Neutrophil Extracellular Traps Are Associated With Early Neurological Deterioration in Patients With Acute Ischemic Stroke Receiving Intravenous Thrombolysis: A Prospective Cohort Study

BACKGROUND: Neutrophil extracellular traps contribute to thrombolytic resistance and the no-reflow phenomenon after acute ischemic stroke, thereby impairing microvascular reperfusion and leading to unfavorable clinical outcomes. This study investigated the association between prethrombolytic circulating neutrophil extracellular trap biomarkers, CitH3 (citrullinated histone 3) and MPO (myeloperoxidase)-DNA complexes, and early neurological deterioration (END) in patients with acute ischemic stroke treated with intravenous thrombolysis alone. 

METHODS: We prospectively enrolled patients with acute ischemic stroke who received standard-dose alteplase within 4.5 hours of symptom onset (January 2019-April 2023). Venous blood was drawn before intravenous thrombolysis to measure serum CitH3 and MPO-DNA. The primary outcome was END, defined as an increase of ≥4 points in NIHSS score at 24 hours versus baseline. Logistic regression with restricted cubic splines assessed associations between neutrophil extracellular trap biomarkers and END. 

RESULTS: Among 287 patients (mean age 61.69±12.41 years, 70.4% male), 45 (15.7%) developed END. Serum CitH3 >17.67 ng/mL (odds ratio [OR], 3.81 [95% CI, 1.75-8.29]) and MPO-DNA >79.72 ng/mL (OR, 5.58 [95% CI, 2.36-13.21]) were independently associated with END. The associations remained significant when treated as continuous variables. Restricted cubic splines confirmed a linear dose-response relationship between higher CitH3 levels and END risk (P for nonlinearity=0.475). Subgroup analyses revealed stronger associations for CitH3 in patients with coronary artery disease or stroke history (P for interaction=0.018) and D-dimer <0.50 μg/mL (P for interaction=0.013). A significant interaction of smoking was found between MPO-DNA and END (P for interaction=0.026). 

CONCLUSIONS: Serum neutrophil extracellular traps may serve as promising biomarkers associated with END after intravenous thrombolysis in patients with acute ischemic stroke.