Neutrophil Extracellular Traps in Patients with Intracerebral Hemorrhage

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BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke frequently resulting in severe disability. Secondary mechanisms after ICH include neuroinflammation and development of perihematomal edema. Neutrophil extracellular traps (NETs) mediate infection defense and are involved in disease processes affecting the nervous system, including immunothrombosis and blood-brain barrier disruption. We aimed to assess NETs in ICH and their potential contribution to outcome measures. METHODS: We conducted a prospective, single-center cohort study recruiting patients with ICH within 24 h after symptom onset and collected clinical, laboratory, imaging, and 3-month outcome data. NET components [citrullinated histone H3[H3Cit]-DNA complexes and myeloperoxidase (MPO)-DNA complexes, cell-free DNA (cfDNA)] and DNase activity were measured in plasma collected on admission, on day 2/3, and on day 6 (± 1 day) after admission. We assessed ICH volume and perihematomal edema (PHE) semiquantitatively. RESULTS: We enrolled 50 patients with ICH (mean age 72 years) with mainly supratentorial ICH (86%), a median ICH volume of 16 ml [interquartile range (IQR) 5.8-38], and a median PHE volume of 11 ml (IQR 5-26). Compared with healthy controls, NETs were detectable in patients with ICH on admission at higher levels (H3Ccit-DNA, p < 0.001; cfDNA, p < 0.001) together with lower DNase activity (p = 0.012). During the first 6 days after ICH, we observed an increase of NET components H3Cit-DNA (baseline, median 6.0 ng/ml [IQR 1.4-9.5] vs. day 6, 12.0 ng/ml [IQR 5.7 vs. 19.0], p < 0.001), MPO-DNA (1.4 ng/ml [IQR 0.59-2.2] vs. 2.6 ng/ml [IQR 1.4-3.4], p < 0.001) and cfDNA (115 ng/ml [IQR 106-125] vs. 137 ng/ml [IQR 127-152], p < 0.001), and a decline in DNase activity (median 85% [IQR 66-102] vs. 66% [IQR 59-80], p < 0.001). NET trajectories correlated with imaging outcomes (ICH volume, PHE volume) and clinical outcome measures. CONCLUSIONS: Increasing NETs and a decrease in DNase activity were observed during the early course after ICH onset and correlated with imaging and clinical outcomes. Future studies should evaluate the functional role of NETs in patients with ICH.

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