Cancer and Metastasis Reviews

, Volume 33, Issue 2–3, pp 771–789

Clinical models and biochemical predictors of VTE in lung cancer

  • M. Roselli
  • S. Riondino
  • S. Mariotti
  • F. La Farina
  • P. Ferroni
  • F. Guadagni
Clinical

Abstract

Venous thromboembolism (VTE) is a frequent complication of lung cancer and its treatment, especially in the advanced stages of disease. The risk of a pro-thrombotic state might increase through the activation of hemostasis, occurring both via the induction of a pro-coagulant activity and with platelet involvement, ultimately leading to the development of metastases. Despite the acknowledgement of an increased thrombophilic condition in cancer patients, and the experimental evidence that heparin compounds may have direct anticancer benefits, there is no univocal consent regarding VTE prevention in cancer outpatients receiving therapy. Thus, many authors highlighted the need for the development of stratification techniques to identify at-risk patients who might benefit from thromboprophylaxis. Clinical risk models were developed and validated, in order to assign high-risk patients to a proper thromboprophylaxis regimen that, however, might not be justified in all clusters. Besides, efforts have been devoted to identify candidate biomarkers that may be used in VTE risk assessment, although none has been recognized, so far, as a predictor for VTE in lung cancer patients. In this review, we will summarize the latest information concerning this very controversial topic, with focus on some of the proposed strategies to select the appropriate patients for prophylaxis.

Keywords

Lung cancer Venous thromboembolism Metastasis Thromboprophylaxis 

References

  1. 1.
    Battinelli, E. M., Murphy, D. L., & Connors, J. M. (2012). Venous thromboembolism overview. Hematology/Oncology Clinics of North America, 26(2), 345–367.PubMedGoogle Scholar
  2. 2.
    Prandoni, P., Piccioli, A., & Girolami, A. (1999). Cancer and venous thromboembolism: an overview. Haematologica, 84(5), 437–445.PubMedGoogle Scholar
  3. 3.
    Roselli, M., Ferroni, P., Riondino, S., Mariotti, S., Laudisi, A., Vergati, M., et al. (2013). Impact of chemotherapy on activated protein C-dependent thrombin generation—association with VTE occurrence. International Journal of Cancer, 133(5), 1253–1258.Google Scholar
  4. 4.
    Martinelli, I. (2001). Risk factors in venous thromboembolism. Thrombosis and Haemostasis, 86(1), 395–403.PubMedGoogle Scholar
  5. 5.
    Di Nisio, M., Ferrante, N., De Tursi, M., Iacobelli, S., Cuccurullo, F., Büller, H. R., et al. (2010). Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Thrombosis and Haemostasis, 104(5), 1049–1054.PubMedGoogle Scholar
  6. 6.
    Falanga, A., & Donati, M. B. (2001). Pathogenesis of thrombosis in patients with malignancy. International Journal of Hematology, 73(2), 137–144.PubMedGoogle Scholar
  7. 7.
    Jain, S., Harris, J., & Ware, J. (2010). Platelets: linking hemostasis and cancer. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(12), 2362–2367.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Wood, S., Jr. (1958). Pathogenesis of metastasis formation observed in vivo in the rabbit ear chamber. AMA Archaeological Pathology, 66(4), 550–568.Google Scholar
  9. 9.
    Lee, A. Y., & Levine, M. N. (2003). Venous thromboembolism and cancer: risk and outcomes. Circulation, 107(23 Suppl 1), 117–121.Google Scholar
  10. 10.
    Tas, F., Kilic, L., Serilmez, M., Keskin, S., Sen, F., & Duranyildiz, D. (2013). Clinical and prognostic significance of coagulation assays in lung cancer. Respiratory Medicine, 107(3), 451–457.PubMedGoogle Scholar
  11. 11.
    Hoffman, M., & Monroe, D. M., III. (2001). A cell-based model of haemostasis. Thrombosis and Haemostasis, 85(6), 958–965.PubMedGoogle Scholar
  12. 12.
    Monroe, D. M., & Hoffman, M. (2006). What does it take to make the perfect clot? Arteriosclerosis, Thrombosis, and Vascular Biology, 26(1), 41–48.PubMedGoogle Scholar
  13. 13.
    Strukova, S. (2006). Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Frontiers in Bioscience, 11, 59–80.PubMedGoogle Scholar
  14. 14.
    Mackman, N. (2004). Role of tissue factor in hemostasis, thrombosis, and vascular development. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(10), 1015–1022.PubMedGoogle Scholar
  15. 15.
    Gordon, S. G., & Cross, B. A. (1981). A factor X-activating cysteine protease from malignant tissue. The Journal of Clinical Investigation, 67(6), 1665–1671.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Kasthuri, R. S., Taubman, M. B., & Mackman, N. (2009). Role of tissue factor in cancer. Journal of Clinical Oncology, 27(29), 4834–4838.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Gay, L. J., & Felding-Habermann, B. (2011). Contribution of platelets to tumour metastasis. Nature Reviews. Cancer, 11(2), 123–134.PubMedGoogle Scholar
  18. 18.
    Wahrenbrock, M., Borsig, L., Le, D., Varki, N., & Varki, A. (2003). Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. The Journal of Clinical Investigation, 112(6), 853–862.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Bogdanov, V. Y., Balasubramanian, V., Hathcock, J., Vele, O., Lieb, M., & Nemerson, Y. (2003). Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nature Medicine, 9(4), 458–462.PubMedGoogle Scholar
  20. 20.
    Dvorak, H. F., Van DeWater, L., Bitzer, A. M., Dvorak, A. M., Anderson, D., Harvey, V. S., et al. (1983). Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Research, 43(9), 4434–4442.PubMedGoogle Scholar
  21. 21.
    Yu, J. L., & Rak, J. W. (2004). Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released form human cancer cells. Journal of Thrombosis and Haemostasis, 2(11), 2065–2067.PubMedGoogle Scholar
  22. 22.
    Censarek, P., Bobbe, A., Grandoch, M., Schror, K., & Weber, A. A. (2007). Alternatively spliced human tissue factor (asHTF) is not procoagulant. Thrombosis and Haemostasis, 97(1), 11–14.PubMedGoogle Scholar
  23. 23.
    Davila, M., Amirkhosravi, A., Coll, E., Desai, H., Robles, L., Colon, J., et al. (2008). Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. Journal of Thrombosis and Haemostasis, 6(9), 1517–1524.PubMedGoogle Scholar
  24. 24.
