Thromb Haemost 2018; 118(09): 1535-1544
DOI: 10.1055/s-0038-1667014
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

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

Georges Jourdi
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
3  AP-HP, Hôpital Cochin, Paris, France
,
Isabelle Gouin-Thibault
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
4  CHU Pontchaillou, Rennes, France
,
Virginie Siguret
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
5  AP-HP, Hôpital Lariboisière, Paris, France
,
Sophie Gandrille
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
6  AP-HP, Hôpital Européen Georges Pompidou, Paris, France
,
Pascale Gaussem
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
6  AP-HP, Hôpital Européen Georges Pompidou, Paris, France
,
Bernard Le Bonniec
1  INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2  Université Paris Descartes, Sorbonne Paris Cité, Paris, France
› Author Affiliations
Funding This study was funded by the CONNY-MAEVA Charitable Foundation and INSERM. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data.
Further Information

Publication History

05 March 2018

06 June 2018

Publication Date:
02 August 2018 (eFirst)

Abstract

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 α2-macroglobulin (GDFXa-α2M) may neutralize the xabans without interfering with normal blood coagulation.

Purified α2M was incubated with GDFXa to form GDFXa-α2M. Affinity of apixaban and rivaroxaban for GDFXa-α2M was only slightly decreased compared to FXa. Efficacy and harmlessness of GDFXa-α2M were tested in vitro and in vivo. Stoichiometric excess of GDFXa-α2M neutralized rivaroxaban and apixaban as attested by clot waveform assay and rotational thromboelastometry, whereas GDFXa-α2M alone had no effect on these assays. Efficacy and pro-thrombotic potential of GDFXa-α2M were also assessed in vivo. Half-life of GDFXa-α2M 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-α2M significantly decreased the rivaroxaban-induced bleeding time (p < 0.001) and blood loss (p < 0.01). GDFXa-α2M did not increase D-dimer or thrombin–antithrombin complex formation, suggesting a lack of pro-thrombotic potential.

GDFXa-α2M is therefore an attractive candidate for xaban neutralization neither pro- nor anticoagulant in vitro as well as in vivo.

Authors' Contributions

B.L.B. conceived the study and together with G.J. designed and performed research, analysed data and wrote the manuscript; I.G.-T., V.S., S.G. and P.G. critically discussed the data, revised the manuscript and gave final approval.