重组人组织型纤溶酶原激活剂及其突变体的溶血栓研究

目的 比较重组人组织型纤溶酶原激活剂(rht-PA)及其突变体FsGGI和FrGGI的溶血栓作用,验证突变体的构建思想。方法 采用兔颈静脉溶栓模型和体外溶栓试验对纯化的rht-PA及其突变体FsGGI和FrGGI进行家兔体内外溶栓研究。结果 rht-PA、FsGGI及FrGGI三者均有体内外溶栓作用,体外溶栓能力基本相似;体内溶栓活力突变体FsGGI与FrGGI类似,均显著高于rht-PA,溶栓度分别为20.1％、49.1％和46.6％。在体内溶栓作用的同时均未引起血浆纤维蛋白原滴度下降。结论 溶栓作用是血栓特异性的,两种突变体是优于野生型t-PA的溶栓剂,上游的构建思想是正确的。

Studies on thrombolysis of recombinant human tissue-type plasminogen activator (rht-PA) and its mutants

Purpose To evaluate the in vivo/in vitro thrombolytic potential and fibrinolytic activity of rht-PA and its mutants. Methods The thrombolytic potential of the rht-PA and its mutants was assessed in the rabbit jugular vein thrombosis model, and rabbit plasma clot lysis assay was used for measuring rht-PA and its mutants in vitro fibrinolytic activity. Results Both the wild-type rht-PA and two mutants revealed thrombolystic effect. However, the two mutants exhibited a much greater thrombolytic potency than that of the wild-type rht-PA. The mutants-induced thrombolysis is 49.1% and 46.6% respectively. The rht-PA-induced thrombolysis is 20.1%. Furthermore, no fibrinogen degradation was observed when the wild-type rht-PA and its mutants (FrGGI and FsGGI)were administered at a dose of 50 000 IU/kg. rht-PA and its mutants are similar in fibrinolytic activity. Conclusion These findings suggest that two variants with longer half-lives in vivo are more efficient thrombolytic agent than the wild-type rht-PA.