Pharmacodynamic interplay of the P2Y1, P2Y12, and TxA2 pathways in platelets: The potential of triple antiplatelet therapy with P2Y1 receptor antagonism

Abstract

IntroductionPrevious work suggests that the extent of platelet inhibition by P2Y1 receptor antagonism may be underappreciated, particularly in the context of dual antiplatelet therapy with aspirin and clopidogrel. Materials and MethodsUsing P2Y1, P2Y12, and TxA2 receptor antagonists individually and in combination, we assessed the incremental changes from baseline platelet reactivity in blood collected from healthy volunteers. ResultsThe P2Y1 receptor antagonist further inhibited platelet activation and aggregation in several assay conditions ex vivo when combined with P2Y12 and/or TxA2 receptor blockers. Collagen and TRAP-induced platelet aggregation measured by light transmittance aggregometry was inhibited to a greater extent with the triple combination relative to each of the antagonists alone. The triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists also significantly shifted adenosine diphosphate (ADP)-stimulated platelet glycoprotein IIb/IIIa receptor and P-selectin expression compared to individual or dual antagonists. ConclusionsThese results substantiate that additional platelet inhibition occurs with the triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists and support further testing of P2Y1 receptor antagonists as an option for alternative, synergistic, or triple antiplatelet therapy.