CELL MEDIATED HEMOSTASIS

点击翻译按钮获取中文摘要

DESCRIPTION (Applicant's Description Verbatim): The hypothesis underlying this proposal is that cells, rather than proteins, direct the coagulation reactions. Corollaries of this are: 1) the cellular location of the activated coagulation factors determines their function in the coagulation cascade; and 2) specific features of different cell types, such as the presence of specific receptors, determine the anti- and pro-coagulant features of the cells. These studies will use a cell based model system of coagulation we have developed. We have proposed studies that fall within four specific aims. The first aim examines how the function of activated protein C on endothelial cells is different from its activity on phospholipid vesicles or activated platelets. These studies will use factor V molecules that have cleavage site mutations. We will also look at the ability of factor V and cleaved forms of factor V to act as a cofactor for activated protein C inactivation of factor VIII. The second aim examines how cellular tissue factor activity is controlled. These studies will look at tissue factor encryption and de-encryption, the role of oxidants in altering cellular tissue factor activity, and the roles of tissue factor pathway inhibitor and anti-thrombin Ill in inactivating the factor VIla/tissue factor complex. The third aim examines what factors determine the rate and amount of thrombin generated on activated platelets. These studies will examine mechanisms that limit thrombin generation on the platelet surface. The fourth aim examines how the amount of thrombin generated in the cell-based model correlates with formation of a stable hemostatic clot in vivo? These studies will examine fibrinogen structure and susceptibility to lysis as well as the role of thrombin activatable fibrinolysis inhibitor.