Advantages of fast-acting ADP receptor blockade in ischemic heart disease.

Abstract

The stimulatory role of ADP in platelet aggregation has received much attention in recent years.1 Not only is ADP a major physiological agonist on its own, it also plays a key role in promoting aggregation by other stimuli of which collagen and epinephrine are excellent examples. Released from damaged tissues and blood cells, including secreting platelets, ADP is a major factor in coronary artery disease favoring platelet accumulation at sites of stenosis and fissured atherosclerotic plaques. Recent advances have defined how ADP activates platelets in a process involving two receptors, P2Y1 and P2Y12, both belonging to the G-protein–coupled seven-transmembrane domain receptor family. Studies were advanced by the discovery of patients in which P2Y12 is congenitally deficient2,3⇓ and by the recent cloning of P2Y12 which had proved a most elusive receptor.2–5⇓⇓⇓ According to current thinking, interaction of platelets with P2Y1 leads to shape change, calcium mobilization, and a rapidly reversible aggregation. Simultaneous binding to P2Y12 permits the formation of large, stable platelet aggregates. It appears that P2Y1 starts the aggregation, and then P2Y12 takes over. This role of P2Y12 had been speculated on before its cloning when, as the mysterious “P2T,” it was already considered to be a primary target for antithrombotic therapy. It has now been confirmed that P2Y12 is the site of action of the long-acting antithrombotic drugs clopidogrel and ticlopidine, widely used to downregulate platelet reactivity in coronary artery disease.6 A third purported platelet receptor for ADP, the ion channel P2X1, is now known to react primarily with ATP. See page 357 In a …