Residual platelet activation through protease-activated receptors (PAR)-1 and -4 in patients on P2Y12 inhibitors

Dual antiplatelet therapy with aspirin and thienopyridines has improved outcomes of patients after coronary stent implantation. However, current knowledge suggests that thrombin generation is not affected by inhibition of the P2Y12 receptor, and therefore, platelet activation may still occur.

The response to agonists specific for protease-activated receptors (PAR)-1 and -4 was tested by multiple electrode impedance aggregometry in 82 patients on stable doses of clopidogrel or prasugrel, and in 55 healthy controls.

Based on the consensus cut-off value for adenosine diphosphate (ADP) responsiveness, only one out of 19 patients on prasugrel, but 22 out of 63 patients on clopidogrel had high on-treatment residual platelet reactivity in response to exogenous ADP (p=0.01). Among the patients with adequate ADP P2Y12 receptor inhibition (n=59), we still observed 32 patients (54.2%) with normal response to the PAR-1 activator SFLLRN (26 patients on clopidogrel, 81.2%; 6 patients on prasugrel, 18.8%), and 37 patients (63.8%) with a normal response to the PAR-4 activator AYPGKF (29 patients on clopidogrel, 78.4%; 8 patients on prasugrel, 21.6%). The degree of PAR-agonists inducible platelet activation was directly correlated with the activation induced by ADP (r>0.5 and p<0.001 for both agonists). Moreover, SFLLRN and AYPGKF inducible platelet reactivities were strongly correlated (r=0.75, p<0.001).

PAR responsiveness is preserved in the majority of patients with adequate clopidogrel-mediated inhibition of the platelet P2Y12 receptor, and still in about 20% of those with adequate inhibition by prasugrel.