Overcoming limitations of current antiplatelet drugs: a concerted effort for more profitable strategies of intervention

Abstract

Platelets play a central role in the pathophysiology of atherothrombosis, an inappropriate platelet activation leading to acute ischemic complications (acute myocardial infarction, ischemic stroke). In view of this, platelets are a major target for pharmacotherapy. Presently, the main classes of antiplatelet agents approved for the use in such complications are aspirin and thienopyridines. Although antiplatelet treatment with these two types of drugs, alone or in combination, leads to a significant reduction of non-fatal myocardial infarction (-32%), non-fatal stroke (-25%), and of cardiovascular death (-17%), a residual risk persists. Newer antiplatelet agents have addressed some, but not all, these limitations. Vis-à-vis their net clinical benefit, the higher potency of some of them is associated with a rise in bleeding complications. Moreover, newer thienopyridines do not show advantages over and above the older ones as to reduction of stroke. A concerted effort that takes into consideration clinical, genetic, and laboratory information is increasingly recognized as a major direction to be pursued in the area. The well-established road signs of clinical epidemiology will provide major information to define newer potentially useful targets for platelet pharmacology.

Figure 1

Platelet activation pathways and drug molecular targets. Thrombin binds to PAR-1 receptor, which leads to shape change, phospholipase C (PLC) activation, thromboxane A2 (T×A2) generation, and activation of the glycoprotein (GP) IIb/IIIa receptor, resulting in sustained platelet aggregation. Cyclooxygenase (COX)-l catalyzes the production of T×A2, a potent platelet aggregator, generated by platelets activated by thrombin and other agonists. Adenosine 5'-diphosphate (ADP) binds to its 7-transmembrane domain receptors, P2Y1 and P2Y12, to activate platelets. P2Y1 is coupled to Gαq and G12. Gαq is linked to a signaling pathway involving PLC activation, resulting in a rise in the intracellular calcium concentration ([Ca+2]i) and protein kinase C (PKC) activation, leading to GP IIb/IIIa activation and transient platelet aggregation. G12 mediates platelet shape change. P2Y12 is linked to Gai-coupled signaling cascades associated with adenylcyclase (Ac) down-regulation and decreased cyclic-3',5'-monophosphate (cAMP) production, which mediates GP IIb/IIIa receptor activation, leading to sustained platelet aggregation.