International Journal of Hematology

, Volume 73, Issue 2, pp 137–144 | Cite as

Pathogenesis of Thrombosis in Patients with Malignancy

  • Anna Falanga
  • Maria Benedetta Donati
Progress in hematology


Cancer cells can contribute to activation of the clotting system by their capacity to produce and release procoagulant/fibrinolytic substances and inflammatory cytokines, and by their interaction with host cells (endothelial, monocytes, platelets, and neutrophils). Moreover, anticancer drugs (chemotherapy/hormone therapy) may greatly affect the risk of thromboembolic complications in cancer patients by similar mechanisms, eg, through the release of procoagulants by tumor cells, through endothelial damage, or stimulation of tissue factor production by host cells. The interactions between cancer/metastatic processes and thrombosis have been reviewed here from the pathogenetic viewpoint. We hope that better knowledge of these pathogenetic pathways will lead to the development of more targeted strategies to prevent thromboembolism in cancer patients.

Key words

Thrombosis Cancer Metastasis Tumor procoagulants Cancer chemotherapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited.Blood. 1983;62:14–31.PubMedGoogle Scholar
  2. 2.
    Donati MB. Cancer and thrombosis: from phlegmasia alba dolens to transgenic mice.Thromb Haemost. 1995;74:278–281.PubMedGoogle Scholar
  3. 3.
    Bini A, Mesa-Tejada R, Fenoglio JJ Jr, et al. Immunoistochemical characterization of fibrin(ogen)-related antigens in human tissues using monoclonal antibodies.Lab Invest. 1989;60:814–821.PubMedGoogle Scholar
  4. 4.
    Barbui T, Finazzi G, Falanga A. The impact of all-trans—retinoic acid on the coagulopathy of acute promyelocytic leukemia.Blood. 1998;91:3093–3102.PubMedGoogle Scholar
  5. 5.
    Rickles FR, Levine MN, Edwards RL. Hemostatic alterations in cancer patients.Cancer Metastasis Rev. 1992;11:237–248.CrossRefPubMedGoogle Scholar
  6. 6.
    Falanga A, Barbui T, Rickles FR, Levine MN. Guidelines for clotting studies in cancer patients.Thromb Haemost. 1993;70:343–350.Google Scholar
  7. 7.
    Falanga A, Ofosu FA, Delaini F, et al. The hypercoagulable state in cancer: evidence for impaired thrombin inhibition.Blood Coagul Fibrinolysis. 1994;(suppl 1):S19-S23.Google Scholar
  8. 8.
    Donati MB, Poggi A, Semeraro N. Coagulation and malignancy. In: Poller EL, ed.Recent Advances in Blood Coagulation. New York, NY, Churchill Livingstone; 1981:227–259.Google Scholar
  9. 9.
    Monreal M, Prandoni P. Venous thromboembolism as first manifestation of cancer.Semin Thromb Hemost. 1999;25:131–136.CrossRefPubMedGoogle Scholar
  10. 10.
    Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.New Engl J Med. 1992;327:1128–1133.CrossRefPubMedGoogle Scholar
  11. 11.
    Prins MH, Lensing AWA, Hirsh J. Idiopathic deep venous thrombosis: is a search for malignant disease justified.Arch Intern Med. 1994;154:1310–1315.CrossRefPubMedGoogle Scholar
  12. 12.
    Piccioli A, Lensing AWA, Prandoni P. Screening for occult malignancy in patients with venous thromboembolism (SOMIT): study design [abstract].Thromb Haemost. 1997;(suppl):120.Google Scholar
  13. 13.
    Kakkar AK, Williamson RCN. Prevention of venous thromboembolism in cancer patients.Semin Thromb Hemost. 1999;25:239–243.CrossRefPubMedGoogle Scholar
  14. 14.
    Falanga A, Ofosu FA, Cortelazzo S, et al. Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery.Br J Haematol. 1993;85:745–750.CrossRefPubMedGoogle Scholar
  15. 15.
    Falanga A. Mechanisms of hypercoagulation in malignancy and during chemotherapy.Haemostasis. 1998;28(suppl 3):50–60.PubMedGoogle Scholar
  16. 16.
    Levine MN, Gent M, Hirsh J, et al. The thrombogenic effect of anti-cancer drug therapy in women with stage II breast cancer.New Engl J Med. 1988;318:404–407.CrossRefPubMedGoogle Scholar
  17. 17.
    Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer.J Clin Oncol. 1991;9:286–294.CrossRefPubMedGoogle Scholar
  18. 18.
    Levine MN, Gent M, Hirsh J, et al. Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.Lancet. 1994;343:886–889.CrossRefPubMedGoogle Scholar
  19. 19.
