Y Hisada1,2, C Ay1,3, A C Auriemma1, B C Cooley4, N Mackman1,4. 1. Department of Medicine, Division of Hematology and Oncology, Thrombosis and Hemostasis Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2. K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway. 3. Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. 4. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract
Essentials Tumor-bearing mice have larger venous clots than controls. Human tissue factor is present in clots in tumor-bearing mice. Inhibition of human tissue factor reduces clot size in tumor-bearing mice. This new mouse model may be useful to study mechanisms of cancer-associated thrombosis. SUMMARY: Background Pancreatic cancer patients have a high rate of venous thromboembolism. Human pancreatic tumors and cell lines express high levels of tissue factor (TF), and release TF-positive microvesicles (TF+ MVs). In pancreatic cancer patients, tumor-derived TF+ MVs are present in the blood, and increased levels are associated with venous thromboembolism and decreased survival. Previous studies have shown that mice with orthotopic human or murine pancreatic tumors have circulating tumor-derived TF+ MVs, an activated clotting system, and increased incidence and mean clot weight in an inferior vena cava stenosis model. These results suggest that TF+ MVs contribute to thrombosis. However, the specific role of tumor-derived TF+ MVs in venous thrombosis in mice has not been determined. Objectives To test the hypothesis that tumor-derived TF+ MVs enhance thrombosis in mice. Methods We determined the contribution of TF+ MVs derived from human pancreatic tumors grown orthotopically in nude mice to venous clot formation by using an anti-human TF mAb. We used an inferior vena cava stasis model of venous thrombosis. Results Tumor-bearing mice had significantly larger clots than control mice. Clots from tumor-bearing mice contained human TF, suggesting the incorporation of tumor-derived MVs. Importantly, administration of an anti-human TF mAb reduced clot size in tumor-bearing mice but did not affect clot size in control mice. Conclusions Our results indicate that TF+ MVs released from orthotopic pancreatic tumors increase venous thrombosis in mice. This new model may be useful for evaluating the roles of different factors in cancer-associated thrombosis.
Essentials Tumor-bearing mice have larger venous clots than controls. Humantissue factor is present in clots in tumor-bearing mice. Inhibition of humantissue factor reduces clot size in tumor-bearing mice. This new mouse model may be useful to study mechanisms of cancer-associated thrombosis. SUMMARY: Background Pancreatic cancerpatients have a high rate of venous thromboembolism. Humanpancreatic tumors and cell lines express high levels of tissue factor (TF), and release TF-positive microvesicles (TF+ MVs). In pancreatic cancerpatients, tumor-derived TF+ MVs are present in the blood, and increased levels are associated with venous thromboembolism and decreased survival. Previous studies have shown that mice with orthotopic human or murinepancreatic tumors have circulating tumor-derived TF+ MVs, an activated clotting system, and increased incidence and mean clot weight in an inferior vena cava stenosis model. These results suggest that TF+ MVs contribute to thrombosis. However, the specific role of tumor-derived TF+ MVs in venous thrombosis in mice has not been determined. Objectives To test the hypothesis that tumor-derived TF+ MVs enhance thrombosis in mice. Methods We determined the contribution of TF+ MVs derived from humanpancreatic tumors grown orthotopically in nude mice to venous clot formation by using an anti-humanTF mAb. We used an inferior vena cava stasis model of venous thrombosis. Results Tumor-bearing mice had significantly larger clots than control mice. Clots from tumor-bearing mice contained humanTF, suggesting the incorporation of tumor-derived MVs. Importantly, administration of an anti-humanTF mAb reduced clot size in tumor-bearing mice but did not affect clot size in control mice. Conclusions Our results indicate that TF+ MVs released from orthotopic pancreatic tumors increase venous thrombosis in mice. This new model may be useful for evaluating the roles of different factors in cancer-associated thrombosis.
Authors: Alok A Khorana; Nigel Mackman; Anna Falanga; Ingrid Pabinger; Simon Noble; Walter Ageno; Florian Moik; Agnes Y Y Lee Journal: Nat Rev Dis Primers Date: 2022-02-17 Impact factor: 65.038
Authors: Yohei Hisada; Kenison B Garratt; Anaum Maqsood; Steven P Grover; Tomohiro Kawano; Brian C Cooley; Jonathan Erlich; Florian Moik; Matthew J Flick; Ingrid Pabinger; Nigel Mackman; Cihan Ay Journal: Blood Adv Date: 2021-01-26