Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2.

Aims: Patients with acute coronary syndromes (ACSs) are treated with acetylsalicylic acid (ASA) and antagonists of the P2Y receptor (P2YR) for adenosine diphosphate (ADP). Based on the demonstration that P2YR antagonists inhibit thromboxane A (TxA) production (target of ASA), it was surmised that ACS patients might be treated with P2YR antagonists only. However, this demonstration contrasts with the results of previous studies. The aim of this study was to test whether P2YR antagonists have off-target/indirect inhibitory effects on platelet TxA production.

Methods And Results: We studied 3 patients with inherited P2YR deficiency and 33 healthy subjects. Serum TxB (TxA metabolite) levels were similar in P2YR-deficient patients and healthy subjects and were not decreased by P2YR antagonists in vitro. Serum TxB levels did not decrease in 20 patients treated with prasugrel (10 mg q.i.d.) or placebo for 14 days. Arachidonic acid- and collagen-induced platelet aggregation (PA) and TxB production in platelet-rich plasma (PRP) of healthy subjects were inhibited in vitro by P2YR antagonists. However, P2YR antagonists did not inhibit TxB production when PA was prevented by avoiding the stirring of PRP in the aggregometer. The P2Y ADP-receptor antagonist MRS2500 had similar effects on PA and TxB production as P2YR antagonists. Acetylsalicylic acid inhibited TxB production more effectively than a P2YR antagonist; only the combination of ASA and a P2YR antagonist inhibited PA induced by high concentration of collagen.

Conclusion: Inherited deficiency or pharmacological inhibition of P2YR does not affect the platelet capacity to synthesize TxA. There is no pharmacological evidence that ACS patients may be safely treated with P2YR antagonists without ASA.