Activation of Clotting Factors in Cancer

  • Frederick R. Rickles
  • Anna Falanga
Part of the Cancer Treatment and Research book series (CTAR, volume 148)

Evidence for “hypercoagulability” is commonly found in patients with cancer and increases the risk of thromboembolism (TE) [1]. While the pathophysiology of TE in cancer is complex, it can be viewed classically as related to abnormalities of Virchow’s triad: stasis of the blood; vascular injury; hypercoagulability (or, as described by Virchow himself, as “abnormalities of the fixed elements of the blood”) [2]. Epidemiologic, laboratory, pathologic and clinical evidence supports this important association. However, association is clearly not the same as causation and, until recently, TE was thought largely to be an epiphenomenon in cancer – a secondary manifestation of the inflammatory response to tumor growth and/or to the therapy (e.g. chemotherapy, surgery, radiation therapy).


Vascular Endothelial Growth Factor Tissue Factor Disseminate Intravascular Coagulation Tumor Endothelium Vascular Endothelial Growth Factor Gene Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations and the risk of venous thrombosis. J Am Med Assoc 2005;293:715–722.CrossRefGoogle Scholar
  2. 2.
    Falanga A. Thrombophilia in cancer. Semin Thromb Hemost 2005;31:104–110.PubMedCrossRefGoogle Scholar
  3. 3.
    Boccaccio C, Sabatino G, Medico E, Girolami F, Follenzi A, Reato G, Sottile A, Naldini L, Comoglio PM. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 2005;434:396–400.PubMedCrossRefGoogle Scholar
  4. 4.
    Rong Y, Post DE, Pieper RO, Burden DL, Van Meir EG, Brat DJ. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 2005;65:1406–1413.PubMedCrossRefGoogle Scholar
  5. 5.
    Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI, Coomber BL, Mackman N, Rak JW. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105:1734–1741.PubMedCrossRefGoogle Scholar
  6. 6.
    Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay D, Nawroth PP, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999;96: 8663–8668.PubMedCrossRefGoogle Scholar
  7. 7.
    Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signaling. J Thromb Haemost 2003;1:1495–1503.PubMedCrossRefGoogle Scholar
  8. 8.
    Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Natl Med 2004;10:502–509.CrossRefGoogle Scholar
  9. 9.
    Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004;104:2746–2751.PubMedCrossRefGoogle Scholar
  10. 10.
    Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy: risk analysis using Medicare claims data. Medicine 1999;78: 285–291.PubMedCrossRefGoogle Scholar
  11. 11.
    Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846–1850.PubMedCrossRefGoogle Scholar
  12. 12.
    Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632–634.PubMedCrossRefGoogle Scholar
  13. 13.
    Gross CP, Galusha DH, Krumholz HM. The impact of venous thromboembolism on risk of death or hemorrhage in older cancer patients. J Gen Intern Med 2007;22:321–326.PubMedCrossRefGoogle Scholar
  14. 14.
    von Templehoff GF, Harenberg J, Niemann F, Hommel G, Kirkpatrick CJ, Heilmann L. Effect of low molecular weight heparin (Certoparin) versus unfractinated heparin on cancer survival following breast and pelvic surgery: a prospective randomized, double-blind trial. Int J Oncol 2000;16:815–824.Google Scholar
  15. 15.
    Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RCN. Low molecular weight heparin, therapy with Dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol 2004;21:1944–1948.CrossRefGoogle Scholar
  16. 16.
    Altinbass M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266–1271.CrossRefGoogle Scholar
  17. 17.
    Lee AYY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123–2129.PubMedCrossRefGoogle Scholar
  18. 18.
    Klerk CPW, Smorenburg SM, Otten H-M, Lensing AWA, Prins MH, Piovella F, Prandoni P, Bos MMEM, Richel DJ, van Tienhoven G, Buller HR. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005;23:2130–2135.PubMedCrossRefGoogle Scholar
  19. 19.
    Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 1997;275:547–550.PubMedCrossRefGoogle Scholar
  20. 20.
    Hu Z, Sun Y, Garen A. Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model. Proc Natl Acad Sci USA 1999;96:8161–8166.PubMedCrossRefGoogle Scholar
  21. 21.
    Nilsson F, Kosmehl H, Zardi L, Neri D. Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res 2001;61:711–716.PubMedGoogle Scholar
  22. 22.
    El-Sheikh A, Borgstrom P, Bhattacharjee G, Belting M, Edgington TS. A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment. Cancer Res 2005;65:11109–11117.PubMedCrossRefGoogle Scholar
  23. 23.
    Hu Z, Garen A. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. Proc Natl Acad Sci USA 2001;98:12180–12185.PubMedCrossRefGoogle Scholar
  24. 24.
    Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, Camalier RF, Hollingshead MG, Kaur G, Sausville EA, Rickles FR, Snyder JP, Liotta DC, Shoji M. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg Med Chem 2004;12:3871–3883.PubMedCrossRefGoogle Scholar
