Abstract Number: PB0852
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic
Background: Patients with hemophilia A can be treated with emicizumab, a bivalent antibody which enhances factor IXa (FIXa) activation of factor X (FX). Breakthrough bleeding in patients with inhibitors has been treated safely with recombinant FVIIa (rFVIIa). At therapeutic levels rFVIIa can activate FX and FIX by both TF-dependent and lipid dependent mechanisms.
Aims: The goal of this study was to assess the role of rFVIIa activation of FIX on thrombin generation in the presence of emicizumab.
Methods: Thrombin generation assays were done in hemophilia AB plasma (HemAB), prepared from hemophilia B plasma depleted of FVIII by adding a neutralizing antibody. Emicizumab was added at 55 µg/mL (clinical steady state levels). rFVIIa was added in at varying doses with 25 nM corresponding to a clinical dose of 90 µg/mL.
Results: In the HemAB plasma with 1 pM tissue factor, there was essentially no thrombin generation (Figure 1). Addition of emicizumab did not increase thrombin generation. Addition of rFVIIa gave an increase in thrombin generation, which did not change by addition of plasma levels of FIX. In contrast emicizumab with FIX gave measurable thrombin generation through FVIIa/TF activation of FIX (Figure 2). An additional increase in thrombin generation was observed by the combination of rFVIIa and emicizumab in the presence of FIX.
Conclusions: In hemophilia A or B plasma, rFVIIa activation of FX is the only source of the FXa needed for thrombin generation; FIX activation does not contribute to thrombin generation. In the presence of emicizumab, while rFVIIa can still activate FX, the emicizumab complex with FIXa is an additional source of FX activation. Thus rFVIIa activation of FIX explains the synergistic effect in thrombin generation observed when combining rFVIIa with emicizumab. The generation of FIXa at a site of injury is consistent with the safety profile observed in clinical use.
[Figure 1. Effect of 25 nM factor VIIa on thrombin generation in Hemophilia AB plasma with and without emicizumab.]
[Figure 2. Effect of 25 nM factor VIIa on thrombin generation in Hemophilia A plasma with and without emicizumab.]
To cite this abstract in AMA style:
Monroe D, Ezban M, Hoffman M. The Synergistic Effect of Emicizumab and Factor VIIa on Thrombin Generation Is Dependent on Factor VIIa Activation of Factor IX [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-synergistic-effect-of-emicizumab-and-factor-viia-on-thrombin-generation-is-dependent-on-factor-viia-activation-of-factor-ix/. Accessed September 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-synergistic-effect-of-emicizumab-and-factor-viia-on-thrombin-generation-is-dependent-on-factor-viia-activation-of-factor-ix/