Basic research has established that platelets play a major role in haemorrhagic/thrombotic and cardiovascular diseases including atherosclerosis and cerebral/myocardial infarction. This work highlights areas of platelet physiology, pathophysiology and pharmacology in which the understanding of the molecular structure, function and regulation is rapidly expanding.

Table of Contents:
Section I: Platelet Development, Morphology and Physiology.- 1 Megakaryocytopoiesis: The Megakaryocyte/Platelet Haemostatic Axis.- A. Introduction.- B. Megakaryocyte Anatomy.- I. Structure.- II. Site of Platelet Production.- III. Ploidy.- C. Megakaryocytopoiesis and Thrombopoiesis.- I. Perturbations of the Steady State.- II. Megakaryocyte Progenitor Cells.- III. Megakaryocyte Growth Factors.- IV. Thrombopoietin/cMpl Ligand.- V. Negative Regulation of Megakaryocytopoiesis.- D. Signal Transduction Events and Mechanisms of Polyploidisation.- I. Involvement of Protein Kinase C in Megakaryocyte Differentiation.- II. Induction of Tyrosine Phosphorylation by TPO.- III. Cell Cycle Control and Polyploidisation.- E. Megakaryocytes in Atherosclerosis.- F. Conclusion.- References.- 2 Human Platelet Morphology/Ultrastructure.- A. General Morphology: Shape and Properties of Platelets.- B. Electron-Microscopic Techniques.- C. Morphometric Data.- D. Ultrastructure of Platelets.- I. Cytosol and Cytoskeleton.- 1. Cytosol.- 2. Submembranous Cytoskeleton.- 3. Contractile Gel.- II. Plasmalemma and Surface.- III. Surface-Connected Membranes.- 1. Surface-Connected (Open Canalicular) System.- 2. Coated Membranes.- IV. Cell Organelles.- 1. Mitochondria.- 2. Dense Tubular System.- 3. Alpha-Granules.- 4. Dense Granules.- 5. Lysosomes and Peroxisomes.- E. Functional Morphology.- I. Focal Adhesion Contacts.- II. Internalization and Endocytosis.- 1. Receptor Transport and Membrane Recycling.- 2. Internalization of Ligands by the Contractile Gel.- III. Exocytosis.- 1. Secretory Pathway.- 2. Shedding of "Microparticles".- F. Synopsis and Conclusions.- References.- 3 Platelet Adhesion.- A. Introduction.- B. The Vessel Wall.- C. Platelet Adhesion Under Flow Conditions.- D. Platelet Adhesion to the Adhesive Proteins.- I. Von Willebrand Factor.- II. Collagen.- III. Fibronectin.- IV. Fibrin(ogen).- V. Other Proteins.- 1. Laminin.- 2. Thrombospondin.- 3. Proteoglycans.- E. Conclusion.- References.- 4 Platelet Aggregation.- A. Introduction.- B. Mechanism of Platelet Aggregation.- I. The Glycoprotein IIb-IIIa Complex.- II. Adhesive Ligands of the GPIIb-IIIa Complex.- III. Redistribution of the GpIIb-IIIa Complex and Internalization of the Ligands.- C. Platelet Aggregation Testing.- I. Sample Preparation.- II. Optical Aggregometry.- III. Lumi-aggregometry.- IV. Determination of Platelet Aggregation by Particle Counting 90.- V. Potential and Limitations of Platelet Aggregation Testing.- D. Inhibition of Platelet Aggregation as a Therapeutic Principle.- E. Conclusions.- References.- Section II: Platelet Biochemistry, Signal Transduction.- 5 Platelet Receptors: The Thrombin Receptor.- A. Introduction.- B. The Seven-Transmembrane Domain Receptor.- I. Structure and Activation Mechanism.- II. Receptor Desensitization and Resensitization.- C. Glycoprotein Ib.- D. Receptor Signaling and Platelet Responses.- E. Thrombin Receptor Inhibitors.- References.- 6 Platelet ADP/Purinergic Receptors.