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Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers

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Abstract

Angiogenesis plays an important role in the biology of hematological malignancies, including essential thrombocythemia (ET) and polycythemia vera (PV). Some data suggests that it has a role in the pathogenesis of thrombosis, the major clinical problem in ET and PV. The number of different subpopulations of circulating endothelial cells (CECs), plasma levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 1 and 2 (sVEGFR-1,2) and placenta growth factor (PlGF) were determined in 30 patients with ET and 16 patients with PV. Correlations between angiogenesis and JAK2-V617F mutational status, risk factors for thrombosis and coagulation activation markers were also assessed. The number of CEC subpopulations, were markedly higher in ET and PV patients, irrespective of JAK2-V617F status, when compared to the control group. The median values of activated CECs were markedly higher in PV patients with WBC >8.7 (×109/l). Significantly higher VEGF plasma levels were found in ET patients and a similar trend was seen in PV patients in relation to healthy volunteers. The plasma levels of sVEGFR-1 were significantly higher, and PlGF levels markedly lower, in the ET and PV group than in controls. Our study also demonstrated markedly increased levels of D-dimer and TAT complexes in the patient groups. In conclusion, we found that angiogenesis, as measured by CEC numbers, is increased in ET and PV patients regardless of JAK2-V617F mutational status. Our results demonstrated that angiogenic cytokines interact with known thrombotic risk factors. We confirmed the coagulation activation in ET and PV patients but found no differences in levels of coagulation activation markers in relation to JAK2-V617F mutational status.

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References

  1. Alonci A, Allegra A, Bellomo G, Penna G, D’Angelo A, Quartarone E, et al. Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases. Hematol Oncol. 2008;26:235–9.

    Article  CAS  PubMed  Google Scholar 

  2. Medinger M, Skoda R, Gratwohl A, Theocharides A, Buser A, Heim D, et al. Angiogenesis and vascular endothelial growth factor-/receptor expression in myeloproliferative neoplasms: correlation with clinical parameters and JAK2-V617F mutational status. Br J Haematol. 2009;146:150–7.

    Article  CAS  PubMed  Google Scholar 

  3. Musolino C, Calabro’ L, Bellomo G, Martello F, Loteta B, Pezzano C, et al. Soluble angiogenic factors: implications for chronic myeloproliferative disorders. Am J Hematol. 2002;69:159–63.

    Article  CAS  PubMed  Google Scholar 

  4. Panteli K, Bai M, Hatzimichael E, Zagorianakou N, Agnantis NJ, Bourantas K. Serum levels, and bone marrow immunohistochemical expression of, vascular endothelial growth factor in patients with chronic myeloproliferative diseases. Hematology. 2007;12:481–7.

    Article  CAS  PubMed  Google Scholar 

  5. Wierzbowska A, Robak T, Krawczyńska A, Wrzesień-Kuś A, Pluta A, Cebula B, et al. Circulating endothelial cells in patients with acute myeloid leukemia. Eur J Haematol. 2005;75:492–7.

    Article  PubMed  Google Scholar 

  6. Gora-Tybor J, Jamroziak K, Szmigielska-Kaplon A, Krawczynska A, Lech-Maranda E, Wierzbowska A, et al. Evaluation of circulating endothelial cells as noninvasive marker of angiogenesis in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:62–7.

    Article  CAS  PubMed  Google Scholar 

  7. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14–22.

    Article  CAS  PubMed  Google Scholar 

  8. Mesa RA, Hanson CA, Li CY, Yoon SY, Rajkumar SV, Schroeder G, Tefferi A. Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia. Blood. 2002;99:4131–7.

    Article  CAS  PubMed  Google Scholar 

  9. Wróbel T, Mazur G, Surowiak P, Wołowiec D, Jeleń M, Kuliczkowski K. Increased expression of vascular endothelial growth factor (VEGF) in bone marrow of patients with myeloproliferative disorders (MPD). Pathol Oncol Res. 2003;9:170–3.

    Article  PubMed  Google Scholar 

  10. Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 1999;59:728–33.

    CAS  PubMed  Google Scholar 

  11. Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA. 2001;98:10857–62.

    Article  CAS  PubMed  Google Scholar 

  12. Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell’Agnola C, Gobbi A, et al. Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res. 2001;61:4341–4.

    CAS  PubMed  Google Scholar 

  13. Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood. 2001;97:3658–61.

