Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Patients With Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) after spontaneous subarachnoid hemorrhage (SAH) is not well understood. Recent studies suggest the involvement of neutrophil-mediated immunothrombosis via neutrophil extracellular traps (NETs). We aimed to assess whether trajectories of NET biomarkers in patients with acute SAH are associated with DCI. METHODS: This was a prospective single-center study of patients within 48 hours of SAH onset. We collected clinical, laboratory, imaging, and 3-month outcome data. NET markers (H3Cit [citrullinated histone H3]-DNA complexes, myeloperoxidase-DNA complexes, cell-free DNA), along with peptidylarginine deiminase 4, and deoxyribonuclease activity were measured in plasma collected on admission (baseline), and post-SAH days 5 and 10. DCI was defined by clinical and imaging criteria. Generalized estimating equations examined differences in NET trajectories comparing patients with and without DCI. RESULTS: We enrolled 40 patients with SAH (mean age, 57 years; n=21 [53%] women; 32 [80%] aneurysmal). DCI occurred in 12 (30%) patients. All NET levels were similar between groups at baseline. On day 5, those with DCI compared with those without DCI had elevated median H3Cit-DNA complex (63 ng/mL versus 31 ng/mL, P=0.049), myeloperoxidase-DNA complex (5.9 ng/mL versus 0.4 ng/mL, P=0.029), and cell-free DNA (651 ng/mL versus 515 ng/mL, P=0.04) levels, which trended back down on day 10. In the DCI group, generalized estimating equations indicated heightened trajectories of H3Cit-DNA complex (day 5 [compared with baseline]: β=0.7; SE, 0.3; P=0.01; day 10: β=0.5; SE, 0.3; P=0.09), and myeloperoxidase-DNA complex levels (day 5: β=3.1; SE, 0.4; P<0.001; day 10: β=1.6; SE, 1.0; P=0.10). CONCLUSIONS: In patients with acute SAH, elevated plasma trajectories of NETs are associated with DCI.