to hemostasis and thrombosis. Because of this reason, platelet research has clearly led the way in the continuing development of new strategies and drugs that can help prevent and treat arterial thrombosis, stroke and atherosclerosis. Unquestionably, platelet research has also impacted concepts dealing with many other diseases. Nevertheless, considerable progress has been made in the development of new antiplatelet agents in recent years. These newer agents are aimed at interrupting specific sites and pathways of platelet activation. Inhibitors of specific platelet agonist-receptor interactions include antithrombins, thromboxane A 2 receptor antagonists, and adenosine diphosphate receptor blockers (i.e. ticlopidine, clopidogrel). In addition, inhibitors of arachidonic acid metabolism and thromboxane A 2 include aspirin, newer COX-2 inhibitors, other NSAIDs, thromboxane A 2 synthase inhibitors and o>-3 fatty acids. Moreover, long awaiting drugs that block ligand binding to the platelet glycoprotein Ilb/IIIa complex (i.e. tirofiban) have now entered the market. In this book, the chapters are organized into six major sections, including Introduction, Receptor Biology, Platelet Biochemistry, Experimental Physiology, Platelet Pathology and Platelet Pharmacology. Authoritative chapters in each section have provided a collective strength to our initial philosophy of accomplishing a comprehensive review of current concepts in each discipline. Although every attempt has been made to provide an interdisciplinary discussion on the subject of platelets in this book, there may still be some gaps and lapses for which readers are urged to consult other articles and reviews. I have deliberately avoided going into any specific comments on reviews in order to let the imagination of the readers flow freely. I believe that the readers are intelligent enough to judge and form their own critical opinion. I must humbly express my deep gratitude to thirty five scientists in the field for their invaluable contributions. I now honestly believe that this publication would not have been possible without their meritorious contributions. I am deeply indebted to my dear friend and close research collaborator, Mahadev Murthy, Ph. D., Director of Research, Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA, for his commitment and contribution to this project. He has spent countless hours during this project in reviewing and preparing camera ready manuscripts for final submission to the Kluwer Academic Publisher. In addition, he has written two excellent chapters for the book. I must confess that this publication would not have been completed without his generous and truly dedicated efforts. I would like to take this opportunity to thank Charles W. Schmieg, Jr., Acquisitions Editor, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA, for facilitating the publication of this book. I am specially thankful for his cooperation and patience even though this project was delayed by about four months. Finally, I would not be in this field today without my mentor, James G. White, M. D., Regents' Professor & Associate Dean, Academic Health Center, University of Minnesota, Minneapolis, MN, USA. I humbly dedicate this publication to James G. White, M. D., who has been my mentor, teacher, associate and dear friend, during my long career in platelet research. In the end, my academic success and accomplishments over the years, would not have been possible without the support of my wife Yashoda, my daughter Aupama and my son Prashanth. I sincerely acknowledge and appreciate their patience and support throughout my career. Gundu H. R. Rao University of Minnesota Professor Minneapolis, MN 55455 v This page has been reformatted by Knovel to provide easier navigation. Contents Contributors ix Preface xiii Introduction 1 1. Platelet Physiology & Pharmacology: an Overview 1 1.1 Introduction 1 1.2 Role of Platelets in Hemostasis and Thrombosis 2 1.3 Platelet Morphology and Biochemistry 2 1.4 Platelet Physiology 5 1.5 Altered Physiology and Function 6 1.6 Platelet Pharmacology 8 1.7 Platelet Function Inhibitory Drugs 9 1.8 Acknowledgements 14 References 15 Receptor Biology 21 2. Human Platelet Thrombin Receptors and the Two Receptor Model for Platelet Activation 21 2.1 Introduction 21 2.2 Binding Studies 22 2.3 Membrane Microviscosity 24 2.4 Candidate Receptors 26 vi Contents This page has been reformatted by Knovel to provide easier navigation. 2.5 The GPIb-IX-V Complex 27 2.6 Two Receptor Model 31 References 33 3. Platelet Thromboxane Receptors: Biology and Function 38 3.1 Introduction 38 3.2 Biological Effects of TP Receptor Activation 39 3.3 Smooth Muscle Contraction 39 3.4 TP Receptor Structure 41 3.5 TP Receptor Function 49 3.6 Altered TP Receptor Function 58 References 66 4. Collagen Receptors: Biology and Functions 80 4.1 Introduction 80 4.2 Collagens 82 4.3 Von-Willebrand-Factor 83 4.4 P65 84 4.5 CD36 84 4.6 a 2 b 1 -Integrin (GPIa/IIa, VLA 2 , ECMRII) 87 4.7 GPVI/FcRg 89 4.8 Collagen-Induced Signal Transduction 90 References 92 5. Adenosine Receptors: Biology and Function 102 5.1 Introduction 102 5.2 Adenosine Receptors 103 5.3 Antiplatelet Action of Adenosine 104 5.4 Adenosine Production and Platelet Inactivation 106 5.5 Agents Affecting Adenosine Actions 109 Contents vii This page has been reformatted by Knovel to provide easier navigation. 