Mechanisms of Venous Thromboembolism in Cancer

Summary

Principal Investigator: Nigel Mackman
Abstract: 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.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Triggers, targets and treatments for thrombosis
    Nigel Mackman
    Division of Hematology Oncology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Nature 451:914-8. 2008
  2. pmc Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients
    Julia E Geddings
    Department of Pathology and Laboratory Medicine, and
    Blood 122:1873-80. 2013
  3. ncbi Bench to bedside: new developments in our understanding of the pathophysiology of thrombosis
    Nigel S Key
    Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    J Thromb Thrombolysis 35:342-5. 2013
  4. ncbi Microparticle-associated tissue factor activity in patients with pancreatic cancer: correlation with clinicopathological features
    Johannes Thaler
    Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Eur J Clin Invest 43:277-85. 2013
  5. ncbi Microvesicles as risk markers for venous thrombosis
    Pierre Emmanuel Rautou
    Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 27599, USA
    Expert Rev Hematol 6:91-101. 2013
  6. pmc New insights into the mechanisms of venous thrombosis
    Nigel Mackman
    Division of Hematology Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    J Clin Invest 122:2331-6. 2012
  7. ncbi Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients
    J Thaler
    Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
    J Thromb Haemost 10:1363-70. 2012
  8. ncbi Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers
    Anubha Bharthuar
    Departments of Medicine and Biostatistics, Roswell Park Cancer Institute, Buffalo, N Y USA
    Thromb Res 132:180-4. 2013
  9. pmc Venous thromboembolism: a need for more public awareness and research into mechanisms
    Stephan Moll
    Division of Hematology Oncology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7035, USA
    Arterioscler Thromb Vasc Biol 28:367-9. 2008
  10. pmc Use of mouse models to study the role of tissue factor in tumor biology
    Rafal Pawlinski
    Department of Immunology, The Scripps Research Institute, La Jolla, California, USA
    Semin Thromb Hemost 34:182-6. 2008

Scientific Experts

  • Nigel S Key
  • Nigel Mackman
  • A Phillip Owens
  • Jian guo Wang
  • David A Manly
  • Troy A McEachron
  • Rafal Pawlinski
  • Julia E Geddings
  • Julie C Williams
  • N Mackman
  • Frank C Church
  • James P Luyendyk
  • Anubha Bharthuar
  • Johannes Thaler
  • Pierre Emmanuel Rautou
  • R D Lee
  • D A Barcel
  • J Thaler
  • Jeremiah C Boles
  • Daniel Kirchhofer
  • Jianguo Wang
  • Sam L Glover
  • Karen M Kassel
  • Janusz Rak
  • E O Jenkins
  • G Mark Anderson
  • Joanne Yu
  • Chloe C Milsom
  • Chirag Amin
  • Stephan Moll
  • Cihan Ay
  • Michael Gnant
  • Renuka V Iyer
  • Ingrid Pabinger
  • Sylvia Metz-Schimmerl
  • Judith Stift
  • Alexandra Kaider
  • Werner Scheithauer
  • Alan Hutson
  • Leonhard Müllauer
  • Alok A Khorana
  • Shanmugam Nagarajan
  • Alisa S Wolberg
  • A Kaider
  • C Marosi
  • Linda K Curtiss
  • Douglas G Johns
  • Julie Ann Dutton
  • J C Boles
  • Pichika Chantrathammachart
  • Alan Daugherty
  • Raj S Kasthuri
  • Brian K Hubbard
  • Maria M Aleman
  • Freda H Passam
  • W Scheithauer
  • C Zielinski
  • Patrick M Moriarty
  • G Kornek
  • J G Wang
  • Lawrence Rudel
  • David A Barcel
  • R M Bertina
  • Ryan E Temel
  • Rachel M Hollingsworth
  • I Pabinger
  • Jessica C Cardenas
  • Allison L McDaniel
  • J C Williams
  • Jen Jen Yeh
  • Silvio Antoniak
  • Peter S Tobias
  • Ronald R Bach
  • Vladimir Y Bogdanov
  • C Ay
  • Bruce Furie
  • D A Manly
  • Barbara C Furie
  • Stephanie M Marshall
  • Bradley P Sullivan
  • Grace L Guo
  • Guodong Li
  • Ruipeng Wang
  • Cheryl E Rockwell
  • Ossama Tawfik
  • Jeremiah Boles
  • Howard A Liebman
  • Kristy L Richards
  • Raj Kasthuri
  • D Schiff