    Del Conde, I., Bharwani, L. D., Dietzen, D. J., Pendurthi, U., Thiagarajan, P., & López, J. A. (2007). Microvesicle-associated tissue factor and Trousseaus syndrome. Journal of Thrombosis and Haemostasis, 5(1), 70–74.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Tesselaar, M. E., Romijn, F. P., Van Der Linden, I. K., Prins, F. A., Bertina, R. M., & Osanto, S. (2007). Microparticles-associated tissue factor activity: a link between cancer and thrombosis? Journal of Thrombosis and Haemostasis, 5(3), 520–527.PubMedGoogle Scholar
  26. 26.
    Tesselaar, M. E., & Osanto, S. (2007). Risk of venous thromboembolism in lung cancer. Current Opinion in Pulmonary Medicine, 13(5), 362–367.PubMedGoogle Scholar
  27. 27.
    de Meis, E., Azambuja, D., Ayres-Silva, J. P., Zamboni, M., Pinheiro, V. R., Levy, R. A., et al. (2010). Increased expression of tissue factor and protease-activated receptor-1 does not correlate with thrombosis in human lung adenocarcinoma. Brazilian Journal of Medical and Biological Research, 43(4), 403–408.PubMedGoogle Scholar
  28. 28.
    Milsom, C., Anderson, G. M., Weitz, J. I., & Rak, J. (2007). Elevated tissue factor procoagulant activity in CD133-positive cancer cells. Journal of Thrombosis and Haemostasis, 5(12), 2550–2552.PubMedGoogle Scholar
  29. 29.
    Falati, S., Liu, Q., Gross, P., Merrill-Skoloff, G., Chou, J., Vandendries, E., et al. (2003). Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. Experimental Medicine, 197(11), 1585–1598.Google Scholar
  30. 30.
    Furie, B., & Furie, B. C. (2004). Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends in Molecular Medicine, 10(4), 171–178.PubMedGoogle Scholar
  31. 31.
    Langer, F., & Bokemeyer, C. (2012). Crosstalk between cancer and haemostasis. Implications for cancer biology and cancer-associated thrombosis with focus on tissue factor. Hamostaseologie, 32(2), 95–104.PubMedGoogle Scholar
  32. 32.
    Panes, O., Matus, V., Saez, C. G., Quiroga, T., Pereira, J., & Mezzano, D. (2007). Human platelets synthesize and express functional tissue factor. Blood, 109(12), 5242–5250.PubMedGoogle Scholar
  33. 33.
    Läubli, H., & Borsig, L. (2010). Selectins promote tumor metastasis. Seminars in Cancer Biology, 20(3), 169–177.PubMedGoogle Scholar
  34. 34.
    Läubli, H., & Borsig, L. (2010). Selectins as mediators of lung metastasis. Cancer Microenvironment, 3(1), 97–105.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Gasic, G. J., Tuszynski, G. P., & Gorelik, E. (1986). Interaction of the hemostatic and immune systems in the metastatic spread of tumor cells. International Review of Experimental Pathology, 29, 173–212.PubMedGoogle Scholar
  36. 36.
    Deryugina, E. I., & Quigley, J. P. (2012). Cell surface remodeling by plasmin: a new function for an old enzyme. Journal of Biomedicine and Biotechnology, 2012, 564259.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Foekens, J. A., Peters, H. A., Look, M. P., van Putten, W. L., Portengen, H., & Klijn, J. G. (2000). The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Research, 60(3), 636–643.PubMedGoogle Scholar
  38. 38.
    Castello, R., Landete, J. M., Espana, F., Vázquez, C., Fuster, C., Almenar, S. M., et al. (2007). Expression of plasminogen activator inhibitors type 1 and type 3 and urokinase plasminogen activator protein and mRNA in breast cancer. Thrombosis Research, 120(5), 753–762.PubMedGoogle Scholar
  39. 39.
    Meo, S., Dittadi, R., Peloso, L., & Gion, M. (2004). The prognostic value of vascular endothelial growth factor, urokinase plasminogen activator and plasminogen activator inhibitor-1 in node-negative breast cancer. The International Journal of Biological Markers, 19(4), 282–288.PubMedGoogle Scholar
  40. 40.
    Kuhn, W., Schmalfeldt, B., Reuning, U., Pache, L., Berger, U., Ulm, K., et al. (1999). Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIC. British Journal of Cancer, 79(11–12), 1746–1751.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Nielsen, H. J., Christensen, I. J., Sørensen, S., Moesgaard, F., & Brünner, N. (2000). Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer. The RANX05 Colorectal Cancer Study Group. Annals of Surgical Oncology, 7(8), 617–623.PubMedGoogle Scholar
  42. 42.
    Harbeck, N., Alt, U., Berger, U., Kates, R., Krüger, A., Thomssen, C., et al. (2000). Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer. The International Journal of Biological Markers, 15(1), 79–83.PubMedGoogle Scholar
  43. 43.
    Palmirotta, R., Ferroni, P., Savonarola, A., Martini, F., Ciatti, F., Laudisi, A., et al. (2009). Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer. Thrombosis Research, 124(4), 403–408.PubMedGoogle Scholar
  44. 44.
    Gasic, G. J., Gasic, T. B., & Stewart, C. C. (1968). Antimetastatic effects associated with platelet reduction. Proceedings of the National Academy of Sciences of the United States of America, 61(1), 46–50.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Gasic, G. J., Gasic, T. B., Galanti, N., Johnson, T., & Murphy, S. (1973). Platelet-tumor cell interactions in mice: the role of platelets in the spread of malignant disease. International Journal of Cancer, 11(3), 704–718.Google Scholar
  46. 46.
    Slupsky, J. R., Kalbas, M., Willuweit, A., Henn, V., Kroczek, R. A., & Muller-Berghaus, G. (1998). Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thrombosis and Haemostasis, 80(6), 1008–1014.PubMedGoogle Scholar
  47. 47.
    Honn, K. V., Tang, D. G., & Chen, Y. Q. (1992). Platelets and cancer metastasis: more than an epiphenomenon. Seminars Thrombosis Haemostasis, 18(4), 390–413.Google Scholar
  48. 48.
    Rickles, F. R., Levine, M. N., & Dvorak, H. F. (2001). Abnormalities of hemostasis in malignancy. In R. W. Colman, J. Hirsh, V. J. Marder, A. W. Clowes, & J. N. George (Eds.), Hemostasis and thrombosis. Basic principles and clinical practice (pp. 1131–1152). Philadelphia: Lippincott Williams & Wilkins.Google Scholar
  49. 49.
    Bastida, E., Ordinas, A., & Jamieson, G. A. (1981). Differing platelet aggregating effects by two tumor cell lines: absence of role for platelet-derived ADP. American Journal of Hematology, 11(4), 367–378.PubMedGoogle Scholar
  50. 50.
    Jurasz, P., Alonso-Escolano, D., & Radomski, M. W. (2004). Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. British Journal of Pharmacology, 143(7), 819–826.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Sakurai, T., & Kudo, M. (2011). Signaling pathways governing tumor angiogenesis. Oncology, 81(Suppl 1), 24–29.PubMedGoogle Scholar
  52. 52.
