Center of Excellence on Aging, G. d'Annunzio University Foundation, Via Colle dell'Ara, 66013, Chieti, Italy.
Intern Emerg Med. 2011 Jun;6(3):203-12. doi: 10.1007/s11739-010-0440-3. Epub 2010 Aug 24.
Patients with type 2 diabetes mellitus are characterized by increased incidence of cardiovascular events and enhanced thromboxane-dependent platelet activation. Urinary enzymatic TXA(2) metabolites (such as 11-dehydro-TXB(2)), reflecting the whole TXA(2) biosynthesis by platelet and extra-platelet sources, are significantly increased in diabetes with the absolute post-aspirin values of 11-dehydro-TXB(2) in diabetics being comparable to non-aspirated controls and such residual TXA(2) biosynthesis despite low-dose aspirin treatment is predictive of vascular events in high-risk patients. Thus, elevated urinary 11-dehydro-TXB(2) levels identify patients who are partially insensitive to aspirin and who may benefit from alternative antiplatelet therapies or treatments that more effectively block in vivo TXA(2) production or activity. Potential mechanisms relatively insensitive to aspirin include extraplatelet, nucleate sources of TXA(2) biosynthesis, possibly triggered by inflammatory stimuli, or lipid peroxidation with enhanced generation of F2-isoprostane (reflecting ongoing in vivo oxidative stress) than can activate platelets via the platelet TP receptor thus escaping inhibition by aspirin. In fact, aspirin does not inhibit isoprostane formation. Moreover, intraplatelet or extraplatelet thromboxane generation may be only partly inhibited by aspirin under certain pathological conditions, at least at the usual low doses given for cardiovascular protection. TXA(2) receptors (TP) are expressed on several cell types and exert antiatherosclerotic, antivasoconstrictive and antithrombotic effects, depending on the cellular target. Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA(2) as well as for isoprostanes, may be an useful antithrombotic intervention in clinical settings, such as diabetes mellitus characterized by persistently enhanced thromboxane-dependent platelet activation.
2 型糖尿病患者的特点是心血管事件发生率增加，血栓素依赖性血小板活化增强。尿酶 TXA（2）代谢物（如 11-脱氢-TXB（2））反映了血小板和血小板外源性来源的整个 TXA（2）生物合成，在糖尿病中显著增加，糖尿病患者的绝对阿司匹林后 11-脱氢-TXB（2）值与未接受阿司匹林的对照组相当，尽管接受低剂量阿司匹林治疗，但这种残余 TXA（2）生物合成可预测高危患者的血管事件。因此，升高的尿 11-脱氢-TXB（2）水平可识别出对阿司匹林部分不敏感的患者，这些患者可能受益于替代抗血小板治疗或更有效地阻断体内 TXA（2）产生或活性的治疗方法。对阿司匹林相对不敏感的潜在机制包括血小板外源性核酶源 TXA（2）生物合成，可能由炎症刺激触发，或脂质过氧化增强 F2-异前列腺素生成（反映体内氧化应激持续存在），可通过血小板 TP 受体激活血小板，从而逃避阿司匹林的抑制。事实上，阿司匹林并不抑制异前列腺素的形成。此外，在某些病理条件下，阿司匹林可能仅部分抑制血小板内或血小板外源性血栓素的生成，至少在用于心血管保护的常用低剂量下如此。血栓素 A2 受体（TP）表达在几种细胞类型上，并根据细胞靶标发挥抗动脉粥样硬化、抗血管收缩和抗血栓形成作用。因此，针对 TP 受体，这是血小板和血小板外源性 TXA（2）以及异前列腺素的共同下游途径，可能是一种有用的抗血栓形成干预措施，例如以持续增强的血栓素依赖性血小板活化为特征的糖尿病。
