Abstract Number: VPB0576
Meeting: ISTH 2022 Congress
Background: Several genetically modified variants of activated coagulation factor Xa (FXa) were proposed to achieve reversal of direct FXa inhibitor action during bleeding or perioperative management. The properties of FXa variants are often compared to unmodified, plasma-derived (pd) FXa, but little is known about the efficacy and safety of pd-FXa for this indication as examined in animal models of bleeding.
Aims: The aim of the study was to test the ability of pd-FXa to safely reverse the action of a direct FXa inhibitor (apixaban) in vitro and in vivo.
Methods: Escalation of pd-FXa dose was studied by mouse tail bleeding and thrombin generation in human plasma. CD1 mice were injected intravenously with apixaban or vehicle, followed by pd-FXa 5 minutes later. After another 5 minutes, 3 mm of tail were cut, and bleeding was observed for 30 minutes.
Results: In vitro, reversal of apixaban effect on thrombin peak height in normal plasma was dependent on apixaban dose, e.g., 0.5 µM of apixaban was reversed with 33 µg/mL of pd-FXa, and 2 µM of apixaban with 200 µg/mL. Progressive reduction and normalization of blood loss at 4 mg/kg of apixaban was observed at 0.25 to 8 mg/kg of pd-FXa. pd-FXa failed to reduce bleeding time. Without apixaban, pd-FXa induced mortality within 30 minutes of injection at doses as low as 0.05 mg/kg.
Conclusion(s): High doses of human pd- FXa reverse some aspects of apixaban-induced anticoagulation in vitro and in vivo. However, in agreement with its known thrombogenic effect, pd-FXa shows substantial toxicity at sub-pharmacological doses. Future development of FXa variants should focus on achieving reversal effects at doses that are sufficiently safe for patients with unknown or low level of direct FXa inhibitor.
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, Jankowski W, Sauna Z, Ovanesov M. Is plasma-derived coagulation factor Xa safe for reversal of direct factor Xa inhibitor? [abstract]. https://abstracts.isth.org/abstract/is-plasma-derived-coagulation-factor-xa-safe-for-reversal-of-direct-factor-xa-inhibitor/. Accessed March 4, 2024.
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