Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy

Abstract

Aspirin and P2Y(12) antagonists are commonly used anti-platelet agents. Aspirin produces its effects through inhibition of thromboxane A(2) (TXA(2)) production, while P2Y(12) antagonists attenuate the secondary responses to ADP released by activated platelets. The anti-platelet effects of aspirin and a P2Y(12) antagonist are often considered to be separately additive. However, there is evidence of an overlap in effects, in that a high level of P2Y(12) receptor inhibition can blunt TXA(2) receptor signalling in platelets and reduce platelet production of TXA(2). Against this background, the addition of aspirin, particularly at higher doses, could cause significant reductions in the production of prostanoids in other tissues, e.g. prostaglandin I(2) from the blood vessel wall. This review summarizes the data from clinical studies in which dose-dependent effects of aspirin on prostanoid production have been evaluated by both plasma and urinary measures. It also addresses the biology underlying the cardiovascular effects of aspirin and its influences upon prostanoid production throughout the body. The review then considers whether, in the presence of newer, more refined P2Y(12) receptor antagonists, aspirin may offer less benefit than might have been predicted from earlier clinical trials using more variable P2Y(12) antagonists. The possibility is reflected upon, that when combined with a high level of P2Y(12) blockade the net effect of higher doses of aspirin could be removal of anti-thrombotic and vasodilating prostanoids and so a lessening of the anti-thrombotic effectiveness of the treatment.

Figure 1

Schematic representation of predominant pathways of prostanoid formation and effect with regard to platelets and blood vessels

Figure 2

Schematic representation of effects of aspirin and P2Y₁₂-receptor blockers on platelet pathways. (A) In physiological conditions there is balance between anti-aggregatory and pro-aggregatory influences on the platelet from the prostanoid and P2Y₁₂ pathways. PGI₂ formed by the blood vessel wall is anti-aggregatory through the stimulation of adenylyl cyclase (AC) secondary to activation of platelet PGI₂ receptors (IP receptors). Thromboxane A₂ (TXA₂) produced by the activity of cyclooxygenase (COX) within the platelet is pro-aggregatory, acting through platelet TXA₂ receptors (TP receptors). Activation of TP receptors also promotes the release of ADP from platelets which further drives aggregation. ADP produces its pro-aggregatory effects through activation of platelet ADP receptors (P2Y₁₂ receptors) and inhibition of platelet AC. Activation of P2Y₁₂ receptors drives more production of TXA₂ and more release of ADP. (B) In the presence of aspirin, platelet COX is blocked and the TXA₂ pathway of aggregation abolished. The P2Y₁₂ pathway of platelet activation is unaffected. Overall, there is a lessening of pro-aggregatory drive. There is an accompanying lessening in anti-aggregatory influence, as aspirin will also reduce the production of PGI₂ by the blood vessel wall. (C) In the presence of a blocker of P2Y₁₂ receptors, AC inhibition is lessened and so the anti-aggregatory effects of PGI₂ are enhanced. As the effects of the TXA₂ pathway are amplified through the P2Y₁₂ pathway, the pro-aggregatory effects of TXA₂ are also lessened and TXA₂ production is reduced. (D) When aspirin is added to a P2Y₁₂-receptor blocker, there may be some small additional reduction in pro-aggregatory influences by the complete removal of TXA₂ production; however, there is also a loss of PGI₂ which might lead to an even greater reduction in anti-aggregatory influence