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

Daniël Verhoef, Koen M. Visscher, C. Ruben Vosmeer, Ka Lei Cheung, Pieter H. Reitsma, Daan P. Geerke and Mettine H. A. Bos ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00647-9

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