Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors

Yohei Hisada, Steven P. Grover, Anaum Maqsood, Reaves Houston, Cihan Ay, Denis F. Noubouossie, Brian C. Cooley, Håkan Wallén, Nigel S. Key, Charlotte Thålin, Ádám Z. Farkas, Veronika J. Farkas, Kiril Tenekedjiev, Krasimir Kolev, Nigel Mackman

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Abstract

Pancreatic cancer is associated with a high incidence of venous thromboembolism. Neutrophils have been shown to contribute to thrombosis in part by releasing neutrophil extracellular traps (NET). A recent study showed that increased plasma levels of the NET biomarker, citrullinated histone H3 (H3Cit), are associated with venous thromboembolism in patients with pancreatic and lung cancer but not in those with other types of cancer, including breast cancer. In this study, we examined the contribution of neutrophils and NET 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 NET contribute to venous thrombosis in patients with pancreatic cancer.

Original languageEnglish
Pages (from-to)218-225
Number of pages8
JournalHaematologica
Volume105
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

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ASJC Scopus subject areas

  • Hematology

Cite this

Hisada, Y., Grover, S. P., Maqsood, A., Houston, R., Ay, C., Noubouossie, D. F., Cooley, B. C., Wallén, H., Key, N. S., Thålin, C., Farkas, Á. Z., Farkas, V. J., Tenekedjiev, K., Kolev, K., & Mackman, N. (2020). Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors. Haematologica, 105(1), 218-225. https://doi.org/10.3324/haematol.2019.217083