Michael Smith Laboratories.
Centre for Blood Research, and.
Blood. 2020 Dec 17;136(25):2946-2954. doi: 10.1182/blood.2020004976.
The activated form of coagulation factor XIII (FXIII-A2B2), FXIII-A*, is a hemostatic enzyme essential for inhibiting fibrinolysis by irreversibly crosslinking fibrin and antifibrinolytic proteins. Despite its importance, there are no modulatory therapeutics. Guided by the observation that humans deficient in FXIII-B have reduced FXIII-A without severe bleeding, we hypothesized that a suitable small interfering RNA (siRNA) targeting hepatic FXIII-B could safely decrease FXIII-A. Here we show that knockdown of FXIII-B with siRNA in mice and rabbits using lipid nanoparticles resulted in a sustained and controlled decrease in FXIII-A. The concentration of FXIII-A in plasma was reduced by 90% for weeks after a single injection and for more than 5 months with repeated injections, whereas the concentration of FXIII-A in platelets was unchanged. Ex vivo, crosslinking of α2-antiplasmin and fibrin was impaired and fibrinolysis was enhanced. In vivo, reperfusion of carotid artery thrombotic occlusion was also enhanced. Re-bleeding events were increased after challenge, but blood loss was not significantly increased. This approach, which mimics congenital FXIII-B deficiency, provides a potential pharmacologic and experimental tool to modulate FXIII-A2B2 activity.
凝血因子 XIII（FXIII-A2B2）的激活形式 FXIII-A* 是一种止血酶，对于通过不可逆地交联纤维蛋白和抗纤维蛋白溶解蛋白来抑制纤维蛋白溶解至关重要。尽管它很重要，但目前还没有调节治疗方法。基于观察到 FXIII-B 缺乏的人类没有严重出血而 FXIII-A 减少的现象，我们假设针对肝脏 FXIII-B 的合适小干扰 RNA（siRNA）可以安全地降低 FXIII-A。在这里，我们展示了使用脂质纳米粒在小鼠和兔中用 siRNA 敲低 FXIII-B 可导致 FXIII-A 的持续和受控降低。单次注射后数周内，血浆中 FXIII-A 的浓度降低了 90%，重复注射后超过 5 个月，而血小板中 FXIII-A 的浓度保持不变。在体外，α2-抗纤溶酶和纤维蛋白的交联受到损害，纤维蛋白溶解增强。在体内，颈动脉血栓闭塞再灌注也得到了增强。在挑战后，再出血事件增加，但失血量没有明显增加。这种方法模拟了先天性 FXIII-B 缺乏症，为调节 FXIII-A2B2 活性提供了一种潜在的药理学和实验工具。
