The dabigatran antidote aDabi-Fab bound dabigatran with ~350 times stronger affinity than thrombin and rapidly reversed its anticoagulant activity in vivo in a rat model.
Does aDabi-Fab reverse the anticoagulant activity of dabigatran in preclinical models?
A specific antidote for dabigatran (aDabi-Fab) rapidly reverses its anticoagulant activity in preclinical models, offering a potential strategy for managing bleeding or emergency procedures.
Dabigatran etexilate is a direct thrombin inhibitor and used widely as an anticoagulant for the prevention of stroke in patients with atrial fibrillation. However, anticoagulation therapy can be associated with an increased risk of bleeding. Here, we present data on the identification, humanization, and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab). The X-ray crystal structure of dabigatran in complex with the antidote reveals many structural similarities of dabigatran recognition compared with thrombin. By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is ~350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, the antidote does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. In addition we demonstrate that the antidote rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the first report of a specific antidote for a next-generation anticoagulant that may become a valuable tool in patients who require emergency procedures.
Schiele et al. (Sat,) conducted a other in Anticoagulation reversal. aDabi-Fab (antidote for dabigatran) was evaluated on Affinity for dabigatran and reversal of anticoagulant activity. The dabigatran antidote aDabi-Fab bound dabigatran with ~350 times stronger affinity than thrombin and rapidly reversed its anticoagulant activity in vivo in a rat model.