Antidotes for anti-coagulants have been sought ever since a dairy farmer named Ed Carson walked into the laboratory of Karl Paul Link at the University of Wisconsin with a dead cow and asked how spoiled clover hay could cause his livestock to bleed to death. This encounter lead to the discovery of dicumarol and the synthesis of warfarin (patented in 1945 and named in recognition of the support provided by the Wisconsin Alumni Research Foundation) and the rest is history. Every clinician is familiar with the bleeding risk that accompanies warfarin therapy. Fortunately, warfarin-induced hemorrhage can be effectively treated with vitamin K, fresh frozen plasma, or coagulation factor concentrates. Likewise, unfractionated heparin can be neutralized with cationic protamine, which can also partially inhibit the activity of low-molecular-weight heparins (LMWHs) such as enoxaparin, but not the short, synthetic heparin derivatives such as the pentasaccharide fondaparinux. In case of severe hemorrhage in patients being treated with LMWHs and synthetic heparin derivatives, fresh frozen plasma, prothrombin concentrates, or recombinant VIIa can be used to support hemostasis while awaiting metabolism of the offending anticoagulant. Now with the approval of the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban and apixaban, we have entered a new era of anticoagulation. These agents have been enthusiastically embraced, especially for management of patients with atrial fibrillation, as they are administer orally at a fixed dose, have a rapid onset of action, and require no monitoring of anticoagulant activity. A major criticism of these agents, however, is that reversal of their anticoagulant activity is problematic. Recombinant VIIa, 3- or 4-factor-activated prothrombin complex concentrates, anti-fibrinolytic agents such as tranexamic acid, and dialysis (in the case of dabigatran) have been used to control hemorrhage induced by the novel oral anticoagulants (NOACs). The relatively short half-life of the NOACs also works in the favor of patients who experience bleeding complications.
In the current paper, Lu and colleagues report development of an antidote for the group of anticoagulants that mediate their effect through anti-Xa inhibition. The reagent, called r-Antidote, is a recombinant, truncated form of factor Xa that is catalytically inactive and lacks the membrane binding γ-carboxylglutamates (Gla) residues, while retaining the capacity to bind the direct factor Xa inhibitors (Figure) as well as LMWH-activated anti-thrombin III. r-Antidote dose-dependently reversed the inhibitory activity of the small-molecule fXa inhibitors betrixaban, rivaroxaban, and apixaban, but, in the absence of an inhibitor, it did not produce a change in the rate of peptidyl substrate cleavage by fXa. Inhibition of anticoagulant effects in human and rat plasma by r-Antidote was concentration-dependent, and prolongation of the prothrombin time by rivaroxaban was reversed by an equimolar concentration of r-Antidote. In rat models, r-Antidote rapidly reversed the anticoagulant effects of three fXa inhibitors. Hemostasis was restored and bleeding was reduced by treatment with r-Antidote in two animal models of bleeding due to fXa inhibitors, one involving aspirin-treated mice and the other that used a liver laceration model in rabbits. Lu and colleagues also demonstrated that r-Antidote reversed the anti-thrombin III dependent anti-Xa activity of enoxaparin and fondaparinux.
As part of a commentary that accompanied the article, Jack Ansell illustrated a model of the action of r-Antidote (Figure).1 He noted that immunogenicity may limit usefulness of r-Antidote and that cost of reversal of NOAC-induced bleeding, relative to the expense of reversal of warfarin-associated bleeding, might impact on the decision to use warfarin instead of NOACs. Also noted were other strategies for reversing the anticoagulant activity of Xa inhibitors including aptamers, antibodies, and PER977, a synthetic small molecule that blocks the new oral anti-coagulants binding to fXa.
In Brief
This proof-of-concept study addresses a major concern about the use of NOACs. Still, establishing the place of NOACs relative to warfarin, LMWHs, and synthetic heparin derivatives is a work in progress. NOACs may not be better than warfarin, just different, and we need to sort out how and when it’s best to use them. And remember, it all started with a dead cow.
