Abstract Number: OC 48.1
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia
Background: Previously, factor (F)IX-FIAV has been generated that functions independently of the cofactor VIIIa and ameliorates the hemophilia A (HA) phenotype in vitro/vivo [Quade-Lyssy et al. J.Thromb.Haemost. 2014].
Aims: Efficacy and potency assessment of purified recombinant FIX-FIAV in mild, moderate, and severe HA patient plasma using thrombin generation (TG) and intrinsic clotting activity (aPTT) analyses.
Methods: Plasma was obtained from 21 HA patients (>18yrs; seven/phenotype) and analyzed for FVIII/FIX levels, FVIII mutation, Bethesda Units, and aPTT. Plasma was spiked with FIX-FIAV and the FXIa-triggered TG lag-time and aPTT were quantified in terms of FVIII-like activity using a FVIII calibration for each patient plasma. This study was approved by the local medical ethics committee, and patients provided written informed consent.
Results: Supplementation of patient plasma with FIX-FIAV demonstrated a dose-dependent improvement in TG parameters and aPTT (Fig.1). For severe HA, a linear response in TG lag-time and aPTT was observed with a maximum at ~400-600% FIX-FIAV added, solely resulting from FIX-FIAV’s FVIII-independent activity. A higher potency was observed in moderate/mild HA plasma with a maximal effect at ~200-250% FIX-FIAV, which is in line with the residual FVIII activity in moderate/mild HA and demonstrates the contribution of the cofactor-dependent FIX-FIAV activity. Importantly, addition of an inhibitory anti-FVIII antibody to moderate/mild HA patient plasma resulted in a FIX-FIAV response similar to severe HA, confirming the cofactor-independent activity of FIX-FIAV. Efficacy assessment using the TG lag-time revealed that 100% (5 µg/ml) FIX-FIAV mitigated the HA phenotype from severe to moderate (<0.01% → 5±4% FVIII-like activity), from moderate to mild (4±2% → 13±5% FVIII-like activity), and from mild to normal (17±13% → 34±12% FVIII-like activity) (Fig.2).
Representative reference curves of the % FVIII activity over % FIX-FIAV supplementation in severe, moderate, or mild HA patient plasma. Dotted lines represent 1, 5, or 40% FVIII activity. The FVIII activity was quantified using a FVIII calibration of the TG lag-time for each patient plasma.
Phenotype improvement determined as FVIII activity at 100% (5 µg/ml) FIX-FIAV addition to severe, moderate, or mild HA patient plasma. Dotted lines represent 1, 5, or 40% FVIII activity. The FVIII activity was quantified using a FVIII calibration of the TG lag-time for each patient plasma.
Conclusions: FIX-FIAV is capable of increasing the FVIII-like activity and coagulation activity in HA patient plasma, thereby mitigating the HA phenotype. Hence, FIX-FIAV could serve as a potential treatment for HA.
To cite this abstract in AMA style:
Strijbis VJ, Romano LG, Cheung KL, Liu YP, McCreary AC, Leebeek FW, Bos MH. A Blood Coagulation Factor IX Variant that Functions Independently of Factor VIII Mitigates the Hemophilia A Phenotype in Patient Plasma [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-blood-coagulation-factor-ix-variant-that-functions-independently-of-factor-viii-mitigates-the-hemophilia-a-phenotype-in-patient-plasma/. Accessed January 24, 2022.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-blood-coagulation-factor-ix-variant-that-functions-independently-of-factor-viii-mitigates-the-hemophilia-a-phenotype-in-patient-plasma/