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Thromb Haemost 2012; 108(06): 1180-1191
DOI: 10.1160/TH12-05-0310
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor

Mark Y. Chan
1   National University Heart Centre, Singapore
,
Min Lin
2   Duke Translational Medicine Institute, Durham, North Carolina, USA
,
Joseph Lucas
3   Center for Applied Genomics and Technology, Duke Institute for Genome Sciences &Policy, Durham, North Carolina, USA
,
Arthur Moseley
4   Proteomics Core Facility, Duke Institute for Genome Sciences &Policy, Durham, North Carolina, USA
,
J Will Thompson
4   Proteomics Core Facility, Duke Institute for Genome Sciences &Policy, Durham, North Carolina, USA
,
Derek Cyr
3   Center for Applied Genomics and Technology, Duke Institute for Genome Sciences &Policy, Durham, North Carolina, USA
,
Hitoshi Ueda
5   Bayer Yakuhin Ltd, Osaka, Japan
,
Mariko Kajikawa
5   Bayer Yakuhin Ltd, Osaka, Japan
,
Thomas L. Ortel
6   Duke University Medical Center Hemostasis &Thrombosis Center Core Laboratory, Durham, North Carolina, USA
,
Richard C. Becker
6   Duke University Medical Center Hemostasis &Thrombosis Center Core Laboratory, Durham, North Carolina, USA
7   Duke Clinical Research Institute, Durham, North Carolina, USA
› Author Affiliations Financial support:This study was funded by Bayer Yakuhin Ltd, Osaka, Japan. Bayer Yakuhin had no direct role in the laboratorial and statistical analysis, data interpretation or drafting of the manuscript. Dr. Mark Y. Chan receives salary support from the National Medical Research Council as a recipient of the Singapore Clinician-Scientist Award (NMRC/ CSA/028/2010).
Further Information

Publication History

Received: 13 May 2012

Accepted after major revision: 11 September 2012

Publication Date:
30 November 2017 (online)

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Summary

Plasma proteins mediate thrombogenesis, inflammation, endocardial injury and structural remodelling in atrial fibrillation (AF). We hypothesised that anti-coagulation with rivaroxaban, a direct factor Xa inhibitor, would differentially modulate biologically-relevant plasma proteins, compared with warfarin, a multi-coagulation protein antagonist. We performed unbiased liquid chromatography/tandem mass spectroscopy and candidate multiplexed protein immunoassays among Japanese subjects with non-valvular chronic AF who were randomly assigned to treatment with 24 weeks of rivaroxaban (n=93) or warfarin (n=94). Nine metaproteins, including fibulin-1 (p=0.0033), vitronectin (p=0.0010), haemoglobin α(p=0.0012), apolipoproteins C-II (p=0.0017) and H (p=0.0023), complement C5 precursor (p=0.0026), coagulation factor XIIIA (p=0.0026) and XIIIB (p=0.0032) subunits, and 10 candidate proteins, including thrombomodulin (p=0.0004), intercellular adhesion molecule-3 (p=0.0064), interleukin-8 (p=0.0007) and matrix metalloproteinase-3 (p=0.0003), were differentially expressed among patients with and without known clinical risk factors for stroke and bleeding in AF. Compared with warfarin, rivaroxaban treatment was associated with a greater increase in thrombomodulin (Δ0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase-9 (Δ2.2 vs. –4.9 pg/ml, p=0.0757) over 24 weeks. Only modest correlations were observed between protein levels and prothrombin time, factor Xa activity and prothrombinase-induced clotting time. Plasma proteomics can identify distinct functional patterns of protein expression that report on known stroke and bleeding risk phenotypes in an ethnically-homogeneous AF population. The greater upregulation of thrombomodulin among patients randomised to rivaroxaban represents a proof-of-principle that pharmacoproteomics can be employed to discern novel effects of factor Xa inhibition beyond standard pharmacodynamic measures.

Keywords

Atrial fibrillation - Proteomics - Thrombomodulin - warfarin and factor Xa inhibitor

 

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