NETs and the thrombo-immune microenvironment: immune heterogeneity in recanalization, reperfusion, hemorrhagic transformation, and antithrombotic strategies.

Reperfusion therapies have revolutionized the treatment of acute ischemic stroke (AIS), but target-artery recanalization, downstream angiographic reperfusion, microvascular tissue reperfusion, and functional recovery are distinct endpoints. Patients may have persistent occlusion or early reocclusion, incomplete modified Thrombolysis in Cerebral Infarction (mTICI) reperfusion, microvascular no-reflow despite high-grade mTICI/eTICI reperfusion, hemorrhagic transformation (HT), or poor 90-day functional outcome. Neutrophil extracellular traps (NETs) form a mechanistic link between thrombus structure, innate immune activation, endothelial injury, and antithrombotic responses. NETs provide a DNA-histone scaffold that stabilizes fibrin-rich thrombi, recruits platelets and coagulation factors, and exposes the neurovascular unit to cytotoxic granular proteins. The biological characteristics of NETs nevertheless vary among patients. Differences in neutrophil priming, platelet activation, monocyte-endothelial signaling, thrombus composition, collateral status, concurrent inflammation, and reperfusion injury create distinct thrombo-immune microenvironments. This article reviews how NET-driven immunothrombosis affects arterial recanalization, angiographic and tissue reperfusion, HT, and emerging antithrombotic strategies. It also proposes an operational immune-phenotyping framework with candidate biomarkers, assay-dependent research thresholds, sampling time points, and trial-level decision rules.