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    Poster Networking

    Hemophilia and Rare Bleeding Disorders

    Poster Networking Session

    PB0700 - FXI inhibitor safety in hemophilia patients: computational prediction of thrombin generation.

    Monday, June 26, 2023
    18:30 – 19:30 ET
    Room: Exhibition
    Background: FXI inhibitors are being developed as a safer anticoagulant strategy to reduce pathological clotting with minimal bleeding risk. They may be particularly useful for anticoagulating patients with propensities for bleeding. Yet, it remains to be seen whether FXI inhibitors will be safe for use in patients with disorders such as hemophilia, who present with an increased bleeding risk due to low blood concentrations of FIX (Hemophilia B) or FVIII (Hemophilia A).

    Aims: Evaluate the effect of FXI on thrombin generation in a computational model of hemophilia.

    Methods: The thrombin generation curves of virtual patients with reduced blood concentrations of FIX or FVIII were generated in an extended Hockin-Mann model of coagulation based on initiating clotting with tissue factor. The effect of FXI inhibition was modeled in the virtual hemophilia patients. Endogenous thrombin potential (ETP) and peak thrombin concentration were analyzed.

    Results: As expected, thrombin generation steadily decreased as FVIII or FIX concentrations were reduced. A healthy virtual patient with a physiological FXI concentration exhibited a modeled ETP of 2549 units, and peak thrombin of 153 nM. In contrast, a virtual patient with mild hemophilia B (40% FIX concentration) had an ETP of 20 units and a peak thrombin of 5 nM. Next, we set FXI levels to 0% and modeled 100% vs. 40% FIX; ETP and peak thrombin generation dropped to 1146 and 48 nM, while for 40% FIX the ETP and peak thrombin generation dramatically dropped to 7 and 1nM, respectively. Similar reductions in thrombin generation were predicted for Hemophilia A virtual patients.

    Conclusion(s): Our model predicts decreased thrombin generation in hemophilia patients and provides information on the combined impact of low FVIII or FIX in the setting of reduced FXI activity. Future work will compare these results with functional assays to validate behavior of current FXI inhibitors in hemophilia.