Platelets, Second Edition

PLATELETS is the definitive current source of state-of-the-art knowledge about platelets and covers the entire field of platelet biology, pathophysiology, and clinical medicine. Recently there has been a rapid expansion of knowledge in both basic biology and the clinical approach to platelet-related diseases including thrombosis and hemorrhage. Novel platelet function tests, drugs, blood bank storage methods, and gene therapies have been incorporated into patient care or are in development. This book draws all this information into a single, comprehensive and authoritative resource. · First edition won Best Book in Medical Science Award from the Association of American Publishers · Contains fourteen new chapters on topics such as platelet genomics and proteomics, inhibition of platelet function by the endothelium, clinical tests of platelet function, real time in vivo imaging of platelets, and inherited thrombocytopenias · A comprehensive full color reference comprising over 70 chapters, 1400 pages, and 16,000 references Front cover......Page 1 Title page......Page 5 ISBN 0123693675......Page 6 Part One - Platelet Biology......Page 9 Part Three - The Role of Platelets in Disease......Page 10 Part Four - Disorders of Platelet Number and Function......Page 11 Index......Page 12 Contributors......Page 13 Preface......Page 23 Foreword: A Brief History of Ideas about Platelets in Health and Disease......Page 25 Part One: Platelet Biology......Page 45 II. Invertebrates......Page 47 III. Nonmammalian Vertebrates......Page 49 IV. Comparative Hemostasis......Page 50 V. A Comparison of Human Platelets and Limulus Amebocytes......Page 53 VI. The Evolution of Hemostasis and Blood Coagulation......Page 57 VII. Megakaryocytes and Mammals......Page 58 References......Page 62 II. Megakaryocyte Development......Page 67 III. Platelet Formation......Page 71 V. Murine Model Systems and Human Diseases as Tools to Study Platelet Biogenesis......Page 81 References......Page 83 II. Peripheral Zone......Page 89 III. The Sol–Gel Zone......Page 96 IV. Organelle Zone......Page 103 V. Platelet Membrane Systems......Page 110 References......Page 115 II. The Structure of the Resting Platelet......Page 119 III. The Cytoskeleton of the Resting Platelet......Page 121 IV. The Structure of the Activated Platelet......Page 125 VI. Membrane Dynamics and Actin Filament Turnover in Platelets......Page 131 VIII. Diseases of the Platelet Cytoskeleton......Page 132 References......Page 134 II. Platelet Genomics......Page 143 III. Platelet Proteomics......Page 149 IV. Overview and Future Directions......Page 157 References......Page 158 I. Introduction......Page 161 II. Integrins......Page 162 III. Leucine-Rich Repeat (LRR) Family......Page 164 IV. Seven Transmembrane Receptors......Page 165 V. Immunoglobulin Superfamily......Page 167 VII. Tetraspanins......Page 172 X. Tyrosine Kinase Receptors......Page 173 XI. Miscellaneous Platelet Membrane Glycoproteins......Page 175 References......Page 178 I. Introduction/Structure......Page 189 II. Function......Page 192 III. Signaling......Page 199 IV. The End of the Beginning......Page 201 References......Page 202 III. Structure of aIIbb3......Page 209 IV. “Inside-Out” Signaling and aIIbb3 Activation......Page 212 V. Conclusion......Page 216 References......Page 217 II. Cellular Actions of Thrombin......Page 223 III. Role of PARs in Disease......Page 227 IV. Molecular and Developmental Genetics of PARs......Page 228 V. Thrombin Signaling in Platelets......Page 231 VI. Development of PAR Inhibitors......Page 234 References......Page 235 II. Roles of Adenine Nucleotides in Platelet Function......Page 245 III. P2Y1......Page 246 IV. P2Y12......Page 248 V. P2X1......Page 252 VIII. Conclusions......Page 254 References......Page 255 III. Expression and Adhesive Properties of the Extracellular