Efforts are focused in two distinct, yet interrelated areas. One goal is to define how the generation of thrombin at the human platelet surface is effected and regulated. Our second goal is to begin to define how thrombin, once formed, interacts with platelet proteins to modulate its activity and the fibrinolytic response. Since thrombin is generated through the proper assembly and function of prothrombinase at the platelet surface we will test several hypotheses relevant to how functional complex assembly occurs and how the platelet actively regulates these processes. The multiple interactions of thrombin with platelet membrane proteins and how they modulate thrombin-induced platelet activation is central to our studies since thrombin activation of platelets has a dramatic effect on the assembly and function of prothrombinase. Hypotheses suggesting that platelet membrane proteins serve to modulate thrombin activity both positively and negatively will be tested in multiple ways. We hypothesize that platelets are active participants in both effecting thrombin production and modulating thrombin activity and function. Platelets appear to perform these functions in part through the regulated receptor-mediated assembly of proteolytic activities at their membrane surface subsequent to platelet activation. Alternatively, proteins may be released or constitutively expressed which serve to regulate platelet responsiveness and function either positively or negatively. Clearly, several potentially important mechanisms have been discussed here with respect to thrombin production and regulation which require additional study. Since thrombin is an active participant in the hemostatic, thrombotic, and fibrinolytic processes, delineation of these regulatory processes is central to understanding how homeostasis is maintained.
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