Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SB, Scotland, UK.
Int J Mol Sci. 2021 Feb 20;22(4):2115. doi: 10.3390/ijms22042115.
The resolution of arterial thrombi is critically dependent on the endogenous fibrinolytic system. Using well-established and complementary whole blood models, we investigated the endogenous fibrinolytic potential of the tissue-type plasminogen activator (tPA) and the intra-thrombus distribution of fibrinolytic proteins, formed ex vivo under shear. tPA was present at physiologically relevant concentrations and fibrinolysis was monitored using an FITC-labelled fibrinogen tracer. Thrombi were formed from anticoagulated blood using a Chandler Loop and from non-anticoagulated blood perfused over specially-prepared porcine aorta strips under low (212 s) and high shear (1690 s) conditions in a Badimon Chamber. Plasminogen, tPA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured by ELISA. The tPA-PAI-1 complex was abundant in Chandler model thrombi serum. In contrast, free tPA was evident in the head of thrombi and correlated with fibrinolytic activity. Badimon thrombi formed under high shear conditions were more resistant to fibrinolysis than those formed at low shear. Plasminogen and tPA concentrations were elevated in thrombi formed at low shear, while PAI-1 concentrations were augmented at high shear rates. In conclusion, tPA primarily localises to the thrombus head in a free and active form. Thrombi formed at high shear incorporate less tPA and plasminogen and increased PAI-1, thereby enhancing resistance to degradation.
动脉血栓的溶解高度依赖于内源性纤维蛋白溶解系统。我们使用成熟且互补的全血模型，研究了组织型纤溶酶原激活物（tPA）的内源性纤维蛋白溶解潜能，以及在切变下体外形成的纤维蛋白溶解蛋白在血栓内的分布。tPA 以生理相关浓度存在，使用 FITC 标记的纤维蛋白原示踪剂监测纤维蛋白溶解。使用 Chandler 环从抗凝血液中形成血栓，使用专门制备的猪主动脉条在 Badimon 室中在低（212 s）和高剪切（1690 s）条件下从未抗凝血液中灌注形成血栓。通过 ELISA 测量纤溶酶原、tPA 和纤溶酶原激活物抑制剂-1（PAI-1）的浓度。Chandler 模型血栓血清中富含 tPA-PAI-1 复合物。相比之下，游离 tPA 存在于血栓头部，并与纤维蛋白溶解活性相关。在高剪切条件下形成的 Badimon 血栓比在低剪切条件下形成的血栓更能抵抗纤维蛋白溶解。在低剪切下形成的血栓中，纤溶酶原和 tPA 的浓度升高，而在高剪切速率下，PAI-1 的浓度增加。总之，tPA 主要以游离和活跃的形式定位于血栓头部。在高剪切下形成的血栓包含较少的 tPA 和纤溶酶原，并增加了 PAI-1，从而增强了对降解的抵抗力。
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