Domain......Page 265 IV. Phosphorylation, Cytoskeletal Association, and Protein Interactions of the PECAM-1 Cytoplasmic Domain......Page 266 V. PECAM-1 as a Bidirectional Regulator of Platelet Reactivity and Thrombosis......Page 268 VI. Allelic and Soluble Isoforms of PECAM-1 and Their Association with Cardiovascular Disease......Page 270 References......Page 271 II. Platelet Thrombus Formation on Subendothelial Surfaces under Flow......Page 275 III. Leukocyte Adhesion to Endothelial Cells under Flow......Page 277 V. Platelet Adhesion to Endothelial Cells under Flow......Page 281 VII. Multicellular Interactions of Platelets, Leukocytes, and Endothelial Cells under Flow......Page 282 VIII. Consequences of Leukocyte–Platelet–Endothelial Cell Interactions in Vivo......Page 284 IX. Conclusions......Page 285 References......Page 286 II. Nitric Oxide......Page 295 III. Prostacyclin......Page 301 IV. CD39 (NTPDase-1)......Page 306 References......Page 310 I. Introduction......Page 325 II. The Molecular Basis for Platelet Polymorphisms......Page 326 III. Clinical Consequences of Platelet Polymorphisms......Page 335 IV. Conclusions......Page 339 References......Page 340 III. Mechanisms of Platelet Exocytosis......Page 353 V. Platelet Cytoskeleton and Secretion......Page 356 VII. Disorders of Platelet Secretion......Page 357 References......Page 358 II. Stages in Platelet Plug Formation......Page 363 III. Conclusion......Page 382 References......Page 383 II. Structural Basis for Integrin aIIbb3-Dependent Signaling......Page 391 III. Effectors of Outside-In aIIbb3 Signaling......Page 393 IV. Role of Phosphorylation of the aIIb and b3 Cytoplasmic Tails......Page 396 References......Page 397 II. Initial Events in Thrombus Formation under Flow......Page 403 III. Secondary Events Leading to Thrombus Propagation under Flow......Page 409 References......Page 415 II. Enzyme Complex Formation Regulates the Coagulant Response......Page 421 III. Model Systems Defining the Role of Platelets in Tissue Factor-Initiated Thrombin Generation......Page 424 IV. Intrinsic Platelet Proteins Involved in the Coagulant Response......Page 425 V. Coagulation Reactions Supported by the Activated Platelet Surface......Page 429 VI. Positive and Negative Effectors of Platelet Coagulant Activity......Page 434 References......Page 437 II. Microparticle Structure......Page 447 III. Detection of Microparticles......Page 448 IV. Formation of Platelet Microparticles......Page 450 V. Microparticle Function......Page 452 VI. Clinical Disorders Associated with Microparticles......Page 453 VII. Future Developments......Page 454 References......Page 455 II. Key Mediators......Page 459 III. Mechanisms of Fibrinolysis......Page 464 IV. Platelet–Fibrin(ogen) Interactions......Page 465 V. Surgery, Fibrinolysis, and the Platelet......Page 467 VI. Fibrinolytic Response to Inflammation and Infection......Page 468 VII. Fibrinolysis, the Platelet, and Angiogenesis......Page 469 References......Page 470 III. Platelet Production......Page 475 IV. Platelet Structure......Page 476 V. Measurements of Platelet Function......Page 477 VI. Platelet Activation during Delivery......Page 479 VIII. Platelet Signal Transduction......Page 480 XI. Effects of Drugs on Fetal and Neonatal Platelet Function......Page 481 XIII. Conclusions......Page 482 References......Page 483 Part Two: Tests of Platelet Function......Page 487 II. History of Platelet Function Testing and Overview of Currently Available Tests......Page 489 III. Clinical Utility of Platelet Function Testing......Page 499 IV. Summary and the Future of Platelet Function Testing......Page 509 References......Page 510 I. Introduction......Page 519 III. Automated Platelet Counting......Page 520 IV. Conclusions......Page 525 References......Page 526 II. The Development of the Bleeding Time......Page 529 IV. Contributions and Benefi