Venous thromboembolism (VTE) is a leading cause of death and disability in cancer patients. The incidence of VTE in these patients in further increased by the administration of anti-neoplastic drugs, such as the chemotherapy drugs gemcitabine and cisplatin, as well as combination therapies. However, the mechanisms of VTE in cancer patients are largely unknown. The overall goal of this proposal is to determine whether an association exists between tissue factor (TF) activity in circulating microparticles (MPs) and venous thrombosis in patients with pancreatic or colon cancer, and in tumor-bearing mice. MPs are small (<1 micron) membrane vesicles that are released from activated or apoptotic cells. Our general hypothesis is that chemotherapy drugs increase the release of TF-positive MPs from both tumor cells and host cells into the circulation, and that an increase in the level of these MPs is associated with an increase in the incidence of asymptomatic and symptomatic VTE in pancreatic and colon cancer patients, and an increase in thrombus size in tumor-bearing mice. The proposal is divided into two aims.
In Specific Aim 1 we will determine the effect of treatment of tumor-bearing mice with chemotherapeutic drugs on circulating TF-positive MPs derived from tumor cells and different host cells as well as their role in a model of venous thrombosis. We will measure the levels of TF activity in isolated MPs in tumor-bearing mice treated with either gemcitabine or gemcitabine and cisplatin. We will use a series of novel mouse lines to distinguish between TF-positive MPs derived from i/ tumor versus host cells, and ii/ different host cells (monocytes, endothelial cells and platelets). These include HCV mice, which express human TF in the absence of mouse TF, and mice with various cell type-specific deletions of the TF gene generated using the Cre-loxP technology. Finally, we will selectively analyze the role of either tumor cell- derived or host cell-derived TF-positive MPs in a model of venous thrombosis.
In Specific Aim 2 we will determine if there is an association between TF activity in circulating MPs and VTE in patients with advanced pancreatic and colon cancer treated with anti-neoplastic drugs in a multi-center prospective observational study. Blood samples will be obtained from patients before and after treatment with anti-neoplastic drugs. Asymptomatic deep vein thrombosis will be assessed using compression ultrasound before and after treatment with anti-neoplastic drugs. We will measure levels of TF activity in isolated MPs and determine if this is associated with asymptomatic and/or symptomatic VTE. We will also measure whole blood TF activity, cellular origin of the TF-positive MPs and coagulation activation markers (thrombin anti thrombin complexes and D- dimer). The results of this study will determine the role of TF-positive MPs in venous thrombosis associated with cancer and chemotherapy. TF activity in isolated MPs may be a useful biomarker that can be used either alone or as an adjunctive biomarker in clinical predictive models of thrombotic risk in cancer patients undergoing chemotherapy. Public Health Relevance: Development of blood clots in veins or venous thrombosis is a leading cause of death and disability among cancer patients. Both the underlying cancer and the chemotherapy used to treat it are known to increase the risk of venous thrombosis. It is the goal of this research proposal to study the mechanism by which cancer and treatment of cancer with anti-cancer drugs lead to development of blood clots. We will also determine if increase in an important clotting protein in the blood (called tissue factor) is associated with development of blood clots in cancer patients, and if so, whether it could be used to predict which cancer patients are at increased risk for blood clots. This is of enormous importance as physicians will be able to institute measures to prevent thrombosis in high-risk patients and improve clinical outcomes.
Development of blood clots in veins or venous thrombosis is a leading cause of death and disability among cancer patients. Both the underlying cancer and the chemotherapy used to treat it are known to increase the risk of venous thrombosis. It is the goal of this research proposal to study the mechanism by which cancer and treatment of cancer with anti-cancer drugs lead to development of blood clots. We will also determine if increase in an important clotting protein in the blood (called tissue factor) is associated with development of blood clots in cancer patients, and if so, whether it could be used to predict which cancer patients are at increased risk for blood clots. This is of enormous importance as physicians will be able to institute measures to prevent thrombosis in high-risk patients and improve clinical outcomes.
|Hisada, Yohei; Mackman, Nigel (2017) Cancer-associated pathways and biomarkers of venous thrombosis. Blood 130:1499-1506|
|Rautou, Pierre-Emmanuel; Tatsumi, Kohei; Antoniak, Silvio et al. (2016) Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury. J Hepatol 64:53-9|
|Geddings, J E; Hisada, Y; Boulaftali, Y et al. (2016) Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost 14:153-66|
|Hisada, Y; Geddings, J E; Ay, C et al. (2015) Venous thrombosis and cancer: from mouse models to clinical trials. J Thromb Haemost 13:1372-82|
|Rautou, Pierre-Emmanuel; Vion, Anne-Clémence; Luyendyk, James P et al. (2014) Circulating microparticle tissue factor activity is increased in patients with cirrhosis. Hepatology 60:1793-5|
|Bharthuar, Anubha; Khorana, Alok A; Hutson, Alan et al. (2013) Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res 132:180-4|
|Rautou, Pierre-Emmanuel; Mackman, Nigel (2013) Microvesicles as risk markers for venous thrombosis. Expert Rev Hematol 6:91-101|
|Thaler, Johannes; Ay, Cihan; Mackman, Nigel et al. (2013) Microparticle-associated tissue factor activity in patients with pancreatic cancer: correlation with clinicopathological features. Eur J Clin Invest 43:277-85|
|Geddings, Julia E; Mackman, Nigel (2013) Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 122:1873-80|
|Key, Nigel S (2013) Bench to bedside: new developments in our understanding of the pathophysiology of thrombosis. J Thromb Thrombolysis 35:342-5|
Showing the most recent 10 out of 38 publications