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DOI: 10.1055/a-2315-8199
Additional Factor X Enhances Emicizumab-Driven Coagulation Function in Patients with Hemophilia A and Hemophilia A Mice
Funding This research was supported, in part, by KM Biologics Co., Ltd. And Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to K.N. (21K07804) and Y.N. (22K15928).
Abstract
Background Bypassing agents are used for breakthrough bleedings in patients with hemophilia A with inhibitor (PwHAwI) receiving emicizumab prophylaxis. Previous study demonstrated a weak binding affinity between emicizumab and factor (F)X (K d; 1.85 μM), and that this value was much greater than the plasma FX concentration (∼130 nM). We speculated that increased FX levels could enhance coagulation potential in emicizumab-treated patients with hemophilia A (PwHA). To investigate the relationship between FX concentrations and emicizumab-driven coagulation.
Methods Plasma FX (up to 1,040 nM) and emicizumab (50 µg/mL) were added to FVIII-deficient plasmas, and plasma-derived FX (520 nM) or recombinant (r)FVIIa (2.2 µg/mL) was added to plasmas from three emicizumab-treated PwHAwI. The adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (PeakTh) by thrombin generation assay in them were evaluated. Emicizumab (3.0 mg/kg), human (h)FIX (100 IU/kg), and various doses of hFX (100–500 IU/kg) were intravenously administered to HA mice. Clotting time/clot formation time (CT/CFT) were assessed using rotational thromboelastometry, and blood loss was estimated by a tail-clip assay.
Results The addition of FX to FVIII-deficient plasma with emicizumab increased Ad|min1| and PeakTh. The coagulation parameters in emicizumab-treated PwHAwI spiked with additional FX remained within the normal range as well as the additional rFVIIa. In animal models, hFX injection shortened the CT and CT + CFT. The shorter CT and CT + CFT, and the lower blood loss were evident after 200 or 500 IU/kg hFX administration, and those indices were comparable to those in wild-type mice.
Conclusion Supplementation with FX may improve emicizumab-driven hemostasis in PwHA.
Note
An account of this work was presented at the annual meeting of ISTH2023 Congress, Montréal, Quebec, Canada.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' Contribution
K.S. performed the experiments, analyzed the data, made the figures, and wrote the paper. Y.N. designed all experiments, interpreted the data, prepared figures, wrote and edited the manuscript, and approved the final version to be published. E.T. and H.N. supervised the study and prepared pd-FVIIa/FX, FIX, and FX concentrates. K.N. designed the research, supported the data, interpreted the data, wrote the paper, and edited the manuscript.
Publication History
Received: 06 December 2023
Accepted: 25 April 2024
Accepted Manuscript online:
27 April 2024
Article published online:
15 May 2024
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