ts of the Bleeding Time......Page 531 V. Is There a Need for More Clinical Research Using the Bleeding Time?......Page 532 References......Page 534 I. Introduction......Page 539 II. Variables of Platelet Aggregation Testing......Page 542 III. Platelet Agonists......Page 545 V. Medications That May Affect Platelet Aggregation......Page 547 VI. Inherited Platelet Function Defects......Page 549 References......Page 550 II. Mechanism......Page 553 III. Correlation with Other Measures of Platelet Inhibition......Page 557 IV. Association of Platelet Function Results and Clinical Outcomes......Page 558 V. Conclusions......Page 560 References......Page 561 II. Disorders of Platelet Function......Page 563 IV. PFA-100......Page 564 V. Conclusions......Page 573 References......Page 574 II. Impact: The Cone and Plate(let) Analyzer (CPA) Technology......Page 579 III. Modifying the Impact for Testing Platelet Aggregation......Page 580 IV. Testing Congenital Primary Hemostasis Abnormalities......Page 582 VII. Testing Aspirin and Clopidogrel Effects......Page 583 VIII. Diagnosis of Thrombotic Microangiopathies......Page 585 References......Page 587 I. Introduction......Page 589 II. Measurement of Platelet Activation......Page 590 III. Diagnosis of Specific Disorders......Page 595 IV. Monitoring of Antiplatelet Agents......Page 596 V. Monitoring of Thrombopoiesis......Page 597 VIII. Platelet Count......Page 598 IX. Other Research Applications......Page 599 References......Page 601 II. Thromboxane Biosynthesis......Page 609 III. TxA2 Signaling......Page 610 IV. The Biological Activity of TxA2......Page 611 V. Thromboxane Metabolism......Page 612 VI. Monitoring of TxA2 Metabolites......Page 613 References......Page 614 II. Influences of Shear Stress on Platelet Transport......Page 619 III. Perfusion Devices......Page 620 V. Perfusate......Page 623 VII. Methods to Quantify Platelet Deposition......Page 624 VIII. Influence of Shear on Platelet Reactivity......Page 625 References......Page 626 II. Simulating Platelet Disorders in Animals......Page 631 III. Measurement of Platelet Function and Survival in Animals......Page 639 References......Page 643 I. Introduction......Page 655 II. Equipment and Methods......Page 656 III. Data Acquisition and Analysis......Page 660 IV. Study of Thrombus Formation......Page 661 V. Conclusions......Page 667 References......Page 668 Part Three: The Role of Platelets in Disease......Page 671 I. Introduction......Page 673 III. Inflammation in Atherothrombosis......Page 674 IV. Platelets: An Essential Mediator in Atherothrombosis......Page 677 V. The Atheromatous Plaque and Plaque Rupture......Page 679 VI. Atherothrombosis and Endothelial Progenitor Cells......Page 681 VIII. Genetics and Genomics of Atherothrombosis......Page 682 IX. Clinical Aspects and Management of Coronary Atherothrombosis......Page 685 References......Page 689 II. Ischemic Cerebrovascular Disease......Page 701 III. Platelet Activation in the Development of Focal Cerebral Ischemia......Page 702 IV. Hemorrhagic Transformation......Page 708 V. Antiplatelet Interventions in Cerebral Ischemia......Page 709 VI. Carotid Artery Atherothrombotic Disease......Page 715 VII. Cerebral Embolism from a Cardiac Source......Page 716 VIII. Conclusions......Page 717 References......Page 718 I. Overview of Peripheral Arterial Disease......Page 729 II. Platelet-Vessel Wall Interactions in PAD......Page 730 III. Characteristics of Platelet Function in PAD......Page 732 IV. Platelet-Mediated Therapy in PAD......Page 733 References......Page 735 III. Pathophysiological Contributions of Platelets to Diabetic Vascular Disease......Page 741 IV. The Diabetic Thrombocytopathy and the Stem Cell Hypothesis......Page 743 V. Platelet Activation......Page 745 VI. Leukocyte-Platelet Cross-Talk in Diabetes......Page 746 VII. Therapeutic Consequences......Page 747 