Abstract Number: PB0470
Meeting: ISTH 2021 Congress
Background: Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors and other indications. The mechanism of rFVIIa action is mediated by the platelet phospholipids (PL) and tissue factor (TF). Traditional laboratory assays have not been useful in guiding rFVIIa therapy, and the PL- and/or TF-triggered thrombin generation (TG) assay was proposed for this purpose.
Aims: Study the predictive value of plasma levels of FVIIa activity and TG assays for the effect of rFVIIa treatment on tail bleeding in FVIII knockout mice.
Methods: Mice were treated with 5 mg/kg of rFVIIa and blood was collected 5, 30, 60 minutes and 2 hours (2h), 4h, 8h, 16h and 24h after drug administration. TG was triggered with combinations of PL, TF and human or mouse soluble TF (sTF). FVIIa activity was measured with an sTF-based clotting StaClot assay. In a parallel tail clip study, bleeding was evaluated for 30 minutes after injury.
Results: Tail bleeding studies demonstrated gradual weakening of rFVIIa effect between 5 minute and 1h points, with no hemostatic effect by 2h after administration. All TG assays showed difference in thrombin peak height readouts between the 1h and 2h time points. The peak height responses of sTF+PL and TF+PL triggered TG assays continued to decline until 16h after administration, and for the remaining TG assays – until 4h to 8h. The greatest gradient in thrombin peak responses at 1h time point was provided by the PL trigger.
Conclusions: TG assay may be suitable for evaluation of the duration of hemostatic action of rFVIIa. PL-triggered TG assay offers better correlation with the loss of hemostatic effect which may be explained by the primarily PL-dependent activity of human rFVIIa in mice.
Disclosure: This paper is an informal communication and represents the authors’ best judgment. These comments do not bind or obligate FDA.
To cite this abstract in AMA style:Surov S, Ovanesov M. Predicting the Duration of Recombinant Factor VIIa Effect on Tail Bleeding by the Thrombin Generation Assay in Hemophilia A Mice [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/predicting-the-duration-of-recombinant-factor-viia-effect-on-tail-bleeding-by-the-thrombin-generation-assay-in-hemophilia-a-mice/. Accessed March 4, 2024.
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