Factor XI is a key component of the intrinsic pathway of coagulation. The functions of this protein in fibrin formation initiated by contact activation in vitro are well described; however, the mechanisms responsible for factor XI activation in vivo and the role of this protein in normal hemostasis and pathologic coagulation are not clear. In current models of hemostasis, normal coagulation is initiated by the factor VIIa/tissue factor complex, and not through contact activation. Factor XI would function in these schemes to sustain coagulation by activating factor IX, after initial thrombin formation through factor VIIa/tissue factor. The protease that activates factor XI in the absence of contact activation in vivo is not known, but thrombin has been demonstrated to activate factor XI in vitro plasma systems. The goals of this proposal are to evaluate the mechanisms by which zymogen factor XI becomes an active serine protease and to investigate the contributions of factor XI to normal hemostasis. We have expressed and purified chimeric recombinant factor XI molecules in which domains have been replaced with corresponding domains from the related protease prekallikrein. These proteins have been used to identify binding sites for the proteases known to activate factor XI. The mechanism of activation and role of factor XI in a recently developed model of fibrin clot resistance to fibrinolysis will also be studied. Ultimately, to fully understand the contributions of factor XI to coagulation, studies in animals will be required. Using the technique of homologous recombination in murine embryonic stem cells, a murine model of factor XI deficiency has been created in our laboratory. These animals will be used to evaluate the role of factor XI in primary hemostasis and in bleeding in the presence of activators of fibrinolysis, anti-platelet agents, and anticoagulants. The studies will substantially increase our knowledge of factor XI biochemistry and physiology and provide a firmer knowledge base from which to study the contribution of this protein to thromboembolic diseases.
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