Human platelet protease-activated receptor-1 responsiveness to thrombin related to P2Y12 inhibition

Dual antiplatelet therapy with aspirin and adenosine diphosphate (ADP) receptor inhibitors significantly improves the outcome of patients with stable coronary heart disease. However, abundant thrombin generation, which is not influenced by this dual antiplatelet therapy, is a major reason for recurrent thromboembolic disease in these patients. We, therefore, assessed in a hypothesis generating study in patients with stable coronary artery disease specifically the relation of responsiveness of the platelet thrombin receptor protease-activated receptor (PAR)-1 to the magnitude of the inhibition of the ADP receptor. PAR-1 regulation was studied prospectively in 86 consecutive patients with stable coronary artery disease treated with aspirin and clopidogrel (67 patients) or prasugrel (19 patients) and correlated the data to ADP inducible platelet reactivity by impedance aggregometry. PAR-1 expression did not differ between patients on aspirin and clopidogrel vs patients on aspirin and prasugrel (P > 0.5). PAR-1 levels were correlated to P-selectin expression (P < 0.0001). The higher the PAR-1 expression the more profound was the in vitro thrombin-inducible platelet activation. However, neither ex vivo PAR-1 expression nor in vitro thrombin-inducible PAR-1 were correlated to ADP-inducible platelet aggregation (P > 0.5). Thus, like in a real life scenario, patients with stable ischemic heart disease on dual antiplatelet therapy may express high levels of PAR-1, which are associated with profound thrombin-inducible platelet activation. This responsiveness cannot be predicted by the magnitude of ADP responsiveness.