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Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models.

Abstract

Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.

Authors+Show Affiliations

Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31808871

Citation

Hisada, Yohei, and Nigel Mackman. "Update From the Laboratory: Mechanistic Studies of Pathways of Cancer-associated Venous Thrombosis Using Mouse Models." Hematology. American Society of Hematology. Education Program, vol. 2019, no. 1, 2019, pp. 182-186.
Hisada Y, Mackman N. Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. Hematology Am Soc Hematol Educ Program. 2019;2019(1):182-186.
Hisada, Y., & Mackman, N. (2019). Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. Hematology. American Society of Hematology. Education Program, 2019(1), pp. 182-186. doi:10.1182/hematology.2019000025.
Hisada Y, Mackman N. Update From the Laboratory: Mechanistic Studies of Pathways of Cancer-associated Venous Thrombosis Using Mouse Models. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):182-186. PubMed PMID: 31808871.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. AU - Hisada,Yohei, AU - Mackman,Nigel, PY - 2020/12/06/pmc-release PY - 2019/12/7/entrez PY - 2019/12/7/pubmed PY - 2019/12/7/medline SP - 182 EP - 186 JF - Hematology. American Society of Hematology. Education Program JO - Hematology Am Soc Hematol Educ Program VL - 2019 IS - 1 N2 - Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer. SN - 1520-4383 UR - https://www.unboundmedicine.com/medline/citation/31808871/Update_from_the_laboratory:_mechanistic_studies_of_pathways_of_cancer-associated_venous_thrombosis_using_mouse_models L2 - https://ashpublications.org/hematology/article-lookup/doi/10.1182/hematology.2019000025 DB - PRIME DP - Unbound Medicine ER -