Cover -- Half-title -- Title -- Copyright -- Contents -- Contributors -- Preface -- Part I Physiology -- 1 History of platelets -- Introduction -- Platelets, hemostasis and thrombosis -- Platelets and the endothelium -- Platelets and vessel injury -- Fate of arterial thrombi and atherosclerosis -- Clot retraction -- Source of platelets -- Thrombopoietin -- Platelet lifespan -- Platelet transfusion -- Isolation of platelets -- Platelet aggregation and platelet receptors -- Thrombin -- Collagen -- ADP -- Arachidonic acid and thromboxane A2 (TXA2) -- Serotonin -- Epinephrine (adrenaline) -- Platelet activating factor (PAF) -- Ristocetin, von Willebrand factor, and glycoprotein I -- Fibrinogen, von Willebrand factor, and GPIIb/IIIa -- Platelets in infectious diseases and immune reactions -- Platelet granules and the release reaction -- Platelet procoagulant activity, PF3, and microparticles -- Aspirin -- Prostaglandins -- Cyclic AMP -- Cyclic GMP and nitric oxide -- Signal transduction -- Calcium and phosphoinositides -- G proteins -- Contractile proteins and the cytoskeleton -- Conclusion -- References -- 2 Production of platelets -- Introduction -- Cellular aspect of platelet production -- MK localization -- MK diploid precursor -- MK maturation and differentiation -- Nucleus and endomitosis -- Nucleus -- Endomitosis -- Cytoplasmic differentiation -- Demarcation membrane system -- Secretion granules -- The endoplasmic reticulum -- Platelet production -- Mechanism and site of platelet release by MKs -- Transendothelial migration of MK:MK chemotaxis -- Knockout and transgenic animal models -- Regulation of platelet production -- Thrombopoietin (TPO) search and discovery -- TPO gene, cDNA and protein -- TPO production and regulation -- TPO biological activities in vitro (cell culture) -- TPO can promote MK colony formation.

TPO promotes MK differentiation and maturation -- TPO effect on proplatelet and platelet formation is controversial -- TPO has also in vitro effects on platelets -- TPO shows pleiotropic biological effects and can act on various cell types -- In vivo TPO biological activities: genetically manipulated mice confirm the major megakaryocytopoietic effects of TPO -- Other thrombopoietic growth promoting cytokines -- Thrombopoietic negative regulators -- Microenvironment and megakaryocytopoiesis regulation -- Preclinical studies -- Human clinical trials -- References -- 3 Morphology and ultrastructure of platelets -- Introduction -- Structural organization -- Peripheral zone -- Exterior coat -- Sol-gel zone -- Microtubules -- Microfilaments -- Organelle zone -- Dense bodies -- Alpha (Alpha) granules -- Lysosomes -- Internal membrane system -- Dense tubular system (DTS) -- Membrane complexes -- References -- 4 Platelet heterogeneity: physiology and pathological consequences -- Introduction -- Causes of heterogeneity -- Platelet ageing as a cause of heterogeneity -- Thrombopoiesis as the origin of platelet heterogeneity -- Theories of platelet production -- MK fragmentation in the bone marrow -- Platelet production from the demarcation membrane system (DMS) -- Platelet production in the peripheral circulation -- Platelet production from circulating MKs in the lungs -- Pathophysiology -- Conclusions -- References -- 5 Platelet membrane proteins as adhesion receptors -- Platelet adhesion receptors -- Platelet integrins -- Structure -- Function -- Deficiency -- Leucine-rich motif (LRM) family -- Structure -- Function -- Deficiency -- CD36 (Glycoprotein IV) -- Structure -- Functions -- Deficiency -- Glycoprotein VI -- Structure -- Function -- Deficiency -- Conclusions -- References -- 6 Dynamics of the platelet cytoskeleton -- Introduction.

The cytoskeleton of the resting platelet -- The cytoskeleton of the activated platelet -- Regulation of actin assembly -- De novo actin nucleation by WASp and the Arp2/3 complex -- Signalling leading to platelet shape change -- Cytosolic calcium increase -- Small GTPases and new production of membrane polyphosphoinositides -- Conclusion -- Acknowledgements -- References -- 7 Platelet organelles -- Introduction -- Dense granules (also termed dense bodies, dense core granules, and Delta-granules) -- Structure, size, and number -- Properties -- Content -- Membrane -- Origin -- Means of study -- Functions -- Defects in dense granules -- Alpha granules -- Structure, size and number -- Properties -- Content -- Membrane -- Origin -- Means of study -- Functions -- Defects in alpha granules -- Lysosomes -- Structure -- Properties -- Content -- Membrane -- Origin -- Means of study -- Functions -- Defects in lysosomes -- Conclusions -- References -- 8 Platelet receptors for thrombin -- Introduction -- Platelet responses to thrombin -- Biology of the PAR family of receptors -- Genetics and tissue distribution -- Identification of the ligand binding domain -- Inactivation and replacement of PAR family members -- PARs and platelets -- Mice are different -- Expression levels and the location of thrombin receptors on platelets -- Cleavage and recycling of thrombin receptors on human platelets -- Interactions of platelet protease-activated receptors with proteases other than thrombin -- Other potential thrombin receptors on platelets -- Conclusion: things are fitting together, but some pieces may still be missing -- References -- 9 Platelet receptors: ADP -- Introduction -- Effects of ADP on platelets -- Signal transduction of a weak platelet agonist -- ADP is a necessary cofactor for platelet activation -- Molecular identity of the platelet ADP receptors.