Detail Information

Publications33

  1. pmc Triggers, targets and treatments for thrombosis
    Nigel Mackman
    Division of Hematology Oncology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Nature 451:914-8. 2008
    ..The pathogenic changes that occur in the blood vessel wall and in the blood itself resulting in thrombosis are not fully understood. Understanding these processes is crucial for developing safer and more effective antithrombotic drugs...
  2. pmc Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients
    Julia E Geddings
    Department of Pathology and Laboratory Medicine, and
    Blood 122:1873-80. 2013
    ..Taken together, these results suggest that TF-positive MPs may be a useful biomarker to identify patients with cancer who are at high risk for thrombosis. ..
  3. ncbi Bench to bedside: new developments in our understanding of the pathophysiology of thrombosis
    Nigel S Key
    Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    J Thromb Thrombolysis 35:342-5. 2013
    ..These insights are likely to result in novel disease biomarkers and perhaps even adjunctive anti-thrombotic therapies...
  4. ncbi Microparticle-associated tissue factor activity in patients with pancreatic cancer: correlation with clinicopathological features
    Johannes Thaler
    Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
    Eur J Clin Invest 43:277-85. 2013
    ..We hypothesized that elevated levels of plasma microparticle (MP)-associated TF activity might indicate the presence of poorly differentiated pancreatic cancer, disease dissemination and infiltration of peripancreatic vessels...
  5. ncbi Microvesicles as risk markers for venous thrombosis
    Pierre Emmanuel Rautou
    Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 27599, USA
    Expert Rev Hematol 6:91-101. 2013
    ..However, further studies are needed to determine if TF-positive MVs are a good biomarker for venous thrombosis in cancer and other diseases...
  6. pmc New insights into the mechanisms of venous thrombosis
    Nigel Mackman
    Division of Hematology Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    J Clin Invest 122:2331-6. 2012
    ..Subsequent activation of the leukocytes induces expression of the potent procoagulant protein tissue factor that triggers thrombosis. Understanding the mechanisms of venous thrombosis may lead to the development of new treatments...
  7. ncbi Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients
    J Thaler
    Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
    J Thromb Haemost 10:1363-70. 2012
    ..Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF-positive microparticles (MPs) may contribute to venous thromboembolism (VTE)...
  8. ncbi Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers
    Anubha Bharthuar
    Departments of Medicine and Biostatistics, Roswell Park Cancer Institute, Buffalo, N Y USA
    Thromb Res 132:180-4. 2013
    ..We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival...
  9. pmc Venous thromboembolism: a need for more public awareness and research into mechanisms
    Stephan Moll
    Division of Hematology Oncology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7035, USA
    Arterioscler Thromb Vasc Biol 28:367-9. 2008
  10. pmc Use of mouse models to study the role of tissue factor in tumor biology
    Rafal Pawlinski
    Department of Immunology, The Scripps Research Institute, La Jolla, California, USA
    Semin Thromb Hemost 34:182-6. 2008
    ..The role of host TF in tumor progression is less clear. Recently developed mouse models with altered levels of TF may be useful in further analysis of the role of host cell TF in cancer...
  11. pmc Contribution of host-derived tissue factor to tumor neovascularization
    Joanne Yu
    Henderson Research Centre, McMaster University, Hamilton, ON, Canada
    Arterioscler Thromb Vasc Biol 28:1975-81. 2008
    ..The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study...
  12. pmc Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis
    Chloe C Milsom
    Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada
    Cancer Res 68:10068-76. 2008
    ..Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies...
  13. ncbi Microparticles and cancer
    Chirag Amin
    Department of Medicine and Program in Hemostasis and Thrombosis, Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
    Pathophysiol Haemost Thromb 36:177-83. 2008
    ....
  14. pmc Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet
    Karen M Kassel
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
    Am J Pathol 179:2278-89. 2011
    ..Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet...
  15. pmc Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin
    A Phillip Owens
    Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Clin Invest 122:558-68. 2012
    ..Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex...
  16. pmc Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer
