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Suppressing upregulation of fibrinogen after polytrauma mitigates thrombosis in mice
Monica S Seadler1, Francesca Ferraresso, Muskan Bansal
1From 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.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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