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Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors

Author

Listed:
  • Daniël Verhoef

    (Leiden University Medical Center)

  • Koen M. Visscher

    (Vrije Universiteit)

  • C. Ruben Vosmeer

    (Vrije Universiteit)

  • Ka Lei Cheung

    (Leiden University Medical Center)

  • Pieter H. Reitsma

    (Leiden University Medical Center)

  • Daan P. Geerke

    (Vrije Universiteit)

  • Mettine H. A. Bos

    (Leiden University Medical Center)

Abstract

The absence of an adequate reversal strategy to prevent and stop potential life-threatening bleeding complications is a major drawback to the clinical use of the direct oral inhibitors of blood coagulation factor Xa. Here we show that specific modifications of the substrate-binding aromatic S4 subpocket within the factor Xa active site disrupt high-affinity engagement of the direct factor Xa inhibitors. These modifications either entail amino-acid substitution of S4 subsite residues Tyr99 and/or Phe174 (chymotrypsinogen numbering), or extension of the 99-loop that borders the S4 subsite. The latter modifications led to the engineering of a factor Xa variant that is able to support coagulation in human plasma spiked with (supra-)physiological concentrations of direct factor Xa inhibitors. As such, this factor Xa variant has the potential to be employed to bypass the direct factor Xa inhibitor-mediated anticoagulation in patients that require restoration of blood coagulation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00647-9
    DOI: 10.1038/s41467-017-00647-9
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    Cited by:

    1. 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.

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