Pancreatic cancer is associated with high incidence of venous thromboembolism. Neutrophils
have been shown to contribute to thrombosis in part by releasing neutrophil extracellular
traps (NETs). A recent study showed that increased plasma levels of the NET biomarker,
citrullinated histone H3 (H3Cit), are associated with venous thromboembolism in pancreatic
and lung cancer but not in other types of cancer, including breast cancer. In this
study, we examined the contribution of neutrophils and NETs to venous thrombosis in
nude mice bearing human pancreatic tumors. We found that tumor-bearing mice had increased
circulating neutrophil counts and levels of granulocyte-colony stimulating factor,
neutrophil elastase, H3Cit and cell-free DNA compared with controls. In addition,
thrombi from tumor-bearing mice contained increased levels of the neutrophil marker
Ly6G, as well as higher levels of H3Cit and cell-free DNA. Thrombi from tumor-bearing
mice also had denser fibrin with thinner fibers consistent with increased thrombin
generation. Importantly, either neutrophil depletion or administration of DNase I
reduced the thrombus size in tumor-bearing but not in control mice. Our results, together
with clinical data, suggest that neutrophils and NETs contribute to venous thrombosis
in pancreatic cancer patients.
