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Ferrata Storti Foundation
Haematologica 2019 Volume 105(1):218-225
Coagulation & its Disorders
Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors
Yohei Hisada,1 Steven P. Grover,1 Anaum Maqsood,1 Reaves Houston,1 Cihan Ay,2 Denis F. Noubouossie,1 Brian C. Cooley,3 Håkan Wallén,4 Nigel S. Key,1 Charlotte Thålin,5 Ádám Z. Farkas,6 Veronika J. Farkas,6 Kiril Tenekedjiev,7,8 Krasimir Kolev6 and Nigel Mackman1
1Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; 3Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Karolinska Institutet, Stockholm, Sweden; 6Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary; 7Australian Maritime College, University of Tasmania, Launceston, Australia and 8Department of Information Technology, Nikola Vaptsarov Naval Academy, Varna, Bulgaria
ABSTRACT
Pancreatic cancer is associated with a high incidence of venous throm- boembolism. Neutrophils have been shown to contribute to thrombo- sis in part by releasing neutrophil extracellular traps (NET). A recent study showed that increased plasma levels of the NET biomarker, citrulli- nated 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 contribu- tion 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 gener- ation. 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 con- tribute to venous thrombosis in patients with pancreatic cancer.
Introduction
Cancer patients have a 4- to 7-fold increased risk of venous thromboembolism (VTE) compared with the general population.1 However, the rates of VTE vary in different cancer types. For instance, breast cancer has a low rate whereas pancreatic cancer has a high rate of VTE.2 This variability suggests that there may be cancer type-specific mechanisms of VTE.3 For instance, we found an association between levels of circulating extracellular vesicle tissue factor activity and VTE in pancreatic cancer in two studies and a borderline significance in a third study.4-6 Circulating tumor-derived, tissue factor-positive extracellular vesicles are also observed in mice bearing human pancreatic tumors.7-10 Importantly, we have shown that these tumor- derived, human tissue factor-positive extracellular vesicles enhance venous throm- bosis in mice.10
Leukocytosis is often observed in cancer patients, particularly patients with lung and colorectal cancer.3 Leukocytosis is also associated with VTE in cancer patients, and is a component of the Khorana Risk Score for predicting chemotherapy-asso-
Correspondence:
NIGEL MACKMAN
nmackman@med.unc.edu
Received: January 18, 2019. Accepted: April 24, 2019. Pre-published: May 2, 2019.
doi:10.3324/haematol.2019.217083
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/218
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