The Effects of Tranexamic Acid and Recombinant Activated Factor VII on Traumatic Bleeding and Mortality in Mice

Introduction

Trauma-associated bleeding and coagulopathy are often lethal. Early administration of tranexamic acid (TXA) is included in massive transfusion protocols since it somewhat reduces mortality. Recombinant activated factor VIIa (rFVIIa) is used variably during exsanguination when its procoagulant effects may outweigh potential prothrombotic risks. Since a comprehensive understanding of the effects of TXA and rFVIIa on bleeding, coagulopathy, and mortality is lacking, we investigated those in a murine trauma model.

Materials and Methods

C57BL/6J mice (8-10 weeks old, ~20 per group) were pretreated (within 5 minutes of trauma) intravenously with saline, TXA (10mg/kg), or rFVIIa (3mg/kg) and subjected to liver laceration. Blood loss (weighing blood-soaked sponges from the abdomen), coagulopathy [APTT, Factor (F)II, FV, FVIII, FX, and fibrinogen), thrombin-antithrombin (TAT), plasmin-antiplasmin (PAP) complexes, and D-dimer] were analyzed at 60 minutes after trauma. Data were expressed as median and compared by Mann-Whitney test. Seven-day survival was analyzed using Kaplan-Meier curves and pulmonary fibrin burden was determined by Orcein and Martius Scarlet Blue staining.

Results

Blood loss in saline-treated mice (21 µL/g) was reduced significantly by both agents, TXA or rFVIIa (~16 µL/g). Saline-treated mice developed acute traumatic coagulopathy (ATC), characterized by elevated APTT (35 seconds vs 23 seconds baseline [BL]), TAT-complex formation (334 ng/mL vs 7 ng/mL BL), and reductions of FV (14% vs 94% BL) FVIII (4% vs 101% BL)), and fibrinogen (47% vs 99% BL). Consistent with ATC, FII, and FX remained unaffected. Whereas TXA normalized the ATC, rFVIIa over-corrected the APTT, and increased TAT complexes and FVIII levels. While both agents reduced PAP complex formation similarly, suggestive of fibrinolysis control, rFVIIa was unable to suppress D-dimer formation, suggestive of persistent clot turnover. Seven-day survival was ~80% for mice treated with saline or TXA, but only ~50% for mice treated with rFVIIa. Pronounced pulmonary fibrin depositions (luminal thrombi) were noted in the surviving mice treated with rFVIIa, but were absent in TXA-treated mice

Conclusion

Peri-traumatic TXA and rFVIIa resulted in similar bleed reduction. However, while TXA normalized ATC, rFVIIa promoted prothrombotic coagulation abnormalities associated with increased mortality and thromboembolic complications. Since TXA mitigates but does not abolish bleeding and death in humans, our findings highlight the urgent need for alternative, targeted interventions to reduce ATC, traumatic bleeding, and death in humans.

von Drygalski:Biomarin: Consultancy, Honoraria; Sparx Therapeutics: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; CSL-Behring: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Research Funding; Genentech: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Hematherix LLC: Other: Co-founder; Takeda: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria.