Tumor-derived Tissue Factor Activates Coagulation and Enhances Thrombosis in a Mouse Xenograft Model of Human Pancreatic Cancer

Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In this study, we analyzed tissue factor (TF) expression in four different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that two of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Importantly, only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF antibody. Of the two TF-positive lines only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, <5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor bearing and control mice in an inferior vena cava stenosis model. Our studies suggest that in a xenograft mouse model tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis. 8 human tumor pancreatic cell lines