CELL MEDIATED HEMOSTASIS

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The complex interactions among blood coagulation proteins was initially described as a cascade. That model has been refined to take into account the organization of coagulation factors into complexes that consist of a protease and its substrate zymogen protein both bound to a membrane- associated protein cofactor. The interactions between proteins within the complex provide one level of regulation for coagulation. We suggest that there are at least two other levels of regulation in blood coagulation. One level involves the traffic of activated proteins between coagulation complexes. A second level involves the active participation of cells to regulate the amounts of key factors needed for coagulation. This proposal examines important cellular interactions involved in hemostasis. Platelets and monocytes will be used as surfaces to assemble three coagulation complexes: tissue factor-factor Vlla (TF-VIIa), factor VIIIa-factor IXa (Xase), and factor Va-factor Xa (llase). Platelets quickly localize at the site of an injury and provide a primary plug as well as a surface for assembling a fibrin plug. Monocytes will be examined because they are a model TF-containing cell, and they also have a TF independent mechanism for activating factor X. Ee hypothesize that cellular interactions between platelets and TF-bearing cells mediate interactions between the coagulation complexes assembled on these cells. We believe that the totality of this type of procoagulant system is more than the sum of its parts, and that a study of only the individual parts will not lead to an adequate model of in vivo hemostasis. So the overall goal of this grant is to examine the concerted and interrelated activity of TF-Vlla, Xase, and liase on isolated platelets and monocytes by kinetic analysis and immunochemical methods. An understanding of this relatively simple system of three protein complexes on two different cell types should allow us to model other cell-protein interactions that are important in coagulation in an effort to expand our concept of in vivo hemostasis and our understanding of thrombosis and hemorrhage.