Apixaban Interacts with Haemoglobin: Effects on Its Plasma Levels

Monica Sacco; Stefano Lancellotti; Federico Berruti; Alessandro Arcovito; Andrea Bellelli; Tiziana Ricciardelli; Ida Autiero; Luigi Cavallo; Romina Oliva; Raimondo De Cristofaro

doi:10.1055/s-0038-1669920

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(10): 1701-1712
DOI: 10.1055/s-0038-1669920

Coagulation and Fibrinolysis

Georg Thieme Verlag KG Stuttgart · New York

Apixaban Interacts with Haemoglobin: Effects on Its Plasma Levels

Monica Sacco^*

¹Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy

,

Stefano Lancellotti^*

¹Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy

,

Federico Berruti

¹Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy

,

Alessandro Arcovito

²Institute of Biochemistry and Clinical Biochemistry, Catholic University of Sacred Heart, Rome, Italy

,

Andrea Bellelli

³Department of Biochemical Sciences “A. Rossi Fanelli,” Sapienza University of Rome, Rome, Italy

,

Tiziana Ricciardelli

⁴KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

⁵Department of Sciences and Technologies, Parthenope University of Naples, Naples, Italy

,

Ida Autiero

⁴KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

,

Luigi Cavallo

⁴KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

,

Romina Oliva

⁵Department of Sciences and Technologies, Parthenope University of Naples, Naples, Italy

,

Raimondo De Cristofaro

¹Institute of Internal Medicine & Geriatrics, Haemostasis and Thrombosis Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Area of Hematology, Catholic University of the Sacred Heart School of Medicine, Rome, Italy

› Author Affiliations

Abstract

The direct oral anticoagulant apixaban (APX), a strong factor Xa inhibitor, binds also to plasma proteins, especially albumin, and minimally to α₁-acid glycoprotein. Although APX can cross the red cell membrane, due to its chemical structure, and could bind to haemoglobin (Hb), no investigation was performed on this possible phenomenon that could affect the APX plasma concentration and thus its pharmacokinetics and pharmacodynamics. We addressed this issue by (1) measuring the levels of APX and haematological/biochemical parameters in 90 patients on APX therapy; (2) assessing the effect of APX on oxygen saturation curves of Hb; (3) testing the direct APX binding to Hb by fluorescence spectroscopy and a zinc-induced precipitation of Hb coupled to a reversed-phase high-performance liquid chromatography (HPLC)-based method; and (4) simulating in silico by molecular docking the APX interaction with human Hb. In a multivariable analysis, Hb was the only independent variable significantly and inversely associated in 90 patients with APX peak plasma level, at variance with patients treated with rivaroxaban (n = 86) and dabigatran (n = 34) therapy. APX causes a progressive left-shift of the oxygen dissociation curve of purified Hb solution, with a K_d ≅300 µM. Fluorescence- and HPLC-based assays concordantly showed that APX binds to Hb with a K_d ≅350 µM. Finally, docking simulations showed that APX can fit into in the central cavity of Hb. These findings support the hypothesis that APX does bind to Hb, which, due to its millimolar concentration in blood, can act as ‘buffer’ for the drug and consequently affect its free plasma level.

Keywords

anticoagulants - apixaban - erythrocytes - haemoglobin - molecular docking simulation - individualized therapy

Full Text

References

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Supplementary Material