The effect of emicizumab and bypassing agents in patients with hemophilia – An in vitro study
Nina Haagenrud Schultz, Heidi Glosli, Stine Bjørnsen, Pål André Holme
Abstract
BACKGROUND: Emicizumab is a nonfactor replacement therapy for hemophilia A (HA) and is a bispecific monoclonal antibody mimicking factor VIII by binding both factors IXa and X. Although it reduces the frequency of bleeding episodes, there is still need for bypassing agents in case of breakthrough bleeds or need for surgery. The HAVEN-1 study showed an increased risk of thrombotic events and episodes of thrombotic microangiopathic hemolytic anemia with simultaneous treatment with emicizumab and activated prothrombin complex concentrate (aPCC) in high doses (>100 U/kg daily) for more than 1 day, and it is suspected that these drugs have a synergistic hemostatic effect. OBJECTIVES: To evaluate and compare the hemostatic effect of bypassing agents in vitro in people with HA before and after starting treatment with emicizumab to investigate if dosing should be adjusted to optimize treatment. PATIENTS/METHODS: Blood collected before and after start of treatment with emicizumab was spiked with aPCC and recombinant factor VIIa (rFVIIa) at different concentrations. The effect of aPCC and rFVIIa was assessed by thrombin generation assay and thromboelastometry. RESULTS: Six people with HA were included. The response to aPCC in thrombin generation after starting emicizumab was significantly stronger than before. This synergistic effect was less pronounced for emicizumab and rFVIIa. Furthermore, aPCC shortened thromboelastometry clotting time more effectively after starting emicizumab than before starting this treatment. CONCLUSIONS: We demonstrated a strong synergistic effect of emicizumab and aPCC and a similar but less pronounced effect of rFVIIa in people treated with emicizumab.