Abstract Number: OC 46.4
Meeting: ISTH 2021 Congress
Background: Reversal of anticoagulation is important for safe usage of direct oral factor FXa-inhibiting anticoagulants (DOACs). Andexanet alfa and prothrombin complex concentrates (PCCs) are used to stop bleeding associated with use of FXa-DOACs but both increase thrombotic risk. VMX-C001 is a modified human FX zymogen that is insensitive to FXa-DOACs and in development as a reversal agent.
Aims: Compare FXa-DOAC reversal by VMX-C001, andexanet alfa and 4PCC using thrombin generation analysis (TG).
Methods: TG was performed in platelet poor plasma (PPP) from healthy donors spiked with VMX-C001, andexanet alfa (Andexxa®) or 4-factor PCC (Beriplex®) and FXa-DOAC. The endogenous thrombin potential (ETP) parameter from the TG curve was used as endpoint.
VMX-C001 (15–60 µg/ml) displayed dose dependent reversal of anticoagulation to the normal ETP range that was independent of FXa-DOAC type (Figure.1). Overshooting of ETP was not observed for VMX-C001 under any condition studied. 4PCC (0.25–1.0 U/mL) was not able to reverse the anticoagulant effect of apixaban and edoxaban and only partly reversed rivaroxaban inhibition. Reversal by andexanet alfa (50–200 µg/ml) consistently resulted in higher-than-normal ETP levels, irrespective of dose-level. In the absence of FXa-DOACs, overshooting of TG was also observed in the presence of andexanet alfa and 4PCC, supporting the thrombogenic potential of these agents. As tissue factor pathway inhibitor (TFPI) binding is a known property of andexanet alfa, an anti-TFPI-K2 antibody was included to study the effect of TFPI inhibition. After anti-TFPI-K2 antibody addition ETP overshooting closely mimicked the overshooting following andexanet alfa, supporting neutralization of TFPI by andexanet alfa (Figure.2).
Conclusions: VMX-C001 restores thrombin generation in the presence of FXa-DOACs and does not induce overshooting of ETP. PCC does not restore thrombin generation and leads to overshooting of ETP in the absence of FXa-DOACs. Andexanet alfa restores thrombin generation, but ETP overshoots due to neutralization of TFPI.
To cite this abstract in AMA style:Verhoef D, Gomes T, Short G, Reitsma PH. VMX-C001 Is an Effective FXa-DOAC Reversal Agent and Displays No Thrombogenic Potential in Comparison to Andexanet Alfa and 4PCC [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/vmx-c001-is-an-effective-fxa-doac-reversal-agent-and-displays-no-thrombogenic-potential-in-comparison-to-andexanet-alfa-and-4pcc/. Accessed July 26, 2021.
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