Dysregulation of Hemostasis by Cancer

  • Dougald M. Monroe
  • Maureane Hoffman
Part of the Cancer Treatment and Research book series (CTAR, volume 148)

Dysregulation of the coagulation system in cancer patients can lead to both thrombosis and bleeding. An examination of the normal hemostatic processes suggests possible mechanisms by which a breakdown in the physiologic mechanisms might lead to the dysregulations observed in cancer.


Tissue Factor Thrombin Generation Tissue Factor Expression Platelet Surface Coagulation Protein 
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.
    Miller GJ, Howarth DJ, Attfield JC, Cooke CJ, Nanjee MN, Olszewski WL, Morrissey JH, Miller NE. Haemostatic factors in human peripheral afferent lymph. Thromb Haemost 2000;83:427–432.PubMedGoogle Scholar
  2. 2.
    Hatton MW, Blajchman MA, Sridhara S, Southward SM, Ross B, Kulzcycky M, Clarke BJ. Metabolism of rabbit plasma-derived factor VII in relation to prothrombin in rabbits. Am J Physiol Endocrinol Metab 2001;281:E507–515.PubMedGoogle Scholar
  3. 3.
    Gui T, Lin H, Jin D, Hoffman M, Straight DL, Roberts HR, Stafford DW. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood 2002;100:153–158.PubMedCrossRefGoogle Scholar
  4. 4.
    Drake TA, Morrissey JH, Edgington. TS Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989;134:1087–1097.PubMedGoogle Scholar
  5. 5.
    Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 1990;59:421–437.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoffman M, Colina CM, McDonald AG, Arepally GM, Pedersen L, Monroe DM. Tissue factor around dermal vessels has bound factor VII in the absence of injury. J Thromb Haemost 2007;5:1403–1408.PubMedCrossRefGoogle Scholar
  7. 7.
    Jesty J, Beltrami E. Positive feedbacks of coagulation: their role in threshold regulation. Arterioscler Thromb Vasc Biol 2005;25:2463–2469.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen J, López JA. Interactions of platelets with subendothelium and endothelium. Microcirculation 1994;12:235–246.CrossRefGoogle Scholar
  9. 9.
    Monković DD, Tracy PB. Functional characterization of human platelet-released factor V and its activation by factor Xa and thrombin. J Biol Chem 1990;265: 17132–17140.PubMedGoogle Scholar
  10. 10.
    Østerud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977;74:5260–5264.PubMedCrossRefGoogle Scholar
  11. 11.
    Sixma JJ, van den Berg A. The haemostatic plug in haemophilia A: a morphological study of haemostatic plug formation in bleeding time skin wounds of patients with severe haemophilia A. Br J Haematol 1984;58:741–753.PubMedCrossRefGoogle Scholar
  12. 12.
    Hoffman M, Harger A, Lenkowski A, Hedner U, Roberts HR, Monroe DM. Cutaneous wound healing is impaired in hemophilia B. Blood 2006;108:3053–3060.PubMedCrossRefGoogle Scholar
  13. 13.
    De Marco L, Mazzucato M, Masotti A, Ruggeri ZM. Localization and characterization of an alpha-thrombin-binding site on platelet glycoprotein Ib alpha. J Biol Chem 1994;269:6478–6484.PubMedGoogle Scholar
  14. 14.
    Bevers EM, Comfurius P, Zwaal RF. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 1983;736:57–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Alberio L, Safa O, Clemetson KJ, Esmon CT, Dale GL. Surface expression and functional characterization of alpha-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Blood 2000;95:1694–1702.PubMedGoogle Scholar
  16. 16.
    Kempton CL, Hoffman M, Roberts HR, Monroe DM. Platelet heterogeneity: variation in coagulation complexes on platelet subpopulations. Arterioscler Thromb Vasc Biol 2005;25:861–866.PubMedCrossRefGoogle Scholar
  17. 17.