    Shibuya, M. (2013). Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. Journal of Biochemistry, 153(1), 13–19.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Kopp, H. G., Placke, T., & Salih, H. R. (2009). Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Research, 69(19), 7775–7783.PubMedGoogle Scholar
  54. 54.
    Sawicki, G., Salas, E., Murat, J., Miszta-Lane, H., & Radomski, M. W. (1997). Release of gelatinase A during platelet activation mediates aggregation. Nature, 386(6625), 616–619.PubMedGoogle Scholar
  55. 55.
    Menashi, S., He, L., Soria, C., Soria, J., Thomaidis, A., & Legrand, Y. (1991). Modulation of endothelial cells fibrinolytic activity by platelets. Thrombosis and Haemostasis, 65(1), 77–81.PubMedGoogle Scholar
  56. 56.
    Huang, S., van Arsdall, M., Tedjarati, S., McCarty, M., Wu, W., Langley, R., et al. (2002). Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. Journal of the National Cancer Institute, 94(15), 1134–1142.PubMedGoogle Scholar
  57. 57.
    Nalla, A. K., Gorantla, B., Gondi, C. S., Lakka, S. S., & Rao, J. S. (2010). Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells. Cancer Gene Therapy, 17(9), 599–613.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Dilly, A. K., Ekambaram, P., Guo, Y., Cai, Y., Tucker, S. C., Fridman, R., et al. (2013). Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K/Akt/NF-κB. International Journal of Cancer, 133(8), 1784–1791.Google Scholar
  59. 59.
    Ferroni, P., Vazzana, N., Riondino, S., Cuccurullo, C., Guadagni, F., & Davì, G. (2012). Platelet function in health and disease: from molecular mechanisms, redox considerations to novel therapeutic opportunities. Antioxidants and Redox Signaling, 17(10), 1447–1485.PubMedGoogle Scholar
  60. 60.
    Giannarelli, C., Zafar, M. U., & Badimon, J. J. (2010). Prostanoid and TP-receptors in atherothrombosis: is there a role for their antagonism? Thrombosis and Haemostasis, 104(5), 949–954.PubMedGoogle Scholar
  61. 61.
    Honn, K. V., Bockman, R. S., & Marnett, L. J. (1981). Prostaglandins and cancer: a review of tumor initiation through tumor metastasis. Prostaglandins, 21(5), 833–864.PubMedGoogle Scholar
  62. 62.
    Honn, K. V., Busse, W. D., & Sloane, B. F. (1983). Prostacyclin and thromboxanes. Implications for their role in tumor cell metastasis. Biochemistry and Pharmacology, 32(1), 1–11.Google Scholar
  63. 63.
    Nie, D., & Honn, K. V. (2002). Cyclooxygenase, lipoxygenase and tumor angiogenesis. Cell Mole Life Science, 59(5), 799–807.Google Scholar
  64. 64.
    Ermert, L., Dierkes, C., & Ermert, M. (2003). Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clinical Cancer Research, 9(5), 1604–1610.PubMedGoogle Scholar
  65. 65.
    Kreutzer, M., Fauti, T., Kaddatz, K., Seifart, C., Neubauer, A., Schweer, H., et al. (2007). Specific components of prostanoids signaling pathways are present in non-small cell lung cancer cells. Oncology Reports, 18(2), 497–501.PubMedGoogle Scholar
  66. 66.
    Yoshimoto, A., Kasahara, K., Kawashima, A., Fujimura, M., & Nakao, S. (2005). Characterization of the prostaglandin biosynthetic pathway in non-small cell lung cancer: a comparison with small-cell lung cancer and correlation with angiogenesis, angiogenic factors and metastases. Oncology Reports, 13(6), 1049–1057.PubMedGoogle Scholar
  67. 67.
    Cathcart, M. C., Gately, K., Cummins, R., Kay, E., O'Byrne, K. J., & Pidgeon, G. P. (2011). Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer. Molecular Cancer, 10, 25.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Li, Y., Miao, L. Y., Xiao, Y. L., Cai, H. R., & Zhang, D. P. (2014). Elevated platelets enhance cancer cell migration, promote hematogenous metastasis and associate with a poor prognosis in advanced non-small cell lung cancer cases. Asian Pacific Journal of Cancer Prevention, 15(1), 139–143.PubMedGoogle Scholar
  69. 69.
    Costantini, V., Zacharski, L. R., Moritz, T. E., & Edwards, R. L. (1990). The platelet count in carcinoma of the lung and colon. Thrombosis and Haemostasis, 64(4), 501–505.PubMedGoogle Scholar
  70. 70.
    Pedersen, L. M., & Milman, N. (1996). Prognostic significance of thrombocytosis in patients with primary lung cancer. The European Respiratory Journal, 9(9), 1826–1830.PubMedGoogle Scholar
  71. 71.
    Engan, T., & Hannisdal, E. (1990). Blood analyses as prognostic factors in primary lung cancer. Acta Oncologica, 29(2), 151–154.PubMedGoogle Scholar
  72. 72.
    Tomita, M., Shimizu, T., Hara, M., Ayabe, T., & Onitsuka, T. (2008). Prognostic impact of thrombocytosis in resectable non-small cell lung cancer. Interactive Cardiovascular and Thoracic Surgery, 7(4), 613–615.PubMedGoogle Scholar
  73. 73.
    Yu, D., Liu, B., Zhang, L., & Du, K. (2013). Platelet count predicts prognosis in operable non-small cell lung cancer. Experiment Ther Medicine, 5(5), 1351–1354.Google Scholar
  74. 74.
    Inagaki, N., Kibata, K., Tamaki, T., Shimizu, T., & Nomura, S. (2014). Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer. Lung Cancer, 83(1), 97–101.PubMedGoogle Scholar
  75. 75.
    Milroy, R., Douglas, J. T., Campbell, J., Carter, R., Lowe, G. D., & Banham, S. W. (1988). Abnormal haemostasis in small cell lung cancer. Thorax, 43(12), 978–981.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Jain, R., Tabor, D. C., & Engle, J. C. (1983). Plasma beta-thromboglobulin levels in lung cancer. Southern Medical Journal, 76(11), 1380–1382.PubMedGoogle Scholar
  77. 77.
    Prisco, D., Paniccia, R., Coppo, M., Filippini, M., Francalanci, I., Brunelli, T., et al. (1995). Platelet activation and platelet lipid composition in pulmonary cancer. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 53(1), 65–68.PubMedGoogle Scholar
  78. 78.
    Roselli, M., Mineo, T. C., Martini, F., Mariotti, S., Ambrogi, V., Spila, A., et al. (2002). Serum concentrations of soluble selectins in patients with lung cancer. The International Journal of Biological Markers, 17(1), 56–62.PubMedGoogle Scholar
  79. 79.
