CD177⁺ neutrophil-platelet aggregates contribute to thromboinflammation via NETs in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants, yet its precise pathogenic mechanisms remain unclear. While immunothrombosis, an interplay between inflammation and coagulation, is well recognized in systemic inflammatory diseases, its role in NEC pathogenesis and local intestinal regulation has been incompletely characterized. Here, we combine multi-omics profiling, histopathological analyses, and functional studies using clinical NEC samples and neonatal mouse models. We demonstrate prominent intestinal thromboinflammation in NEC, histologically characterized by immunothrombosis with infiltrating CD177⁺ neutrophils, activated platelets, and fibrin deposition. We show that extensive formation of CD177⁺ neutrophil-platelet aggregates (NPAs) amplifies intestinal injury through neutrophil extracellular trap (NET)-mediated thromboinflammation. Blocking CD177⁺ NPAs or inhibiting NET formation significantly alleviates NEC severity in mouse models. Clinically, elevated CD177⁺ NPA levels correlate with NEC severity and increased thrombotic biomarkers, highlighting their potential as diagnostic and prognostic biomarkers. Importantly, prophylactic administration of low-molecular-weight heparin (LMWH) disrupts NPA formation, reduces NET burden, and improves survival in experimental NEC. Collectively, these findings establish CD177⁺ NPAs as central drivers of NEC pathogenesis, support a thromboinflammatory framework for NEC, and highlight LMWH therapy and CD177⁺ NPA monitoring as possible clinically translatable strategies for neonatal care.