Antiplatelet Therapy: Targeting the TxA₂ Pathway

The thromboxane (Tx) A₂ pathway is a major contributor to the amplification of the initial platelet activation process. TxA₂ mediates its effect through the thromboxane prostanoid (TP) receptor that is expressed not only in platelets, but also in endothelial cells, macrophages, and monocytes, and thus contributes to the development of atherosclerotic lesions. The TxA₂ pathway is therefore a major target in the treatment of cardiovascular disease. Aspirin—the most widely used antiplatelet drug—is very effective at inhibiting platelet-derived TxA₂ synthesis. However, aspirin’s effects can be overcome by several other soluble agonists such as isoprostanes, which are aspirin-insensitive ligands of the TP receptor that are preferentially produced in diabetes mellitus. Other drugs, with either inhibitory effects on Tx synthase or antagonist effects on TP, have been developed with the hope of providing a better, more complete inhibition of the TxA₂ pathway.