Abstract
Emicizumab reduces bleeding in hemophilia A patients with inhibitor (HA-inh). A combination of immune tolerance induction therapy (ITI) and emicizumab prophylaxis may provide additional benefits, but coagulation potential during this treatment remains unknown. We assessed coagulation potentials in simulated ITI models in vitro using modified-clot waveform analysis. Factor (F)VIII-deficient plasma preincubated with anti-A2 and anti-C2 monoclonal antibodies was reacted with emicizumab (50 µg/mL) (emicizumab–HA–plasma), then spiking bypassing agents (BPAs): activated prothrombin complex concentrates (aPCC 1.3 IU/mL; 50 IU/kg), recombinant factor (rF)VIIa (2.2 µg/mL; 90 µg/kg), and FVIIa/FX (1.5 µg/mL; 60 µg/kg), and/or FVIII (100, 200 IU/dL). Coagulation potentials in emicizumab–HA–plasma (10 BU/mL) remained within the normal range when BPA and FVIII were both present. In emicizumab–HA–plasma (1 BU/mL) with BPA and FVIII (200 IU/dL), they were near or beyond the normal range, but those with a half concentration of rFVIIa based on the half-life in blood were within the normal range. In samples without inhibitor, coagulation potentials with combined BPA and FVIII were far beyond the normal range but with FVIII (100 IU/dL) and rFVIIa at half concentration they remained within the normal range. These results may provide information on the feasibility of concurrent ITI under emicizumab prophylaxis.
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Funding
This work was partly supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to KN (Grant No. 18K07885).
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YN designed and performed the experiments, analyzed the data, constructed the figures and wrote the paper; HT performed normal control experiments; MN-S prepared emicizumab, interpreted the data, and supervised this study; KN designed the research, interpreted the data, organized the study, edited the manuscript, and approved the final version to be published.
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YN and KN receive research support from Chugai Pharmaceutical Co., Ltd. (Chugai), and are engaged in clinical studies sponsored by Chugai and F. Hoffmann-La Roche. KN receives (consulting) honoraria from these companies, and is an inventor of the patents relating to emicizumab. MN-S is an employee of Chugai. HT has no conflict of interest.
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Nakajima, Y., Tonegawa, H., Noguchi-Sasaki, M. et al. Predicted coagulation potential using an in vitro simulated model of emicizumab prophylaxis and immune tolerance induction therapy in hemophilia A patients with inhibitor. Int J Hematol 113, 789–796 (2021). https://doi.org/10.1007/s12185-021-03108-8
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DOI: https://doi.org/10.1007/s12185-021-03108-8