References......Page 748 II. Platelet Interactions with the Endothelium......Page 757 III. Platelet Interactions with Leukocytes......Page 759 IV. Platelet-Derived Infl ammatory and Immune-Modulating Factors......Page 761 V. Inflammatory Receptors Modulating Hemostasis and Thrombosis......Page 762 VII. Conclusions......Page 764 References......Page 765 II. Mammalian Platelets are Multipurpose Inflammatory Cells......Page 771 III. Early Studies Were Interpreted to Suggest Platelets Promote Infection......Page 772 IV. Platelets Likely Play Multiple and Key Roles in Antimicrobial Host Defense......Page 773 V. Platelets Contain Antimicrobial Effector Molecules That Contribute to Host Defense......Page 777 VI. Platelet Antimicrobial Peptides Likely Function via Multiple Mechanisms of Action......Page 782 VIII. PMPs Likely Modulate Pathogen Interactions with Platelets and Endothelial Cells......Page 784 X. Platelets Potentiate the Antimicrobial Functions of Leukocytes......Page 785 XI. Platelets Are Integral to Antimicrobial Host Defense In Vivo......Page 786 XIII. Summary......Page 789 References......Page 790 III. Angiogenesis-Related Intraplatelet Compounds......Page 801 IV. Angiogenesis-Related Properties of Platelets: Experimental Data......Page 804 V. Platelet-Derived Microparticles: Possible Mediators of the Angiogenic Response......Page 805 VI. Platelets and Angiogenesis in Diseases......Page 806 References......Page 808 II. Platelet-Tumor Aggregation......Page 813 III. Platelet-Tumor Adhesion......Page 814 IV. Effect of Thrombin on Platelet-Tumor Adhesion and Pulmonary Metastasis......Page 815 V. Effect of Thrombin-Treated Tumor Cells on Adhesion to Naïve Platelets and Endothelial Cells in Vitro and Pulmonary Metastasis in Vivo......Page 816 VII. Summary......Page 818 References......Page 819 II. The Amyloid Precursor Proteins and Alzheimer’s Disease......Page 823 III. The Proposed Functions of Platelet APP and Ab......Page 826 IV. Platelets and Alzheimer’s Disease......Page 827 V. Conclusions......Page 828 References......Page 829 I. Introduction......Page 835 II. Anxiety Disorders......Page 836 III. Mood Disorders......Page 838 IV. Alcoholism......Page 842 VII. Schizophrenia......Page 843 VIII. Childhood Developmental and Psychiatric Disorders......Page 846 References......Page 847 Part Four: Disorders of Platelet Number and Function......Page 867 II. Clinical History......Page 869 III. Physical Examination......Page 871 V. Differential Diagnosis......Page 872 Reference......Page 874 I. Introduction......Page 875 III. Etiology......Page 876 IV. Diagnosis......Page 878 V. Treatment......Page 880 References......Page 885 II. Historical Descriptions......Page 891 IV. Treatment......Page 892 V. Mechanisms of Thrombocytopenia......Page 893 VI. Composition of Immune Complexes......Page 895 References......Page 900 II. Historical Aspects of HIT......Page 905 IV. Pathogenesis......Page 906 V. Frequency of HIT......Page 908 VI. Clinical Features of HIT......Page 911 VII. Diagnosis......Page 912 VIII. Management......Page 916 References......Page 924 II. Drug-Induced Suppression of Platelet Production......Page 931 III. Drug-Induced Platelet Destruction by Nonimmune Mechanisms......Page 932 IV. Drug-Induced Platelet Destruction by Immune Mechanisms......Page 933 References......Page 941 III. Thrombotic Thrombocytopenic Purpura......Page 947 IV. The Hemolytic-Uremic Syndrome......Page 954 V. Other Types of Thrombotic Microangiopathies......Page 959 References......Page 960 II. Specific Causes of Pregnancy-Associated Thrombocytopenia......Page 969 References......Page 980 II. Fetal Megakaryocytopoiesis and Platelet Production......Page 987 III. Incidence of Neonatal Thrombocytopenia......Page 988 IV. Natural History of Neonatal Thrombocytopenias......Page 989 V. Conditions Leading to Clinically Significant Neonatal