Factor VIII is a high molecular weight plasma glycoprotein complex which is an important regulator of blood coagulation and is also required for the recognition of damaged endothelial surfaces by blood platelets. A convenient model for the function of Factor VIII in platelet-mediated hemostasis is provided by the binding of bovine Factor VIII to human platelets. We propose to identify and to isolate the protein(s) on the platelet surface to which Factor VIII binds. The purified binding protein(s) will be characterized by biochemical techniques and the mechanism of association with Factor VIII determined. Chemical and enzymatic modification of the isolated binding protein(s) will be used to identify the regions responsible for functional activity. The effects of agents, such as ADP, which alter the responsiveness of platelets to Factor VIII, will be examined for their effects on the availability of binding sites on the platelet surface. We will also examine the effects of Factor VIII binding on the metabolic and functional responses of platelets and will study how this binding alters the responsiveness of platelets to other agonists. A congenital deficiency of the Factor VIII protein in humans (von Willebrand's disease) can cause a severe bleeding syndrome, because of the resulting defect in platelet-mediated hemostasis. Replacement therapy with concentrates of Factor VIII can correct this defect. On the other hand, a deficiency of Factor VIII (in swine) has been shown to be associated with a decreased tendency to form atherosclerotic plaques - probably because of a decreased responsiveness of the platelets to the early stages of damage to the vascular intima. These observations suggest that the interaction of Factor VIII with platelets plays a key role not only in protective hemostatic mechanisms but also in those which could lead to thrombotic conditions. A better understanding of this interaction is thus essential for a rational approach to the therapeutic management of these conditions.
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