    Barbui T, Finazzi G, Grassi A, Marchioli M. Thrombosis in cancer patients treated with hemotopietic growth factors—a meta-analysis.Thromb Haemost. 1996;75:368–371.PubMedGoogle Scholar
  20. 20.
    Falanga A, Marchetti M, Evangelista V, et al. Neutrophil activation and hemostatic changes in healthy donors given granulocytecolony stimulating factor.Blood. 1999;93:2506–2514.PubMedGoogle Scholar
  21. 21.
    Falanga A, Iacoviello L, Evangelista V, et al. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia given all-transretinoic acid.Blood. 1995;86:1072–1084.PubMedGoogle Scholar
  22. 22.
    Lindhal AK, Sandset PM, Abilgaard U. Indices of hypercoagulation in cancer as compared with those with acute inflammation and acute infarction.Haemostasis. 1990;20:253–262.Google Scholar
  23. 23.
    Seitz R, Rappe N, Kraus M, et al. Activation of coagulation and fibrinolysis in patients with lung cancer: relation to tumor stage and prognosis.Blood Coagul Fibrinolysis. 1993;4:249–254.CrossRefPubMedGoogle Scholar
  24. 24.
    Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RCN. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor.Lancet. 1995;346:1004–1005.CrossRefPubMedGoogle Scholar
  25. 25.
    Falanga A, Levine MN, Consonni R, et al. The effect of very low dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial.Thromb Haemost. 1998;79:23–27.CrossRefPubMedGoogle Scholar
  26. 26.
    Gadducci A, Baicchi U, Marrai R, Del Bravo B, Fosella PV, Facchini V. Pretreatment plasma levels of fibrinopeptide A (FPA), D-Dimer (DD), and von Willebrand factor (vWF) in patients with ovarian carcinoma.Gynecol Oncol. 1994;53:352–356.CrossRefPubMedGoogle Scholar
  27. 27.
    Licciarello JTW, Moake JL, Rudi CK, Karp DD, Hong WK. Elevated plasma von Willebrand Factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy.Oncology. 1985;42:296–300.CrossRefGoogle Scholar
  28. 28.
    Bazarbachi A, Scrobohachi ML, Gisselbrecht C, et al. Changes in protein C, factor VII and endothelial markers after autologous bone marrow transplantation: possible implications in the pathogenesis of veno-occlusive disease.Nouv Rev Fr Hematol. 1993;35:135–140.PubMedGoogle Scholar
  29. 29.
    Catani L, Gugliotta L, Vianelli N, et al. Endothelium and bone marrow transplantation.Bone Marrow Transplant. 1996;17:277–280.PubMedGoogle Scholar
  30. 30.
    Semeraro N, Montemurro P, Conese M, et al. Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynaecological malignancies.Int J Cancer. 1990;45:251–254.CrossRefPubMedGoogle Scholar
  31. 31.
    Poggi A, Stella M, Donati MB. The importance of blood cell-vessel wall interactions in tumor metastasis.Balliére’s Clin Haemotol. 1993;6:731–751.CrossRefGoogle Scholar
  32. 32.
    Falanga A, Marchetti M, Evangelista V, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with Essential Thrombocythemia and Polycythemia Vera.Blood. 2000;96:4261–4266.PubMedGoogle Scholar
  33. 33.
    Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA Jr. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin-1.Proc Natl Acad Sci U S A. 1986;83:4533–4537.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture.Blood. 1989;73:159–165.PubMedGoogle Scholar
  35. 35.
    Falanga A, Marchetti M, Giovanelli S, Barbui T. All-trans-retinoic acid counteracts endothelial cell procoagulant activity induced by a human promyelocytic leukemia-derived cell line (NB4).Blood. 1996;87:613–617.PubMedGoogle Scholar
  36. 36.
    Van Hinsberg VWM, Bauer KA, Kooistra T, et al. Progress of fibrinolysis during tumor necrosis factor infusion in humans: concomitant increase of tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products.Blood. 1990;76:2284–2289.Google Scholar
  37. 37.
    Honn KV, Tang DG, Chen YQ. Adhesion molecules and site-specific metastases. In: Neri Serneri GG, Abbate R, Gensini G, Prisco D, eds.Thrombosis an Update. Florence, Italy: Scientific Press. 1992:269–303.Google Scholar
  38. 38.
    Marchetti M, Falanga A, Giovanelli S, Oldani E, Barbui T. All-trans-retinoic acid increases the adhesion to endothelium of the acute promyelocytic leukemia cell line NB4.Br J Haematol. 1996;93:360–366.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    Poggi A, Rossi C, Beviglia L, Calabrese R, Donati MB. Platelets-tumor cell interactions. In: Joseph M, ed.The Handbook of Immunopharmacology. London, UK: Academic Press. 1995:151–165.Google Scholar
