P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries

The critical role for ADP in arterial thrombogenesis was established by the clinical success of P2Y(12) antagonists, currently used at doses that block 40-50% of the P2Y(12) on platelets. This study was designed to determine the role of P2Y(12) in platelet thrombosis and how its complete absence affects the thrombotic process. P2Y(12)-null mice were generated by a gene-targeting strategy. Using an in vivo mesenteric artery injury model and real-time continuous analysis of the thrombotic process, we observed that the time for appearance of first thrombus was delayed and that only small, unstable thrombi formed in P2Y(12)(-/-) mice without reaching occlusive size, in the absence of aspirin. Platelet adhesion to vWF was impaired in P2y(12)(-/-) platelets. While adhesion to fibrinogen and collagen appeared normal, the platelets in thrombi from P2Y(12)(-/-) mice on collagen were less dense and less activated than their WT counterparts. P2Y(12)(-/-) platelet activation was also reduced in response to ADP or a PAR-4-activating peptide. Thus, P2Y(12) is involved in several key steps of thrombosis: platelet adhesion/activation, thrombus growth, and stability. The data suggest that more aggressive strategies of P2Y(12) antagonism will be antithrombotic without the requirement of aspirin cotherapy and may provide benefits even to the aspirin-nonresponder population.