Key role of the P2Y(1) receptor in tissue factor-Induced thrombin-dependent acute thromboembolism - Studies in P2Y(1)-knockout mice and mice treated with a P2Y(1) antagonist

Background-ADP plays a key role in hemostasis, acting through 2 platelet re ceptors: the P2Y(1) receptor and an unidentified P2 receptor, called P2cyc, coupled to adenylyl cyclase inhibition, which is the target of the antipla telet drug clopidogrel. We showed that the P2Y(1) receptor is an essential cofactor in thrombotic states induced by intravenous infusion of collagen a nd epinephrine. The aim of the present study was to assess the role of this receptor in thrombin-dependent tissue factor-induced thromboembolism. Methods and Results-Human thromboplastin was injected intravenously into wi ld-type or P2Y(1)-deficient mice, and the effects on platelet count and mor tality were determined and plasma thrombin-antithrombin III (TAT) complexes were quantified. P2Y(1)-deficient mice were resistant to the thromboemboli sm induced by injection of thromboplastin. Whereas the platelet count decre ased sharply in wild-type mice, there was no significant drop in platelets in P2Y(1)-knockout mice. The platelet consumption in wild-type mice was pro bably due to thrombin generation, because it was abolished by hirudin. Thro mboplastin also led to a rise in TAT complexes in plasma, again reflecting thrombin formation. This effect, however, was less important in P2Y(1)-knoc kout mice than in wild-type mice, indicating that less thrombin was generat ed in the absence of P2Y(1). Similar results were obtained after intravenou s administration of N6-methyl-2'-deoxyadenosine3':5'-bisphosphate, a select ive antagonist of the P2Y(1) receptor, to wild-type mice. Conclusions-Our results demonstrate a role of the P2Y(1) receptor in thromb otic states involving thrombin generation and provide further evidence for the potential relevance of this receptor as a target for antithrombotic dru gs.