The P2Y receptor is an ADP receptor -- Evidence for another platelet ADP receptor -- Identification of the P2Y receptor -- The P2X receptor -- Pharmacology of the platelet ADP receptors -- Agonists -- Antagonists -- Ticlopidine and clopidogrel -- Congenital defects of platelet ADP receptors -- Respective roles of the… -- The P2Y receptor is necessary to trigger response and is responsible for shape change and transient platelet aggregation -- The P2Y receptor serves to amplify and complete the responses -- A role for the P2X receptor? -- The platelet ADP receptors as target for antithrombotic drugs -- Conclusion -- Acknowledgements -- References -- 10 Platelet receptors: prostanoids -- Introduction -- Thromboxane A receptor (TP) -- Structure -- Signal transduction -- Regulation -- Prostacyclin receptor (IP) -- Structure -- Signal transduction -- Regulation -- Prostaglandin E receptors (EPs) -- Structure -- Signal transduction -- Regulation -- Prostaglandin D receptor (DP) -- Structure -- Signal transduction -- Regulation -- Summary -- Acknowledgements -- References -- 11 Platelet receptors: collagen -- Introduction -- Collagens of the vascular system -- Importance of platelet-collagen interaction in haemostasis and thrombosis -- Platelet receptors for collagen -- The integrin Alpha2Beta1 (Gp Ia/IIa, CD49b/CD29, VLA) -- Glycoprotein VI -- CD36 (GpIV, GpIIIb) -- Other collagen receptors -- 65, 68/72 (TIIICBP)and 47 kDa receptors -- p85 -- cC1q-receptor -- Affinity regulation of receptors and accessory molecules -- Affinity regulation of Alpha2Beta1 -- Protein disulphide isomerase -- Integrin-associated protein (CD47) -- Fc receptors -- Calreticulin -- PECAM-1 (CD31) -- CD9 -- Venoms, etc. -- Signalling through collagen receptors -- Second messenger pathways stimulated by collagen -- GpVI signalling -- Alpha2Beta1 signalling.

Models for platelet-collagen interaction -- Closing remarks -- References -- 12 Platelet receptors: von Willebrand factor -- Historical perspective and overview -- Structure -- Gene structure and expression -- Congenital deficiencies -- The Bernard-Soulier syndrome -- Platelet-type von Willebrand disease -- Biologic function -- Ligand binding - vWF -- Ligand binding - thrombin -- Cytoplasmic interactions -- Platelets and inflammation of the endothelium -- Megakaryocytopoiesis -- Conclusions -- References -- 13 Platelet receptors: fibrinogen -- Introduction and historic perspectives -- Platelet fibrinogen receptors: AlphaIIbBeta3 -- Structure of AlphqIIbBeta3 -- Interaction of fibrinogen with AlphaIIbBeta3: a multistep reaction -- Receptor activation -- Fibrinogen engagement -- Postreceptor occupancy events -- Recognition of fibrinogen by AlphqIIbBeta3 -- Other platelet fibrinogen receptors -- Other integrins -- Still other fibrinogen receptors? -- References -- 14 Platelet signalling: GTP-binding proteins -- Introduction -- G-proteins and small GTPases -- G-proteins -- Small GTPases -- G-proteins in platelets and megakaryocytes -- G-proteins as integrators of signal transduction -- The stimulatory G-protein of adenylyl cyclase Gs -- The inhibitory G-protein of adenylyl cyclase G -- G, a key step in platelet activation -- G12 and G13 -- G15 /G16 -- Gz -- Gh -- Independent role of BetaGama subunits -- Small GTPases in platelets and megakaryocytes -- Ras-like GTPases -- Rho-like GTPases -- Rab GTPases -- Acknowledgements -- References -- 15 Platelet phospholipases A2 -- Introduction -- Metabolism of AA in platelets -- Mammalian PLA2s -- PLA2s in platelets -- Role of cPLA2-Alpha platelet AA release -- Regulation of cPLA2-Alpha in platelets -- Regulation of platelet cPLA2-Alpha Ca2+ -- Regulation of cPLA-Alpha phosphorylation.

Evidence that group IIA sPLA2 may not be involved in AA release in platelets stimulated with physiological agonists.