Abstract 041: Neutrophil Extracellular Traps Enhance Venous Thrombosis in Mice Bearing Human Pancreatic Tumors

Introduction: Cancer patients have an increased risk of venous thromboembolism (VTE) compared with healthy individuals. Pancreatic cancer has one of the highest rates of VTE. We are interested in elucidating the pathways that contribute to cancer-associated thrombosis (CAT) particularly in pancreatic cancer. A recent study reported an association between plasma levels of citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), and VTE in a population of patients with a variety of cancer-types. Importantly, subgroup analysis showed that increased levels of H3Cit are associate with VTE in patients with pancreatic and lung cancer but not in patients with other types of cancer. We use mouse models to investigate the role of different pathways in CAT. Aim: To test the hypothesis that NETs enhance thrombosis in mice bearing human pancreatic tumors. Methods: We recently established a CAT model in which venous thrombosis is induced by infrarenal vena cava (IVC) stasis in nude mice bearing human pancreatic tumors (BxPc-3). Results: We found that tumor-bearing mice had increased levels of plasma granulocyte-colony stimulating factor and neutrophilia. In addition, levels of plasma cell-free DNA are increased, which is used as a marker of NET formation. Tumor-bearing mice also had larger thrombi in an IVC stasis model compared with controls. Thrombi from tumor-bearing mice had increased levels of neutrophils and decreased levels of red blood cells compared with thrombi from control mice. Importantly, administration of DNAse I reduced thrombus size in tumor-bearing mice but not in control mice. Conclusions: Our study indicates that the presence of human pancreatic tumors in mice induces neutrophilia and increases NET formation that enhances venous thrombosis. These results suggest that neutrophils and/or NETs represent new targets to prevent VTE in pancreatic cancer patients.