Tài liệu HANDBOOK OF PLATELET PHYSIOLOGY AND PHARMACOLOGY ppt

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 <[email protected]>

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 <[email protected]>

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 A2 receptor

antagonists, and adenosine diphosphate receptor blockers (i.e. ticlopidine, clopidogrel).

In addition, inhibitors of arachidonic acid metabolism and thromboxane A2 include

aspirin, newer COX-2 inhibitors, other NSAIDs, thromboxane A2 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

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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

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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 a2b1-Integrin (GPIa/IIa, VLA2, 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

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5.6 Adenosine Effects on Intracellular Ca2+

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

viii Contents

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8. Fibrinogen Receptors: Biology and Function ...................... 162

8.1 Introduction ........................................................... 162

8.2 Characterization of the Platelet Fibrinogen

Receptor ............................................................... 163

8.3 Function ................................................................ 166

8.4 Post-Fibrinogen Binding Events ............................ 171

8.5 Conclusion ............................................................ 177

References .................................................................... 178

Platelet Biochemistry ........................................................ 188

9. Biochemistry of Platelet Activation ...................................... 188

9.1 Function ................................................................ 188

9.2 Morphology and Subcellular Organelles ............... 189

9.3 Platelet Activation and Responses ........................ 190

9.4 Signal Transduction Systems ................................ 194

9.5 Platelet Agonists and Their Signaling

Systems ................................................................ 206

9.6 Inhibition of Platelet Activation .............................. 211

9.7 Autocrine Stimulation and Inhibition ...................... 213

9.8 Crosstalk Between Different Signaling

Systems ................................................................ 214

9.9 Communication Between Platelets and Other

Blood Cells ........................................................... 215

9.10 Summary .............................................................. 217

References .................................................................... 217

10. GTP Binding Proteins in Platelets ....................................... 238

10.1 Introduction ........................................................... 238

10.2 G-Proteins and Signal Transduction ..................... 240

10.3 Low Molecular Weight GTP-Binding Proteins ........ 243

10.4 Summary .............................................................. 247

Contents ix

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References .................................................................... 247

11. Platelet Cyclic Nucleotide Phosphodiesterases .................. 251

11.1 Introduction ........................................................... 251

11.2 Regulation of Platelet Activation By cAMP and

cGMP .................................................................... 252

11.3 Classification of Cyclic Nucleotide PDEs .............. 252

11.4 Platelet cGI-PDE (PDE3A) .................................... 255

11.5 CGI-PDE Regulatory Domain ............................... 257

11.6 Platelet cGMP-Stimulated PDE (PDE2) ................ 260

11.7 Platelet cGMP-Binding, cGMP-Specific

Phosphodi-Esterase (cGB-PDE, PDE5) ................ 262

References .................................................................... 263

12. Polyenoic Fatty Acids and Platelet Function ....................... 268

12.1 Introduction ........................................................... 268

12.2 Platelet Function and Its Relevance to

Thrombosis ........................................................... 269

12.3 Polyunsaturated Fatty Acids (PUFAs) ................... 270

12.4 Platelet Membranes and Their Lipid

Composition .......................................................... 271

12.5 Arachidonic Acid and Platelet Elcosanoids ........... 273

12.6 Omega-3 Fatty Acids ............................................ 276

12.7 Omega-3 Fatty Acids and Platelet Function .......... 279

12.8 Docoshexaenoic Acid and Platelets ...................... 280

12.9 PUFAs and Their Newly Discovered Roles ........... 281

Concluding Comments .................................................. 284

Acknowledgements ....................................................... 285

References .................................................................... 286

13. Phospholipase A2 in Platelets .............................................. 293

13.1 Introduction ........................................................... 293

x Contents

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13.2 Pathways of Arachidonic Acid Release in

Platelets ................................................................ 294

13.3 Phospholipid Breakdown Measurements in

Stimulated Platelets .............................................. 296

13.4 Phospholipase A2 in Platelets ............................... 296

13.5 Calcium and Phospholipase A2 ............................. 298

13.6 Hydroperoxides and Phospholipase A2 ................. 302

13.7 Phosphatidic 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 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

Suspensions: Role of Pseudopods ....................... 323

Contents xi

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14.5 Model Cell Aggregation in Near-Stasis Versus

Stirred Suspensions .............................................. 324

14.6 Dynamics of Soluble Fg Binding (Receptor

Occupancy) and Platelet Aggregation as

Function of Shear Rate (66,67) ............................. 324

14.7 Dynamics of Von Willebrand Factor-Mediated

Platelet Aggregation ............................................. 327

14.8 Some New Directions ........................................... 330

14.9 Summary .............................................................. 332

Acknowledgements ....................................................... 333

References .................................................................... 333

15. Platelet Vessel Wall Interactions ......................................... 342

15.1 Introduction ........................................................... 342

15.2 Interaction of Platelets with Vascular

Subendothelium .................................................... 343

15.3 Interaction of Platelets with Extracellular

Matrices, Isolated Components of the Vessel

Wall or Purified Plasma Proteins ........................... 350

15.4 Concluding Remarks ............................................. 354

Acknowledgements ....................................................... 355

References .................................................................... 355

16. Platelet-Biomaterial Interactions .......................................... 362

16.1 Introduction ........................................................... 362

16.2 Contribution of Platelets to Thrombus

Formation ............................................................. 363

16.3 Platelet Adhesion on Biomaterials ........................ 364

16.4 Role of Plasma Proteins on Platelet Adhesion ...... 364

16.5 Effect of Shear on Platelet-Surface

Interaction ............................................................. 370

16.6 Role of Erythrocytes and White Cells on

Platelet-Biomaterial Interactions ........................... 370

xii Contents

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16.7 Platelet Activation and Morphological

Changes ............................................................... 371

16.8 Concluding Remarks ............................................. 374

Acknowledgements ....................................................... 375

References .................................................................... 375

17. Comparative Physiology of Platelets from Different

Species ................................................................................ 379

17.1 Introduction ........................................................... 379

17.2 Horse .................................................................... 380

17.3 Ruminants ............................................................ 382

17.4 DOG ..................................................................... 383

17.5 CAT ...................................................................... 385

17.6 PIG ....................................................................... 386

17.7 Rabbit ................................................................... 387

17.8 Rat and Mouse ..................................................... 387

17.9 Guinea PIG ........................................................... 388

Conclusions ................................................................... 389

References .................................................................... 389

Platelet Pathology ............................................................. 394

18. The Molecular Pathology of Glanzmann’s

Thrombasthenia ................................................................... 394

18.1 Introduction ........................................................... 394

18.2 Glanzmann Thrombasthenia ................................. 395

18.3 Genetics and Expression of the Platelet

GPIIb/IIIa Receptor ............................................... 397

18.4 Molecular Identification of Mutations ..................... 399

18.5 Mutations Resulting in Biosynthetic Defects .......... 408

18.6 Mutation Hotspots ................................................. 412