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Integrated Model Linking Hemolysis, NETosis, Ferroptosis, Lysosomal Dysfunction, and DIC in Sepsis
Toshiaki Iba1,2, Cheryl L Maier3, Ricard Ferrer4
1Juntendo University, Department of Emergency and Disaster Medicine, Tokyo, Japan, Bunkyo.
Seminars in Thrombosis and Hemostasis
|July 30, 2026
Summary
Sepsis-associated coagulopathy involves iron dysregulation, leading to cell death and thrombosis. Targeting iron metabolism, neutrophil extracellular trap formation (NETosis), and ferroptosis may offer new sepsis treatments.
Area of Science:
- Immunology
- Hematology
- Cell Biology
Background:
- Sepsis-associated coagulopathy (SIC) and disseminated intravascular coagulation (DIC) are critical in sepsis mortality.
- Emerging evidence links iron metabolism, oxidative stress, and cell death to sepsis-induced thromboinflammation.
Purpose of the Study:
- To propose an integrated framework connecting hemolysis, NETosis, ferroptosis, and lysosomal dysfunction in sepsis-induced immunothrombosis and DIC.
- To reframe SIC and DIC as consequences of iron-driven immunometabolic dysregulation.
Main Methods:
- A narrative review of studies on NETosis, ferroptosis, lysosomal pathways, and SIC.
- Structured literature search in PubMed/MEDLINE.
Main Results:
- Hemolysis releases iron, promoting oxidative stress, NETosis, thrombosis, and impaired fibrinolysis.
- Iron-driven ferroptosis contributes to endothelial damage and organ injury.
- Lysosomes regulate iron and heme, amplifying oxidative damage and potentially linking NETosis and ferroptosis in a positive feedback loop.
Conclusions:
- An iron-driven immunothrombotic endotype in sepsis is characterized by elevated cell-free hemoglobin, ferritin, NET markers, and D-dimer.
- Targeting hemolysis, iron metabolism, NETosis, and ferroptosis offers novel therapeutic strategies beyond anticoagulation.
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