Elevated factor VIIa—antithrombin complexes are associated with stroke or cardiovascular death in patients with atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) is associated with a prothrombotic state. We investigated whether factor VIIa-antithrombin (FVIIa-AT) complexes, a marker of tissue factor (TF) exposure, are associated with thromboembolic events in AF. METHODS: VASc score 4), 71% on direct oral anticoagulants, we measured FVIIa-AT complexes, along with endogenous thrombin potential (ETP), von Willebrand factor (VWF) and 8-isoprostane, reflecting oxidative stress. During a median follow-up of 53 [interquartile range, IQR 47-57] months, we recorded a composite endpoint: ischemic stroke, systemic thromboembolism or cardiovascular (CV) death. RESULTS: FVIIa-AT complexes (median 145 [IQR 125-170] pM) were higher in patients with permanent AF (p < .001), vascular disease (p = .02), previous stroke (p < .001) and smoking (p = .006) as compared with patients without these comorbidities. FVIIa-AT correlated with NT-proBNP (r = .15, p = .022) and ETP (r = .25, p < .001). During follow-up, the composite endpoint was recorded in 30 patients (13.4%, 3.0% per year) including 20 with ischemic stroke (8.9%, 2.0% per year, respectively). Patients with the composite endpoint had 29.2% higher baseline FVIIa-AT complexes compared with the remainder. Patients with FVIIa-AT complexes in the top quartile (>170 pM) had an increased risk of the composite endpoint (HR 12.0, 95% CI 5.2-28.0, p < .0001). FVIIa-AT complexes, along with VWF, remained independently associated with the composite endpoint. CONCLUSIONS: This study is the first to show that high plasma FVIIa-AT complexes are independently associated with thromboembolic events or CV death in AF, suggesting the need for more potent anticoagulation to suppress the residual TF-mediated coagulation.