Platelet activation by ADP: the role of ADP antagonists

ADP plays a key role in haemostasis and thrombosis. Despite its early identification in 1961 as the first known aggregating agent, the molecular basis of ADP-induced platelet activation is only beginning to be understood. Two purinergic receptors contribute separately to the complex process of ADP-induced platelet aggregation: the P2Y1 metabotropic receptor responsible for mobilization of ionized calcium from internal stores, which initiates aggregation, and P2Y receptor coupled to adenylyl cyclase inhibition, which is essential for the full aggregation response to ADP and stabilization of platelet aggregates. The latter is the molecular target of the ADP-selective antiaggregating drugs ticlopidine and clopidogrel and the ATP analogues of the AR-C series. In addition, it is probably defective in patients with a bleeding diathesis characterized by selective impairment of platelet responses to ADP. Finally, the P2X1 ionotropic receptor is also present in platelets, but its role is not yet known. Studies with P2Y1 knock-out mice as well as the use of selective P2Y1 antagonists have shown that, in addition to the P2Y receptor, which is the target of clopidogrel, the P2Y1 receptor is an important potential target for new antithrombotic drugs.