Enhanced potency of prasugrel on protease-activated receptors following bivalirudin treatment for PCI as compared to clopidogrel

摘要

ACS patients undergoing percutaneous coronary intervention (PCI) when treated with bivalirudin and clopidogrel had increased frequency of early stent thrombosis. 24 patients referred for intervention with planned bivalirudin therapy, not previously treated with a P2Y(12) inhibitor and not receiving heparins or alpha IIb beta 3 inhibitors were randomized to treatment with either clopidogrel (600 mg) or prasugrel (60 mg). Platelet aggregation (PA) was measured by light transmission aggregometry (LTA) of platelet-rich plasma in response to ADP, PAR1/PAR4 thrombin receptor agonists and collagen at baseline and at 1, 2, 4 and 16 h following the cessation of bivalirudin infusion. Prasugrel-mediated inhibition of PA was significantly greater than that of clopidogrel at all time points for ADP as well as PAR1. There was an unanticipated, significantly greater protection of PAR4-mediated platelet aggregation only detected with prasugrel and not observed with clopidogrel. We further examined the effect of the hyperreactive PAR4 Thr120 variant in the protease-activated receptor 4 (PAR4), single nucleotide polymorphism (SNP) rs773902 on aggregation protection. The PAR4 protective effect with prasugrel was lost in individuals carrying the PAR4 Thr120 variant, and not in Ala120 homozygote. PAR1, ADP and collagen inhibition was not significantly affected in the hyperreactive PAR4 Thr120 variant. We documented that the P2Y(12) ADP receptor-mediated regulation of the strength of the high-affinity conformation of alpha IIb beta 3 as detected by PAC-1 ab, and in control of platelet adhesiveness through Rap1 GTPase protein activation. Importantly, the PAR4 Thr120 variant resulted in the increased rate and magnitude of Rap1 activation. Human platelet PAR4 mediated-activation of alpha IIb beta 3 was phospholipase C beta (PLC beta)-dependent and unlike mouse platelet PI3K-independent. These data identify a PAR4-dependent inhibitory mechanism for the prasugrel-mediated platelet inhibition, not seen with clopidogrel that could explain the reduction in stent thrombosis documented in clinical trials with prasugrel.