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Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

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Listed:
  • Wojciech Jankowski

    (Center for Biologics Evaluation & Research, US FDA)

  • Stepan S. Surov

    (Center for Biologics Evaluation & Research, US FDA)

  • Nancy E. Hernandez

    (Center for Biologics Evaluation & Research, US FDA)

  • Atul Rawal

    (Center for Biologics Evaluation & Research, US FDA)

  • Marcos Battistel

    (Center for Biologics Evaluation & Research, US FDA)

  • Daron Freedberg

    (Center for Biologics Evaluation & Research, US FDA)

  • Mikhail V. Ovanesov

    (Center for Biologics Evaluation & Research, US FDA)

  • Zuben E. Sauna

    (Center for Biologics Evaluation & Research, US FDA)

Abstract

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

Suggested Citation

  • Wojciech Jankowski & Stepan S. Surov & Nancy E. Hernandez & Atul Rawal & Marcos Battistel & Daron Freedberg & Mikhail V. Ovanesov & Zuben E. Sauna, 2024. "Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48278-1
    DOI: 10.1038/s41467-024-48278-1
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    References listed on IDEAS

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    1. Daniël Verhoef & Koen M. Visscher & C. Ruben Vosmeer & Ka Lei Cheung & Pieter H. Reitsma & Daan P. Geerke & Mettine H. A. Bos, 2017. "Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    2. Christine E. Tinberg & Sagar D. Khare & Jiayi Dou & Lindsey Doyle & Jorgen W. Nelson & Alberto Schena & Wojciech Jankowski & Charalampos G. Kalodimos & Kai Johnsson & Barry L. Stoddard & David Baker, 2013. "Computational design of ligand-binding proteins with high affinity and selectivity," Nature, Nature, vol. 501(7466), pages 212-216, September.
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