- A. Introduction.- B. Platelet Responses to ADP.- I. Platelet Functions.- 1. Shape Change.- 2. Binding of Fibrinogen.- 3. ADP-Induced Platelet Aggregation.- 4. Desensitization.- II. Signal Transduction.- 1. Changes in Cytosolic Free Calcium Concentration.- 2. Changes in Inositol Phospholipids.- 3. Inhibition of Adenylyl Cyclase.- 4. Involvement of G Proteins.- C. Platelet ADP Receptors.- I. Binding Studies.- II. ADP-Binding Proteins.- III. The P2 Purinoceptor Family.- IV. Current Hypothesis of a Two-Receptor Model.- V. Future Perspectives.- D. Conclusions.- References.- 7 Platelet Prostaglandin Receptors.- A. Introduction.- B. Thromboxane A2 Receptor.- I. Structure and Ligand Binding Specificity.- II. Signal Transduction.- III. Regulation.- C. Prostacyclin Receptor.- I. Structure and Ligand Binding Specificity.- II. Signal Transduction.- III. Regulation.- D. Prostaglandin D Receptor.- I. Structure.- II. Ligand Binding Specificity and Signal Transduction.- E. Prostaglandin E Receptor Subtype; the EP3 Receptor.- References.- 8 Platelet Adhesion and Aggregation Receptors.- A. Introduction.- B. Platelet Surface Glycoproteins.- C. The Glycoprotein Ib-V-IX Complex.- I. Introduction.- 1. Glycoprotein Ib?.- 2. Glycoprotein Ib?.- 3. Glycoprotein IX.- 4. Glycoprotein V.- 5. Polymorphism Within GPIb?.- II. Function of the Glycoprotein Ib-V-IX Complex.- 1. Bleeding Disorders.- a) Bernard-Soulier Syndrome.- b) Platelet-Type von Willebrand's Disease.- 2. GPIb-vWf Binding.- 3. Non-physiological Activators of the GPIb/vWF Axis.- III. Expression of GPIb-V-IX.- D. GPIIb-IIIa.- E. GPIa-IIa.- F. GPIc-IIa.- G. GPIc'-IIa.- H. CD36 (GPIIIb or GPIV).- I. P-selectin (CD62, GMP-140, PADGEM).- J. PECAM-1 (CD31).- K. Inhibition of Platelet Adhesion/Aggregation as a Prophylactic Tool or for Treatment of Acute Thrombotic Events.- References.- 9 Platelet G Proteins and Adenylyl and Guanylyl Cyclases.- A. Introduction.- B. G Proteins.- I. General Considerations.- 1. Activation of G Proteins.- 2. Diversity of G Proteins.- 3. Structure of G Proteins.- 4. Co- and Posttranslational Modifications of Platelet G Proteins.- II. G Proteins Expressed in Platelets.- III. G Proteins as Modulators of Platelet Activation.- 1. Platelet-Activating G Proteins.- 2. Platelet-Inhibiting G Proteins.- C. Adenylyl Cyclases.- D. Guanylyl Cyclases.- I. Membrane-Bound Guanylyl Cyclases.- II. Soluble Guanylyl Cyclases.- 1. Regulation of Soluble Guanylyl Cyclases.- 2. Biosynthesis of Nitric Oxide.- III. cGMP Receptor Proteins.- 1. cGMP-Dependent Protein Kinases.- 2. cGMP-Gated Channels.- E. Physiological Role of Cyclic Nucleotides in Platelets.- I. cGMP-Formation in Platelets.- II. cGMP- and cAMP-Dependent Protein Kinases in Platelets.- III. Substrates for cAMP- and cGMP-Dependent Protein Kinases in Platelets.- IV. Cellular Responses Leading to Platelet Inhibition.- References.- 10 Platelet Phosphodiesterases.- A. Introduction.- B. Catalytic and Regulatory Properties of Human Platelet Phosphodiesterases.- I. cGMP-Stimulated Phosphodiesterase.- II. cGMP-Inhibited Phosphodiesterase.- III. cGMP-Specific Phosphodiesterase.- C. Synergistic Inhibition of Platelet Function by Cyclic Nucleotide Elevating Agents.- D. Regulation of Platelet Phosphodiesterases by Insulin.- E. Effect of Phosphodiesterase Inhibitors on Platelet Function.- I. General Aspects.- II. Specificity.