    Roselli, M., Mineo, T. C., Basili, S., Mariotti, S., Martini, F., Bellotti, A., et al. (2003). Vascular endothelial growth factor (VEGF-A) plasma levels in non-small cell lung cancer: relationship with coagulation and platelet activation markers. Thrombosis and Haemostasis, 89(1), 177–184.PubMedGoogle Scholar
  80. 80.
    Roselli, M., Mineo, T. C., Basili, S., Martini, F., Mariotti, S., Aloe, S., et al. (2004). Soluble CD40 ligand plasma levels in lung cancer. Clinical Cancer Research, 10(2), 610–614.PubMedGoogle Scholar
  81. 81.
    Amirkhosravi, A., Mousa, S. A., Amaya, M., Blaydes, S., Desai, H., Meyer, T., et al. (2003). Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thrombosis and Haemostasis, 90(3), 549–554.PubMedGoogle Scholar
  82. 82.
    Ferroni, P., Santilli, F., Guadagni, F., Basili, S., & Davì, G. (2007). Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis. Current Medicinal Chemistry, 14(20), 2170–2180.PubMedGoogle Scholar
  83. 83.
    Sabel, M. S., Yamada, M., Kawaguchi, Y., Chen, F. A., Takita, H., & Bankert, R. B. (2000). CD40 expression on human lung cancer correlates with metastatic spread. Cancer Immunology, Immunotherapy, 49(2), 101–108.PubMedGoogle Scholar
  84. 84.
    Rickles, F. R., Levine, M., & Edwards, R. L. (1992). Hemostatic alterations in cancer patients. Cancer and Metastasis Reviews, 11(3–4), 237–248.PubMedGoogle Scholar
  85. 85.
    Lyman, G. H., Khorana, A. A., Kuderer, N. M., Lee, A. Y., Arcelus, J. I., Balaban, E. P., et al. (2013). Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology, 31(17), 2189–2204.PubMedGoogle Scholar
  86. 86.
    Gao, S., & Escalante, C. (2004). Venous thromboembolism and malignancy. Expert Review of Anticancer Therapy, 4(2), 303–320.PubMedGoogle Scholar
  87. 87.
    Paskauskas, S., Pundzius, J., & Barauskas, G. (2008). Venous thromboembolism and prophylaxis in cancer patients. Medicina (Kaunas, Lithuania), 44(3), 175–181.Google Scholar
  88. 88.
    Lyman, G. H., & Khorana, A. A. (2009). Cancer, clots and consensus: new understanding of an old problem. Journal of Clinical Oncology, 27(29), 4821–4846.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Khorana, A. A., Francis, C. W., Culakova, E., Kuderer, N. M., & Lyman, G. H. (2007). Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. Journal of Thrombosis and Haemostasis, 5(3), 632–634.PubMedGoogle Scholar
  90. 90.
    Kalweit, G., Huwer, H., Volkmer, I., Petzold, T., & Gams, E. (1996). Pulmonary embolism: a frequent cause of acute fatality after lung resection. European Journal of Cardio-Thoracic Surgery, 10(4), 242–246.PubMedGoogle Scholar
  91. 91.
    Chuang, Y. M., & Yu, C. J. (2009). Clinical characteristics and outcomes of lung cancer with pulmonary embolism. Oncology, 77(2), 100–106.PubMedGoogle Scholar
  92. 92.
    Mason, D. P., Quader, M. A., Blackstone, E. H., Rajeswaran, J., DeCamp, M. M., Murthy, S. C., et al. (2006). Thromboembolism after pneumonectomy for malignancy: an independent marker of poor outcome. The Journal of Thoracic and Cardiovascular Surgery, 131(3), 711–718.PubMedGoogle Scholar
  93. 93.
    Hicks, L. K., Cheung, M. C., Ding, K., Hasan, B., Seymour, L., Le Maître, A., et al. (2009). Venous thromboembolism and nonsmall cell lung cancer: a pooled analysis of National Cancer Institute of Canada Clinical Trials Group trials. Cancer, 115(23), 5516–5525.PubMedGoogle Scholar
  94. 94.
    Chew, H. K., Davies, A. M., Wun, T., Harvey, D., Zhou, H., & White, R. H. (2008). The incidence of venous thromboembolism among patients with primary lung cancer. Journal of Thrombosis and Haemostasis, 6(4), 601–608.PubMedGoogle Scholar
  95. 95.
    Khorana, A. A., Francis, C. W., Culakova, E., Kuderer, N. M., & Lyman, G. H. (2007). Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer, 110(10), 2339–2346.PubMedGoogle Scholar
  96. 96.
    Lee, A.Y., Levine, M.N., Baker, R.I., Bowden, C., Kakkar, A.K., Prins, M., et al. Randomized comparison of low-molecular-weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer (CLOT) investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. New England Journal of Medicine, 349(2), 146–153.Google Scholar
  97. 97.
    Chew, H. K., Wun, T., Harvey, D., Zhou, H., & White, R. H. (2006). Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Archives of Internal Medicine, 166(4), 458–464.PubMedGoogle Scholar
  98. 98.
    Connolly, G. C., Dalal, M., Lin, J., & Khorana, A. A. (2012). Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer. Lung Cancer, 78(3), 253–258.PubMedGoogle Scholar
  99. 99.
    Bohlius, J., Wilson, J., Seidenfeld, J., Piper, M., Schwarzer, G., Sandercock, J., et al. (2006). Erythropoietin or darbepoetin for patients with cancer. Cochrane Database System Review, 3, CD003407Google Scholar
  100. 100.
    Connolly, G. C., Menapace, L., Safadjou, S., Francis, C. W., & Khorana, A. A. (2013). Prevalence and clinical significance of incidental and clinically suspected venous thromboembolism in lung cancer patients. Clinical Lung Cancer, 14(6), 713–718.PubMedGoogle Scholar
  101. 101.
    Blom, W., Doggen, C. J., Osanto, S., & Rosendaal, F. (2005). Malignancies prothrombotic mutations, and the risk of venous thrombosis. JAMA, 293(6), 715–722.PubMedGoogle Scholar
  102. 102.
    Hansson, P. O., Welin, L., Tibblin, G., & Eriksson, H. (1997). Deep vein thrombosis and pulmonary embolism in the general population.’The study of men born in 1913’. Archives of Internal Medicine, 157(15), 1665–1670.PubMedGoogle Scholar
  103. 103.
    White, R. H. (2003). The epidemiology of venous thromboembolism. Circulation, 107(23 Suppl 1), 14–18.Google Scholar
  104. 104.
    Pal, S. K., Katheria, V., & Hurria, A. (2010). Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. CA: A Cancer Journal for Clinicians, 60(2), 120–132.Google Scholar
  105. 105.
