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

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.