Sabovic M, Blinc A
Department of Vascular Medicine, University of Ljubljana Medical Center, Slovenia.
Pflugers Arch. 2000;440(5 Suppl):R134-6.
We have studied how pharmacological dissolution of blood clots was affected by clot retraction, the mode of transport of fibrinolytic agents into the clot and the thickness of the composite fibrin fibers. Retracted clots were resistant to fibrinolysis in a milieu without dissolved plasminogen, because the amount of fibrin-bound plasminogen in retracted clots was insufficient for successful clot lysis. In plasma containing plasminogen, retracted clots were successfully lysed with fibrin-specific plasminogen activators, but not with non-fibrin-specific activators. Preincubation of retracted clots in plasma increased their plasminogen content as well as their sensitivity to fibrinolysis. The rate of lysis was increased up to 100-times when plasminogen activator and plasminogen were introduced into cylindrical clots by pressure-induced bulk flow in comparison with diffusion alone. The magnitude of the increase was similar in retracted and nonretracted clots, but the absolute rate of lysis was faster in non-retracted clots. The influence of fibrin fiber thickness on fibrinolysis was studied by atomic force microscopy. The time to complete lateral section of fibers did not differ between thick and thin composite fibers, and the rate of diameter reduction was faster in thick fibers than in thin ones. Taken together our results suggest that lysis of retracted clots proceeds in circular stages: (a) activation of bound plasminogen followed by partial degradation of fibrin, (b) opening of new plasminogen-binding sites on partly degraded fibrin, (c) binding of plasminogen to the new binding sites which enhances the susceptibility of clots to lysis. Lysis is accelerated by bulk flow of plasminogen activator and plasminogen into clots in comparison to diffusion alone. Fibrinolysis of thick composite fibrin fibers proceeds more efficiently than lysis of thin fibers.
我们研究了血凝块回缩、纤溶酶原激活剂进入血凝块的运输方式以及复合纤维蛋白纤维的厚度对药物溶解血凝块的影响。在没有溶解纤溶酶原的环境中，回缩的血凝块对纤维蛋白溶解具有抗性，因为回缩血凝块中与纤维蛋白结合的纤溶酶原量不足以成功溶解血凝块。在含有纤溶酶原的血浆中，回缩的血凝块可被纤维蛋白特异性纤溶酶原激活剂成功溶解，但不能被非纤维蛋白特异性激活剂溶解。回缩的血凝块在血浆中预孵育会增加其纤溶酶原含量以及对纤维蛋白溶解的敏感性。与仅通过扩散相比，当通过压力诱导的整体流动将纤溶酶原激活剂和纤溶酶原引入圆柱形血凝块时，溶解速率提高了100倍。回缩和未回缩的血凝块增加的幅度相似，但未回缩的血凝块的绝对溶解速率更快。通过原子力显微镜研究了纤维蛋白纤维厚度对纤维蛋白溶解的影响。粗、细复合纤维完成横向切割的时间没有差异，粗纤维的直径减小速率比细纤维快。综合我们的结果表明，回缩血凝块的溶解按循环阶段进行：(a) 结合的纤溶酶原激活，随后纤维蛋白部分降解；(b) 在部分降解的纤维蛋白上打开新的纤溶酶原结合位点；(c) 纤溶酶原与新的结合位点结合，增强血凝块对溶解的敏感性。与仅通过扩散相比，纤溶酶原激活剂和纤溶酶原整体流入血凝块可加速溶解。粗复合纤维蛋白纤维的纤维蛋白溶解比细纤维更有效。