  25. 24a.
    Shoji M, Sun A, Kisiel W, Lu YJ, Shim H, McCarey BE, Nichols C, Parker ET, Pohl J, Moseley CA, Alizadeh AR, Liotta DC, Snyder JP. Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa. J Drug Targeting 2008;16:185–197.Google Scholar
  26. 25.
    Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Int Med 2002;162:1245–1248.CrossRefGoogle Scholar
  27. 26.
    Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100;3484–3488.PubMedCrossRefGoogle Scholar
  28. 27.
    Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. ACTA Haematol (Suppl) 2001;106:6–12.PubMedCrossRefGoogle Scholar
  29. 28.
    Dvorak HF, Rickles FR. Malignancy and hemostasis. In: Hemostasis and thrombosis: basic principles and clinical practice, 5th edn (Eds. R.W. Colman, J Hirsh, VJ Marder, AW Clowes, and JN George). Lippincott-Raven Publishers, Philadelphia, PA, Chap 57, 2006;851–873.Google Scholar
  30. 29.
    Virchow R. Weitere Unter-suchungen ϋber die Verstopgung der Lungenarterie und ihre Folgen. In: Virchow R, ed. Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Meidinger Sohn: Frankfurt am Main, 1856, pp. 227–380.Google Scholar
  31. 30.
    Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003;112:853–862.PubMedGoogle Scholar
  32. 31.
    Boccaccio C, Comoglio PM. A functional role for hemostasis in early cancer development. Cancer Res 2005;65:8579–8582.PubMedCrossRefGoogle Scholar
  33. 32.
    Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin and cancer. Chest (Supplement) 2003;124:58S–68S.PubMedCrossRefGoogle Scholar
  34. 33.
    Contrino J, Hair GA, Schmeizl M, Rickles FR, Kreutzer DL. In situ characterization of antigenic and functional tissue factor expression in human tumors utilizing monoclonal antibodies and recombinant factor VIIa as probes. Am J Pathol 1994;145:1315–1322.PubMedGoogle Scholar
  35. 34.
    Contrino J, Hair GA, Kreutzer DL, Rickles FR. In situ expression of antigenic and functional tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med 1996;2:209–215.PubMedCrossRefGoogle Scholar
  36. 35.
    Mousa S, Patil G, Lansing L, Dier E, Kannanayakal T, Rickles, FR, Mousa SA. Modulation of cancer cell-associated procoagulant activity (PCA) with a novel, small molecule, orally active inhibitor of oxidative stress pathways. Blood 2008;112:921 (Abstr. 2666).Google Scholar
  37. 36.
    Mousa SA, Thangirala S, Dier E, Rebbaa A, Patil G, Rickles F. OT-304, a unique anti-tumor agent with multiple inhibitory effects on the cell cycle, cancer cell proliferation and the development of drug resistance. In: Proceed 99th Ann Mtg Amer Assoc Cancer Res. 2008; abstract #2316.Google Scholar
  38. 37.
    Bora PS, Hu Z, Tezel TH, Sohn J-H, Kang, SG, Cruz JMC, Bora NS, Garen A, Kaplan HJ. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration. Proc Natl Acad Sci USA 2003;100: 2679–2684.PubMedCrossRefGoogle Scholar
  39. 38.
    Hettiarachchi RJK, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Buller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost 1999;82:947–952.PubMedGoogle Scholar
  40. 39.
    Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983;221:719–725.PubMedCrossRefGoogle Scholar
  41. 40.
    Collen A, Smorenburg SM, Peters E, Lupu F, Koolwijk P, Van Noorden C, van Hinsbergh VWM. Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro. Cancer Res 2001;60:6196–6200.Google Scholar
  42. 41.
    Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003;1:1972–1976.PubMedCrossRefGoogle Scholar
  43. 42.
    Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparase in cancer metastasis and angiogenesis. J Clin Invest 2001;108:341–347.PubMedGoogle Scholar
  44. 43.
    Hasan J, Shnyder SD, Clamp AR, McGown AT, Bicknell R, Presta M, Bibby M, Double J, Craig S, Leeming D, Stevenson K, Gallagher JT, Jayson GC. Heparin octasaccharides inhibit angiogenesis in vivo. Clin Cancer Res 2005;11:8172–8179.PubMedCrossRefGoogle Scholar
  45. 44.
    Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins – correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005;11:7003–7011.PubMedCrossRefGoogle Scholar
  46. 45.
    Fernandez PM, Chou DS, Aquilina JW, Patierno SR, Rickles FR. Unfractionated heparin (UFH) and a low molecular weight heparin (dalteparin) exhibit antiangiogenic effects using in vitro, ex vivo and in vivo angiogenesis models. Proc Am Assoc Cancer Res 2003;44:698–699.Google Scholar
  47. 46.
    Marchetti M, Vignoli A, Russo L, Balducci D, Pagnoncelli M, Barbui T, Falanga A. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thromb Res 2008;121:637–645.PubMedCrossRefGoogle Scholar
  48. 47.
    Rickles FR. Mechanisms of cancer-induced thrombosis. J Pathophysiol Haemost Thromb 2006;35:103–111.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Hematology-Oncology, Department of MedicineThe George Washington UniversityWashingtonUSA

Personalised recommendations