Residual platelet ADP reactivity after clopidogrel treatment is dependent on activation of both the unblocked P2Y1 and the P2Y12 receptor and is correlated with protein expression of P2Y12

Two ADP receptors have been identified on human platelets: P2Y 1 and P2Y 12 . The P2Y 12 receptor blocker clopidogrel is widely used to reduce the risks in acute coronary syndromes, but, currently, there is no P2Y 1 blocker in clinical use. Evidence for variable responses to clopidogrel has been described in several reports. The mechanistic explanation for this phenomenon is not fully understood. The aim of this study was to examine mechanisms responsible for variability of 2MeS-ADP, a stable ADP analogue, induced platelet reactivity in clopidogrel-treated patients. Platelet reactivity was assessed by flow cytometry measurements of P-selectin (CD62P) and activated GpIIb/IIIa complex (PAC-1). Residual 2MeS-ADP activation via the P2Y 12 and P2Y 1 receptors was determined by co-incubation with the selective antagonists AR-C69931 and MRS2179 in vitro. P2Y 1 and P2Y 12 receptor expression on both RNA and protein level were determined, as well as the P2Y 12 H1 or H2 haplotypes. Our data suggest that the residual platelet activation of 2MeS-ADP after clopidogrel treatment is partly due to an inadequate antagonistic effect of clopidogrel on the P2Y 12 receptor and partly due to activation of the P2Y 1 receptor, which is unaffected by clopidogrel. Moreover, a correlation between increased P2Y 12 protein expression on platelets and decreased response to clopidogrel was noticed, r 2 =0.43 ( P