Platelets playa fundamental, life-saving role in hemostasis and blood clotting at sites of vascular injury. Unwanted platelet activation and arterial thombus formation are, however, implicated in the onset of myocardial infarction, stroke, and other cardiovascular diseases. Acceptance that platelets play a major role in the pathogenesis of atherosclerosis including coronary heart disease has revolutionized the pharmacological treatment of cardiovascular diseases, and aspirin is now an essential antiplatelet drug and the golden standard for future developments. Yet the search for better and perhaps safer antiplatelet drugs is one of the most active areas of investigation in both basic and clinical research. Platelets, especially human platelets, have also emerged as one of the major models for the study of inter- and intracellular signal transduction pathways. Many biochemists, cell biologists, pharmacologists, pathologists, hematologists, and cardiologists find platelets useful for studying processes such as adhesion, inside-out and outside-in signalling through the plasma membrane, channels, calcium homeostasis, protein kinases, the network of intracellular signal transduction cascades, and the release of vasoactive substances. The aim of the editors has been to compile chapters summarizing the current state-of-the-art information on the biochemistry, cell biology, pharmacology, and physiologic and pathophysiologic roles of human platelets. We hope that this volume represents the major aspects of current platelet research although it is perhaps inevitable that certain areas are covered less thoroughly than others. We would like to acknowledge the excellent help and support of the Springer-Verlag staff, in particular that of Ms. Doris Walker.
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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. Re…