Seadler Monica S, Ferraresso Francesca, Bansal Muskan, Haugen Amber, Hayssen William G, Flick Matthew J, de Moya Marc, Dyer Mitchell R, Kastrup Christian J
From the Department of Surgery (M.S.S., M.B., A.H., W.G.H., M.d.M., C.J.K.), Division of Trauma, Medical College of Wisconsin; Versiti Blood Research Institute (M.S.S., F.F., M.B., A.H., W.G.H., M.R.D., C.J.K.), Milwaukee, Wisconsin; Michael Smith Laboratories (F.F., C.J.K.), and Department of Biochemistry and Molecular Biology (F.F., C.J.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine (M.J.F.), and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (M.J.F.); UNC Blood Research Center (M.J.F.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Surgery (M.R.D.), Division of Vascular Surgery, and Departments of Biochemistry (C.J.K.), Biomedical Engineering (C.J.K.), and Pharmacology and Toxicology (C.J.K.), Medical College of Wisconsin, Milwaukee, Wisconsin.
J Trauma Acute Care Surg. 2024 Sep 6. doi: 10.1097/TA.0000000000004442.
Polytrauma results in systemic inflammation and increased circulating fibrinogen, which increases the risk of microvascular and macrovascular thrombosis that contributes to secondary organ damage and venous thromboembolism (VTE). There are no clinically approved agents to prevent hyperfibrinogenemia after polytrauma. We hypothesized that preventing the increase in fibrinogen levels after polytrauma would suppress thrombosis.
Small-interfering ribonucleic acid (siRNA) against fibrinogen was encapsulated in lipid nanoparticles (siFibrinogen). Mice underwent a model of polytrauma and were then given varying doses of siFibrinogen, control siRNA, or no treatment. Fibrinogen was measured for 1 week via enxyme-linked immunosorbent assay (ELISA). To model postinjury VTE, the inferior vena cava was ligated 2 days after polytrauma in a portion of the mice. Thrombus weight was measured 48 hours after the inferior vena cava was ligated.
Treatment with siFibrinogen prevented hyperfibrinogenemia after trauma without exacerbating the hypofibrinogenemic state that occurs in the acute injury period (1 hour). In treated groups, fibrinogen was significantly lower from 6 hours postinjury through the 7-day monitoring period. Maximal fibrinogen reduction was observed at 72 hours. Here, mice that received 2.0 mg/kg of siFibrinogen had 1% of normal values relative to untreated mice, and mice that received 1.0 or 0.5 mg/kg had 4%. Mice treated with siFibrinogen that underwent the postinjury VTE model had significantly reduced thrombus weight compared with control siRNA-treated animals. More notably, among all siFibrinogen treated mice, 12 of 18 were completely protected from thrombosis, compared with 0 of 9 displaying protection in the control group.
The rise of fibrinogen and the size of thrombi after polytrauma can be mitigated via the administration of siRNA against fibrinogen. siFibrinogen represents a promising novel target for VTE prophylaxis posttrauma.
多发伤会导致全身炎症反应和循环纤维蛋白原增加，这会增加微血管和大血管血栓形成的风险，进而导致继发性器官损伤和静脉血栓栓塞（VTE）。目前尚无临床批准的药物可预防多发伤后的高纤维蛋白原血症。我们推测，预防多发伤后纤维蛋白原水平升高可抑制血栓形成。
将针对纤维蛋白原的小干扰核糖核酸（siRNA）包裹在脂质纳米颗粒中（siFibrinogen）。对小鼠进行多发伤模型，然后给予不同剂量的siFibrinogen、对照siRNA或不进行治疗。通过酶联免疫吸附测定（ELISA）测量纤维蛋白原水平，为期1周。为模拟伤后VTE，在部分小鼠多发伤2天后结扎下腔静脉。在下腔静脉结扎48小时后测量血栓重量。
用siFibrinogen治疗可预防创伤后高纤维蛋白原血症，且不会加重急性损伤期（1小时）出现 的低纤维蛋白原血症状态。在治疗组中，从伤后6小时至7天监测期，纤维蛋白原水平显著降低。在72小时时观察到纤维蛋白原最大程度降低。在此，接受2.0mg/kg siFibrinogen的小鼠相对于未治疗小鼠，其纤维蛋白原水平为正常值的1%，接受1.0或0.5mg/kg的小鼠为4%。与对照siRNA治疗的动物相比，接受siFibrinogen治疗并进行伤后VTE模型的小鼠血栓重量显著降低。更值得注意的是，在所有接受siFibrinogen治疗的小鼠中，18只中有12只完全免受血栓形成，而对照组9只中无一例显示有保护作用。
通过给予针对纤维蛋白原的siRNA可减轻多发伤后纤维蛋白原的升高和血栓大小。siFibrinogen是创伤后VTE预防的一个有前景的新靶点。
