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High coagulation factor VIII and von Willebrand factor in patients with lymphoma and leukemia

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Abstract

The risk of venous thromboembolism is increased in patients with lymphoma and leukemia; however, little is known about the potential underlying hereditary or acquired thrombophilia. We prospectively analyzed procoagulant markers and gene mutations in patients with lymphoma (n = 35) and leukemia (n = 10) at diagnosis and over the course of treatment. Global coagulation tests were normal in all patients, as were antithrombin and protein S. Activated protein C resistance caused by the factor V Leiden mutation was found in four patients, one patient had the G20210A mutation of the prothrombin gene, and one patient had protein C deficiency. The most striking findings were sustained very high levels of factor VIII (>150 %) in 30 patients (68 %), which correlated with high von Willebrand factor. An acute phase response in these patients was ruled out by absence of fever and normal IL-6 and -α. Elevated factor VIII is an independent thrombophilic risk factor and may play an etiologic role in thromboembolic complications in patients with malignant lymphoma. Since high von Willebrand factor is most likely caused by endothelial cell injury, an additional, unknown pathophysiological association with malignant lymphoma and acute leukemia is possible.

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References

  1. Baron J, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer. The Lancet. 1998;351:1077–80.

    Article  CAS  Google Scholar 

  2. Deitcher R. Cancer and thrombosis: mechanism and treatment. J Thromb Thrombolysis. 2003;16:1–31.

    Article  Google Scholar 

  3. Sorensen H, Mellemkjaer L, Flemming H, Olsen J, Nielson G. The risk of a cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;338:1169–73.

    Article  CAS  PubMed  Google Scholar 

  4. Murchison J, Wylie L, Stockton D. Excess risk of cancer in patients with primary venous thromboembolism: a national, population-based cohort study. Br J Cancer. 2004;91:92–5. doi:10.1038/sj.bjc.6601964.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Sorensen H, Mellemkjaer L, Olsen J, Baron J. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343:1846–50.

    Article  CAS  PubMed  Google Scholar 

  6. Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of thromboembolism in patients with malignant lymphoma: a single centre analysis. Brit J Cancer. 2005;92:1349–51.

    Article  CAS  PubMed  Google Scholar 

  7. Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer. 2006;94:200–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Miller C, Dilley A, Drews A, Richardson L, Evatt B. Changes in von Willebrand factor and factor VIII levels during the menstrual cycle. Thromb Haemost. 2002;87:1082–3.

    CAS  PubMed  Google Scholar 

  9. Sanchez-Luceros A, Meschengieser S, Marchese C, Votta R, Woods C, Nadal M, et al. Factor VIII and von Willebrand factor changes during normal pregnancy and puerperium. Blood Coagul Fibrinolysis. 2003;14:647–51.

    Article  CAS  PubMed  Google Scholar 

  10. Catani L, Gugliotta L, Mattioli Belmonte M, Vianelli N, Gherlinzoni M, Belardinelli A, et al. Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematologic malignancies. Bone Marrow Transplant. 1993;12:253–9.

    CAS  PubMed  Google Scholar 

  11. Chojnowski K, Wawrzyniak E, Trelinski J, Niewiarowska J, Ciernie C. Assessment of coagulation disorders in patients with acute leukaemia before and after cytostatic treatment. Leuk Lymphoma. 1999;36:77–84.

    Article  CAS  PubMed  Google Scholar 

  12. Bairey O, Gabbay U, Blickstein D, Stark P, Prokocimer M, Epstein O, et al. Levels of proteins C and S do not decline subsequent to first line chemotherapy in lymphoma patients. Hematol Oncol. 1998;15:121–7.

    Article  Google Scholar 

  13. Notoya A, Sawada K, Leko M, Tarumi T, Koizumi K, Fukada Y, et al. Subclinical alterations in coagulation and fibrinolysis in patients undergoing autologous peripheral blood stem cell transplantation. Leuk Lymphoma. 1998;28:405–13.

    CAS  PubMed  Google Scholar 

  14. van der Meer F, Koster T, Vandenbroucke J, Briet E, Rosendaal F. The Leiden Thrombophilia Study (LETS). Thromb Haemost. 1997;78:631–5.

    PubMed  Google Scholar 

  15. Lindmarker P, Schulman S, Sten-Lindner M, Wiman B, Egberg N, Johnsson H, the DURAC Trial Study Group. The risk of recurrent venous thromboembolism in carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost. 1999;81:684–9.

    CAS  PubMed  Google Scholar 

  16. Poort S, Rosendaal FR, Reitsma P, Bertina R. A common genetic variation In the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–703.

    CAS  PubMed  Google Scholar 

  17. Lane D, Mannucci P, Bauer K, Bertina R, Bochkov N, Boulyjenkov V, et al. Inherited thrombophilia: part 1. Thromb Haemost. 1996;76:651–62.

    CAS  PubMed  Google Scholar 

  18. Genvresse I, Luftner D, Spath-Schwalbe E, Buttgereit F. Prevalence and clinical significance of anticardiolipin and anti-beta-glycoprotein-I antibodies in patients with non-Hodgkin`s lymphoma. Eur J Haematol. 2002;68:84–90.

    Article  CAS  PubMed  Google Scholar 

  19. Tuddenham E. Factor VIII-Novel insights into form and function. Br J Haematol. 2002;119:323–31.

    Article  CAS  PubMed  Google Scholar 

  20. Bhopale G, Nanda R. Blood coagulation factor VIII: an overview. J Biosc. 2003;28:783–9.

    Article  CAS  Google Scholar 

  21. Federici A. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 2003;88(9):3–12.

    Google Scholar 

  22. Kaufmann R, Pipe S. Regulation of F VIII expression and activity by von Willebrand factor. Thromb Haemost. 1999;82:201–8.

