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Reversal of Factor Xa Inhibitors by Andexanet Alfa May Increase Thrombogenesis Compared to Pretreatment Values.

Authors
  • Siddiqui, Fakiha1
  • Tafur, Alfonso2
  • Ramacciotti, Lorenzo Storino1
  • Jeske, Walter1
  • Hoppensteadt, Debra1
  • Ramacciotti, Eduardo3
  • Iqbal, Omer1
  • Fareed, Jawed1
  • 1 1 Cardiovascular Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, IL, USA.
  • 2 2 Northshore Cardiovascular Institute, NorthShore University HealthSystem, Skokie, IL, USA.
  • 3 3 Vascular and Endovascular Surgery, Santa Casa School of Medicine, São Paulo, Brazil. , (Brazil)
Type
Published Article
Journal
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
Publication Date
Jan 01, 2019
Volume
25
Identifiers
DOI: 10.1177/1076029619863493
PMID: 31298056
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.

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