Nielsen Vance G, Kirklin James K
Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama 35249-6810, USA.
Blood Coagul Fibrinolysis. 2008 Dec;19(8):793-800. doi: 10.1097/MBC.0b013e328317f5aa.
Direct thrombin inhibitors enhance fibrinolysis more efficiently than heparin. Direct thrombin inhibitors and heparin enhance fibrinolysis by inhibition of activation of thrombin activatable fibrinolysis inhibitor (TAFI); however, the role played by other thrombin-activated proteins [e.g., factor XIII (FXIII)] in fibrinolysis remained to be elucidated. Our goal was thus to define the roles of TAFI and FXIII in direct thrombin inhibitor-mediated fibrinolysis enhancement. Plasma was exposed to argatroban or heparin, with coagulation initiated with kaolin/tissue factor and fibrinolysis initiated with tissue plasminogen activator. Additional experiments utilized TAFI and FXIII-deficient plasmas. Coagulation/fibrinolysis kinetics were monitored with thrombelastography. Argatroban (1.25, 2.5 microg/ml) significantly decreased clot lysis time and increased the maximum rate of lysis compared with unexposed plasma, whereas heparin exposure only diminished clot lysis time. When changes in maximum rate of lysis were related to changes in the maximum rate of thrombus generation, argatroban was associated with a greater increase in maximum rate of lysis per decrease in maximum rate of thrombus generation compared with heparin. Experiments with TAFI-deficient and FXIII-deficient plasma demonstrated a sparing of thrombin-mediated FXIII activation with concurrent inhibition of TAFI activation. The mechanism by which argatroban more efficiently enhanced fibrinolysis was via a differential inhibition of thrombin-mediated activation of TAFI and FXIII.
直接凝血酶抑制剂比肝素更有效地增强纤维蛋白溶解。直接凝血酶抑制剂和肝素通过抑制凝血酶激活的纤维蛋白溶解抑制剂(TAFI)的激活来增强纤维蛋白溶解;然而,其他凝血酶激活蛋白[如因子 XIII(FXIII)]在纤维蛋白溶解中所起的作用仍有待阐明。因此,我们的目标是确定TAFI和FXIII在直接凝血酶抑制剂介导的纤维蛋白溶解增强中的作用。将血浆暴露于阿加曲班或肝素,用高岭土/组织因子启动凝血,用组织型纤溶酶原激活剂启动纤维蛋白溶解。额外的实验使用了缺乏TAFI和FXIII的血浆。用血栓弹力图监测凝血/纤维蛋白溶解动力学。与未暴露的血浆相比,阿加曲班(1.25、2.5微克/毫升)显著缩短了凝块溶解时间并增加了最大溶解速率,而暴露于肝素仅缩短了凝块溶解时间。当最大溶解速率的变化与最大血栓形成速率的变化相关时,与肝素相比,阿加曲班每降低最大血栓形成速率,其最大溶解速率的增加幅度更大。用缺乏TAFI和缺乏FXIII的血浆进行的实验表明,在抑制TAFI激活的同时,凝血酶介导的FXIII激活得到了保留。阿加曲班更有效地增强纤维蛋白溶解的机制是通过对凝血酶介导的TAFI和FXIII激活的差异抑制。