Davì G, Averna M, Catalano I, Barbagallo C, Ganci A, Notarbartolo A, Ciabattoni G, Patrono C
Department of Medicine, University of Palermo School of Medicine, Italy.
Circulation. 1992 May;85(5):1792-8. doi: 10.1161/01.cir.85.5.1792.
Increased platelet thromboxane (TX)A2 production has been described in type IIa hypercholesterolemia. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo, we studied the urinary excretion of its major enzymatic metabolites in 46 patients with type IIa hypercholesterolemia and 20 age-matched controls.
Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. The excretion rate of 11-dehydro-TXB2 was significantly (p less than 0.001) higher in patients (68.7 +/- 35.1 ng/hr, mean +/- SD) than in controls (22.4 +/- 9.4 ng/hr), with metabolite excretion greater than 2 SD of the normal mean in 74% of the patients. Urinary 11-dehydro-TXB2 was significantly (p less than 0.01) correlated with the threshold aggregating concentration of collagen (r = -0.641) and arachidonate (r = -0.734) and with agonist-induced platelet TXB2 production in vitro (r = 0.647 and 0.748, respectively). Moreover, a statistically significant correlation (r = 0.673, p less than 0.001, n = 66) was found between 11-dehydro-TXB2 excretion and total plasma cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (20 mg/day for 6 months) significantly reduced cholesterol levels by 22-28% and urinary 11-dehydro-TXB2 excretion by 32-42% in 10 patients. However, the reduction in the latter did not correlate with the reduction in the former and may have resulted from a nonspecific effect of simvastatin. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin (50 mg/day for 7 days) was associated with cumulative inhibition of 11-dehydro-TXB2 excretion by approximately 70% in six patients.
TXA2 biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia; this is, at least in part, a consequence of abnormal cholesterol levels, as suggested by the correlation between the two. Low-dose aspirin can largely suppress increased metabolite excretion, thus suggesting that it reflects TXA2-dependent platelet activation in vivo.
IIa型高胆固醇血症患者血小板血栓素（TX）A2生成增加。为了验证这些与能力相关的测量指标与体内TXA2生物合成实际速率的相关性，我们研究了46例IIa型高胆固醇血症患者及其20例年龄匹配的对照者尿液中TXA2主要酶代谢产物的排泄情况。
采用先前验证的放射免疫分析法测定尿中11-脱氢-TXB2和2,3-二去甲-TXB2。患者（68.7±35.1 ng/小时，均值±标准差）尿中11-脱氢-TXB2的排泄率显著高于对照组（22.4±9.4 ng/小时）（p<0.001），74%的患者代谢产物排泄量高于正常均值的2个标准差。尿中11-脱氢-TXB2与胶原蛋白（r = -0.641）和花生四烯酸（r = -0.734）的阈值聚集浓度以及体外激动剂诱导的血小板TXB2生成显著相关（分别为r = 0.647和0.748）。此外，11-脱氢-TXB2排泄与总血浆胆固醇之间存在统计学显著相关性（r = 0.673，p<0.001，n = 66）。10例患者使用3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀（20 mg/天，共6个月）可使胆固醇水平显著降低22% - 28%，尿中11-脱氢-TXB2排泄降低32% - 42%。然而，后者的降低与前者的降低不相关，可能是辛伐他汀的非特异性作用所致。此外，低剂量阿司匹林（50 mg/天，共7天）选择性抑制血小板环氧化酶活性，使6例患者尿中11-脱氢-TXB2排泄累计抑制约70%。
大多数IIa型高胆固醇血症患者TXA2生物合成增强；二者之间的相关性表明，这至少部分是胆固醇水平异常的结果。低剂量阿司匹林可在很大程度上抑制代谢产物排泄增加，因此提示其反映了体内TXA2依赖性血小板活化。
