Löwen Apotheke, Friedrichstr. 11-13, 35392 Giessen, Germany; Centro de Biofisica y Bioquimica, Instituto Venezolano de Investigaciones Cientificas, 1020ª Caracas, Venezuela.
Research and Development Department, Bayer AG, 42096 Wuppertal, Germany.
Thromb Res. 2020 Sep;193:15-21. doi: 10.1016/j.thromres.2020.05.016. Epub 2020 May 13.
Systemic hypercoagulation is often a severe complication of infective and inflammatory diseases, which overcome the hemostatic balance and lead to multiple thrombotic occlusions in the microvasculature and organ damage and is related to high mortality rates. SATI is a potent dual inhibitor of FXa and thrombin with antithrombotic efficacy in venous and arterial thrombosis models. In this study, the antithrombotic efficacy of SATI was investigated in a microthrombosis model in rats with an induced hypercoagulant state.
The hypercoagulant state was generated by infusion of TF in sixty rats (12 groups, consisting of 5 rats each). SATI was administered in two different doses by constant infusion and its antithrombotic efficacy was investigated using two different approaches: 1) measuring I-fibrin deposition in various organs and 2) continuous whole-body imaging of In-platelet biodistribution in anesthetized animals.
After start of the TF infusion in rats with radioactively-labeled fibrinogen, the radioactivity was accumulated in liver, spleen, kidney, and mostly in the lung as a consequence of fibrin generation. SATI efficiently reduced the pulmonary deposition of fibrin in a dose- and time-dependent manner. In the SATI groups the splenic and renal radioactivity was enhanced at later time points probably as consequence of the clearance of I-fibrin(ogen). Imaging of rats that received In-platelets prior to systemic TF administration showed retention of the radioactivity mainly in the lungs in the control group. SATI efficiently blocked the platelet accumulation in the lungs and increased platelet recruitment by the spleen.
SATI is a promising candidate for prevention of microcirculatory disturbances by inhibiting fibrin deposition and platelet accumulation in the lungs and thereby conferring organ protection. Both methods used in this study are suitable for investigating the antithrombotic efficacy of new drugs in microthrombosis. Continuous imaging of In-platelets allowed for follow-up of thrombus formation in living animals without the need for tissue harvesting.
全身性高凝状态通常是感染性和炎症性疾病的严重并发症，它打破了止血平衡，导致微血管和器官中多处血栓形成和损伤，并与高死亡率相关。SATI 是 FXa 和凝血酶的双重强效抑制剂，在静脉和动脉血栓模型中具有抗血栓形成作用。在这项研究中，SATI 在诱导高凝状态的大鼠微血管血栓模型中被评估了抗血栓形成作用。
在 60 只大鼠（分为 12 组，每组 5 只）中通过 TF 输注产生高凝状态。通过持续输注给予 SATI 两种不同剂量，并通过两种不同方法研究其抗血栓形成作用：1）测量各种器官中的 I-纤维蛋白沉积，2）在麻醉动物中连续全身成像 In-血小板的体内分布。
在放射性标记的纤维蛋白原的大鼠中开始 TF 输注后，放射性物质在肝脏、脾脏、肾脏中积累，并且由于纤维蛋白的产生主要在肺中积累。SATI 以剂量和时间依赖的方式有效地减少了肺中纤维蛋白的沉积。在 SATI 组中，脾和肾中的放射性物质在较晚的时间点增强，可能是由于 I-纤维蛋白原的清除。在全身性 TF 给药之前接受 In-血小板的大鼠的成像显示，在对照组中，放射性物质主要在肺中保留。SATI 有效地阻止了血小板在肺中的聚集，并增加了脾脏对血小板的募集。
SATI 是一种有前途的候选药物，可通过抑制纤维蛋白沉积和血小板在肺部的聚集来预防微循环障碍，从而提供器官保护。本研究中使用的两种方法都适用于研究新药物在微血管血栓形成中的抗血栓形成作用。In-血小板的连续成像允许在无需组织收获的情况下对活体动物中的血栓形成进行随访。
