Inflammatory protein signatures associated with high rivaroxaban exposure.

Direct oral anticoagulants, including rivaroxaban, are widely prescribed for the prevention and treatment of thromboembolic disorders. Despite generally predictable pharmacokinetics (PK), real-world data reveal striking interindividual variability in exposure, raising concerns for both efficacy and bleeding risk. Known genetic and clinical determinants explain only part of this variability, underscoring the need to identify additional contributors. This study aimed to explore systemic protein signatures associated with rivaroxaban exposure intensity. Plasma samples were obtained from 64 participants in a phase I clinical study (NCT04180436) including healthy controls, obese patients, and post-bariatric surgery patients. Rivaroxaban PK was assessed after 20 mg once-daily dosing, and patients were stratified into high and low exposure groups. Untargeted plasma proteomic analysis was performed by liquid chromatography coupled with high-resolution mass spectrometry, followed by univariate and multivariate statistical analyses. Targeted C-reactive protein (CRP) quantification and multiplex cytokine assays were used to validate findings. Differential abundance and multivariate modeling identified inflammation and vascular related proteins associated with high rivaroxaban exposure. Notably, CRP and lipoprotein(a) (LPA) were consistently elevated in high exposure groups. Targeted CRP quantification confirmed these results, even in cases of mild to moderate inflammation. Cytokine analyses revealed a pro-inflammatory profile, characterized by increased interferon gamma and reduced Tumor Necrosis Factor alpha in high exposure patients. Protein-protein interaction networks highlighted CRP, LPA, albumin, and Apolipoprotein B as central hubs, while functional enrichment revealed pathways related to acute inflammation, oxidative stress, and vascular regulation. These findings suggest that systemic inflammation may contribute to rivaroxaban overexposure, with CRP emerging as a promising biomarker to support more personalized anticoagulant strategies.