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A rapid pro-hemostatic approach to overcome direct oral anticoagulants

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, FXaI16L, rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXaI16L 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, FXaI16L is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXaI16L also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXaI16L 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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Figure 1: Effects of FXaI16L and GD-FXaS195A on thrombin generation in rivaroxaban-treated plasma.
Figure 2: In vivo effects of FXaI16L and GD-FXaS195A in mice anticoagulated with rivaroxaban.
Figure 3: Blood loss following tail-clipping.
Figure 4: Reversal of rivaroxaban by FXaI16L and GD-FXaS195A in a laser-injury model.
Figure 5: Distribution of FXa in plasma in the presence or absence of rivaroxaban.
Figure 6: Influence of dabigatran on TAT levels and effects on blood loss following tail-clipping.

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Acknowledgements

This work was supported in part by the US National Institutes of Health (NIH) grants F30 HL-120487 (N.K.T.), T32 HL-007439 (N.K.T.), T32 GM-007170 (N.K.T.) and P01 HL-74124 (R.M.C. and S.K.), the Penn–CHOP Blood Center for Patient Care and Discovery (P.A.G.) and research funding from Pfizer (R.M.C.). We are grateful to V. Arruda (Children's Hospital of Philadelphia and University of Pennsylvania) and L. Brass (University of Pennsylvania) for useful suggestions and critical review of the manuscript.

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N.K.T. designed, coordinated and performed experiments; L.I. and R.D. designed and performed experiments; N.K.T., S.K. and R.M.C. designed experiments and analyzed data; P.A.G. analyzed data; and N.K.T., L.I., S.K. and R.M.C. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Rodney M Camire.

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R.M.C. receives licensing fees and research funding from Pfizer for work related to FXaI16L.

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Thalji, N., Ivanciu, L., Davidson, R. et al. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 22, 924–932 (2016). https://doi.org/10.1038/nm.4149

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