    Hamilton, P. J., Allardyce, M., Ogston, D., Dawson, A. A., & Douglas, A. S. (1974). The effect of age upon the coagulation system. Journal of Clinical Pathology, 27(12), 980–982.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Ferroni, P., Della-Morte, D., Palmirotta, R., McClendon, M., Testa, G., Abete, P., et al. (2011). Platinum based compounds and risk for cardiovascular toxicity in the elderly: role of the antioxidants in chemoprevention. Rejuvenation Research, 14(3), 293–308.PubMedGoogle Scholar
  107. 107.
    Roselli, M., Guadagni, F., & Ferroni, P. (2013). Aging: an important risk factor in chemotherapy-associated vascular diseases. Expert Review of Anticancer Therapy, 13(8), 899–901.PubMedGoogle Scholar
  108. 108.
    Horowitz, N., & Brenner, B. (2008). Thrombophilia and cancer. Pathophysiology of Haemostasis and Thrombosis, 36(3–4), 131–136.PubMedGoogle Scholar
  109. 109.
    Anderson, J. A., & Weitz, J. I. (2011). Hypercoagulable states. Critical Care Clinics, 27(4), 933–952.PubMedGoogle Scholar
  110. 110.
    Loreto, M. F., De Martinis, M., Corsi, M. P., Modesti, M., & Ginaldi, L. (2000). Coagulation and cancer: implications for diagnosis and management. Pathology and Oncology Research, 6(4), 301–312.PubMedGoogle Scholar
  111. 111.
    Blom, J. W., Osanto, S., & Rosendaal, F. R. (2004). The risk of a venous thrombotic event in lung cancer patients: higher risk for adenocarcinoma than squamous cell carcinoma. Journal of Thrombosis and Haemostasis, 2(10), 1760–1765.PubMedGoogle Scholar
  112. 112.
    Shoji, M., Hancock, W. W., Abe, K., Micko, C., Camper, K. A., Baine, R. M., et al. (1998). Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. The American Journal of Pathology, 152(2), 399–411.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Bick, R. L. (2003). Cancer-associated thrombosis. The New England Journal of Medicine, 349(2), 109–111.PubMedGoogle Scholar
  114. 114.
    Piccioli, A., & Prandoni, P. (2001). Idiopathic venous thromboembolism as a manifestation of cancer. Haemostasis, 31(Suppl 1), 37–39.PubMedGoogle Scholar
  115. 115.
    Prins, M. H., Hettiarachchi, R. J., Lensing, A. W., & Hirsh, J. (1997). Newly diagnosed malignancy in patients with venous thromboembolism. Search or wait and see? Thromb Haemost, 78(1), 121–125.PubMedGoogle Scholar
  116. 116.
    Prandoni, P., Lensing, A. W., Büller, H. R., Cogo, A., Prins, M. H., Cattelan, A. M., et al. (1992). Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. The New England Journal of Medicine, 327(16), 1128–1133.PubMedGoogle Scholar
  117. 117.
    Bura, A., Cailleux, N., Bienvenu, B., Léger, P., Bissery, A., Boccalon, H., et al. (2002). Incidence and prognosis of cancer associated with bilateral venous thrombosis: a prospective study of 103 patients. Journal of Thromboxane Hemostasis, 2(3), 441–444.Google Scholar
  118. 118.
    Sørensen, H. T., Mellemkjaer, L., Steffensen, F. H., Olsen, J. H., & Nielsen, G. L. (1998). The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. The New England Journal of Medicine, 338(17), 1169–1173.PubMedGoogle Scholar
  119. 119.
    Huang, H., Korn, J. R., Mallick, R., Friedman, M., Nichols, C., & Menzin, J. (2012). Incidence of venous thromboembolism among chemotherapy-treated patients with lung cancer and its association with mortality: a retrospective database study. Journal of Thrombosis and Thrombolysis, 34(4), 446–456.PubMedGoogle Scholar
  120. 120.
    Sørensen, H. T., Mellemkjær, L., Olsen, J. H., & Baron, J. A. (2000). Prognosis of cancers associated with venous thromboembolism. The New England Journal of Medicine, 343(25), 1846–1850.PubMedGoogle Scholar
  121. 121.
    Moore, R. A., Adel, N., Riedel, E., Bhutani, M., Feldman, D. R., Tabbara, N. E., et al. (2011). High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. Journal of Clinical Oncology, 29(25), 3466–3473.PubMedGoogle Scholar
  122. 122.
    Rajeswaran, A., Trojan, A., Burnand, B., & Giannelli, M. (2008). Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer, 59(1), 1–11.PubMedGoogle Scholar
  123. 123.
    Azzoli, C. G., Baker, S., Temin, S., Pao, W., Aliff, T., Brahmer, J., et al. (2011). 2011 focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. Journal of Clinical Oncology, 29(28), 3825–3831.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Lyman, G. H., Eckert, L., Wang, Y., Wang, H., & Cohen, A. (2013). Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. The Oncologist, 18(12), 1321–1329.PubMedGoogle Scholar
  125. 125.
    Agnelli, G., Gussoni, G., Bianchini, C., Verso, M., Mandalà, M., Cavanna, L., et al. (2009). Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. The Lancet Oncology, 10(10), 943–949.PubMedGoogle Scholar
  126. 126.
    Agnelli, G., George, D. J., Kakkar, A. K., Fisher, W., Lassen, M. R., Mismetti, P., et al. (2012). Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. The New England Journal of Medicine, 366(7), 601–609.PubMedGoogle Scholar
  127. 127.
    den Exter, P. L., Hooijer, J., Dekkers, O. M., & Huisman, M. V. (2011). Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. Journal of Clinical Oncology, 29(17), 2405–2409.Google Scholar
  128. 128.
    Shinagare, A. B., Okajima, Y., Oxnard, G. R., Dipiro, P. J., Johnson, B. E., Hatabu, H., et al. (2012). Unsuspected pulmonary embolism in lung cancer patients: comparison of clinical characteristics and outcome with suspected pulmonary embolism. Lung Cancer, 78(2), 161–166.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Ferroni, P., Formica, V., Roselli, M., & Guadagni, F. (2010). Thromboembolic events in patients treated with anti-angiogenic drugs. Current Vascular Pharmacology, 8(1), 102–113.PubMedGoogle Scholar
  130. 130.
    Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., et al. (2006). Paclitaxel- carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England Journal of Medicine, 355(24), 2542–2550.PubMedGoogle Scholar
  131. 131.
    Cohen, M. H., Gootenberg, J., Keegan, P., & Pazdur, R. (2007). FDA drug approval summary: bevacizumab (Avastin®) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. The Oncologist, 12(6), 713–718.PubMedGoogle Scholar
  132. 132.