Thrombocytopenia......Page 991 VI. Clinical Impact of Neonatal Thrombocytopenia......Page 997 VII. Principles of Management of Neonatal Thrombocytopenia......Page 998 VIII. Specific Approach to the Neonate with Significant Thrombocytopenia......Page 999 IX. TPO in the Fetus and Neonate......Page 1001 X. Future Therapeutic Options for Neonatal Thrombocytopenia......Page 1003 References......Page 1004 II. Fetal and Neonatal Alloimmune Thrombocytopenia......Page 1015 III. Posttransfusion Purpura......Page 1022 V. Unresolved Questions and Future Directions......Page 1023 References......Page 1024 II. The Microthrombocytic Thrombocytopenias......Page 1029 III. The Normothrombocytic Thrombocytopenias......Page 1031 IV. The Macrothrombocytic Thrombocytopenias......Page 1034 References......Page 1038 II. EDTA-Dependent Pseudothrombocytopenia......Page 1043 V. Clinical Aspects......Page 1044 VII. Clinical Laboratory Procedures......Page 1045 VIII. Pseudothrombocytopenia due to Platelet Satellitism......Page 1046 IX. Pseudothrombocytopenia due to Therapeutic Monoclonal Antibodies......Page 1047 References......Page 1048 III. Reactive Thrombocytosis......Page 1053 IV. Primary Thrombocythemia and the Myeloproliferative Disorders......Page 1054 V. Distinguishing Reactive Thrombocytosis from Primary Thrombocythemia......Page 1055 VI. Essential Thrombocythemia......Page 1056 VII. Conclusions......Page 1062 References......Page 1063 II. Defects of Platelet Adhesion......Page 1073 III. Other Giant Platelet Syndromes......Page 1079 IV. Inherited Disorders of Agonist Receptors and Signaling Pathways......Page 1080 V. Defects of Secretion (Storage Pool Disease)......Page 1081 VI. Glanzmann Thrombasthenia......Page 1083 VIII. Therapy......Page 1088 References......Page 1089 II. Uremia......Page 1095 III. Myeloproliferative Diseases......Page 1098 VI. Acquired von Willebrand Disease......Page 1100 VIII. Antiplatelet Antibodies and Platelet Dysfunction......Page 1101 XI. Drugs That Inhibit Platelet Function......Page 1102 References......Page 1107 II. Clinical Aspects of CPB Relevant to Platelet Pathophysiology......Page 1121 III. Inflammation and CPB......Page 1123 IV. Clinical Hemostatic Alterations during and after CPB......Page 1124 V. Quantitative Platelet Abnormalities during CPB......Page 1126 VI. Qualitative Platelet Abnormalities during CPB......Page 1127 VII. Diagnostic and Therapeutic Issues in CPB Hemostasis......Page 1129 References......Page 1130 Part Five: Pharmacology: Antiplatelet Therapy......Page 1141 IV. Mechanism of Action......Page 1143 V. Mechanisms of Benefit in Cardiovascular Disease......Page 1145 VI. Pharmacodynamics......Page 1146 VII. Aspirin in the Treatment of Acute Cardiovascular Disease......Page 1147 VIII. Aspirin for Secondary Prevention of Cardiovascular Events......Page 1150 IX. Aspirin for Primary Prevention of Cardiovascular Disease......Page 1152 X. Aspirin Therapy after Revascularization......Page 1155 XI. Aspirin in Other Clinical Settings......Page 1156 XII. Adverse Effects......Page 1157 XV. Conclusions/Recommendations......Page 1159 References......Page 1160 II. The Platelet Purinergic Receptors for ADP......Page 1171 III. P2Y12 Antagonists......Page 1172 V. Conclusions......Page 1180 References......Page 1181 II. aIIbb3 Signaling Mechanisms......Page 1189 III. aIIbb3 Ligand Binding Sites: Targets for Inhibition......Page 1190 IV. The aIIbb3 (GPIIb-IIIa) Antagonists......Page 1191 V. aIIbb3 Blockade during Coronary Interventions......Page 1193 VI. aIIbb3 Blockade in the Medical Management of Acute Coronary Syndromes......Page 1197 VII. Utilization of aIIbb3 Antagonists in ST-Elevation MI......Page 1199 VIII. Benefits of aIIbb3 Antagonists in the Setting of Other Adjunctive Pharmacotherapy......Page 1200 X. Oral aIIbb3 Antagonists......Page 1201 XI. Emerging Indications: Cerebrovascular Disease......Page 