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

Abstract

BackgroundHemophilia 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. MethodsIn 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. ResultsA 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). ConclusionOur results suggest a potential benefit of TXA when used in combination with FVIII in prophylactic settings.