    Johnson, D. H., Fehrenbacher, L., Novotny, W. F., Herbst, R. S., Nemunaitis, J. J., Jablons, D. M., et al. (2004). Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology, 22(11), 2184–2191.PubMedGoogle Scholar
  133. 133.
    Nalluri, S. R., Chu, D., Keresztes, R., Zhu, X., & Wu, S. (2008). Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA, 300(19), 2277–2285.PubMedGoogle Scholar
  134. 134.
    Meyer, T., Robles-Carrillo, L., Robson, T., Langer, F., Desai, H., Davila, M., et al. (2009). Bevacizumab immune complexes activate platelets and induce thrombosis in FcγRIIa transgenic mice. Journal of Thrombosis and Haemostasis, 7(1), 171–181.PubMedGoogle Scholar
  135. 135.
    Khorana, A. A., Francis, C. W., Blumberg, N., Culakova, E., Refaai, M. A., & Lyman, G. H. (2008). Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Archives of Internal Medicine, 168(21), 2377–2381.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Johannesdottir, S. A., Horváth-Puhó, E., Dekkers, O. M., Cannegieter, S. C., Jørgensen, J. O., Ehrenstein, V., et al. (2013). Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA International Medicine, 173(9), 743–752.Google Scholar
  137. 137.
    Vergati, M., Della-Morte, D., Ferroni, P., Cereda, V., Tosetto, L., La Farina, F., et al. (2013). Increased risk of chemotherapy-associated venous thromboembolism in elderly patients with cancer. Rejuvenation Research, 16(3), 224–231.PubMedGoogle Scholar
  138. 138.
    Dutia, M., White, R. H., & Wun, T. (2012). Risk assessment models for cancer-associated venous thromboembolism. Cancer, 118(14), 3468–3476.PubMedGoogle Scholar
  139. 139.
    Kroger, K., Weiland, D., Ose, C., Neumann, N., Weiss, S., Hirsch, C., et al. (2006). Risk factors for venous thromboembolic events in cancer patients. Annals of Oncology, 17(2), 297–303.PubMedGoogle Scholar
  140. 140.
    Clagett, G. P., & Reisch, J. S. (1988). Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Annual Surgery, 208(2), 227–240.Google Scholar
  141. 141.
    Attaran, S., Somov, P., & Awad, W. I. (2010). Randomised high- and low-dose heparin prophylaxis in patients undergoing thoracotomy for benign and malignant disease: effect on thromboelastography. European Journal of Cardio-Thoracic Surgery, 37(6), 1384–1390.PubMedGoogle Scholar
  142. 142.
    Christensen, T. D., Vad, H., Pedersen, S., Hvas, A. M., Wotton, R., Naidu, B., et al. (2014). Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. The Annals of Thoracic Surgery, 97(2), 394–401.PubMedGoogle Scholar
  143. 143.
    Mason, D.P. Comment on: Christensen TD, et al. Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. Annual Thoracic Surgery, 97(2), 401–402.Google Scholar
  144. 144.
    Couban, S., Goodyear, M., Burnell, M., Dolan, S., Wasi, P., Barnes, D., et al. (2005). A randomized double- blind placebo controlled study of low dose warfarin for the prevention thrombosis of symptomatic central venous catheter-associated in patients with cancer. Journal of Clinical Oncology, 23(18), 4063–4069.PubMedGoogle Scholar
  145. 145.
    Heaton, D. C., Han, D. Y., & Inder, A. (2002). Minidose (1 mg) warfarin as prophylaxis for central vein catheter thrombosis. Internal Medicine Journal, 32(3), 84–88.PubMedGoogle Scholar
  146. 146.
    Verso, M., Agnelli, G., Bertoglio, S., Di Somma, F.C., Paoletti, F., Ageno, W., et al. Enoxaparin for the prevention of venous thromboembolism associate with central vein catheter: a double-blind, placebo controlled, randomised study in cancer patients. Journal of Clinical Oncology, 23(18), 4057–4062.Google Scholar
  147. 147.
    Mandalà, M., Falanga, A., & Roila, F. (2011). Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology, 22(suppl 6), 85–92.Google Scholar
  148. 148.
    Streiff, M. B., Bockenstedt, P. L., Cataland, S. R., Chesney, C., Eby, C., Fanikos, J., et al. (2013). Venous thromboembolic disease. Journal of the National Comprehensive Cancer Network, 11(11), 1402–1429.PubMedGoogle Scholar
  149. 149.
    Khorana, A. A. (2013). Venous thromboembolism prevention in cancer outpatients. Journal of the National Comprehensive Cancer Network, 11(11), 1431–1438.PubMedGoogle Scholar
  150. 150.
    Verso, M., Gussoni, G., & Agnelli, G. (2010). Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy: a combined analysis of the PROTECHT and TOPIC-2 studies. Journal of Thrombosis and Haemostasis, 8(7), 1649–1651.PubMedGoogle Scholar
  151. 151.
    Haas, S. K., Freund, M., Heigener, D., Heilmann, L., Kemkes-Matthes, B., von Tempelhoff, G. F., et al. (2012). Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clinical and Applied Thrombosis/Hemostasis, 18(2), 159–165.PubMedGoogle Scholar
  152. 152.
    Guyatt, G. H., Akl, E. A., Crowther, M., Gutterman, D. D., Schuünemann, H. J., & American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. (2012). Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2 suppl), 7S–47S.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Farge, D., Debourdeau, P., Beckers, M., Baglin, C., Bauersachs, R. M., Brenner, B., et al. (2013). International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Journal of Thrombosis and Haemostasis, 11(1), 56–70.PubMedGoogle Scholar
  154. 154.
    Siragusa, S., Armani, U., Carpenedo, M., Falanga, A., Fulfaro, F., Imberti, D., et al. (2011). Prevention of venous thromboembolism in patients with cancer: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thrombosis Research, 129(5), e171–e176.PubMedGoogle Scholar
  155. 155.
    Zhang, J., Zhang, Y. L., Ma, K. X., & Qu, J. M. (2013). Efficacy and safety of adjunctive anticoagulation in patients with lung cancer without indication for anticoagulants: a systematic review and meta-analysis. Thorax, 68(5), 442–450.PubMedGoogle Scholar
  156. 156.
    Barni, S., Labianca, R., Agnelli, G., Bonizzoni, E., Verso, M., Mandalà, M., et al. (2011). Chemiotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study. Journal of Translational Medicine, 9, 179.PubMedCentralPubMedGoogle Scholar
  157. 157.
    Zwicker, J. I., Liebman, H. A., Bauer, K. A., Caughey, T., Campigotto, F., Rosovsky, R., et al. (2013). Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). British Journal of Haematology, 160(4), 530–537.PubMedCentralPubMedGoogle Scholar
  158. 158.
