Davì G, Ferro D, Basili S, Iuliano L, Camastra C, Giammarresi C, Santarone S, Rocca B, Landolfi R, Ciabattoni G, Cordova C, Violi F
Department of Medicine, University of Chieti, Italy.
Thromb Haemost. 1998 Apr;79(4):747-51.
An augmented systemic production of thromboxane (TX) A2, as assessed by urinary excretion of the thromboxane metabolites, has been described in severe liver cirrhosis. However, the significance of this finding remains unclear since in liver cirrhosis a number of phenomena i.e. altered hepatic TXA2 metabolism, increased intrasplenic platelet destruction, may affect TXA2 entry into systemic circulation as well as its metabolism. In order to further clarify this, we measured both major enzymatic metabolites of TXB2 in the urine of 44 patients affected by liver cirrhosis, subdivided in three classes on the basis of Child-Pugh criteria. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were assayed with previously validated RIA techniques. The urinary excretion rate of 11-dehydro-TXB2 was significantly (p = 0.0001) increased in the cirrhotic patients (673.5 pg/mg cr, median) in comparison with the controls (275 pg/mg cr, median) but no significant difference could be demonstrated among the excretion rates of the three patient subgroups. The excretion rate of 2,3 dinor-TXB2 was also significantly (p = 0.0001) increased in the patients (824 pg/mg cr, median) in comparison with controls (175 pg/mg cr, median), with a significant (p < 0.05) increase from class A (381 pg/mg cr) to class C (1337 pg/mg cr). The sum of the two enzymatic metabolites was significantly (p = 0.0001 ) increased in the cirrhotic patients in comparison to controls, with a progressive increase from class A (1003 pg/mg cr, median) to class C (2240 pg/mg cr, median). The urinary excretion of 2,3 dinor-TXB2 was significantly (p = 0.008) related to plasma prothrombin fragment 1+2 (F1+2). This study provides further evidence of increased thromboxane biosynthesis in liver cirrhosis. Moreover, we demonstrate intraliver shift of thromboxane metabolic disposition, due to progressive liver decompensation, because only the fraction undergoing beta-oxidation to 2,3-dinor-TXB2 was progressively increased with the degree of liver failure. We, also, find a significant correlation between urinary excretion of 2,3-dinor-TXB2 and plasma F1+2, suggesting that clotting activation could partly account for in vivo platelet activation.
通过血栓素代谢产物的尿排泄评估发现，严重肝硬化患者体内血栓素（TX）A2的全身生成增加。然而，这一发现的意义仍不明确，因为在肝硬化中，许多现象，如肝脏TX A2代谢改变、脾内血小板破坏增加，可能会影响TX A2进入体循环及其代谢。为了进一步阐明这一点，我们测量了44例肝硬化患者尿液中TXB2的两种主要酶促代谢产物，这些患者根据Child-Pugh标准分为三类。采用先前验证的放射免疫分析技术检测尿中11-脱氢-TXB2和2,3-二去甲-TXB2。与对照组（中位数275 pg/mg肌酐）相比肝硬化患者尿中11-脱氢-TXB2的排泄率显著升高（p = 0.0001）（中位数673.5 pg/mg肌酐），但三个患者亚组的排泄率之间未显示出显著差异。与对照组（中位数175 pg/mg肌酐）相比，患者尿中2,3-二去甲-TXB2的排泄率也显著升高（p = 0.0001）（中位数824 pg/mg肌酐），从A类（381 pg/mg肌酐）到C类（1337 pg/mg肌酐）有显著升高（p < 0.05）。与对照组相比，肝硬化患者中这两种酶促代谢产物的总和显著升高（p = 0.0001），从A类（中位数1003 pg/mg肌酐）到C类（中位数2240 pg/mg肌酐）逐渐升高。尿中2,3-二去甲-TXB2的排泄与血浆凝血酶原片段1+2（F1+2）显著相关（p = 0.008）。本研究进一步证明了肝硬化中血栓素生物合成增加。此外，我们证明了由于肝脏进行性失代偿，血栓素代谢分布发生肝内转移，因为只有经过β氧化生成2,3-二去甲-TXB2的部分随着肝功能衰竭程度的增加而逐渐增加。我们还发现尿中2,3-二去甲-TXB2的排泄与血浆F1+2之间存在显著相关性，这表明凝血激活可能部分解释了体内血小板的激活。
