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Increasing number of patients are treated with direct oral anticoagulants (DOAC). An antidote for dabigatran inhibiting thrombin (idarucizumab) is available but no antidote is yet approved for the factor Xa (FXa) inhibitors (xabans). We hypothesized that a complex between Gla-domainless FXa and α 2 -macroglobulin (GDFXa-α 2 M) may neutralize the xabans without interfering with normal blood coagulation.Purified α 2 M was incubated with GDFXa to form GDFXa-α 2 M. Affinity of apixaban and rivaroxaban for GDFXa-α 2 M was only slightly decreased compared to FXa. Efficacy and harmlessness of GDFXa-α 2 M were tested in vitro and in vivo. Stoichiometric excess of GDFXa-α 2 M neutralized rivaroxaban and apixaban as attested by clot waveform assay and rotational thromboelastometry, whereas GDFXa-α 2 M alone had no effect on these assays. Efficacy and pro-thrombotic potential of GDFXa-α 2 M were also assessed in vivo. Half-life of GDFXa-α 2 M in C57BL6 mice was 4.9 ± 1.1 minutes, but a 0.5 mg/mouse dose resulted in uptake saturation such that 50% persistence was still observed after 170 minutes. Single administration of GDFXa-α 2 M significantly decreased the rivaroxaban-induced bleeding time ( p  &lt; 0.001) and blood loss ( p  &lt; 0.01). GDFXa-α 2 M did not increase D-dimer or thrombin-antithrombin complex formation, suggesting a lack of pro-thrombotic potential.GDFXa-α 2 M is therefore an attractive candidate for xaban neutralization neither pro- nor anticoagulant in vitro as well as in vivo.

FXa-α2-Macroglobulin Complex Neutralizes Direct Oral Anticoagulants Targeting FXa In Vitro and In Vivo