  41. 41.
    Al-Mondhiry H. Betathromboglobulin and platelet factor 4 in patients with cancer: correlation with the stage of disease and the effect of chemotherapy.Am J Hematol. 1983;14:105–111.CrossRefPubMedGoogle Scholar
  42. 42.
    Wehmeier A, Tschope D, Esser J, Menzel C, Nieuwenhuis HK, Schneider W. Circulating activated platelets in myeloproliferative disorders.Thromb Res. 1991;61:271–278.CrossRefPubMedGoogle Scholar
  43. 43.
    Gasic GJ, Gasic TB. Plasma membrane vescicles as mediators of interactions between tumor cells and components of the hemostatic and immune system. In: Jamieson GA, ed.Interactions of Platelets and Tumor Cells. New York, NY: Alan R Liss. 1982:429–432.Google Scholar
  44. 44.
    Grignani G, Jamieson GA. Platelets in tumor metastasis: generation of ADP by tumor cells is specific but not unrelated to metastatic potential.Blood. 1988;71:844–849.PubMedGoogle Scholar
  45. 45.
    Semeraro N, Colucci M. Tissue factor in health and disease.Thromb Haemost. 1997;78:759–764.PubMedCrossRefGoogle Scholar
  46. 46.
    Lorenzet R, Peri G, Locati D, et al. Generation of procoagulant activity by mononuclear phagocytes: a possible mechanism contributing to blood clotting activation within malignant tissue.Blood. 1983;62:2721–2723.Google Scholar
  47. 47.
    Mussoni L, Donati MB. Expression of plasminogen activator as a marker of stimulation in tumor-associated macrophages.Haemostasis. 1988;18:66–71.PubMedGoogle Scholar
  48. 48.
    Gordon SG. Tumor cell procoagulants and their role in malignant disease.Semin Thromb Hemost. 1992;18:424–433.CrossRefPubMedGoogle Scholar
  49. 49.
    Falanga A, Rickels FR. Pathophysiology of the thrombophilic state in the cancer patient.Semin Thromb Hemost. 1999;25:173–182.CrossRefPubMedGoogle Scholar
  50. 50.
    Van de Water L, Tracy PB, Aronson D, Mann KG, Dvorak HF. Tumor cell generation of thrombin via prothrombinase assembly.Cancer Res. 1985;45:5521–5525.Google Scholar
  51. 51.
    Hettasch JM, Bandarenko N, Burchette JL, et al. Tissue transglutaminase expression in human breast cancer.Lab Invest. 1997;75: 637–645.Google Scholar
  52. 52.
    Andoh D, Kubota T, Takada M, Tanaka H, Kobayashi N, Maekawa T. Tissue factor activity in leukemia cells: special reference to disseminated intravascular coagulation.Cancer. 1987;59:748–754.CrossRefPubMedGoogle Scholar
  53. 53.
    Nemerson Y. The tissue factor pathway of blood coagulation.Semin Hematol. 1992;29:170–176.PubMedGoogle Scholar
  54. 54.
    Stephens R, Alitalo R, Tapiovaara H, Vaheri A. Production of an active urokinase by leukemia cells: a novel distinction from cell lines of solid tumors.Leuk Res. 1988;12:419–422.CrossRefPubMedGoogle Scholar
  55. 55.
    Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue.Biochemistry. 1985;24:5558–5567.CrossRefPubMedGoogle Scholar
  56. 56.
    Gordon SG, Mourad AM. The site of activation of factor X by cancer procoagulant.Blood Coagul Fibrinolysis. 1991;2:735–739.CrossRefPubMedGoogle Scholar
  57. 57.
    Mielicki WP, Gordon SG. Three stage chromogenic assay for the analysis of activation properties of factor X by cancer procoagulant.Blood Coagul Fibrinolysis. 1993;4:441–446.CrossRefPubMedGoogle Scholar
  58. 58.
    Donati MB, Gambacorti Passerini C, Casali B, et al. Cancer procoagulant in human tumor cells: evidence from melanoma patients.Cancer Res. 1986;46:6471–6474.PubMedGoogle Scholar
  59. 59.
    Gordon SG, Hashiba U, Poole MA, Cross BA, Falanga A. A cysteine proteinase procoagulant from amnion-chorion.Blood. 1985;66:1261–1265.PubMedGoogle Scholar
  60. 60.
    Falanga A, Consonni R, Marchetti M, et al. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia cells.Blood. 1998;92:143–151.PubMedGoogle Scholar
  61. 61.
    Donati MB, Falanga A, Consonni R, et al. Cancer procoagulant in acute non lymphoid leukemia: relationship of enzyme detection to disease activity.Thromb Haemost. 1990;64:11–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Gordon SG, Cross BA. An enzyme-linked immunosorbent assay for cancer procoagulant and its potential as a new tumor marker.Cancer Res. 1990;50:6229–6234.PubMedGoogle Scholar
