NET-mediated immunothrombosis in ischemic stroke: pathobiology, biomarkers, and therapeutic targeting

Abstract

Ischemic stroke is increasingly understood not as a purely thromboembolic event but as a thromboinflammatory disease in which innate immune and hemostatic pathways interact. Neutrophil extracellular traps (NETs) have emerged as potentially important mediators and biomarkers within this broader immunothrombotic network. Experimental studies provide mechanistic evidence that NETs can stabilize thrombi, impair fibrinolysis, obstruct the microcirculation, and promote neurovascular injury, whereas human studies predominantly demonstrate associations between NET burden, reperfusion difficulty, and adverse clinical outcomes. This review critically synthesizes mechanistic, translational, observational, and emerging interventional evidence linking NETs to ischemic stroke. We distinguish established experimental mechanisms from human associations, place NETs within reciprocal interactions involving platelets, endothelial cells, monocytes/macrophages, complement, coagulation, and inflammatory mediators, and examine current controversies and barriers to therapeutic translation. We further consider DNase-mediated NET degradation, PAD4 inhibition, biomarker-guided patient selection, high-resolution multiomic and spatial technologies, and imaging-based thrombus characterization. This evidence-calibrated framework identifies where NET biology is most strongly supported and where causal and clinical uncertainty remains.