Markers of NET formation and stroke risk in patients with atrial fibrillation: association with a prothrombotic state

Neutrophil extracellular traps (NETs) formation contributes to thrombosis but its role in atrial fibrillation (AF) is poorly explored. We investigated whether increased circulating NETs markers in relation to a hypercoagulable state can predispose to ischemic stroke in anticoagulated AF patients during long-term follow-up.In this cohort study 243 AF patients (median age 69 years) were assessed. Serum levels of citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and peptidylarginine deiminase 4 (PAD4), along with plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolysis proteins were measured. Stroke/transient ischemic attacks (TIA), major bleeding, and mortality were recorded during a median follow-up of 53 months while on anticoagulation.Ischemic cerebrovascular events were observed in 20 patients (1.9%/year) who had at baseline higher H3cit, MPO, and PAD4 levels, all positively associated with CLT. Increased thrombin generation correlated positively with H3cit and PAD4, while Ks was inversely associated with H3cit levels. The independent predictors of ischemic stroke/TIA were H3cit (hazard ratio [HR] 9.48, 95% confidence interval [CI] 3.88-22.41, p < 0.0001) and VWF (HR 1.20, 95% CI 1.11-1.49, p = 0.001). Major bleeding (2.0%/year) and all-cause mortality (1.9%/year) were not related to NETs markers.Enhanced NETs formation related to prothrombotic markers is associated with increased risk of stroke/TIA in AF patients, suggesting a prognostic value of NETosis in AF.