    Google Scholar 

  23. Kamphuisen P, Eikenboom J, Rosendaal F, Koster T, Blann A, Vos H, et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol. 2001;115:156–8.

    Article  CAS  PubMed  Google Scholar 

  24. Mansvelt E, Laffan M, McVey J, Tuddenham E. Analysis of the F8 gene in individuals with high plasma factor VIII:c levels and associated venous thrombosis. Thromb Haemost. 1998;80:561–6.

    CAS  PubMed  Google Scholar 

  25. Bowen D, Maclean R, Pellard S, Collins P. High concentrations of coagulation factor VIII and thrombosis: is the factor VIII binding domain of von Willebrand factor implicated? Br J Haematol. 2001;113:655–7.

    Article  CAS  PubMed  Google Scholar 

  26. O`Donnel J, Mumford A, Manning R, Laffan M. Elevation of FVIII:c in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemostasis. 2000;83:10–3.

    Google Scholar 

  27. Kamphuisen P, Eikenboom J, Vos H, Pablo R, Sturk A, Bertina R, et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactants. Thromb Haemost. 1999;81:680–3.

    CAS  PubMed  Google Scholar 

  28. Schambeck S, Grossmann R, Zonnur S, Berger M, Teuchert K, Spahn A, et al. High factor VIII levels in venous thromboembolism: role of unbound FVIII. Thrombosis Haemost. 2004;92:42–6.

    CAS  Google Scholar 

  29. Bombeli T, Jutzi M, De Conno E, Seifert B, Fehr J. In patients with deep-vein thrombosis elevated levels of factor VIII correlate only with von Willebrand factor but not other endothelial cell derived coagulation and fibrinolysis proteins. Blood Coagul Fibrinolysis. 2002;13:577–81.

    Article  CAS  PubMed  Google Scholar 

  30. Mathonnet F, Mazancourt P, Denninger M, Morot M, Benattat N, Giudicelli Y. Role of factor VIII on activated protein C resistance ratio in inflammatory disease. Br J Haematol. 1996;95:423–5.

    Article  CAS  PubMed  Google Scholar 

  31. Kyrle P, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343:457–62.

    Article  CAS  PubMed  Google Scholar 

  32. Kraaijenhagen R, Anker P, Koopman M, Reitsma P, Prins M, van den Ende A, et al. High plasma concentration of factor VIII:c is a major risk factor for venous thromboembolism. Thromb Haemost. 2000;83:5–9.

    CAS  PubMed  Google Scholar 

  33. Legnani C, Benilde C, Michela C, Mirella F, Guazzaloca G, Palareti G. High plasma levels of factor VIII and risk of recurrence of venous thrombo-embolism. Br J Haematol. 2003;124:504–10.

    Google Scholar 

  34. Libourel E, Balje-Volkers C, Harmulyak K, Prins M, Middeldorp S, Büller H, et al. High factor VIII plasma levels as a risk factor for venous thrombosis: no evidence of inheritance from a family cohort study. Haematologica. 2004;89:118–20.

    CAS  PubMed  Google Scholar 

  35. Tsai A, Cushman M, Rosamond W, Heckbert S, Tracy R, Folsom A. Coagulation factors, inflammation markers and venous thromboembolism: the longitudinal investigation of thrombosis etiology. Am J Med. 2002;113:636–42.

    Article  PubMed  Google Scholar 

  36. Minnema M, Fijnheer R, De Groot P, Lokhorst H. Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients is associated with activity status but not with thalidomide treatment. J Thromb Haemost. 2003;1:445–9.

    Article  CAS  PubMed  Google Scholar 

  37. Medinger M, Fischer N, Tzankov A. Vascular endothelial growth factor-related pathways in hemato-lymphoid malignancies. J Oncol. 2010;. doi:10.1155/2010/729725.

    PubMed Central  PubMed  Google Scholar 

  38. Ruan J, Hajjar K, Rafii S, Leonard JP. Angiogenesis and antiangiogenic therapy in non-Hodgkin`s lymphoma. Ann Oncol. 2009;20:413–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ribatti D, Nico B, Ranieri G, Specchia G, Vacca A. The role of angiogenesis in human non-Hodgkin lymphomas. Neoplasia. 2013;15:231–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Hussong JW, Rodgers G, Shami P. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood. 2000;95:309–13.

    CAS  PubMed  Google Scholar 

  41. Negaard HFS, Iversen N, Bowitz-Lothe IM, Sandset PM, Steinsvik B, Ostenstaad B, et al. Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors. Leukemia. 2009;23:162–9.

    Article  CAS  PubMed  Google Scholar 

  42. Hivert B, Caron C, Petit S, Charpy C, Fankam-Siaka C, Zawadzki C. Clinical and prognostic implications of low or high level von Willebrand factor in patients with Waldenström macroglobulinemia. Blood. 2012;120:3214–21.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology/Oncology, Magdeburg University Hospital, Magdeburg, Germany

    Martin Mohren, Kathleen Jentsch-Ullrich, Michael Koenigsmann, Siegfried Kropf, Enrico Schalk & Gerd Lutze

  2. Klinik für Hämatologie/Onkologie, Johanniter-Krankenhaus Stendal, Wendstr. 31, 39576, Stendal, Germany

    Martin Mohren

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  1. Martin Mohren
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Correspondence to Martin Mohren.

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Mohren, M., Jentsch-Ullrich, K., Koenigsmann, M. et al. High coagulation factor VIII and von Willebrand factor in patients with lymphoma and leukemia. Int J Hematol 103, 189–195 (2016). https://doi.org/10.1007/s12185-015-1913-y

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  • DOI: https://doi.org/10.1007/s12185-015-1913-y

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