Hemostatic effect of tranexamic acid combined with factor VIII concentrate in prophylactic setting in severe hemophilia A: A preclinical study

Abstract

Background: Hemophilia is characterized by a compromised hemostatic response with delayed development of a clot and the formation of clots that are vulnerable to fibrinolysis. We proposed to study, in vitro and in factor VIII knockout mice (FVIII-KO), whether hemostasis is improved with the addition of tranexamic acid (TXA) to low FVIII plasma concentrations. Methods: In vitro, blood samples from adults with severe hemophilia-A, spiked to final concentrations of 0-3-10 and 30IU.dL−1 of FVIII, were studied with and without TXA 0.1 mg/mL using thromboelastography in the presence of tPA (ROTEM-tPA), thrombin generation (TG) assay, and scanning electron microscopy. FVIII-KO mice received prophylaxis before trauma, to obtain circulating plasma FVIII at 3 IU.dL−1 or FVIII 3IU.dL−1 + TXA 0.1 mg/mL. After trauma-induced knee joint bleeding, magnetic resonance imaging, histological analysis, and tail clip assay were used to compare hemostastic efficacy of the two prophylactic strategies. Results: A dose-dependent improvement of TG was observed with recombinant FVIII (rFVIII) alone (P =.024). As expected, no effect of TXA on TG capacity was observed. Fibrin fiber diameters were significantly decreased with TXA + rFVIII compared to rFVIII, suggesting a stronger fibrin network. Surprisingly, ROTEM-tPA was normalized with TXA alone. In FVIII-KO mice, blood loss after tail clip was lower after prophylaxis with rFVIII + TXA compared to rFVIII, with no statistical significance (P =.15). However, MRI results and histological analysis of knee joints showed that the addition of TXA significantly decreased joint bleeding (P =.022). Conclusion: Our results suggest a potential benefit of TXA when used in combination with FVIII in prophylactic settings.