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 with 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 circulating markers related to 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 (DVT) and were associated with disease severity and unfavorable outcomes. In acute pulmonary embolism (PE) elevated citH3 on admission predicted PE-related death. Higher concentrations of NET-related proteins have also been linked to post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH). Recent data suggests links of enhanced NETosis with elevated factor XI. From a clinical perspective, enhanced NETs formation can be implicated in suboptimal effects of anticoagulant therapy in VTE, especially in cancer or sepsis patients. Despite the fact that attenuation of NETosis is an attractive goal in VTE, until now no therapeutic strategies targeting NETs formation, degradation, or inhibition of NETosis-associated pathways are available. This review summarizes the current knowledge on mechanisms by which NETs are linked with thrombosis, discusses the utility of available methods for the analysis of NETosis in patients and clinical implications of NETs-mediated venous thrombosis and its sequelae.