Following blood coagulation, fibrinolysis is essential to effect wound healing, restore vascular patency and re-establish normal hemostasis. Abnormalities of fibrinolysis may have consequences ranging from thrombotic disorders to hemorragic syndromes. Two independent fibrinolytic pathways have been identified: 1) the plasminogen system in which conversion of plasminogen to plasmin is the central event; and, 2) the alternative fibrinolytic system of polymorphonuclear leukocytes, which is activated in association with blood coagulation, i.e., neutrohils undergo a secretory response during clotting, and neutrophil elastase is the primary fibrinolytic enzyme. The overall objective of this proposal is to investigate and define the role of specific cells in these fibrinolytic pathways. In the plasminogen system, the participation of platelets in fibrinolysis will be assessed. Plasminogen binds specifically and saturably to human platelets, and plasmin formation is markedly enhanced on the platelet surface. The hypotheses that the platelet surface provides a unique environment for localization and assembly of the plasminogen system, for activation of plasminogen, and for protection of formed plasmin from inhibition will be tested. Experimental objectives will include: 1) a careful evaluation of the specific binding of plasminogen forms and plasmin to stimulated and nonstimulated platelets and identification of the sites within the molecule which mediate their interaction; 2) identification of the platelet receptors for plasminogen; 3) comparison of the rates of plasmin formation on the platelet surface and in solution; and 4) assessment of the capacity of the primary plasmin inhibitor, Alpha-antiplasmin, to inhibit the platelet bound enzyme. In the alternative pathway, a central focus will be the identification, characterization and mechanisms by which the plasma factor(s) support neutrophil secretion in association with blood coagulation. An immunochemical marker which discriminates elastase from plasmin degradation products of fibrinogen has been identified. The specificity and molecular basis for this neoantigen will be characterized; and, ultimately this marker will be used to assess the contribution of the alternative fibrinolytic pathway to fibrinolysis in selected pathophysiologic circumstances. On an overall basis, these studies should provide insight into the basic mechanisms by which platelets and neutrophils directly mediate or regulate the essential process of fibrinolysis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hematology Subcommittee 2 (HEM)
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Scripps Research Institute
San Diego
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