PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin–enoxaparin complex. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant.
Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs.
Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization.
Anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders.
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