Effects of P2Y1 receptor antagonism on the reactivity of platelets from patients with stable coronary artery disease using aspirin and clopidogrel

BACKGROUND AND PURPOSE P2Y1 is a purine receptor that triggers platelet aggregation. Its inhibition was studied in patients with stable coronary artery disease (CAD) receiving standard anti‐platelet therapy. EXPERIMENTAL APPROACH Blood samples from 10 patients on aspirin therapy (ASA, 80 mg·day−1) were withdrawn before and 24 h after the administration of 450 mg clopidogrel (ASA/C) and were anti‐coagulated with citrate or hirudin/PPACK in the presence or absence of the P2Y1 inhibitor MRS2179 (M, 100 µM). Platelet responses to ADP (2.5 µM) and TRAP (2.5 µM), and collagen‐induced thrombosis under flow conditions were analysed. KEY RESULTS Compared with ASA, ASA + M strongly inhibited ADP‐induced peak platelet aggregation (88%), late aggregation (84%), P‐selectin expression (85%) and αIIbβ3 activation (62%) (28%, 65%, 70% and 51% inhibition, respectively, for ASA/C vs. ASA). ASA + M also inhibited platelet/monocyte and platelet/neutrophil conjugate formation by 69% and 71% (57% and 59% for ASA/C vs. ASA). In TRAP‐activated blood, ASA + M unexpectedly inhibited αIIbb3 activation by 30%. In blood perfused in collagen‐coated glass capillaries (shear rate of 1500 s−1), ASA/C prevented thrombus growth beyond 5 min in relation to thrombus fragments embolization. ASA + M with or without clopidogrel completely prevented thrombus formation. Finally, ex vivo addition of MRS2179 and ASA to the blood of healthy donors markedly blocked thrombus formation on collagen in flow conditions, in contrast to ASA plus the P2Y12 inhibitor 2‐MeSAMP. CONCLUSIONS AND IMPLICATIONS Through particularly efficient complementarities with ASA to inhibit platelet activation and thrombus formation, the inhibition of P2Y1 in the blood of patients with CAD appears to play a more important role than previously anticipated.