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.

Duke Scholars

Author Thomas Lee Ortel Medicine, Hematology

Author Richard Clinton Becker Medicine, Cardiology

Author J. Will Thompson Pharmacology & Cancer Biology

Author Derek Cyr