Clinical Utility of Subcutaneous Factor VIII Replacement Therapies in Hemophilia A: A Review of the Evidence.

Hemophilia therapies have tremendously improved over the last decades with the development of prolonged half-life factor VIII (FVIII) and FIX concentrates, non-factor therapies, such as emicizumab, anti-TFPI antibodies or siRNA antithrombin and gene therapy. All of these new molecules significantly reduced the burden of the disease and improved the quality of life of patients with severe hemophilia. Emicizumab, a non-factor therapy, is currently the only subcutaneous molecule available for prophylactic treatment of severe hemophilia A. Because of the subcutaneous route of delivery and similar efficacy to FVIII replacement therapy, emicizumab has been rapidly adopted by patients and their families. This clinical observation emphasizes the relevance and need for the development of subcutaneous FVIII concentrates. Here, we report evidence-based advantages and interest in the subcutaneous route of administration for the treatment of hemophilia A and review the stages of development of the different subcutaneous FVIII molecules.

Haemostatic effect of adding tranexamic acid to emicizumab prophylaxis in severe haemophilia A: A preclinical study.

BACKGROUND: Patients with severe haemophilia have impaired haemostatic response, delayed clot formation and fibrin clots that are vulnerable to fibrinolysis. Emicizumab is a bispecific antibody that mimics activity of activated factor VIII (FVIII) and increases haemostatic capacity to the level of moderate-to-mild haemophilia, thereby used for prophylaxis. Regardless of the impressive clinical performance of emicizumab, breakthrough bleeds may still occur. We aimed to study, in FVIII knockout mice (FVIII-KO), whether haemostasis is improved with the addition of tranexamic acid (TxAc) to emicizumab. METHODS: FVIII-KO mice received prophylaxis with emicizumab or emicizumab+TxAc before trauma. FVIII-KO mice were given emicizumab 1.5 mg/kg via IV injection. A second retro-orbital IV injection containing human FIX and FX (both 100U/kg) was given 24 h later and 5 min before the tail amputation or knee trauma. After trauma-induced knee joint bleeding, magnetic resonance imaging (MRI), and histological analysis were used to compare haemostatic efficacy of the two prophylactic strategies. Thrombin generation (TG) was measured and clots obtained with TG experiment were analysed by scanning electron microscopy. RESULTS: In FVIII-KO mice, blood loss after tail clip was lower after prophylaxis with emicizumab+TxAc compared to emicizumab. MRI results and histological analysis of knee joints showed that the addition of TxAc significantly decreased joint bleeding. Fibrin fibre diameters of mice treated with emicizumab only was thicker than those who received combined prophylaxis with emicizumab+TxAc. CONCLUSION: Our results suggest a potential benefit of TxAc when used in combination with emicizumab in prophylactic settings, especially in patients presenting breakthrough bleeds.

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

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.