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

Viola J F Strijbis; Lorenzo G R Romano; Ka Lei Cheung; Jeroen Eikenboom; Ying Poi Liu; Andrew C McCreary; Frank W G Leebeek; Mettine H A Bos

doi:10.1016/j.jtha.2023.02.019

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

J Thromb Haemost. 2023 Jun;21(6):1466-1477. doi: 10.1016/j.jtha.2023.02.019. Epub 2023 Feb 28.

Authors

Viola J F Strijbis¹, Lorenzo G R Romano², Ka Lei Cheung³, Jeroen Eikenboom⁴, Ying Poi Liu⁵, Andrew C McCreary⁵, Frank W G Leebeek⁶, Mettine H A Bos⁷

Affiliations

¹ Department of Internal Medicine, Division of Thrombosis and Haemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: https://twitter.com/ViolaStrijbis.
² Department of Haematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address: https://twitter.com/lgrromano.
³ Department of Internal Medicine, Division of Thrombosis and Haemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: https://twitter.com/KaleiCheung.
⁴ Department of Internal Medicine, Division of Thrombosis and Haemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
⁵ uniQure Biopharma B.V., Amsterdam, the Netherlands.
⁶ Department of Haematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address: https://twitter.com/FLeebeek.
⁷ Department of Internal Medicine, Division of Thrombosis and Haemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: M.H.A.Bos@lumc.nl.

PMID: 36863564
DOI: 10.1016/j.jtha.2023.02.019

Abstract

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.

Keywords: emicizumab; factor IX; factor VIII; hemophilia A; hemorrhage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Factor IX / genetics
Factor VIII / genetics
Factor VIII / therapeutic use
Hemophilia A*
Hemostatics*
Humans
Partial Thromboplastin Time
Phenotype

Substances

Factor VIII
Factor IX
Hemostatics