A genetically engineered coagulation factor can reverse the effects of direct oral anticoagulants in vitro and in vivo, according to research published in Nature Medicine.
Researchers altered the shape of the coagulation factor, factor Xa (FXa), into a variant that appears to be more potent and longer-lasting than wild-type FXa.
The team found this variant, FXaI16L, could counteract the effects of rivaroxaban, apixaban, and dabigatran.
“This molecule holds the potential to fill an important unmet clinical need,” said study author Rodney A. Camire, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
“There are limited treatment options to stop uncontrolled bleeding in patients who are using the newer anticoagulant medications.”
Dr Camire and his colleagues first found that FXaI16L could reverse the effects of rivaroxaban and apixaban in vitro, increasing peak thrombin generation to near-normal levels.
The team then showed that FXaI16L restores hemostasis in mice treated with rivaroxaban and significantly decreases blood loss in injured mice treated with the drug.
FXaI16L also significantly decreased blood loss in injured mice treated with dabigatran.
FXaI16L was more than 50 times more potent in the hemostasis models tested than andexanet alfa, a FXa inhibitor antidote currently in clinical development.
The researchers said FXaI16L’s ability to reverse the effects of anticoagulants depends, at least partly, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, which allows uninhibited FXa to persist in plasma.
“Our next steps will be to test this approach in large animals to help determine whether this variant is effective and safe and may progress to clinical trials,” Dr Camire said. “If so, we may be able to develop an important treatment to rapidly control bleeding in both children and adults.”
