NETS AND ENDOTHELIAL ACTIVATION IN IMMUNOTHROMBOSIS: A REVIEW ON THE NEUTROPHIL- PLATELET-THROMBIN AXIS

Resumo

ABSTRACT Introduction: Immunothrombosis corresponds to the interaction between inflammation, innate immunity, and coagulation, playing a significant role in the pathophysiology and outcomes of many clinical scenarios. In this context, neutrophil extracellular traps (NETs) have been recognized as central mediators of thromboinflammation, promoting endothelial activation, platelet aggregation, and amplification of the coagulation cascade. Objective: The present study aimed to analyze the role of NETs in immunothrombosis and endothelial activation associated with cardiovascular, pulmonary, inflammatory, and degenerative diseases. Materials and methods: This is a narrative literature review, conducted through a search in the PubMed database, using a strategy formulated with the DeCS/MeSH descriptors "Thromboinflammation" and "Extracellular traps", combined by the Boolean operator AND. Original articles published in the last three years, related to the role of NETs in immunothrombosis, were selected, focusing on the pathophysiological mechanisms involving endothelium, platelets, and coagulation. Results: The studies analyzed demonstrated that NETs play a vital role in the interface between inflammation and coagulation, acting as pro-thrombotic platforms capable of amplifying immunothrombosis. It has been observed that components of NETs, such as extracellular DNA, his tones, myeloperoxidase (MPO), and neutrophil elastase, promote endothelial activation, increased vascular permeability, expression of adhesion molecules, and platelet activation. Furthermore, NETs were found to be directly involved in thrombin generation, tissue factor activation, and propagation of the coagulation cascade, contributing to the formation of microthrombi and microvascular injury. Significant interaction was also evidenced between NETs, complement, and platelets, establishing inflammatory feedback loops capable of perpetuating vascular damage and systemic thromboinflammation. Some studies have indicated that extracellular histones derived from NETs function as damage -associated molecular patterns (DAMPs), promoting endothelial cytotoxicity, activation of Toll-like receptors, and intensification of the inflammatory response. In cardiovascular diseases, studies have shown an association between NETs and endothelial dysfunction, atherosclerotic progression, plaque instability, and atherothrombotic events. In pulmonary and systemic inflammatory settings, a relationship was observed between thromboinflammation, endothelial damage, and organ dysfunction, mediated by the interaction between neutrophils, platelets, complement, and endothelium. Furthermor e, biomarkers related to NETs, such as circulating cell -free DNA, citrullinated histone H3, and MPO-DNA complexes, have shown potential application in severity stratification and clinical prognosis. Conclusion: It is concluded that NETs play a fundamental role in the pathophysiology of immunothrombosis, acting as a link between inflammation, endothelial activation, and coagulation. Its role in microvascular dysfunction and the amplification of thromboinflammation demonstrates relevance in various clinical s ettings, particularly in cardiovascular and systemic inflammatory diseases. Furthermore, biomarkers related to NETs show potential diagnostic and prognostic utility, while NETosis modulation emerges as a promising therapeutic target for reducing vascular damage and thrombotic complications.