MECHANISMS OF ACTIVATION OF COAGULATION FACTOR XI

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The purpose of this research project is to investigate the mechanisms by which coagulation factor XI becomes an active serine protease. Factor XI is a plasma glycoprotein which is clearly required for normal hemostasis, as persons deficient in this protein have abnormal bleeding, particularly after surgical procedures. In vitro, factor XI is activated by factor XII in conjunction with high molecular weight kininogen and prekallikrein, however, congenital deficiencies of these "contact activation" proteins do not cause clinical hemostatic problems. This observation suggests that an alternative mechanism for factor XI activation exists. The recent findings that the serine protease thrombin is able to activate factor XI in vitro and that factor XI undergoes autoactivation in the presence of certain negatively charged surfaces suggests that factor XI may play a role in sustaining the hemostatic process after some thrombin has been generated at the site of a wound. The activation of factor XI by thrombin and by autoactivation will be studied in physiologic systems containing plasma and in the presence of various cells which may function in normal hemostasis. A search will be conducted for additional, previously undescribed, mechanisms of factor XI activation. Finally, factor XI mutants will be produced to study the interaction of thrombin with factor XI and the autoactivation process. The data obtained will provide far a better understanding of normal hemostasis and will provide a firmer knowledge base from which to study thromboembolic diseases.