    Heemskerk JW, Vuist WM, Feijge MA, Reutelingsperger CP, Lindhout T. Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses. Blood 1997;90:2615–2625.PubMedGoogle Scholar
  18. 18.
    Rapaport SI, Schiffman S, Patch MJ, Ames SB. The importance of activation of antihemophilic globulin and proaccelerin by traces of thrombin in the generation of intrinsic prothrombinase activity. Blood 1963;21:221–236.PubMedGoogle Scholar
  19. 19.
    Monroe DM, Roberts HR, Hoffman M. Platelet procoagulant complex assembly in a tissue factor-initiated system. Br J Haematol 1994;88:364–371.PubMedCrossRefGoogle Scholar
  20. 20.
    Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999;19:170–177.PubMedCrossRefGoogle Scholar
  21. 21.
    Wester J, Sixma JJ, Geuze JJ, Heijnen HF. Morphology of the hemostatic plug in human skin wounds: transformation of the plug. Lab Invest 1979;41:182–192.PubMedGoogle Scholar
  22. 22.
    Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007;21: 131–142.PubMedCrossRefGoogle Scholar
  23. 23.
    Franssen J, Salemink I, Willems GM, Wun TC, Hemker HC, Lindhout T. Prothrombinase is protected from inactivation by tissue factor pathway inhibitor: competition between prothrombin and inhibitor. Biochem J 1997;323:33–37.PubMedGoogle Scholar
  24. 24.
    Brummel-Ziedins KE, Pouliot RL, Mann KG. Thrombin generation: phenotypic quantitation. J Thromb Haemost 2004;2:281–288.PubMedCrossRefGoogle Scholar
  25. 25.
    Orfeo T, Brummel-Ziedins KE, Gissel M, Butenas S, Mann KG. The nature of the stable blood clot procoagulant activities. J Biol Chem 2008;283:9776–9786.PubMedCrossRefGoogle Scholar
  26. 26.
    Pearson JD. Vessel wall interactions regulating thrombosis. Br Med Bull 1994;50:776–788.PubMedGoogle Scholar
  27. 27.
    Oliver JA, Monroe DM, Church FC, Roberts HR, Hoffman M. Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces. Blood 2002;100:539–546.PubMedCrossRefGoogle Scholar
  28. 28.
    Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982;257:7944–7947.PubMedGoogle Scholar
  29. 29.
    Slungaard A, Key NS. Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis. J Biol Chem 1994;269:25549–25556.PubMedGoogle Scholar
  30. 30.
    Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715–722.PubMedCrossRefGoogle Scholar
  31. 31.
    Baron JA, Gridley G, Weiderpass E, Nyrén O, Linet M. Venous thromboembolism and cancer. Lancet 1998;351:1077–1080.PubMedCrossRefGoogle Scholar
  32. 32.
    Day KC, Hoffman LC, Palmier MO, Kretzmer KK, Huang MD, Pyla EY, Spokas E, Broze GJ, Warren TG, Wun TC. Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 1990;76:1538–1545.PubMedGoogle Scholar
  33. 33.
    Gordon SG, Cross BA. A factor X-activating cysteine protease from malignant tissue. J Clin Invest 1981;67:1665–1671.PubMedCrossRefGoogle Scholar
  34. 34.
    Gunji Y, Lewis J, Gorelik E. Fibrin formation inhibits the in vitro cytotoxic activity of human natural and lymphokine-activated killer cells. Blood Coagul Fibrinolysis 1990;1:663–672.PubMedGoogle Scholar
  35. 35.
    Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med 1996;2:209–215.PubMedCrossRefGoogle Scholar
  36. 36.
    Dupuy E, Hainaud P, Villemain A, Bodevin-Phèdre E, Brouland JP, Briand P, Tobelem G. Tumoral angiogenesis and tissue factor expression during hepatocellular carcinoma progression in a transgenic mouse model. J Hepatol 2003;38:793–802.PubMedCrossRefGoogle Scholar
  37. 37.
