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 ag gregate platelets. Platelet aggregation depends upon the binding of ad hesive 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 b inds to alpha(IIb)beta(3) and 2) this interaction accelerates prothrom bin activation. Prothrombin bound to purified alpha(IIb)beta(3) in a s pecific, saturable, and divalent cation-dependent manner, This interac tion 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 wit h alpha(IIb)beta(3) on resting and stimulated platelets as demonstrate d by soluble ligand binding and platelet adhesion assays, Activation o f prothrombin by Factor Xa alone or Factor Xa-Va was accelerated by al pha(IIb)beta(3), and this enhancement was blocked by a monoclonal anti body that inhibited prothrombin binding to the receptor, Taken togethe r, these data identify a previously unrecognized linkage between plate lets and the blood coagulation system that may have a significant regu latory consequence.