- F. Concluding Remarks.- References.- 11 Platelet Phospholipases C and D.- A. Introduction.- B. Receptor-Mediated Activation of Phosphoinositide-Specific Phospholipase C.- I. Activation of Phosphoinositide-Specific Phospholipase C in Platelets.- II. Formation of Second Messengers.- 1. Inositol 1,4,5-trisphosphate.- 2. 1,2-Diacylglycerol.- 3. Phosphatidic Acid and Lysophosphatidic Acid.- III. Modulation of Phosphoinositide-Specific Phospholipase C.- C. Regulation of Phosphoinositide-Specific Phospholipase C.- I. Multiplicity of Phosphoinositide-Specific Phospholipase C.- II. G-Protein-Mediated Phospholipase C-? Activation.- III. Tyrosine Kinase-Mediated Phospholipase C-?Activation.- D. Roles and Regulation of Phospholipase D in Platelet Activation.- I. Activation of Phospholipase D in Platelets.- II. Regulation of Phospholipase D Activity.- E. Remarks.- References.- 12 Protein Kinase C and Its Interactions with Other Serine-Threonine Kinases.- A. Introduction and Definition.- B. Molecular Structure and Heterogeneity.- C. PKC Activation by Lipid Mediators in Platelets.- D. PKC Substrates, Binding Proteins, and Translocation.- E. Functional Roles for PKC in Platelets.- F. Relation of PKC Activation to Other Platelet Serine-Threonine Kinases and Their Effectors.- G. Abnormalities of Platelet PKC in Disease.- H. Summary and Future Areas of Research.- References.- 13 Platelet Protein Tyrosine Kinases.- A. Background.- B. Protein Tyrosine Kinases in Platelets.- I. Src Family Kinases.- 1. Src.- 2. Other Src Family Members.- II. Syk.- III. JAK Family Kinases.- IV. Focal Adhesion Kinase (FAK).- V. Receptor Protein Tyrosine Kinases.- C. Potential Roles of Protein Tyrosine Kinases in Platelet Functions.- I. Second Messenger Pathways.- 1. Phospholipases.- 2. Phosphoinositide 3-Kinase.- 3. GTP-Binding Proteins.- 4. Calcium.- 5. Cyclic Nucleotides.- II. Platelet Responses.- 1. Shape Change.- 2. Aggregation.- 3. Adhesion.- References.- 14 Protein Phosphatases in Platelet Function.- A. Introduction.- B. Protein Serine/Threonine Phosphatases in Platelets.- I. Classification of Serine/Threonine Protein Phosphatases.- II. Inhibitors of Protein Serine/Threonine Phosphatases.- III. The Presence of Protein Serine/Threonine Phosphatases in Platelets.- IV. Effect of Okadaic Acid and Calyculin A in Platelets.- V. Dephosphorylation of Cofilin in Platelets.- VI. Protein Serine/Threonine Phosphatases in Platelets: Concluding Remarks.- C. Protein Tyrosine Phosphatases.- I. Classification of Protein Tyrosine Phosphatases.- II. Distribution of Protein Tyrosine Phosphatases in Platelets.- III. Regulation of Tyrosine Phosphorylation by Irreversible Platelet Aggregation.- IV. Effect of Vanadate and Its Derivatives in Platelets.- V. Effect of Phenylarsine Oxide in Platelets.- VI. Possible Role of Protein Tyrosine Phosphatases in Ca2+ Entry.- VII. Regulation of Protein Tyrosine Phosphatases by Serine/Threonine Phosphorylation.- VIII. Protein Tyrosine Phosphatases in Platelets: Concluding Remarks.- D. Dual Specificity Protein Phosphatases.- E. Concluding Remarks.- References.- 15 Ca2+ Homeostasis in Human Platelets.- A. Introduction.- I. Ca2+ Homeostasis.- B. Maintenance of Low Cytosolic Ca2+ Concentrations.- I. Platelet SERCAs.- II. Membrane Organisation, Properties and Regulation of Platelet SERCAs.- III. Organellar Distribution of Platelet SERCA Pumps.