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A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa


Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin–activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non–protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

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Figure 1: Design of r-Antidote and protein expression in CHO cells.
Figure 2: r-Antidote reverses the inhibitory activity of three direct fXa inhibitors.
Figure 3: Sustained reversal of whole-blood INR by r-Antidote in rats treated with direct fXa inhibitors.
Figure 4: Mitigation of blood loss caused by rivaroxaban-induced anticoagulation with r-Antidote in a rabbit liver laceration model.
Figure 5: Reversal of ATIII-dependent fXa inhibitors by r-Antidote in the rat tail transection model.

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Authors and Affiliations



G. Lu, S.J.H. and U.S. conceived of the study, designed experiments and wrote the manuscript. G. Lu, F.R.D., M.J.K., K.A., G. Lee, P.L., A.H. and M.I. designed and conducted experiments. P.B.C. discussed and interpreted data with G. Lu, M.J.K. and P.L. D.R.P. provided expertise, designed experiments and interpreted data.

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Correspondence to Uma Sinha.

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G. Lu, F.R.D., S.J.H., M.J.K., K.A., G. Lee, P.L., A.H., M.I., P.B.C., D.R.P. and U.S. are current or former employees of Portola Pharmaceuticals Inc.

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Lu, G., DeGuzman, F., Hollenbach, S. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19, 446–451 (2013).

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