Abstract Number: PB0676
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia
Background: New treatment strategies for hemophilia A are emerging. A novel treatment approach is the restoration of the balance between pro- and anticoagulants, by inhibiting natural anticoagulants such as antithrombin (AT) or protein C.
Aims: We used in silico modelling to investigate the effect of AT reduction on thrombin generation (TG) and the hemostatic balance in hemophilia A patients.
Methods: 26 hemophilia A patients and 27 age- and sex-matched control subjects were enrolled in this study. TG was measured with the CAT method using PPP reagent low. Thrombin dynamics analysis was used to extract prothrombin conversion curves from the TG data and to perform in silico experiments to study the effect of AT reduction on TG in hemophilia patients. Each individual prothrombin conversion curve was used to simulate a series of 14 TG curves, by varying the AT level from 100% to 2.5%. TG parameters peak height, ETP and velocity index were quantified.
Results: AT reduction partially normalized TG dose-dependently in all patients. Peak height, ETP and velocity index increased dose-dependently. The average thrombin peak height was 41nM ± 24 nM in hemophilia patients at 100% AT. An AT reduction of 95% could restore TG in hemophilia patients up to an average peak height of 192 ± 94 nM, although the variation between patients was high. At 100% AT, ETP was 570 nM·min ± 281 nM·min on average in hemophilia patients, and a 95% AT reduction increased the ETP to 6100 ± 3212 nM·min. The velocity index of 4.6 nM/min ± 3.3 nM/min at 100% AT in hemophilia patients was increased to 21.7 ± 13.1 nM/min after 95% reduction of AT.
Figure 1: The in silico effect of antithrombin targeting in hemophilia A on thrombin generation. (A) The average TG curve of the hemophilia A patients at the original plasma AT level (100%) in silico generated average thrombin generation curves of the same patients at 90, 80, 70, 60, 50, 40, and 30% AT. (B) The average in silico generated average thrombin generation curves of the hemophilia A patients at 25, 20, 15, 10, 5, and 2.5% AT. The generated TG curves were quantified by their peak height (C), ETP (D) and velocity index (E). References ranges in the healthy subject group are plotted as grey box with the mean value in healthy subjects indicated as a dashed line.
Conclusions: An AT reduction of 95% led to almost normal TG peak height in most patients. The large variation in response to AT reduction indicates that tailoring AT targeting therapeutics could be beneficial.
To cite this abstract in AMA style:
de Laat-Kremers R, Ninivaggi M, van Moort I, de Maat M, de Laat B. Tailoring the Effect of Antithrombin-targeting Therapy in Hemophilia A Using in Silico Thrombin Generation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/tailoring-the-effect-of-antithrombin-targeting-therapy-in-hemophilia-a-using-in-silico-thrombin-generation/. Accessed June 6, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/tailoring-the-effect-of-antithrombin-targeting-therapy-in-hemophilia-a-using-in-silico-thrombin-generation/