- IV. Plasma Membrane Calcium ATPases.- V. Platelet PMCAs.- VI. Na+/Ca2+ Exchanger.- C. Mechanisms of Ca2+ Elevation in Platelets.- I. Ca2+ Release from Intracellular Stores.- 1. Inositol (1,4,5) Trisphosphate.- 2. General Properties of IP3Rs.- 3. Platelet IP3Rs.- 4. In(1,4,5)P3-Induced Ca2+ Release from Platelet Intracellular Stores.- II. Nature of Ca2+ Release from Intracellular Stores.- III. Ca2+ Oscillations in Platelets.- IV. Ca2+ Influx Mechanisms.- V. Capacitative or Store-Regulated Ca2+ Entry.- VI. Possible Direct Involvement of Second Messengers in Ca2+ Entry.- VII. Integrin-Associated Plasma Membrane Ca2+ Flux.- VIII. Ca2+ Influx Via Receptor-Operated Ca2+ Channel (ROC).- IX. Cyclic Nucleotide Effects on Ca2+ Influx.- References.- 16 Regulation of Platelet Function by Nitric Oxide and Other Nitrogen- and Oxygen-Derived Reactive Species.- A. Introduction.- B. A Historical Perspective.- C. Nitric Oxide Synthase Isoenzymes.- I. General Characteristics.- II. Platelet Nitric Oxide Synthase.- III. The Endothelial NOS.- IV. Nitric Oxide Synthase Reaction.- V. Metabolic Fate of NO.- VI. Interactions of NO with Biomolecules.- VII. Nitric Oxide - Physiological Regulator of Platelet Function.- VIII. Role of NO in the Pathogenesis of Vascular Disorders.- IX. Pharmacological Regulation of Platelet Function by NO Gas and NO Donor Drugs.- D. Other Oxygen- and Nitrogen-Derived Reactive Species.- I. Mechanisms of Action of Oxygen-Derived Radicals on Platelets.- 1. Thromboxane Generation.- 2. Cyclic Nucleotides.- 3. Stimulation of Platelet Serotonin Transport.- 4. Activation of Platelet Receptors.- 5. Formation of Nitric Oxide Donors.- E. Conclusions.- References.- 17 Platelet 5-Hydroxytryptamine Transporters.- A. Introduction.- B. The Plasma Membrane 5-Hydroxytryptamine Transporter (SERT).- I. Ionic Requirements.- 1. Coupling to Na+.- 2. Coupling to Cl-.- 3. Coupling to K+.- II. Reversal of Transport.- III. Mechanism.- IV. Purification.- V. Cloning.- VI. Regulation.- C. Dense Granule Membrane Vesicles.- I. Driving Forces.- II. Purification.- III. Cloning.- References.- Section III: Platelet-Derived Factors.- 18 Dense Granule Factors.- A. Introduction.- B. Contents of Platelets.- I. Nucleotides.- II. Divalent Cations.- III. Amines.- IV. Other.- C. Storage Mechanisms.- D. Species Differences.- E. Membrane Proteins.- F. Discussion and Comments.- References.- 19 Protein Granule Factors.- A. Introduction.- B. Platelet Proteins.- C. Platelet-Derived Growth Factors.- D. Thrombospondin.- E. Proteins Similar or Identical to Plasma Proteins.- F. Enzymes.- G. Summary and Conclusions.- References.- 20 Lysosomal Storage.- A. Introduction..- I. Lysosomes in General.- II. Platelet Lysosomes.- B. Lysosomal Hydrolases in Platelets.- I. Glycosidases.- 1. Secretion.- 2. Subcellular Localization.- II. Proteinases.- III. Phospholipases.- IV. Other.- C. Lysosomal Membrane Proteins.- D. Discussion and Comments.- References.- 21 Thromboxane A2 and Other Eicosanoids.- A. Introduction.- B. Platelet Arachidonic Acid Metabolism.- I. Metabolites.- II. Sources of Arachidonic Acid.- III. Release of Arachidonic Acid.- 1. Phospholipase A2.- 2. Other Routes of Arachidonic Acid Liberation.- C. Eicosanoids Affecting Platelet Function.- I. Thromboxane A2.- 1. Introduction.- a) Thromboxane A2 Receptors.- b) Signal Transduction.- ?) Intracellular Calcium.