The effects of recombinant human activated factor VII and tranexamic acid on traumatic bleeding and mortality in mice

Abstract

Background: Tranexamic acid (TXA) and recombinant human activated factor (F)VII (rhFVIIa) both control severe traumatic bleeding, with mortality benefit only demonstrated for TXA. Objectives: To compare the effects of rhFVIIa and TXA on bleeding, trauma-induced coagulopathy (TIC), inflammation, and survival in a murine trauma model. Methods: Liver laceration (LL) was employed to induce TIC. C57BL/6J mice were pretreated intravenously with saline, rhFVIIa (3 mg/kg), or TXA (10 mg/kg). Blood loss, coagulopathy (activated partial thromboplastin time [aPTT], FII, FV, FVIII, FX, thrombin-antithrombin [TAT], and fibrinogen), and fibrinolysis (tissue-type plasminogen activator, plasmin-α2-antiplasmin complexes, and D-dimer) were analyzed 60 minutes after LL. Cytokines were measured at 60 minutes and 6 hours. Pulmonary fibrin deposition and survival were evaluated for up to 7 days. Results: Both rhFVIIa and TXA reduced blood loss compared with saline-treated mice after LL. Saline-treated mice developed TIC (prolonged aPTT, increased TAT complex formation, and selective depletion of FV, FVIII, and fibrinogen). rhFVIIa overcorrected the aPTT and increased TAT complex levels, whereas TXA normalized these parameters. Both agents reduced tissue-type plasminogen activator and plasmin-α2- antiplasmin complex formation; however, rhFVIIa failed to suppress D-dimer formation and exacerbated interleukin-6 formation. Pulmonary fibrin deposition and microthrombi occurred exclusively in rhFVIIa-treated mice (days 1, 2, and 7), accompanied by reduced survival (�50%) compared with TXA (�80%). Conclusion: While both agents reduced bleeding, rhFVIIa promoted prothrombotic and inflammatory responses, which were associated with increased mortality. Our findings highlight the unmet need for targeted interventions to reduce TIC while minimizing thromboinflammatory risk.