5.6 Adenosine Effects on Intracellular Ca 2+ Mobilization 113 5.7 Conclusions 114 References 115 6. Platelet Activating Factor and Platelets 120 6.1 PAF Discovery, Structure and Heterogeneity 120 6.2 PAF Biosynthesis in Platelets 121 6.3 Responses of Platelets to PAF 122 6.4 PAF Receptor and Signal Transduction Pathways in Platelets 123 6.5 Antagonist 124 6.6 PAF Receptor 125 6.7 Phospholipases 126 6.8 Platelet and PAF in Pathophysiological and Disease States 129 6.9 Acknowledgement 133 References 133 7. Platelet Glycoprotein Ib-V-IX: Biology and Function 142 7.1 Introduction 142 7.2 Structure 143 7.3 Post-Translational Modification of GPIb-V-IX 145 7.4 Basic Functions 146 7.5 Signal Transduction 148 7.6 GPIb-V-IX as a Target for Pharmacological Inhibition 149 7.7 Genetic Disorders Affecting GPIb-V-IX 151 7.8 Tissue Specific Expression of GPIb-V-IX Subunits 153 7.9 Future Developments 154 References 155 [...]... both human and animal models Furthermore, a careful correlation between signal-driven responses and platelet function will lead to a better understanding of platelet pathophysiology (27,31, also discussed in other chapters) 1.6 Platelet pharmacology Earlier studies on platelet biochemistry, physiology and function suggest that release of granule contents is essential for recruitment of platelets, irreversible... provide a comprehensive review on various aspects of platelet physiology and pharmacology 1.2 Role of platelets in hemostasis and thrombosis Platelets contribute significantly to the normal hemostatic process (1-6) They play a critical role in the recognition of injured vasculature, formation of hemostatic plugs, prevention of bleeding, retraction of clots and wound healing (6-9) When they develop severe... of Platelet Function 460 21.5 Mechanisms of NO Action on Platelets 461 21.6 Peroxynitrite 462 21.7 Nitric Oxide and Vascular Disorders 463 21.8 Nitric Oxide, Platelets and Septicemia 464 21.9 Pharmacology of NO Generation and Action in the Platelet Microenvironment 465 Acknowledgements 469 References 469 22 Aspirin, Prostaglandins and Platelet Function: Pharmacology. .. aggregation and secretion of granule contents Platelet activation is a prerequisite for the formation of a hemostatic plug and arrest of bleeding at the injured site Although formation of a hemostatic plug is a natural response to injury, the role of platelets in atherosclerosis, thrombosis and stroke are pathological manifestations (1-19) 1.3 Platelet morphology and biochemistry Blood platelets have... discussed in other chapters of this book) Binding results in the activation and stimulation of various effector enzymes and formation of second messengers, leading to aggregation and secretion of granule contents Specific mechanisms involved in the process of centralization of granules and release of their contents are poorly understood(26,27, 31) 1.5 Altered physiology and function Many investigators... easier navigation 1 PLATELET PHYSIOLOGY AND PHARMACOLOGY: AN OVERVIEW Gundu H R Rao, Ph D Departments of Laboratory Medicine & Pathology and Biomedical Engineering Institute Academic Health Center University of Minnesota, Minneapolis, MN 55455, USA 1.1 INTRODUCTION Dr Gundu Rao has spent the last 25 years studying and teaching platelet physiology and pharmacology at the University of Minnesota Over the... antiplatelet and antithrombotic drugs have provided a great deal of excitement and have led to the discovery of many specific antagonists Although the biochemistry of platelets remains highly complex, we now have well defined pathways that could impact platelet functional responses It is very likely that further understanding of the role of these pathways and the specific mechanisms that underlie platelet. .. Activation and Aggregation in Flow 316 14.3 Range of Shear Rates in Normal and Pathological Settings 317 14.4 Flow Regimes and Corresponding Devices Used to Study in Vitro Platelet Aggregation 318 14.2 Ligands and Receptors Involved in Platelet Aggregation 319 14.3 Quantitation of Aggregation: Theoretical and Experimental Approaches 322 14.4 Platelet Aggregation in Non-Stirred Platelet. .. Acid and Platelets 302 13.8 PAF and Phospholipase A2 303 13.9 LDL and Platelet Function 304 Concluding Remarks 304 Acknowledgements 305 References 305 Experimental Physiology 315 14 Platelet Biorheology: Adhesive Interactions in Flow 315 14.1 Introduction: General Overview for Flow Studies of Platelet Aggregation 315 14.2 General Physiology of Platelet. .. Medicine & Pathology and Biomedical Engineering Institute References 1 Marcus AJ, Zucker MB The physiology of blood platelets New York: Crime and Scrutton, 1965 2 Kowalski E, Niewiarowski S Biochemistry of blood platelets New York: Academic Press, 1966 3 Caen J Platelet aggregation Paris: Masson and Cie, 1971 4 Brinkhous KM, Sherman RW, Mostof FK The Platelet Baltimore: Williams and Wilkson Co, 1971 . HANDBOOK OF PLATELET PHYSIOLOGY AND PHARMACOLOGY Edited by Gundu H. R. Rao University of Minnesota KLUWER ACADEMIC. <http://www.wkap.nl> Library of Congress Cataloging-in-Publication Data Handbook of platelet physiology and pharmacology / edited by Gundu H.R.