Soni Hitesh, Sharma Ajay, Bhatt Shvetank, Jain Mukul R, Patel Pankaj R
Zydus Research Centre, Ahmedabad, India.
Pharmacology. 2008;82(4):304-9. doi: 10.1159/000165118. Epub 2008 Oct 21.
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen that can be activated by thrombin. Activated TAFI (TAFIa) cleaves carboxyl-terminal lysine residues from partially degraded fibrin, rendering it resistant to fibrinolysis by endogenous tissue plasminogen activator (tPA). Carboxypeptidase inhibitor (CPI) isolated from potato inhibits TAFIa and reduces clot lysis time in rabbit and mouse plasma. In the present study, we report the effect of CPI on tPA-mediated clot lysis using rat plasma in vitro. CPI at 400, 600 and 800 ng/ml caused a dose-dependent enhancement of tPA-induced clot lysis. In vivo effect of CPI was also investigated using ferric chloride-induced arterial thrombosis model in rat. The results showed that i.v. administration of CPI significantly prolonged the 'time to occlusion' at the dose of 2 and 4 mg/kg. At 2 mg/kg i.v. dose in rat, CPI showed no effect on prothrombin time and activated partial thromboplastin time, indicating noninterference of CPI with other clotting factors in mediating its thrombolytic effect through TAFI inhibition. Furthermore, 2 mg/kg i.v. dose of CPI did not produce significant increase in bleeding time when tested in rat tail-transection bleeding model. These results provide evidence for a role of TAFI in arterial thrombosis in rats and suggest that TAFI inhibition could be explored as an attractive target for the development of new antithrombotic drugs.
凝血酶激活的纤维蛋白溶解抑制剂（TAFI）是一种碱性羧肽酶原，可被凝血酶激活。活化的TAFI（TAFIa）从部分降解的纤维蛋白上切割羧基末端赖氨酸残基，使其对内源性组织纤溶酶原激活剂（tPA）介导的纤维蛋白溶解具有抗性。从马铃薯中分离出的羧肽酶抑制剂（CPI）可抑制TAFIa，并缩短兔和小鼠血浆中的凝块溶解时间。在本研究中，我们报告了CPI在体外使用大鼠血浆对tPA介导的凝块溶解的影响。400、600和800 ng/ml的CPI导致tPA诱导的凝块溶解呈剂量依赖性增强。还使用大鼠的氯化铁诱导的动脉血栓形成模型研究了CPI的体内作用。结果表明，静脉注射2和4 mg/kg剂量的CPI可显著延长“闭塞时间”。在大鼠静脉注射2 mg/kg剂量时，CPI对凝血酶原时间和活化部分凝血活酶时间无影响，表明CPI在通过抑制TAFI介导其溶栓作用时不干扰其他凝血因子。此外，在大鼠尾截断出血模型中测试时，2 mg/kg静脉注射剂量的CPI未使出血时间显著增加。这些结果为TAFI在大鼠动脉血栓形成中的作用提供了证据，并表明抑制TAFI可作为开发新型抗血栓药物的一个有吸引力的靶点进行探索。