    Shoji M, Hancock WW, Abe K, Micko C, Casper KA, Baine RM, Wilcox JN, Danave I, Dillehay DL, Matthews E, Contrino J, Morrissey JH, Gordon S, Edgington TS, Kudryk B, Kreutzer DL, Rickles FR. Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. Am J Pathol 1998;152:399–411.PubMedGoogle Scholar
  38. 38.
    Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F, Freyssinet J. Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol 2006;26:2594–2604.PubMedCrossRefGoogle Scholar
  39. 39.
    Eilertsen K, Østerud B. Tissue factor: (patho)physiology and cellular biology. Blood Coagul Fibrinolysis 2004;15:521–538.PubMedGoogle Scholar
  40. 40.
    Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003;9:458–462.PubMedCrossRefGoogle Scholar
  41. 41.
    Censarek P, Bobbe A, Grandoch M, Schrör K, Weber A. Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb Haemost 2007;97:11–14.PubMedGoogle Scholar
  42. 42.
    Biró E, Sturk-Maquelin KN, Vogel GMT, Meuleman DG, Smit MJ, Hack CE, Sturk A, Nieuwland R. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 2003;1:2561–2568.PubMedCrossRefGoogle Scholar
  43. 43.
    Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie BC, Furie B. Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 2004;104:3190–3197.PubMedCrossRefGoogle Scholar
  44. 44.
    Day SM, Reeve JL, Pedersen B, Farris DM, Myers DD, Im M, Wakefield TW, Mackman N, Fay WP. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 2005;105:192–198.PubMedCrossRefGoogle Scholar
  45. 45.
    Bach RR. Tissue factor encryption. Arterioscler Thromb Vasc Biol 2006;26:456–461.PubMedCrossRefGoogle Scholar
  46. 46.
    Østerud B, Bjørklid E. The tissue factor pathway in disseminated intravascular coagulation. Semin. Thromb Hemost 2001;27:605–617.PubMedCrossRefGoogle Scholar
  47. 47.
    De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol 2004;50:187–196.PubMedCrossRefGoogle Scholar
  48. 48.
    Giesen PL, Rauch U, Bohrmann B, Kling D, Roqué M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999;96:2311–2315.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoffman M, Whinna HC, Monroe DM. Circulating tissue factor accumulates in thrombi, but not in hemostatic plugs. J Thromb Haemost 2006;4:2092–2093.PubMedCrossRefGoogle Scholar
  50. 50.
    Tilley RE, Holscher T, Belani R, Nieva J, Mackman N. Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients. Thromb Res 2008; epub ahead of print.Google Scholar
  51. 51.
    Hron G, Kollars M, Weber H, Sagaster V, Quehenberger P, Eichinger S, Kyrle PA, Weltermann A. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007;97:119–123.PubMedGoogle Scholar
  52. 52.
    Tesselaar MET, Romijn FPHTM, Van Der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 2007;5:520–527.PubMedCrossRefGoogle Scholar
  53. 53.
    Edwards RL, Rickles FR, Cronlund M. Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation. J Lab Clin Med 1981;98:917–928.PubMedGoogle Scholar
  54. 54.
    Semeraro N. Different expression of procoagulant activity in macrophages associated with experimental and human tumors. Haemostasis 1988;18:47–54.PubMedGoogle Scholar
  55. 55.
    Goerge T, Kleinerüschkamp F, Barg A, Schnaeker E, Huck V, Schneider MF, Steinhoff M, Schneider SW. Microfluidic reveals generation of platelet-strings on tumor-activated endothelium. Thromb Haemost 2007;98:283–286.PubMedGoogle Scholar
  56. 56.
    Hanly AM, Hayanga A, Winter DC, Bouchier-Hayes DJ. Thrombomodulin: tumour biology and prognostic implications. Eur J Surg Oncol 2005;31:217–220.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Chapel Hill
  2. 2.Pathology and Laboratory Medicine Service (113), Durham Veterans Affairs Medical CenterDurham

Personalised recommendations