A small-molecule hemostatic agent for the reversal of direct-oral-anticoagulant-induced bleeding.

Background The bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and non-specific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store and administer. Objective To identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent. Methods We sought to identify a small procoagulant molecule by screening a chemical library with a plasma clotting assay. The selected molecule was assessed for its procoagulant properties and its ability to reverse the effects of the DOACs in a thrombin generation assay (TGA). Its activity as a DOAC reversal agent was also evaluated in a tail-clip bleeding assay in mice. Results The hemostatic molecule (HeMo) dose-dependently promoted thrombin generation in plasma, with EC50 values ranging between 3 and 5 μM, depending on the TGA parameter considered. HeMo also restored impaired thrombin generation in DOAC-spiked plasma and reversed DOAC anticoagulant activity in the mouse bleeding model. HeMo significantly reduced apixaban-induced bleeding from 709 to 65 μL (vs. 43 μL in controls, p < 0.01), and dabigatran-induced bleeding from 989 to 155 μL (vs. 126 μL in controls, p < 0.01). Conclusion HeMo is a small-molecule procoagulant that can counterbalance hemostatic disruption by a thrombin inhibitor (dabigatran) or FXa inhibitors (apixaban and rivaroxaban). The compound’s effective clot formation and versatility make it a possible option for managing the inherent hemorrhagic risk during DOAC therapy.