Networking in the hemostatic system - Integrin alpha(IIIb)beta(3) binds prothrombin and influences its activation

Prothrombin activation is a pivotal event in thrombosis and hemostasis because thrombin can mediate fibrin formation and can activate and aggregate platelets. Platelet aggregation depends upon the binding of adhesive proteins to integrin alpha(IIb)beta(3) on the platelet surface. In the present study, a novel interface between the blood coagulation system and platelets is demonstrated by showing that 1) prothrombin binds to alpha(IIb)beta(3) and 2) this interaction accelerates prothrombin activation. Prothrombin bound to purified alpha(IIb)beta(3) in a specific, saturable, and divalent cation-dependent manner, This interaction was inhibited by certain monoclonal antibodies to alpha(IIb)beta(3), by the alpha(IIb)beta(3) ligands fibrinogen and RGD peptides, but not by thrombin or unrelated proteins, Prothrombin also interacted with alpha(IIb)beta(3) on resting and stimulated platelets as demonstrated by soluble ligand binding and platelet adhesion assays, Activation of prothrombin by Factor Xa alone or Factor Xa-Va was accelerated by alpha(IIb)beta(3), and this enhancement was blocked by a monoclonal antibody that inhibited prothrombin binding to the receptor, Taken together, these data identify a previously unrecognized linkage between platelets and the blood coagulation system that may have a significant regulatory consequence.