Ferguson James W, Helmy Ahmed, Ludlam Christopher, Webb David J, Hayes Peter C, Newby David C
Department of Hepatology, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SU, UK.
Thromb Res. 2008;121(5):675-80. doi: 10.1016/j.thromres.2007.07.008. Epub 2007 Sep 17.
Over activity of the fibrinolytic system (hyperfibrinolysis) occurs in cirrhosis and has been shown to correlate with the risk of variceal hemorrhage. We have developed a model for assessing acute tissue plasminogen activator (t-PA) release in vivo in man. The aims of the study were to assess the contribution of basal and stimulated t-PA release to hyperfibrinolysis in patients with alcoholic cirrhosis.
Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 patients with biopsy proven alcohol induced cirrhosis, ascites and portal hypertension, and 8 age and sex matched healthy controls during infusion of bradykinin (100-900 pmol/min; endothelium-dependent vasodilator that releases t-PA) followed by sodium nitroprusside (SNP 2-8 microg/min; a control endothelium-independent vasodilator).
Baseline plasma t-PA antigen concentrations were higher in patients (14+/-2 vs 9+/-1 ng/mL; p<0.05) whereas plasma plasminogen activator inhibitor type-1 (PAI-1) antigen concentrations were similar (59+/-16 vs 55+/-11 ng/mL; p=NS). This resulted in an increased t-PA activity (3+/-1 vs 0+/-0 IU/mL; p<0.05) and reduced PAI-1 activity (9+/-2 vs 21+/-2 AU/mL; p<0.05) indicating a relative deficiency of PAI-1 in patients with cirrhosis. Bradykinin and SNP caused dose-dependent vasodilatation (p<0.001 for both) that did not differ between the two groups. Bradykinin caused a similar release of t-PA antigen (p<0.05 for both) in both patients and controls (24+/-17 vs 23+/-7 ng/100 mL/min; p=ns) without affecting PAI-1 concentrations. Local t-PA activity was increased in patients following acute stimulated t-PA release (5+/-1 vs 3+/-1 IU/mL; p<0.05). SNP caused no significant change in fibrinolytic parameters.
Patients with alcoholic cirrhosis have a higher basal plasma t-PA activity because of a failure to increase plasma concentrations of its inhibitor, PAI-1. Furthermore, despite releasing normal amounts of t-PA acutely, higher t-PA activity remained due to the relative deficiency of PAI-1. This suggests that the pathogenesis of hyperfibrinolysis in alcoholic cirrhosis is the result of a relative PAI-1 deficiency and enhanced basal t-PA release.
纤维蛋白溶解系统活性过高（高纤维蛋白溶解）在肝硬化中出现，并且已被证明与静脉曲张出血风险相关。我们已经开发出一种用于评估人体体内急性组织型纤溶酶原激活物（t-PA）释放的模型。本研究的目的是评估基础和刺激后的t-PA释放在酒精性肝硬化患者高纤维蛋白溶解中的作用。
在8例经活检证实为酒精性肝硬化、腹水和门静脉高压的患者以及8例年龄和性别匹配的健康对照者中，在输注缓激肽（100 - 900 pmol/分钟；可释放t-PA的内皮依赖性血管扩张剂）后接着输注硝普钠（SNP 2 - 8微克/分钟；一种对照性的非内皮依赖性血管扩张剂）期间，测量双侧前臂血流量和血浆纤维蛋白溶解变量。
患者的基线血浆t-PA抗原浓度较高（14±2对9±1纳克/毫升；p<0.05），而血浆纤溶酶原激活物抑制剂1型（PAI-1）抗原浓度相似（59±16对55±11纳克/毫升；p=无显著性差异）。这导致t-PA活性增加（3±1对0±0国际单位/毫升；p<0.05）以及PAI-1活性降低（9±2对21±2任意单位/毫升；p<0.05），表明肝硬化患者中PAI-1相对缺乏。缓激肽和SNP引起剂量依赖性血管扩张（两者p<0.001），两组之间无差异。缓激肽在患者和对照者中引起相似的t-PA抗原释放（两者p<0.05）（24±17对23±7纳克/100毫升/分钟；p=无显著性差异），且不影响PAI-1浓度。急性刺激t-PA释放后患者的局部t-PA活性增加（5±1对3±1国际单位/毫升；p<0.05）。SNP未引起纤维蛋白溶解参数的显著变化。
酒精性肝硬化患者基础血浆t-PA活性较高，原因是其抑制剂PAI-1的血浆浓度未能升高。此外，尽管急性释放的t-PA量正常，但由于PAI-1相对缺乏，t-PA活性仍然较高。这表明酒精性肝硬化中高纤维蛋白溶解的发病机制是PAI-1相对缺乏和基础t-PA释放增强的结果。