    Jian guo Wang
    Division of Hematology Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Blood 119:5543-52. 2012
    ..The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis...
  17. ncbi Regulation of thrombin-induced plasminogen activator inhibitor-1 in 4T1 murine breast cancer cells
    Troy A McEachron
    Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599 7035, USA
    Blood Coagul Fibrinolysis 22:576-82. 2011
    ..These results begin to delineate the mechanism by which thrombin activates a PAR-1/PAR-2 complex to induce PAI-1 expression in the 4T1 murine breast cancer cell line...
  18. ncbi Anthracycline treatment of the human monocytic leukemia cell line THP-1 increases phosphatidylserine exposure and tissue factor activity
    Jeremiah C Boles
    Department of Medicine, Division of Hematology Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Thromb Res 129:197-203. 2012
    ..Malignancy conveys an increased risk for thrombosis and chemotherapy further elevates this risk. The pathophysiological mechanisms underlying this process remain poorly defined...
  19. pmc Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity
    R D Lee
    Division of Hematology Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    Thromb Res 129:80-5. 2012
    ..The aim of this study was to investigate the effects of pre-analytical and analytical variables on TF activity of MPs isolated from blood of healthy volunteers either untreated or treated ex vivo with bacterial lipopolysaccharide...
  20. pmc Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism
    David A Manly
    Division of Hematology Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7035, USA
    Thromb Res 125:511-2. 2010
    ..7+/-3.8 pg/mL vs 0.6+/-0.4 pg/mL, p<0.05). Further prospective studies are required to determine if levels of MP TF activity may be a useful biomarker to identify patients at increased risk for VTE...
  21. pmc Venous thromboembolism in malignant gliomas
    E O Jenkins
    Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    J Thromb Haemost 8:221-7. 2010
    ..Recent studies exploring disordered coagulation, such as increased expression of tissue factor (TF), and tumorigenic molecular signaling may help to explain the increased risk of VTE in patients with malignant gliomas...
  22. pmc Current treatment of venous thromboembolism
    Nigel S Key
    Harold R Roberts Distinguished Professor, Division of Hematology Oncology, Department of Medicine, 932 Mary Ellen Jones Bldg, CB 7035, Chapel Hill, NC 27599, USA
    Arterioscler Thromb Vasc Biol 30:372-5. 2010
    ..In this review, we discuss some of the issues that we believe are among the most critical unanswered questions in the management of venous thromboembolism in the present era...
  23. pmc Analysis of tissue factor positive microparticles
    Nigel S Key
    Department of Medicine, Division of Hematology Oncology, University of North Carolina at Chapel Hill, NC 27599, USA
    Thromb Res 125:S42-5. 2010
    ..Heterogeneity of TF-bearing MPs, such as the variable co-expression of surface phosphatidylserine, may determine not only their procoagulant potential, but also additional properties including rate of clearance from the circulation...
  24. ncbi Membrane microparticles in VTE and cancer
    Nigel S Key
    Department of Medicine, Division of Hematology Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Thromb Res 125:S80-3. 2010
    ..The results of prospective clinical studies that are currently underway should clarify any causative relationship...
  25. pmc Role of tissue factor in venous thrombosis
    David A Manly
    Brody School of Medicine, East Caroline University, Greenville, North Carolina 27834, USA
    Annu Rev Physiol 73:515-25. 2011
    ..Recent studies suggest that elevated levels of MP TF may trigger thrombosis. This review provides an overview of the role of TF in VTE...
  26. ncbi Tissue factor and its measurement in whole blood, plasma, and microparticles
    Nigel S Key
    Division of Hematology Oncology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Semin Thromb Hemost 36:865-75. 2010
    ..We comment on some of the crucial preanalytical and analytical variables that influence the results and their interpretation...
  27. pmc Microparticles in hemostasis and thrombosis
    A Phillip Owens
    Division of Hematology Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, North Carolina, USA
    Circ Res 108:1284-97. 2011
    ..This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis...
  28. pmc Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis
    Troy A McEachron
    Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
    Blood 116:5037-44. 2010
    ..Cells lacking PAR-2 failed to express PAI-1 in response to thrombin and factor Xa did not activate the PAR-1/PAR-2 complex. Our results reveal how PAR-1 and PAR-2 on tumor cells mediate crosstalk between coagulation and fibrinolysis...