Abstract Number: OC 50.3
Meeting: ISTH 2022 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia
Background: While the FVIII-mimetic emicizumab has been widely adapted for hemophilia A (with subcutaneous administration), prophylaxis for hemophilia B (HB) still requires intravenous FIX administration. Previous studies investigating the effect of emicizumab in HB suggested that emicizumab can enhance the FIX activity of wild-type FIX about tenfold, but HB patients with dysfunctional FIX variants were non-responders to emicizumab (Ogiwara et al. 2017). We recently demonstrated that the mechanism of the high-specific activity of FIX-Padua was due to an enhanced interaction between FIXa/FVIIIa and the increased activity of FIX-Padua compared to FIX-WT is ablated with emicizumab (Samelson-Jones et al 2019).
Aims: We now test the converse hypothesis: HB-causing FIX missense variants due to dysfunctional FIXa/FVIIIa interactions can be rescued with FVIII mimetics.
Methods: Procoagulant activity of recombinant FIX protein and patient samples were assayed by either aPTT assay, one-stage FIX activity, TGA, and ROTEM.
Results: Recombinant protein of high-prevalence HB-causing FIX variants with dysfunctional FIXa/FVIIIa interactions (G93S, R338P, E387K, and I397T) and severe-to-mild HB phenotypes demonstrated increased FIX activity with the addition of therapeutic amounts (300 nM) of emicizumab (Figure-1A). The FIX activities of these recombinant FIX variants without emicizumab is comparable to the clinical data. Emicizumab also corrected the thrombin generation of these variants (Figure-1B). In contrast, HB-causing FIX variants with missense mutations outside FVIIIa-interacting motifs (R248Q and A390V) had no improvement in FIX activity or thrombin generation. In samples from patients with FIX-I397T, emicizumab normalized the aPTT-based clotting time in plasma and substantially improved the ROTEM clot time in whole blood (Figure-1C,D).
Conclusion(s): HB-causing FIX missense variants with dysfunctional FIXa/FVIIIa interactions are highly-susceptible to procoagulant improvement with FVIII-mimetics like emicizumab. Given emicuzmab’s excellent safety record in non-inhibitor HA patients with expanding use into mild HA, consideration of treatment of HB patients with these variants could be considered.
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To cite this abstract in AMA style:
Chau J, Sternberg A, Pishko A, George L, Samelson-Jones B. Improved Procoagulant Activity of Hemophilia B Causing Dysfunctional Factor IX Variants with Factor VIII Mimetics [abstract]. https://abstracts.isth.org/abstract/improved-procoagulant-activity-of-hemophilia-b-causing-dysfunctional-factor-ix-variants-with-factor-viii-mimetics/. Accessed October 2, 2023.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/improved-procoagulant-activity-of-hemophilia-b-causing-dysfunctional-factor-ix-variants-with-factor-viii-mimetics/