- ?) Alkalinization of Intraplatelet pH.- ?) Protein Kinase C Activation.- ?) Tyrosine Phosphorylation.- ?) Myosin Light Chain Kinase.- II. Prostacyclin (PGI2, Epoprostanol).- III. 8-Epi-prostaglandin F2?.- IV. Prostaglandin D2 (PGD2).- V. 12-Hete (12-Hydroxyeicosatetraenoic Acid).- D. Alterations in Thromboxane A2 Synthesis in Disease States.- I. Diabetes Mellitus.- II. Acute Coronary Artery Syndromes.- III. Pregnancy-Induced Hypertension.- IV. Cerebral Ischemia.- V. Homocystinuria.- VI. Sickle Cell Disease.- VII. Effects of Fish Oils.- E. Alterations in Thromboxane A2 Receptors in Disease States.- I. Acute Coronary Artery Syndromes.- II. Pregnancy-Induced Hypertension.- III. Diabetes Mellitus.- IV. Regulation by Androgenic Steroids.- F. Aspirin, Thromboxane Synthase Inhibitors, and Thromboxane A2 Receptor Antagonists in Coronary Artery Disease.- References.- 22 Platelet-Activating Factor: Biosynthesis, Biodegradation, Actions.- A. Introduction.- B. Biosynthesis of PAF in Mammalian Cells.- C. Catabolism of PAF in Mammalian Cells.- D. PAF and Bacteria.- E. PAF and Yeast Cells, Protozoans, Amoebas, and Parasites.- F. Effects of PAF on Cell Proliferation.- G. Some Effects of PAF on Several Cell Functions and Tissue Structures.- H. Conclusion.- References.- 23 Qualitative and Quantitative Assessment of Platelet Activating Factors.- A. PAF Molecular Diversity.- B. Estimation of PAF Activity by Bioassay.- I. Platelet Bioassay.- 1. Rabbit Platelet Bioassay.- 2. Platelet Desensitization.- 3. PAF Carriers in Platelet Bioassay.- 4. PAF Molecular Diversity in Platelet Bioassay.- II. Other.- C. Estimation of PAF Activity by Radioimmunoassay (RIA).- I. RIA Development and Use.- II. PAF Molecular Diversity in RIA.- D. Estimation of PAF by Radioreceptor Assay.- E. Estimation of PAF Based on [3H]Acetate Incorporation.- F. Analysis of PAF by Mass Spectrometry.- I. Analysis of Intact PAF.- II. Analysis of PAF After Derivatization.- G. Concluding Comments.- References.- 24 Biosynthetic Inhibitors and Receptor Antagonists to Platelet Activating Factor.- A. PAF: Historical Perspective and Pathology.- B. Biosynthesis Inhibitors.- I. Phospholipase PLA2 Inhibitors.- II. Lyso-PAF-Transferase Inhibitors.- C. Preclinical and Clinical PAF Receptor Antagonists.- I. Abbott Laboratories.- II. Alter S.A.- III. Boehringer Ingelheim KG.- IV. British Biotechnology Ltd.- V. Eisai Co., Ltd.- VI. Fujisawa Pharmaceutical Co.- VII. Hoffmann-La Roche and Co., Ltd..- VIII. Leo Pharmaceutical Products Ltd..- IX. Merck Sharp and Dohme Research Laboratories.- X. Ono Pharmaceutical Co., Ltd..- XI. Pfizer Laboratories.- XII. Rhone-Poulenc Sante Laboratories.- XIII. Sandoz Research Institute.- XIV. Sanofi Research.- XV. Schering-Plough Research Institute.- XVI. Solvay Pharma Laboratories.- XVII. Sumitomo Pharmaceuticals Co., Ltd..- XVIII. Takeda Chemical Co., Ltd..- XIX. Uriach S.A..- XX. Yamanouchi Pharmaceutical Company.- XXI. Yoshitomi Pharmaceutical Industries Ltd..- D. Conclusions.- References.- Section IV: Clinical Aspects of Platelets and Their Factors.- 25 Platelets and the Vascular System: Atherosclerosis, Thrombosis, Myocardial Infarction.- A. Introduction.- B. Atherosclerosis.- C. Thrombosis.- D. Myocardial Infarction.- E. Methodology of Radiolabeling of Platelets.- F. Studies with Radiolabeled Platelets.- I. Platelet Kinetics.