Direct inhibitors of factor Xa (fXa) — such as rivaroxaban — are a new class of anticoagulants but lack effective antidotes. In an effort to identify an antidote, Lu et al. designed a recombinant, catalytically inactive form of fXa that bound to direct fXa inhibitors as well as antithrombin III (which can inhibit fXa). In animal models of anticoagulation and blood loss, the antidote reversed the effects of the direct fXa inhibitors betrixaban, rivaroxaban and apixaban, and also reversed the effects of the indirect fXa inhibitors enoxaparin and fondaparinux, which indicates that this new antidote has the potential to reverse several fXa inhibitors.