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

Abstract

Patients with acute coronary syndromes (ACSs) are treated with acetylsalicylic acid (ASA) and antagonists of the P2Y₁₂ receptor (P2Y₁₂R) for adenosine diphosphate (ADP). Based on the demonstration that P2Y₁₂R antagonists inhibit thromboxane A₂ (TxA₂) production (target of ASA), it was surmised that ACS patients might be treated with P2Y₁₂R antagonists only. However, this demonstration contrasts with the results of previous studies. The aim of this study was to test whether P2Y₁₂R antagonists have off-target/indirect inhibitory effects on platelet TxA₂ production. We studied 3 patients with inherited P2Y₁₂R deficiency and 33 healthy subjects. Serum TxB₂ (TxA₂ metabolite) levels were similar in P2Y₁₂R-deficient patients and healthy subjects and were not decreased by P2Y₁₂R antagonists in vitro. Serum TxB₂ 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 TxB₂ production in platelet-rich plasma (PRP) of healthy subjects were inhibited in vitro by P2Y₁₂R antagonists. However, P2Y₁₂R antagonists did not inhibit TxB₂ production when PA was prevented by avoiding the stirring of PRP in the aggregometer. The P2Y₁ ADP-receptor antagonist MRS2500 had similar effects on PA and TxB₂ production as P2Y₁₂R antagonists. Acetylsalicylic acid inhibited TxB₂ production more effectively than a P2Y₁₂R antagonist; only the combination of ASA and a P2Y₁₂R antagonist inhibited PA induced by high concentration of collagen. Inherited deficiency or pharmacological inhibition of P2Y₁₂R does not affect the platelet capacity to synthesize TxA₂. There is no pharmacological evidence that ACS patients may be safely treated with P2Y₁₂R antagonists without ASA.