Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor.
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 (Δ 0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase-9 (Δ 2.2 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.
National University Heart Centre, Singapore.
Mark Y
MY
Chan
Min
M
Lin
Joseph
J
Lucas
Arthur
A
Moseley
J Will
JW
Thompson
Derek
D
Cyr
Hitoshi
H
Ueda
Mariko
M
Kajikawa
Thomas L
TL
Ortel
Richard C
RC
Becker
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage / Q000097:blood / Q000209:etiology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use*; D040901:Proteomics; D012307:Risk Factors; D000069552:Rivaroxaban; D020521:Stroke / Q000097:blood / Q000209:etiology; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D015415:Biomarkers; D001798:Blood Proteins; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D014859:Warfarin; D000069552:Rivaroxaban