Dipartimento di Scienze Della Salute, Università Degli Studi di Milano, Milano, Italy.
Dipartimento di Scienze Della Salute, Università Degli Studi di Milano, Milano, Italy
Eur Heart J. 2016 Nov 21;37(44):3347-3356. doi: 10.1093/eurheartj/ehv551. Epub 2015 Oct 29.
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.
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.
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.
患有急性冠状动脉综合征 (ACS) 的患者接受乙酰水杨酸 (ASA) 和 P2Y 受体 (P2YR) 拮抗剂治疗二磷酸腺苷 (ADP)。基于 P2YR 拮抗剂抑制血栓素 A (TxA) 产生（ASA 的作用靶点）的证明，推测 ACS 患者可能仅用 P2YR 拮抗剂治疗。然而，这一证明与之前的研究结果相悖。本研究旨在测试 P2YR 拮抗剂是否对血小板 TxA 产生具有非靶向/间接抑制作用。
我们研究了 3 例遗传性 P2YR 缺乏症患者和 33 名健康受试者。P2YR 缺陷患者和健康受试者的血清 TxB（TxA 代谢物）水平相似，体外 P2YR 拮抗剂也未降低其水平。20 例接受普拉格雷（10 mg q.i.d.）或安慰剂治疗 14 天的患者，血清 TxB 水平并未降低。体外，健康受试者的血小板富血浆 (PRP) 中 P2YR 拮抗剂可抑制花生四烯酸和胶原诱导的血小板聚集 (PA) 和 TxB 产生。然而，当在聚集仪中避免 PRP 的搅拌以防止 PA 时，P2YR 拮抗剂并未抑制 TxB 的产生。P2Y ADP 受体拮抗剂 MRS2500 对 PA 和 TxB 产生的作用与 P2YR 拮抗剂相似。乙酰水杨酸比 P2YR 拮抗剂更有效地抑制 TxB 的产生；只有阿司匹林和 P2YR 拮抗剂的联合使用才能抑制高浓度胶原诱导的 PA。
遗传性 P2YR 缺乏或药理学抑制并不影响血小板合成 TxA 的能力。没有药理学证据表明 ACS 患者可以安全地用 P2YR 拮抗剂而无需使用 ASA 进行治疗。
