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*
1  Institute 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*
1  Institute 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
1  Institute 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
2  Institute of Biochemistry and Clinical Biochemistry, Catholic University of Sacred Heart, Rome, Italy
,
Andrea Bellelli
3  Department of Biochemical Sciences “A. Rossi Fanelli,” Sapienza University of Rome, Rome, Italy
,
Tiziana Ricciardelli
4  KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
5  Department of Sciences and Technologies, Parthenope University of Naples, Naples, Italy
,
Ida Autiero
4  KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
,
Luigi Cavallo
4  KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
,
Romina Oliva
5  Department of Sciences and Technologies, Parthenope University of Naples, Naples, Italy
,
Raimondo De Cristofaro
1  Institute 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
Funding R.D.C. acknowledges the Catholic University School of Medicine for the financial support to the study (Linea D1–2015).
Further Information

Publication History

29 March 2018

31 July 2018

Publication Date:
20 September 2018 (eFirst)

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 Kd ≅300 µM. Fluorescence- and HPLC-based assays concordantly showed that APX binds to Hb with a Kd ≅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.

Authors' Contributions

M.S., S.L. and F.B. performed the biochemical experiments and critically read the manuscript. A.A. and A.B. performed some oxygen binding experiments and reviewed the manuscript. T.R., I.A, L. C. and R.O. performed the molecular docking investigation, wrote part of the manuscript and reviewed it. R. D.C. designed the study, performed some biochemical experiments, analysed the data and wrote the manuscript.


* Monica Sacco and Stefano Lancellotti contributed equally to this study.


Supplementary Material