Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We improve hemostasis in vivo using a conformationally pliant variant of coagulation factor Xa (FXa^I16L) rendered partially inactive by a defect in the transition from zymogen to active protease^,. Using mouse models of hemophilia, we show that FXa^I16L has a longer half-life than wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXa^I16L is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXa^I16L is more efficacious than FVIIa, which is used to treat bleeding in hemophilia inhibitor patients. FXa^I16L may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions.