Abstract Number: PB0046
Meeting: ISTH 2021 Congress
Background: Specific antidotes are already commercialized or in development for some anticoagulant compounds while they are still lacking for others. As such, no universal antidote to direct oral anticoagulants (DOAC) and heparins is yet available. Such antidote would make it easier for healthcare professionals to manage anticoagulant compounds in case of major bleeding or urgent procedures.
Aims: We investigated the mechanism and ability of Gla-domainless factor Xa (GDFXa)- and methylamine (MA)-induced α2-Macroglobulin (α2M), to restore coagulation in presence of anticoagulants in vitro, ex vivo and in vivo.
Methods: Induced forms of α2M were prepared and characterized by chromogenic assays, electrophoresis, coagulation assays and immunonephelometry. Samples from healthy volunteers and anticoagulated patients with atrial fibrillation or venous thromboembolism who gave their written informed consent, were included. In vivo neutralization of anticoagulants was evaluated in C57Bl/6JRj mouse bleeding model. Clot waveform assay and rotational thromboelastometry were triggered in plasma and whole blood, respectively. Binding sites of anticoagulants on induced α2M were depicted by computer-aided energy minimization modeling.
Results: GDFXa-induced α2M neutralized anticoagulants in plasma and whole blood samples spiked with DOAC (up to 600 ng/mL) or heparins (up to 1.5 IU/mL). In mouse, a single IV dose of GDFXa-induced α2M given following anticoagulant administration significantly reduced blood loss and bleeding time. Being easier to prepare and less expensive than GDFXa-induced α2M, we investigated the efficacy of MA-induced α2M. Molecular docking analysis evidenced that MA-induced α2M binds non-covalently (hydrogen bonds) to DOAC and heparins via some deeply buried binding sites. MA-induced α2M neutralized anticoagulants in spiked plasma samples in a concentration-dependent manner and in samples from 57 patients receiving DOAC or heparins.
Conclusions: Induced forms of α2M have the potential to neutralize a wide range of anticoagulant drugs and might be developed as a universal antidote in case of major bleeding or urgent surgery in anticoagulated patients.
To cite this abstract in AMA style:Jourdi G, Abdoul J, Siguret V, Decleves X, Frezza E, Pailleret C, Gouin-Thibault I, Gandrille S, Neveux N, Samama C-, Pasquali S, Gaussem P. Induced Forms of α2-Macroglobulin Neutralize Heparin and Direct Oral AntiCoagulant Effects [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/induced-forms-of-%ce%b12-macroglobulin-neutralize-heparin-and-direct-oral-anticoagulant-effects/. Accessed September 23, 2021.
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