Low cellular fibronectin is associated with bleeding in patients with atrial fibrillation during long-term follow-up: a potential novel bleeding mechanism

INTRODUCTION: We examined whether cellular fibronectin (cFn) is associated with thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). CLINICAL RATIONALE FOR THE STUDY: Up to 5% of anticoagulated AF patients experience major bleeding, and identifying those at elevated risk remains challenging. Cellular fibronectin, a marker of endothelial dysfunction and vascular injury, has been linked to altered prothrombotic fibrin clot features in atherosclerosis, stroke, and venous thromboembolism, but its levels and role in AF are unknown. MATERIAL AND METHODS: In this cohort study, we enrolled 185 consecutive AF patients on rivaroxaban aged 70.0 [interquartile range (IQR) 62.0-76.0] years with a median CHA₂DS₂-VASc of 3.0 (IQR 1.0-4.0). We determined plasma cFn along with clinical and laboratory parameters, including fibrin clot permeability. During a median follow-up of 49.0 (IQR 46.0-51.0) months, we recorded both clinically relevant major and nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) and a composite ischemic endpoint involving ischemic cerebrovascular events or cardiovascular (CV) death. RESULTS: Plasma cFn (median 3.5, IQR 2.7-4.5 μg/mL) correlated positively with fibrinogen and C-reactive protein (CRP), and inversely with clot permeability. During follow-up, bleeding occurred in 25 patients (13.5%, 3.55/100 patient-years), including major bleeding in 13 (7.0%, 1.78/100 patient-years). Patients with cFn in the lowest quartile ( < 2.7 μg/mL) had an almost 4-fold higher risk of bleeding compared to those in the highest quartile ( > 4.5 μg/mL) [hazard ratio (HR) 3.85, 95% confidence interval (CI): 1.06-14.00]. On multivariate analysis adjusted for age and sex, low cFn was an independent predictor of bleeding and major bleeding, but not of the ischemic endpoint. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results suggest that low cFn levels might help identify patients with AF at increased bleeding risk during long-term anticoagulation, and this association could partly be related to the formation of looser fibrin networks.