The platelet P2Y₁₂ receptor for adenosine diphosphate: congenital and drug-induced defects.

P2Y₁₂, the G(i)-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y₁₂ defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y₁₂ should be suspected when ADP, even at high concentrations (≥ 10 μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y₁₂ are potent antithrombotic drugs, attesting the central role played by P2Y₁₂ in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y₁₂, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y₁₂-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y₁₂ in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y₁₂ inhibitors.