    Wharin, C., & Tagalakis, V. (2014). Management of venous thromboembolism in cancer patients and the role of the new oral anticoagulants. Blood Reviews, 28(1), 1–8.PubMedGoogle Scholar
  159. 159.
    Gómez-Outes, A., Suárez-Gea, M. L., Lecumberri, R., Terleira-Fernández, A. I., Vargas-Castrillón, E., & Rocha, E. (2013). Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. Vascular Health and Risk Management, 9, 207–228.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Janus, N., Launay-Vacher, V., Byloos, E., Machiels, J. P., Duck, L., Kerger, J., et al. (2010). Cancer and renal insufficiency results of the BIRMA study. British Journal of Cancer, 103(12), 1815–1821.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Kooiman, J., den Exter, P. L., Cannegieter, S. C., le Cessie, S., del Toro, J., Sahuquillo, J. C., et al. (2013). Impact of chronic kidney disease on the risk of clinical outcomes in patients with cancer-associated venous thromboembolism during anticoagulant treatment. Journal of Thrombosis and Haemostasis, 11(11), 1968–1976.PubMedGoogle Scholar
  162. 162.
    Mahmoodi, B. K., Gansevoort, R. T., Næss, I. A., Lutsey, P. L., Brækkan, S. K., Veeger, N. J., et al. (2012). Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. Circulation, 126(16), 1964–1971.PubMedCentralPubMedGoogle Scholar
  163. 163.
    Prandoni, P., Lensing, A. W., Piccioli, A., Bernardi, E., Simioni, P., Girolami, B., et al. (2002). Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood, 100(10), 3484–3488.PubMedGoogle Scholar
  164. 164.
    Zacharski, L. R., Henderson, W. G., Rickles, F. R., Forman, W. B., Cornell, C. J., Jr., Forcier, R. J., et al. (1984). Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: final report of VA Cooperative Study #75. Cancer, 53(10), 2046–2052.PubMedGoogle Scholar
  165. 165.
    Maraveyas, A., Waters, J., Roy, R., Fyfe, D., Propper, D., Lofts, F., et al. (2012). Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. European Journal of Cancer, 48(9), 1283–1292.PubMedGoogle Scholar
  166. 166.
    Pelzer, U., Hilbig, A., Stieler, J. M., Bahra, M., Sinn, M., Gebauer, B., et al. (2014). Intensified chemotherapy and simultaneous treatment with heparin in outpatients with pancreatic cancer—the CONKO 004 pilot trial. BMC Cancer, 14(1), 204.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Warwick, D., Friedman, R. J., Agnelli, G., Gil-Garay, E., Johnson, K., FitzGerald, G., et al. (2007). Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. Journal of Bone and Joint Surgery (British), 89(6), 799–807.Google Scholar
  168. 168.
    Spyropoulos, A. C., Anderson, F. A., Jr., Fitzgerald, G., Decousus, H., Pini, M., Chong, B. H., et al. (2011). Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest, 140(3), 706–714.PubMedGoogle Scholar
  169. 169.
    Akl, E. A., & Schünemann, H. J. (2012). Routine heparin for patients with cancer? One answer, more questions. The New England Journal of Medicine, 366(7), 661–662.PubMedGoogle Scholar
  170. 170.
    Akl, E.A., Labedi, N., Barba, M., Terrenato, I., Sperati, F., Muti, P., et al. (2011). Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database System Review, 6, CD006650.Google Scholar
  171. 171.
    Perry, J. R., Julian, J. A., Laperriere, N. J., Geerts, W., Agnelli, G., Rogers, L. R., et al. (2010). PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. Journal of Thrombosis and Haemostasis, 8(9), 1959–1965.PubMedGoogle Scholar
  172. 172.
    Altinbas, M., Coskun, H. S., Er, O., Ozkan, M., Eser, B., Unal, A., et al. (2004). A randomized clinical trial of combination chemotherapy with and without low molecular-weight heparin in small cell lung cancer. Journal of Thrombosis and Haemostasis, 2(8), 1266–1271.PubMedGoogle Scholar
  173. 173.
    Lebeau, B., Chastang, C., Brechot, J. M., Capron, F., Dautzenberg, B., Delaisements, C., et al. (1994). Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer, 74(1), 38–45.PubMedGoogle Scholar
  174. 174.
    Chahinian, A. P., Propert, K. J., Ware, J. H., Zimmer, B., Perry, M. C., Hirsh, V., et al. (1989). A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. Journal of Clinical Oncology, 7(8), 993–1002.PubMedGoogle Scholar
  175. 175.
    Maurer, L. H., Herndon, J. E., 2nd, Hollis, D. R., Aisner, J., Carey, R. W., Skarin, A. T., et al. (1997). Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. Journal of Clinical Oncology, 15(11), 3378–3387.PubMedGoogle Scholar
  176. 176.
    Robert, F., Busby, E., Marques, M. B., Reynolds, R. E., & Carey, D. E. (2003). Phase II study of docetaxel plus enoxaparin in chemotherapy-naive patients with metastatic non-small cell lung cancer: preliminary results. Lung Cancer, 42(2), 237–245.PubMedGoogle Scholar
  177. 177.
    Lecumberri, R., López Vivanco, G., Font, A., González Billalabeitia, E., Gúrpide, A., Gómez Codina, J., et al. (2013). Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thrombosis Research, 132(6), 666–670.PubMedGoogle Scholar
  178. 178.
    van Doormaal, F. F., Di Nisio, M., Otten, H. M., Richel, D. J., Prins, M., & Buller, H. R. (2011). Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. Journal of Clinical Oncology, 29(15), 2071–2076.PubMedGoogle Scholar
  179. 179.
    Borsig, L. (2010). Heparin as an inhibitor of cancer progression. Progress in Molecular Biology and Translational Science, 93, 335–349.PubMedGoogle Scholar
  180. 180.
    Noble, S. (2012). Low-molecular-weight heparin and survival in lung cancer. Thrombosis Research, 129(Suppl 1), S114–S118.PubMedGoogle Scholar
  181. 181.
    Falanga, A. (2004). The effect of anticoagulant drugs on cancer. Journal of Thrombosis and Haemostasis, 2(8), 1263–1265.PubMedGoogle Scholar
  182. 182.
    Hejna, M., Raderer, M., & Zielinski, C. C. (1999). Inhibition of metastases by anticoagulants. Journal of the National Cancer Institute, 91(1), 22–36.PubMedGoogle Scholar
  183. 183.
    Kuderer, N. M., Khorana, A. A., Lyman, G. H., & Francis, C. W. (2007). A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer, 110(5), 1149–1161.PubMedGoogle Scholar
  184. 184.
    Erpenbeck, L., & Schon, M. P. (2010). Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood, 115(17), 3427–3436.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Caprini, J., Arcelus, J., & Reyna, J. (2001). Effective risk stratification of surgical and nonsurgical patients for venous thromboembolic disease. Seminars in Hematology, 38(2 Suppl 5), 12–19.PubMedGoogle Scholar
  186. 186.
