P2Y12 deficiency in mice significantly delayed the appearance of the first thrombus (P=0.0063) and increased the time to arterial occlusion (P<0.0001), demonstrating its critical role in thrombus stability.
Does the complete absence of the P2Y12 receptor prevent occlusive thrombus formation in injured arteries in mice?
Complete absence of P2Y12 in mice impairs platelet adhesion, activation, and thrombus stability, preventing occlusive thrombosis even without aspirin.
p-value: p=0.0063
The critical role for ADP in arterial thrombogenesis was established by the clinical success of P2Y12 antagonists, currently used at doses that block 40-50% of the P2Y12 on platelets. This study was designed to determine the role of P2Y12 in platelet thrombosis and how its complete absence affects the thrombotic process. P2Y12-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 P2Y12-/- mice without reaching occlusive size, in the absence of aspirin. Platelet adhesion to vWF was impaired in P2Y12-/- platelets. While adhesion to fibrinogen and collagen appeared normal, the platelets in thrombi from P2Y12-/- mice on collagen were less dense and less activated than their WT counterparts. P2Y12-/- platelet activation was also reduced in response to ADP or a PAR-4-activating peptide. Thus, P2Y12 is involved in several key steps of thrombosis: platelet adhesion/activation, thrombus growth, and stability. The data suggest that more aggressive strategies of P2Y12 antagonism will be antithrombotic without the requirement of aspirin cotherapy and may provide benefits even to the aspirin-nonresponder population.
André et al. (Fri,) conducted a other in Arterial thrombosis. P2Y12 gene knockout vs. Wild-type (WT) mice was evaluated on Time for appearance of first thrombus greater than 20 μm (p=0.0063). P2Y12 deficiency in mice significantly delayed the appearance of the first thrombus (P=0.0063) and increased the time to arterial occlusion (P<0.0001), demonstrating its critical role in thrombus stability.