The elucidation of the domain structure and structure-function relationships of plasma factor XI, the discovery of novel pathways of activation of plasma factor XI and renewed interest in platelet factor XI provide the background for this proposal. Preliminary characterization of partially purified platelet factor XI suggests that its subunit structure likely differs from that of plasma factor XI and that platelet factor XI mRNA lacks exon V of the plasma protein. The objectives of the proposal are to characterize the structure and function of platelet factor XI, to understand the mechanisms of activation and regulation of its enzymatic activity, and to define the functional significance of the interaction between plasma factor XI and platelets including the normal physiologic pathways of factor XI activation and expression and regulation of its enzymatic activity. To accomplish these objectives, the applicant will complete the characterization of factor XI mRNA from platelets ongoing in his laboratory, clone and characterize the factor XI cDNA from megakaryocytes, and purify and characterize factor XI isolated from platelets. The mechanisms and pathways of activation of platelet factor XI and the expression and regulation of its enzymatic activity will be investigated. The hypothesis that platelet factor XI can substitute for plasma factor XI in hemostasis will be tested in studies of patients who lack only plasma factor XI or lack both plasma and platelet factor XI. Finally, the applicant will determine the cellular locus for the activation of factor XI by thrombin, factor XIIa, factor XIa and other coagulation proteases and the role of specific binding of plasma factor XI to platelets in the activation of factor XI and in the expression and regulation of its enzymatic activity.
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