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

Introduction: 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.

Materials And Methods: 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 (K), 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.

Results: 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 K 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.

Conclusions: 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.