The formation of platelet thrombi contributes to the pathogenesis of several important occlusive vascular disorders, including myocardial infarction and stroke, and is a crucial event in reocclusion following thrombolytic therapy and transluminal balloon angioplasty. We have demonstrated in preliminary work that tissue plasminogen activator added to platelets induced to aggregate in plasma facilitates dispersal of the aggregates, or disaggregation. Tissue plasminogen activator has been shown to activate plasminogen bound to the platelet surface. We have demonstrated in preliminary studies that focal plasminogen activation in the platelet aggregate by tissue plasminogen activator (but not by streptokinase) initiates selective proteolysis of fibrinogen bound to the platelet surface and, in so doing, facilitates disaggregation. We plan to extend these observations by testing the hypothesis that activation of plasminogen associated with fibrinogen bound to platelet membrane receptors modulates the aggregation response and enhances the effects of other known inhibitors of platelet function, such as prostacyclin. We will analyze 1) the similarities between fibrin and surface- bound fibrinogen as sites of plasminogen activation and the kinetics of activation of plasminogen associated with fibrinogen bound to platelet membrane receptors, 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 activating plasminogen at these sites, 4) the role of platelet surface receptors for fibrinogen in plasminogen activation, 5) the effect of plasminogen activation on adherent platelets, and 6) possible synergy between tissue plasminogen activator and other platelet inhibitors originating in the vessel wall as promoters of disaggregation. These studies should expand our knowledge of the mechanism(s) by which tissue plasminogen activator work(s) in the setting of the platelet thrombus and its adhesive macromolecular components, and should provide new insights into a novel and very likely important protective mechanism afforded by tissue plasminogen activator in the maintenance of vascular patency. From these studies, we hope to gain insight into mechanisms by which vessel wall products facilitate dissolution of the platelet thrombi that are implicated in the pathogenesis of many vascular disorders.
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