  63. 63.
    Gordon SG, Benson B. Analysis of serum cancer procoagulant activity and its possible use as a tumor marker.Thromb Res. 1989;56:431–440.CrossRefPubMedGoogle Scholar
  64. 64.
    Edwards RL, Silver J, Rickles FR. Human tumor procoagulants: registry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society of Thrombosis and Haemostasis.Thromb Haemost. 1993;69:205–213.PubMedCrossRefGoogle Scholar
  65. 65.
    Koyama T, Hirosawa S, Kawamata N, Tohda S, Aoki N. All-trans-retinoic acid upregulates thrombomodulin and downregulates tissue factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells.Blood. 1994;84:3001–3009.PubMedGoogle Scholar
  66. 66.
    De Stefano V, Teofili L, Sica S, et al. Effect of all-trans-retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia.Blood. 1995;86:3535–3541.PubMedGoogle Scholar
  67. 67.
    Falanga A, Alessio MG, Donati MB, Barbui T. A new procoagulant in acute leukemia.Blood. 1988;71:870–875.PubMedGoogle Scholar
  68. 68.
    Alessio MG, Falanga A, Consonni R, et al. Cancer procoagulant in acute lymphoblastic leukemia.Eur J Haematol. 1990;445:78–81.Google Scholar
  69. 69.
    Falanga A, Consonni R, Marchetti M, et al. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by all-trans-retinoic acid.Leukemia. 1994;8:156–159.PubMedGoogle Scholar
  70. 70.
    Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia.Blood. 1998;91:3093–3102.PubMedGoogle Scholar
  71. 71.
    Kwaan HC, Keet HN. Fibrinolysis and cancer.Semin Thromb Hemost. 1990;16:230–235.CrossRefPubMedGoogle Scholar
  72. 72.
    Hajjar KA. Cellular receptors in the regulation of plasmin generation.Thromb Haemost. 1995;74:294–301.PubMedGoogle Scholar
  73. 73.
    Rocha E, P ramo JA, Fernàndez FJ, et al. Clotting activation and impairment of fibrinolysis in malignancy. Thromb Res. 189;54: 699–707.CrossRefPubMedGoogle Scholar
  74. 74.
    Brown LF, Detmas M, Claffey K, et al. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenesis factor. In: Goldberg ID, Rosen EM, eds.Regulation of Angiogenesis. Basel, Switzerland: Birkhauser Verlag. 1998:233–269.Google Scholar
  75. 75.
    Clauss M, Gerlach M, Gerlach H, Brett F, Wang PC. Vascular per- meability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.J Exp Med. 1990;172:1535–1545.CrossRefPubMedGoogle Scholar
  76. 76.
    Abe K, Shoji M, Chen J, et al. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor.Proc Natl Acad Sci U S A. 1999;96:8663–8668.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Shoji M, Abe K, Nawroth PP, Rickles FR. Molecular mechanisms linking thrombosis and angiogenesis in cancer.Trends Cardiovasc Med. 1997;7:52–59.CrossRefPubMedGoogle Scholar
  78. 78.
    Bertomeu MC, Gallo S, Lauri D, Levine MN, Orr FW, Buchanan MR. Chemotherapy enhances endothelial cell reactivity to platelets.Clin Exp Metastasis. 1990;8:511–518.CrossRefPubMedGoogle Scholar
  79. 79.
    Nicolson GL, Custead SE. Effects of chemotherapeutic drugs on platelet and metastatic tumor cell—endothelial cell interactions as a model for assessing vascular endothelial integrity.Cancer Res. 1985;45:331–336.PubMedGoogle Scholar
  80. 80.
    Sporn LA, Rubin P, Marder VJ, Wagner DD. Irradiation induces release of von Willebrand protein from endothelial cells in culture.Blood. 1984;64:567–570.PubMedGoogle Scholar
  81. 81.
    Poggi A, Kornblitt L, Delaini F, et al. Delayed hypercoagulability after a single dose of adriamycin to normal rats.Thromb Res. 1979;16:639–650.CrossRefPubMedGoogle Scholar
  82. 82.
    Walsh J, Wheeler HR, Geczy CL. Modulation of tissue factor on human monocytes by cisplatin and adriamycin.Br J Haematol. 1992;81:480–488.CrossRefPubMedGoogle Scholar
  83. 83.
    Harper PL, Jarvis J, Jennings I, Luddington R, Marcus RE. Changes in the natural anticoagulants following bone marrow transplantation.Bone Marrow Transplant. 1990;5:39–42.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.Hematology DivisionOspedali RiunitiBergamo
  2. 2.Department of Vascular Medicine and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri SudSanta Maria ImbaroItaly

Personalised recommendations