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

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.

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.

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).

In patients with acute SAH, elevated plasma trajectories of NETs are associated with DCI.