    Khorana, A. A., Kuderer, N. M., Culakova, E., Lyman, G. H., & Francis, C. W. (2008). Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood, 111(10), 4902–4907.PubMedCentralPubMedGoogle Scholar
  187. 187.
    Khorana, A. A., Dalal, M., Lin, J., & Connolly, G. C. (2013). Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer, 119(3), 648–655.PubMedGoogle Scholar
  188. 188.
    Khorana, A. A., O'Connell, C., Agnelli, G., Liebman, H. A., Lee, A. Y., & Subcommittee on Hemostasis and Malignancy of the SSC of the ISTH. (2012). Incidental venous thromboembolism in oncology patients. Journal of Thrombosis and Haemostasis, 10(12), 2602–2604.PubMedCentralPubMedGoogle Scholar
  189. 189.
    Ay, C., Dunkler, D., Marosi, C., Chiriac, A. L., Vormittag, R., Simanek, R., et al. (2010). Prediction of venous thromboembolism in cancer patients. Blood, 116(24), 5377–5382.PubMedGoogle Scholar
  190. 190.
    Ferroni, P., Martini, F., Portarena, I., Grenga, I., Riondino, S., La Farina, F., et al. (2012). Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients-a pilot study. Support Care Cancer, 20(11), 2713–2720.PubMedGoogle Scholar
  191. 191.
    Verso, M., Agnelli, G., Barni, S., Gasparini, G., & Labianca, R. (2012). A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Internal and Emergency Medicine, 7(3), 291–292.PubMedGoogle Scholar
  192. 192.
    Sud, R., & Khorana, A. A. (2009). Cancer-associated thrombosis: risk factors, candidate biomarkers and a risk model. Thrombosis Research, 123(Suppl 4), 18–21.Google Scholar
  193. 193.
    Ay, C., Vormittag, R., Dunkler, D., Simanek, R., Chiriac, A. L., Drach, J., et al. (2009). D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. Journal of Clinical Oncology, 27(25), 4124–4129.PubMedGoogle Scholar
  194. 194.
    Buccheri, G., Torchio, P., & Ferrigno, D. (2003). Plasma levels of D-dimer lung carcinoma. Clinical and prognostic significance. Cancer, 97(12), 3044–3052.PubMedGoogle Scholar
  195. 195.
    Antoniou, D., Pavlakou, G., Stathpoulos, G., Karydis, I., Chondrou, E., Papageorgiou, C., et al. (2006). Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer. Lung Cancer, 53(2), 205–210.PubMedGoogle Scholar
  196. 196.
    Altiay, G., Ciftci, A., Demir, M., Kocak, Z., Sut, N., Tabakoglu, E., et al. (2007). High plasma D-dimer level is associated with decreased survival in patients with lung cancer. Clinical Oncology, 19(7), 494–498.PubMedGoogle Scholar
  197. 197.
    Ay, C., Dunkler, D., Pirker, R., Thaler, J., Quehenberger, P., Wagner, O., et al. (2012). High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica, 97(8), 1158–1164.PubMedCentralPubMedGoogle Scholar
  198. 198.
    Zhang, P. P., Sun, J. W., Wang, X. Y., Liu, X. M., & Li, K. (2013). Preoperative plasma D-dimer levels predict survival in patients with operable non-small cell lung cancer independently of venous thromboembolism. European Journal of Surgical Oncology, 39(9), 951–956.PubMedGoogle Scholar
  199. 199.
    Ferroni, P., Martini, F., Portarena, I., Massimiani, G., Riondino, S., La Farina, F., et al. (2012). Novel high-sensitive D-dimer determination predicts chemotherapy-associated venous thromboembolism in intermediate risk lung cancer patients. Clinical Lung Cancer, 13(6), 482–487.PubMedGoogle Scholar
  200. 200.
    Blann, A. D., Gurney, D., Wadley, M., Bareford, D., Stonelake, P., & Lip, G. Y. (2001). Soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagulation and Fibrinolysis, 12(1), 43–50.PubMedGoogle Scholar
  201. 201.
    Ferroni, P., Roselli, M., Martini, F., D'Alessandro, R., Mariotti, S., Basili, S., et al. (2004). Prognostic value of soluble P-Selectin levels in colorectal cancer. International Journal of Cancer, 111(3), 404–408.Google Scholar
  202. 202.
    Ay, C., Simanek, R., Vormittag, R., Dunkler, D., Alguel, G., Koder, S., et al. (2008). High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood, 112(7), 2703–2708.PubMedGoogle Scholar
  203. 203.
    Sousou, T., & Khorana, A. A. (2009). New insights into cancer-associated thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(3), 316–320.PubMedCentralPubMedGoogle Scholar
  204. 204.
    Ay, C., Dunkler, D., Simanek, R., Thaler, J., Koder, S., Marosi, C., et al. (2011). Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. Journal of Clinical Oncology, 29(15), 2099–2103.PubMedGoogle Scholar
  205. 205.
    van Doormaal, F., Kleinjan, A., Berckmans, R. J., Mackman, N., Manly, D., Kamphuisen, P. W., et al. (2012). Coagulation activation and microparticle-associated coagulant activity in cancer patients. An exploratory prospective study. Thrombosis Haemostasis, 108(1), 160–165.PubMedGoogle Scholar
  206. 206.
    Roselli, M., Ferroni, P., Rolfo, C., Peeters, M., Palmirotta, R., Formica, V., et al. (2013). TNF-alpha gene promoter polymorphisms and risk of venous thromboembolism in cancer patients undergoing chemotherapy. Annals of Oncology, 24(10), 2571–2575.PubMedGoogle Scholar
  207. 207.
    Sallah, S., Husain, A., Sigounas, V., Wan, J., Turturro, F., Sigounas, G., et al. Plasma coagulation markers in patients with solid tumors and venous thromboembolic disease receiving oral anticoagulant therapy. Clinical Cancer Research, 10(21), 7238–7243.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • M. Roselli
    • 1
  • S. Riondino
    • 1
  • S. Mariotti
    • 1
  • F. La Farina
    • 2
    • 3
  • P. Ferroni
    • 2
  • F. Guadagni
    • 2
    • 4
  1. 1.Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical CenterUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Biomarker Discovery and Advanced Biotechnology (BioDAT) LaboratoryIRCCS San Raffaele Pisana, Research CenterRomeItaly
  3. 3.San Raffaele FoundationCeglie Messapica HospitalCeglie MessapicaItaly
  4. 4.InterInstitutional Multidisciplinary Biobank (BioBIM), Biomarker Discovery and Advanced Technologies (BioDAT)SR Research Center–IRCCS San Raffaele PisanaRomeItaly

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