Abstract Number: PB0815
Meeting: ISTH 2020 Congress
Background: While emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A, some patients still experience bleeding. One treatment for bleeding in patients with inhibitors is an activated prothrombin complex concentrate (APCC; FEIBA) (disfavored in NHF MASAC #255). APCC contains among other things prothrombin, factor X (FX), and factor IX (FIX), as well as activated factors FIXa and FXa. Previous studies have shown that addition of APCCs to hemophilia A plasma containing emicizumab gives a significant increase in thrombin generation [J Thromb Haemost 2018;16:1580-1591].
Aims: The goal of this study was to assess the contribution of individual components of APCC to increased thrombin generation.
Methods: Thrombin generation assays were done in hemophilia A plasma using 1 pM tissue factor, 100 µM lipid, and 420 µM Z-Gly-Gly-Arg-AMC with or without 55 µg/mL emicizumab (clinical steady state levels). To mimic the expected APCC increases in plasma concentration at a dose of 50 U/kg, added: prothrombin 1800 nM; FX 130 nM; FIX 90 nM; FIXa 0.4 nM.
Results: Under these conditions, hemophilia A plasma alone had essentially no thrombin generation. Addition of emicizumab enhanced thrombin generation. Further addition of prothrombin, FIX, and FX gave a small increase in thrombin generation. Addition of FIXa to emicizumab significantly increased thrombin generation (Figure 1). Addition of prothrombin to FIXa and emicizumab increased thrombin generation and increased the peak level of thrombin; none of the other zymogen components significantly altered thrombin generation (Figure 2).
Conclusions: A previous study of the individual components of APCC in the absence of emicizumab concluded that a combination of FXa and prothrombin had the major effect on thrombin generation [Haemophilia. 2016;22:615-24] and that FIXa did not increase thrombin generation. Surprisingly, given the weak solution affinity of emicizumab for FIXa, with emicizumab, the FIXa provided by APCCs is the most significant contributor to thrombin generation.
To cite this abstract in AMA style:Monroe D, Ezban M, Hoffman M. Contributions of the Individual Components of an Activated Prothrombin Complex Concentrate to Thrombin Generation in the Presence of Emicizumab [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/contributions-of-the-individual-components-of-an-activated-prothrombin-complex-concentrate-to-thrombin-generation-in-the-presence-of-emicizumab/. Accessed January 23, 2022.
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