Circulating NETosis biomarkers predict severity, 12-month functional outcome, and survival after spontaneous intracerebral hemorrhage.

Background: Spontaneous intracerebral hemorrhage (ICH) carries high early mortality and long-term disability; however, circulating biomarkers that capture both bleeding severity and prognosis are lacking. Neutrophil extracellular trap formation (NETosis), quantifiable in plasma as citrullinated histone H3 (H3Cit), cell-free DNA (cfDNA), and nucleosomes, is implicated in secondary brain injury after ICH. Methods: Three hundred fifteen adults with first-ever spontaneous ICH within 24 h of onset and 160 community controls were enrolled. Plasma H3Cit, cfDNA and nucleosomes, admission hematoma volume, NIHSS, and GCS were recorded; the modified Rankin Scale (mRS) was assessed at 12 months. NETosis biomarkers entered linear, logistic, and Cox regressions as log2-transformed continuous variables and were adjusted progressively for time-to-sampling, demographics, vascular risk factors, surgical treatment, NIHSS, and hematoma volume. Incremental predictive value over a clinical baseline model was assessed using area under the receiver operating characteristic curve (AUC)/concordance index (C-index), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: All three biomarkers were higher in ICH than controls (all Conclusion: Plasma H3Cit, cfDNA, and nucleosomes within 24 h of ICH track hemorrhage severity and predict 12-month mRS ≥ 3 and death beyond established clinical scores, with H3Cit showing the most consistent incremental value.