A factor IX variant that functions independently of factor VIII mitigates the hemophilia: a phenotype in patient plasma

Strijbis, V.J.F.; Romano, L.G.R.; Cheung, K.L.; Eikenboom, J.; Liu, Y.P.; McCreary, A.C.; ... ; Bos, M.H.A. (2023)

Article / Letter to editor

Background

Recombinant factor (F)IX-FIAV has previously been shown to function independently of activated FVIII (FVIIIa) and ameliorate the hemophilia A (HA) phenotype in vitro and in vivo.

Objectives

The aim of this study was to assess the efficacy of FIX-FIAV in plasma from HA patients using thrombin generation (TG) and intrinsic clotting activity (activated partial thromboplastin time [APTT]) analyses.

Methods

Plasma obtained from 21 patients with HA (>18 years; 7 mild, 7 moderate, and 7 severe patients) was spiked with FIX-FIAV. The FXIa-triggered TG lag time and APTT were quantified in terms of FVIII-equivalent activity using FVIII calibration for each patient plasma.

Results

The linear, dose-dependent improvement in the TG lag time and APTT reached its maximum with approximately 400% to 600% FIX-FIAV in severe HA plasma and with approximately 200% to 250% FIX-FIAV in nonsevere HA plasma. The cofactor-independent contribution of FIX-FIAV was therefore suggested and confirmed by the addition of inhibitory anti-FVIII antibodies to nonsevere HA plasma, resulting in a FIX-FIAV response similar to severe HA plasma. Addition of 100% (5 μg/mL) FIX-FIAV mitigated the HA phenotype from severe to moderate (from <0.01% to 2.9% [IQR 2.3%-3.9%] FVIII-equivalent activity), from moderate to mild (3.9% [IQR 3.3%-4.9%] to 16.1% [IQR 13.7%-18.1%] FVIII-equivalent activity), and from mild to normal (19.8% [IQR 9.2%-24.0%] to 48.0% [IQR 34.0%-67.5%] FVIII-equivalent activity). No substantial effects were observed when combining FIX-FIAV with current HA therapies.

Conclusion

FIX-FIAV is capable of increasing the FVIII-equivalent activity and coagulation activity in plasma from HA patients, thereby mitigating the HA phenotype. Hence, FIX-FIAV could serve as a potential treatment for HA patients with or without inhibitors.

• emicizumab
• factor VIII
• factor IX
• hemophilia A
• hemorrhage

• All authors: Strijbis, V.J.F.; Romano, L.G.R.; Cheung, K.L.; Eikenboom, J.; Liu, Y.P.; McCreary, A.C.; Leebeek, F.W.G.; Bos, M.H.A.
• Date: 2023-05-11
• Journal: Journal of Thrombosis and Haemostasis
• Volume: 21
• Issue: 6
• Pages: 1466 - 1477
• DOI: doi:10.1016/j.jtha.2023.02.019
• Link: https://www.sciencedirect.com/science/article/pii/S153878362300168X?via%...