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
Affiliations
Yohei Hisada
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Steven P. Grover
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Anaum Maqsood
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Reaves Houston
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Cihan Ay
Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
Denis F. Noubouossie
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Brian C. Cooley
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Håkan Wallén
Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
Nigel S. Key
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Charlotte Thålin
Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Karolinska Institutet, Stockholm, Sweden
Ádám Z. Farkas
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
Veronika J. Farkas
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
Kiril Tenekedjiev
Australian Maritime College, University of Tasmania, Launceston, Australia;Department of Information Technology, Nikola Vaptsarov Naval Academy, Varna, Bulgaria
Krasimir Kolev
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
Nigel Mackman
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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.
