Sciulli Maria G, Renda Giulia, Capone Marta L, Tacconelli Stefania, Ricciotti Emanuela, Manarini Stefano, Evangelista Virgilio, Rebuzzi Antonio, Patrignani Paola
Department of Medicine and Center of Excellence on Aging, G. d'Annunzio University, School of Medicine Gabriele d'Annunzio University Foundation, Chieti, Italy.
Clin Pharmacol Ther. 2006 Aug;80(2):115-25. doi: 10.1016/j.clpt.2006.04.011. Epub 2006 Jul 3.
Complete and persistent suppression of platelet thromboxane (TX) A(2) biosynthesis by aspirin is mandatory to fulfill its cardioprotection. We explored the determinants of heterogeneity of TXB2 generation in clotting whole blood, a capacity index of platelet cyclooxygenase (COX) activity, in patients with coronary heart disease (CHD) versus healthy subjects treated with low-dose aspirin on a long-term basis.
We studied 30 patients with CHD (ie, chronic stable angina, unstable angina, and acute myocardial infarction) and 10 healthy subjects, who were treated with low-dose aspirin (100 mg daily) on a long-term basis, 12 hours after the administration of 160 mg aspirin to ensure saturation of platelet COX-1 activity. Serum TXB2 levels were assessed. The contribution of blood COX-2 to TXA2 biosynthesis was explored by evaluation of the effect of a selective COX-2 inhibitor (L-745,337) added to heparinized whole blood stimulated with Ca++ ionophore A23187 (20 micromol/L) for 1 hour or lipopolysaccharide (0.1 microg/mL) for 4 hours.
In healthy subjects serum TXB2 levels ranged from 0.6 to 7.9 ng/mL (median, 2.1 ng/mL; mean +/- SD, 3.2 +/- 2.6 ng/mL). In CHD patients we detected enhanced variability in serum TXB2 generation (median, 3.1 ng/mL [range, 0.15-47 ng/mL]; mean, 8.5 +/- 12.3 ng/mL), which in 8 patients (27%) exceeded the mean value + 2 SDs detected in healthy subjects (ie, 8.4 ng/mL), set as the limit value for an adequate inhibition of platelet COX-1 by aspirin. Elevated whole-blood TXB2 generation was not dependent on leukocyte count, COX-2 activity, or cigarette smoking but was plausibly a result of defective suppression of platelet COX-1 activity.
Heterogeneity in the suppression of platelet COX-1 activity by aspirin occurred in CHD patients. The measurement of the serum TXB2 level seems to be an appropriate biomarker to identify patients who have an inadequate inhibition of platelet COX-1 activity by aspirin.
阿司匹林必须完全且持续抑制血小板血栓素（TX）A2生物合成才能实现其心脏保护作用。我们探讨了长期服用低剂量阿司匹林的冠心病（CHD）患者与健康受试者凝血全血中TXB2生成异质性的决定因素，TXB2生成是血小板环氧化酶（COX）活性的一个能力指标。
我们研究了30例CHD患者（即慢性稳定型心绞痛、不稳定型心绞痛和急性心肌梗死患者）和10名健康受试者，他们长期服用低剂量阿司匹林（每日100mg），在服用160mg阿司匹林12小时后进行研究，以确保血小板COX-1活性饱和。评估血清TXB2水平。通过评估选择性COX-2抑制剂（L-745,337）添加到用Ca++离子载体A23187（20μmol/L）刺激1小时或脂多糖（0.1μg/mL）刺激4小时的肝素化全血中的效果，探讨血液COX-2对TXA2生物合成的贡献。
健康受试者血清TXB2水平范围为0.6至7.9ng/mL（中位数为2.1ng/mL；平均值±标准差为3.2±2.6ng/mL）。在CHD患者中，我们检测到血清TXB2生成的变异性增强（中位数为3.1ng/mL[范围为0.15 - 47ng/mL]；平均值为8.5±12.3ng/mL），其中8例患者（27%）超过了健康受试者中检测到的平均值 + 2个标准差（即8.4ng/mL），该值被设定为阿司匹林充分抑制血小板COX-1的极限值。全血TXB2生成升高不依赖于白细胞计数、COX-2活性或吸烟，但可能是血小板COX-1活性抑制缺陷的结果。
CHD患者中存在阿司匹林抑制血小板COX-1活性的异质性。血清TXB2水平的测定似乎是识别阿司匹林对血小板COX-1活性抑制不足患者的合适生物标志物。
