Anticoagulants (Thrombin Inhibitors) and Aspirin Synergize With P2Y12 Receptor Antagonism in Thrombosis

Background— This study was designed to determine whether (1) P2Y12 antagonism synergizes with other antithrombotics and (2) anticoagulants (thrombin inhibitors) affect the antithrombotic activity elicited by P2Y12 antagonism. Methods and Results— Thrombosis was achieved by perfusion of human and murine blood through type III collagen–coated capillaries at arterial shear rate. CT50547, a direct-acting P2Y12 antagonist, inhibited thrombosis in PPACK- but not heparin-anticoagulated human blood. In contrast, CT50547 inhibited thrombosis in aspirin-treated individuals independently of the anticoagulant. Thrombin and TXA2 also synergized with P2Y12 in the absence of anticoagulation, because combined treatment of aspirin or C921-78 (a factor Xa inhibitor) with CT50547 or 2-MeSAMP (a P2Y12 antagonist) inhibited the thrombotic process, whereas all treatments failed to inhibit thrombosis when used individually. Synergism was also observed ex vivo when P2Y12-deficient (P2Y12−/−) mice were administered aspirin or coa...