Platelet P2Y₁₂ receptor antagonist pharmacokinetics and pharmaco-dynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies

The platelet P2Y₁₂ receptor is involved in all aspects of arterial thrombosis, including adhesion, activation, aggregation, secretion and development of a stable aggregate on which coagulation proteins can assemble and fibrin strands can mesh. Inhibition of the P2Y₁₂ receptor has been shown convincingly to reduce cardiovascular events among patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous intervention (PCI). Current studies are exploring whether there is a threshold of platelet aggregation below which only more bleeding occurs, without a concomitant reduction in clinical events. The following review considers the potential relevance of reversible and irreversible mechanisms of P2Y₁₂ inhibition to bleeding risk, posing the question, "Is it not only how much but how a platelet P2Y₁₂ receptor is inhibited that determines the attributable safety profile?"