Mechanisms of normal and abnormal platelet homeostasis

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DESCRIPTION (provided by applicant): Thrombotic disorders are among the most common diseases encountered in clinical medicine and are the leading causes of morbidity and mortality in the United States. Platelets play an essential role in the pathogenesis of these diseases because platelet aggregates are responsible for the vaso-occulsive events that puncuate their clinical course. Thus, the focus of this SCCOR in Hemostasis and Thrombosis, entitled "Mechanisms of Normal and Abnormal Platelet Homeostasis", is on related clinical and basic aspects of platelet biology, taking advantage of the extensive experience of investigators at the University of Pennsylvania in these areas of investigation. The SCCOR consists of 3 clinical and 3 basic research projects, plus 2 supporting core units. Project 1, entitled "Understanding the mechanistic basis of heparin-induced thrombocytopenia (HIT)", tests the hypothesis that variations in platelet factor 4 (PF4) secretion are responsible for the variable incidence and clinical manifestations of HIT. Project 2, entitled "Immunobiology of immune-mediated thrombocytopenias" studies the nature of autoantibody responses in patients with ITP, HIT, and TTP. Project 3, entitled "Clinical aspects of aspirin and clopidogrel resistance", addresses the stability, specificity and incidence of the "aspirin resistant" phenotype, defines novel lipidomic and proteomic signatures of aspirin resistance, and relates conventional and novel biomarkers of the phenotype to clinical outcome. Project 4, entitled "Role of pleckstrin in platelet activation", is focused on phospholipid-mediated signaling pathways and the role they play in signaling in platelets and other cells of hematopoietic origin. Project 5, entitled "The role of Sema4D/CD100 and its receptors in platelet biology and thrombosis", studies the role of platelet sema4D/CD100 and its receptors in platelet function and tests the use of soluble sema4D/CD100 as a biomarker for thrombotic events. Project 6, entitled "Regulation of platelet integrin function", continues to study the conformational changes that regulate integrin activation states, focusing on the platelet fibrinogen receptor allb-beta-3. The projects are supported by a Bioinformatics Core to store and analyze clinical data and by a Core for Administration.