1202 References......Page 1203 I. Introduction......Page 1209 II. Absorption and Metabolism......Page 1211 III. Mechanisms of Action......Page 1212 IV. Side Effects......Page 1217 References......Page 1218 II. Mechanism of Action......Page 1225 III. Antiplatelet Effects......Page 1227 V. Other Effects......Page 1228 VI. Clinical Results......Page 1230 References......Page 1232 II. Platelet Biology......Page 1237 III. Current Antiplatelet Therapies......Page 1238 IV. Experimental Antiplatelet Therapies......Page 1241 References......Page 1248 Part Six: Pharmacology: Therapy to Increase Platelet Numbers and/or Function......Page 1253 II. TPO Structure......Page 1255 IV. Functions of TPO......Page 1258 V. Physiology of TPO......Page 1260 VI. Pathophysiology of TPO......Page 1262 VII. Therapeutic Thrombopoietins......Page 1263 VIII. Clinical Uses of Therapeutic Thrombopoietins: Animal Studies......Page 1266 IX. Clinical Uses of Therapeutic Thrombopoietins: Human Studies......Page 1267 X. Adverse Effects of Thrombopoietins......Page 1270 XI. Non-TPO Platelet Growth Factors......Page 1271 References......Page 1272 II. Desmopressin in the Management of Hemophilia A and von Willebrand Disease......Page 1281 III. Desmopressin as a General Hemostatic Agent......Page 1283 IV. Side Effects......Page 1286 V. Mechanisms of Action of Desmopressin......Page 1287 References......Page 1288 II. Pharmacology......Page 1295 III. rFVIIa in the Treatment of Thrombocytopenia......Page 1296 IV. rFVIIa in the Treatment of Platelet Function Disorders......Page 1297 V. Adverse Events......Page 1299 VI. Mechanisms of Action......Page 1300 References......Page 1302 Part Seven: Platelet Transfusion Medicine......Page 1307 II. Platelet Preparation......Page 1309 III. Platelet Storage and Storage Injury......Page 1312 IV. Postcollection Processing......Page 1317 V. Platelet Transfusion Therapy......Page 1318 VI. Adverse Reactions to Platelet Transfusion......Page 1323 VII. Thrombopoietic Growth Factors in Platelet Transfusion Therapy......Page 1326 References......Page 1327 II. Novel Platelet Products......Page 1341 III. Platelet Substitutes......Page 1346 IV. Challenges in the Development of Novel Platelet Products and Substitutes......Page 1348 References......Page 1349 Part Eight: Gene Therapy for Platelet Disorders......Page 1355 I. Introduction......Page 1357 II. Approach to Gene Transfer for Platelet Disorders......Page 1358 III. Advances in Retrovirus-Mediated Transduction for Platelets......Page 1362 IV. State-of-the-Art Animal Models for Disorders Affecting Platelets......Page 1364 References......Page 1365 A......Page 1371 B,C......Page 1373 D,E......Page 1375 G......Page 1376 H......Page 1378 J,K......Page 1379 N......Page 1380 O,P......Page 1381 Q,R......Page 1384 S,T......Page 1385 W,X,Z......Page 1387 Platelets, Second Edition is the definitive current source of state-of-the-art knowledge about platelets and covers the entire field of platelet biology, pathophysiology, and clinical medicine. Recently there has been a rapid expansion of knowledge in both basic biology and the clinical approach to platelet-related diseases including thrombosis and hemorrhage. Novel platelet function tests, drugs, blood bank storage methods, and gene therapies have been incorporated into patient care or are in development. This book draws all this information into a single, comprehensive and authoritative resource. First edition won Best Book in Medical Science Award from the Association of American Publishers Contains fourteen new chapters on topics such as platelet genomics and proteomics, inhibition of platelet function by the endothelium, clinical tests of platelet function, real time in vivo imaging of platelets, and inherited thrombocytopenias A comprehensive full color reference comprising over 70 chapters, 1400 pages, and 16,000 references