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 g 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.
Nature Medicine