Abstract
Background
Thromboembolism is the second leading cause of death among patients with non-small
cell lung cancer (NSCLC), but the precise mechanisms of thrombogenesis in NSCLC remain
largely unknown. Our objectives were to evaluate the definitive role of neutrophil
extracellular traps (NETs) in the hypercoagulability in NSCLC and to explore its interactions
with platelets and endothelial cells (ECs).
Methods
The levels of NET markers in samples from 100 NSCLC patients and 30 healthy controls
were measured by ELISA. NET formation was detected using immunofluorescence. Procoagulant
activity was assessed based on purified coagulation complex, thrombin, clotting time,
and fibrin formation assays.
Results
The plasma levels of NETs were increased in a stage-dependent manner in NSCLC patients
and were markedly higher than those in controls. Neutrophils from NSCLC patients were
more prone to form NETs, resulting in shortened coagulation time, significantly increased
thrombin–antithrombin complexes and fibrin compared to controls. Moreover, NETs generation
was mediated by High Mobility Group Box 1 from activated platelets in NSCLC patients.
Conversely, NETs from NSCLC patients also induce phosphatidylserine exposure on platelets,
leading to markedly enhanced procoagulant activity (PCA). Furthermore, NETs can damage
endothelial cells and convert them to a procoagulant phenotype. The administration
of NETs inhibitors (DNase I/activated protein C) could markedly diminish the PCA of
NETs, activated platelets, and ECs.
Conclusion
Our results suggest that NETs contribute to hypercoagulability and may represent a
potential therapeutic target to prevent cancer-associated thrombosis in NSCLC patients.
Keywords
neutrophil extracellular traps - non-small cell lung cancer - platelet - endothelial
cells - procoagulant activity
