A rapid pro-hemostatic approach to overcome direct oral anticoagulants

Thalji, Nabil K; Ivanciu, Lacramioara; Davidson, Robert; Gimotty, Phyllis A; Krishnaswamy, Sriram; Camire, Rodney M

doi:10.1038/nm.4149

Cited by 43Blood Coagulation and Thrombosis MechanismsHemophilia Treatment and ResearchHemostasis and retained surgical items

A rapid pro-hemostatic approach to overcome direct oral anticoagulants

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Thalji, Nabil K, Ivanciu, Lacramioara, Davidson, Robert, Gimotty, Phyllis A, Krishnaswamy, Sriram, Camire, Rodney M·2016·Nature Medicine

DOI 10.1038/nm.4149PMC PMC12887842

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Abstract

Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.

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Self-citation

Authors: Thalji, N. K., Ivanciu, L., Davidson, R., Gimotty, P. A., Krishnaswamy, S., & Camire, R. M.
Affiliations: Children's Hospital of Philadelphia (US)
University of Pennsylvania (US)
Corresponding author: Camire, Rodney M
ORCID: Thalji, Nabil K
Ivanciu, Lacramioara
Gimotty, Phyllis A
Krishnaswamy, Sriram
Camire, Rodney M
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2016-07-25
Volume: 22
Issue: 8
Pages: 924-932
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm.4149
PMC: PMC12887842
OpenAlex: W2480311966
Cited by: 43
References: 65
Citations by year: 2025: 1 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 1 · 2018: 8 · 2017: 9 · 2016: 1
FWCI: 6.02
Type: journal article
Language: en
Open access: green
pmc.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (F30HL120487, P01HL074124, T32HL007439)
National Institute of General Medical Sciences (T32GM007170)
Topics: Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
Health Sciences › Medicine › Hematology › Hemostasis and retained surgical items
Keywords: direct oral anticoagulants, anticoagulant reversal, factor Xa inhibitors, hemostasis, dabigatran, thrombin inhibitors, antithrombin III, hemorrhage, antidotes
MeSH terms: Rivaroxaban, Animals, Antidotes, Blood Coagulation, Hemostasis, Humans, Thrombelastography, Factor Xa, Mice, Factor Xa Inhibitors, In Vitro Techniques

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A rapid pro-hemostatic approach to overcome direct oral anticoagulants

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