Table 2.

Proposed NET-biology framework across NEC subtypes.

Subtype	Dominant upstream drivers	Likely NET position	Priority markers	Intervention implication
Classical inflammatory NEC (very preterm)	Dysbiosis, TLR4 signaling, feeding stress	Execution module of histone/protease injury and immunothrombosis	Tissue H3cit/MPO/NE co-localization; MPO-DNA, H3cit, fecal calprotectin	PAD4/DNase window plausible after bacterial control
Ischemia-dominant/cardiac-related NEC	Mesenteric hypoperfusion, venous congestion, platelet activation	Amplification of endothelial injury and microthrombosis rather than initiation	Platelet count/trajectory, CD177+ aggregates, mesenteric Doppler flow	Prefer platelet/endothelial nodes (IP6K1, TREM1) over global NET blockade
Transfusion-associated/viral-triggered	Immune-complex-like signals, complement, altered disease tolerance	Modulated by complement and tolerance state; contribution least established	Complement fragments, extracellular cold-inducible RNA-binding protein, NET panel	Exploratory only; no NET-directed inference yet
SIP/focal perforation	Localized wall stress, often minimal systemic inflammation	Probably distinct from segmental necrosis; do not pool with NEC	Perforation site histology, low systemic NET panel	Analyze separately in all NET studies