Integrated Model Linking Hemolysis, NETosis, Ferroptosis, Lysosomal Dysfunction, and DIC in Sepsis

Abstract: Sepsis-associated coagulopathy (SIC) and disseminated intravascular coagulation (DIC) are major determinants of organ failure and mortality in sepsis. While traditionally viewed as disorders of coagulation and fibrinolysis, emerging evidence highlights the roles of iron metabolism, oxidative stress, and regulated cell death in thromboinflammation. This article aims to propose an integrated conceptual framework linking hemolysis, neutrophil extracellular trap formation (NETosis), ferroptosis, and lysosomal dysfunction as central drivers of immunothrombosis and DIC in sepsis. A narrative review was conducted based on a structured search of NETosis, ferroptosis, lysosomal pathways, and SIC in PubMed/MEDLINE. Hemolysis releases cell-free hemoglobin and heme, leading to accumulation of redox-active iron and oxidative stress. These processes promote neutrophil activation and NET formation, thereby enhancing thrombosis and impairing fibrinolysis. In parallel, iron-driven lipid peroxidation induces ferroptosis in endothelial and parenchymal cells, contributing to barrier disruption and organ injury. Lysosomes act as central cellular regulators by controlling iron trafficking through ferritinophagy and heme degradation, thereby amplifying intracellular iron availability and oxidative damage. Experimental studies suggest that NETosis and ferroptosis may participate in a bidirectional amplification process that could further propagate thromboinflammation, although direct evidence in human sepsis remains limited. Clinically, this axis may define an iron-driven immunothrombotic endotype characterized by elevated cell-free hemoglobin, ferritin, NET markers, and D-dimer. This integrated model reframes SIC and DIC as manifestations of iron-driven immunometabolic dysregulation. Biomarker-guided identification of this endotype may enable targeted therapeutic strategies to address hemolysis, iron metabolism, NETosis, and ferroptosis, beyond conventional anticoagulation.