NETosis and venous thromboembolism: from mechanisms to practical implications

Neutrophil extracellular traps (NETs) are increasingly recognized as key mediators in the development of venous thromboembolism (VTE). Animal models and in vitro studies showed that NETs form a prothrombotic scaffold that supports platelet adhesion and aggregation, promotes activation of blood coagulation, and accelerates thrombin generation, leading to the formation of compact fibrin networks that exhibit increased resistance to fibrinolysis. Although clinical data remain limited, available studies support the translational relevance of these mechanisms in VTE. Elevated levels of circulating markers related to NETs formation (NETosis), such as citrullinated histone H3 (citH3), cell‑free DNA, and neutrophil protein-DNA complexes, have been detected in patients with acute deep vein thrombosis and correlated with disease severity and unfavorable outcomes. In acute pulmonary embolism (PE), elevated citH3 level on admission predicted PE‑related death. Higher concentrations of NET‑related proteins have also been linked to post‑thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Recent data suggest an association between enhanced NETosis and elevated levels of factor XI. From a clinical perspective, enhanced NETosis can be implicated in suboptimal effects of anticoagulant therapy in VTE, especially in cancer or septic patients. Despite the fact that attenuation of NETosis is an attractive goal in VTE, at present, no therapeutic strategies targeting NETosis, NETs degradation, or inhibition of NETosis‑associated pathways are available. This review summarizes the current knowledge on the mechanisms linking NETs with thrombosis. It also discusses the utility of available methods for the quantification of NET-related markers in patients and clinical implications of NET‑mediated venous thrombosis and its sequelae.