The studies presented here focus on endogenous mechanisms for dispersing platelet thrombi, the formation of which contributes to the pathogenesis of occlusive vascular disorders. These studies represent outgrowths of our initial observation that tissue plasminogen activator initiates the kinetically selective proteolysis of fibrinogen bound to the platelet surface and, in so doing facilitates disaggregation. We plan to test the hypothesis that activation of plasminogen associated with fibrinogen bound to the platelet surface modulates the aggregation response and enhances the effects of other known inhibitors of platelet function, such as prostacyclin and endothelial-derived relaxing factor. We will analyze 1) the structural and functional properties of fibrin and surface-bound fibrinogen important for plasminogen activation, 2) the role of other adhesive macromolecules associated with the platelet aggregate in plasminogen activation and disaggregation, 3) structural determinants of tissue plasminogen activator important for binding to macromolecules in the platelet aggregate, and 4) interactions among endothelial inhibitors of platelet function in promoting disaggregation. These studies should expand our knowledge of the mechanism(s) by which tissue plasminogen activator work(s) within the platelet thrombus, and should provide new insights into mechanisms by which vessel wall (endothelial) products facilitate dissolution of the platelet thrombi that are implicated in the pathogenesis of many common vascular disorders and in reocclusion following interventional vascular therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Modified Research Career Development Award (K04)
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Hematology Subcommittee 2 (HEM)
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Brigham and Women's Hospital
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