- II. Imaging.- 1. Atherosclerosis.- 2. Thrombosis.- 3. Myocardial Infarction.- G. Platelet Aggregation.- H. Conclusions.- References.- 26 Platelets, Vessel Wall, and the Coagulation System.- A. Platelet-Endothelium Interaction.- I. Role of Platelets in Maintaining Vascular Integrity.- II. Control of Platelet Reactivity by Endothelial Cells.- 1. 13-Hydroxy-octadecadienoic Acid (13-HODE) - An Antiadhesive Fatty Acid Metabolite.- 2. Endothelium-Derived Platelet Inhibitors.- 3. Platelet Effects on PGI2 and EDRF/NO Synthesis.- 4. Mechanisms of Platelet Inhibition by PGI2 and EDRF/NO.- 5. Endothelial-Bound Antiplatelet Factors.- 6. Platelet Adhesion to Endothelial Cells.- III. Platelet-Mediated Inflammatory and Procoagulant Alterations of Endothelial Cells.- B. Platelets and Coagulation.- I. Membrane-Dependent Reactions in Blood Coagulation.- II. Platelet Procoagulant Activity.- III. Mechanisms Involved in the Maintenance of Membrane Lipid Asymmetry.- IV. Mechanisms Involved in the Expression of Procoagulant Activity.- V. Platelet Microvesicles.- VI. Platelets and Coagulation Disorders.- 1. Scott Syndrome.- 2. Antiphospholipid Syndrome.- 3. Factor V Quebec.- VII. Anticoagulant Activities of Platelets and Microvesicles.- VIII. Role of Platelets in Fibrinolysis.- References.- 27 Platelet Flow Cytometry - Adhesive Proteins.- A. Introduction.- I. Procedures for the Diagnosis of Platelet Disease States.- 1. Problems.- 2. Requirements.- B. Single Platelet Flow Cytometry (SPFC).- I. Principle.- II. Pitfalls and Standardization Requirements.- III. Assay Systems.- C. Platelet Adhesion Molecules as Diagnostic Targets.- I. Megakaryocytic Conditioning.- II. Platelet Membrane Processing.- III. Defining Diagnostic Epitopes.- 1. The Constitutive Stain.- 2. The Functional Stain.- IV. Platelet-Leukocyte Coaggregates.- D. Applications in Platelet Pathology.- I. Hemorrhagic Diathesis.- II. Thrombotic Diathesis.- III. Inflammation.- E. Pharmacology.- References.- 28 Pathological Aspects of Platelet-Activating Factor (PAF).- A. Introduction.- B. Involvement of PAF in Inflammatory and Allergic Responses.- I. Inflammatory Cellular Responses by PAF.- II. Involvement of PAF in Allergic Reactions.- C. Involvement of PAF in Cardiovascular Diseases.- I. PAF in Vascular Disturbances.- II. PAF in Endotoxin-Induced Shock.- III. Thrombovascular Diseases.- IV. Myocardial Infarction and Stroke.- D. Involvement of PAF in Cerebral Disturbances.- E. PAF in Respiratory Diseases.- I. Bronchial Hyperresponsiveness.- II. PAF in Asthma Bronchiale.- III. Pulmonary Edema.- IV. Adult Respiratory Distress Syndrome (ARDS).- V. Lung Fibrosis.- F. Involvement of PAF in Gastrointestinal Diseases.- I. Gastric Diseases.- II. Intestinal Diseases.- G. Involvement of PAF in Function and Disturbances of Reproduction.- I. Ovulation.- II. Gametocytes (Oocytes, Sperm).- III. Fertilization.- IV. Oviduct Passage and Preimplantation State.- V. Nidation.- VI. Embryonic Development.- H. Involvement of PAF in Skin Diseases.- I. Involvement of PAF in Diseases of Other Organs.- I. Renal Diseases.- II. Hepatic Disturbances.- III. Acute Pancreatitis.- IV. Transplant Rejection.- V. Tumor Growth.- J. Conclusion.- References.- 29 Therapeutic Aspects of Platelet Pharmacology.- Aspirin.- Selective Thromboxane Blockade.- Ticlopidine and Clopidogrel.- Fibrinogen Receptor Antagonism.- References.