Impact of Neutrophil Extracellular Traps on Clinical Outcome after Subarachnoid Hemorrhage: A Translational Narrative Review

Aneurysmal subarachnoid hemorrhage (aSAH) remains associated with substantial morbidity and mortality despite best medical treatment. Increasing evidence implicates thrombo-inflammation (TI), driven by neutrophils and neutrophil extracellular traps (NETs), in the pathogenesis of delayed cerebral ischemia (DCI) and cognitive impairment. This narrative review summarizes experimental and clinical data linking neutrophil activation and NETs formation to DCI after aSAH and outlines emerging therapeutic strategies. This review was structured according to the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines and followed general recommendations for narrative reviews. A comprehensive PubMed and clinicaltrials.gov search identified experimental and clinical studies published in English without time window, focusing on TI, neutrophil activation, or NETosis in the acute phase of aSAH. Past and ongoing clinical trials were classified by mechanism of action. Experimental models and human data show early and sustained neutrophil activation within cerebral and systemic compartments after aSAH. NETs promote microvascular thrombosis, blood-brain barrier disruption, microglial activation, and neuronal injury, ultimately contributing to DCI and long-term cognitive impairment. Outside the brain, NETs may also aggravate neurogenic pulmonary edema and cardiac dysfunction. In animal models, deoxyribonuclease I (DNase I) effectively degrades NETs, improving perfusion, limiting neuronal apoptosis, and enhancing recovery. Several ongoing trials target TI pathways, including the RESET trial, which evaluates the impact of IV DNase I on clinical outcome after aSAH. NETs produced after neutrophil activation may be central to DCI. Targeting NETs represents a promising translational path to improve cerebral and systemic outcomes after aSAH.