    Article  CAS  PubMed  Google Scholar 

  14. Beerepoot LV, Mehra N, Vermaat JS, Zonnenberg BA, Gebbink MF, Voest EE. Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol. 2004;15:139–45.

    Article  CAS  PubMed  Google Scholar 

  15. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest. 2000;105:71–7.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L, et al. Endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005;105:3286–94.

    Article  CAS  PubMed  Google Scholar 

  17. Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol. 2005;128:275–90.

    Article  CAS  PubMed  Google Scholar 

  18. Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006;81:159–66.

    Article  PubMed  Google Scholar 

  19. Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood. 2007;109:2310–3.

    Article  CAS  PubMed  Google Scholar 

  20. Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110:840–6.

    Article  CAS  PubMed  Google Scholar 

  21. Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V, MPD Research Consortium, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21:1952–9.

    Article  CAS  PubMed  Google Scholar 

  22. Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer. 1998;77:956–64.

    CAS  PubMed  Google Scholar 

  23. Weltermann A, Wolzt M, Petersmann K, Czerni C, Graselli U, Lechner K, et al. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler Thromb Vasc Biol. 1999;19:1757–60.

    CAS  PubMed  Google Scholar 

  24. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.

    CAS  PubMed  Google Scholar 

  25. Cortelezzi A, Fracchiolla NS, Mazzeo LM, Silvestris I, Pomati M, Somalvico F, et al. Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes. Leuk Lymphoma. 2005;46:1345–51.

    Article  CAS  PubMed  Google Scholar 

  26. Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G, et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood. 2006;108:452–9.

    Article  CAS  PubMed  Google Scholar 

  27. Boveri E, Passamonti F, Rumi E, Pietra D, Elena C, Arcaini L, et al. Bone marrow microvessel density in chronic myeloproliferative disorders: a study of 115 patients with clinicopathological and molecular correlations. Br J Haematol. 2008;140:162–8.

    PubMed  Google Scholar 

  28. Falanga A, Marchetti M, Evangelista V, Vignoli A, Licini M, Balicco M, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96:4261–6.

    CAS  PubMed  Google Scholar 

  29. Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk HM, ten Cate H, Leyte A, et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94:911–8.

    Article  CAS  PubMed  Google Scholar 

  30. Treliński J, Tybura M, Smolewski P, Robak T, Chojnowski K. The influence of low-dose aspirin and hydroxyurea on platelet–leukocyte interactions in patients with essential thrombocythemia. Blood Coagul Fibrinolysis. 2009;20:646–51.

    Article  PubMed  Google Scholar 

  31. Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte–platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol. 2005;33:523–30.

    Article  CAS  PubMed  Google Scholar 

  32. Musolino C, Alonci A, Bellomo G, Tringali O, Spatari G, Quartarone C, et al. Myeloproliferative disease: markers of endothelial and platelet status in patients with essential thrombocythemia and polycythemia vera. Hematology. 2000;4:397–402.

    CAS  PubMed  Google Scholar 

  33. Rość D, Kremplewska-Nalezyta E, Gadomska G, Kowalewska A, Buczkowska E. Thrombinogenesis in chronic myeloproliferative syndromes. Pol Merkur Lekarski. 2006;20:717–20.

    PubMed  Google Scholar 

  34. Robertson B, Urquhart C, Ford I, Townend J, Watson HG, Vickers MA, et al. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J Thromb Haemost. 2007;5:1679–85.

    Article  CAS  PubMed  Google Scholar 

  35. Dahabreh IJ, Zoi K, Giannouli S, Zoi C, Loukopoulos D, Voulgarelis M. Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res. 2009;33:67–73.

    Article  CAS  PubMed  Google Scholar 

  36. Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res. 2009;124:409–17.

    Article  CAS  PubMed  Google Scholar 

  37. Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica. 2006;91:169–75.

    CAS  PubMed  Google Scholar 

  38. De Stefano V, Fiorini A, Rossi E, Za T, Farina G, Chiusolo P, Sica S, Leone G. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost. 2007;5:708–14.

    Article  PubMed  Google Scholar 

  39. Carobbio A, Finazzi G, Antonioli E, et al. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol. 2009;37:1016–21.

    Article  CAS  PubMed  Google Scholar 

  40. Palandri F, Ottaviani E, Salmi F, et al. JAK2 V617F mutation in essential thrombocythemia: correlation with clinical characteristics, response to therapy and long-term outcome in a cohort of 275 patients. Leuk Lymphoma. 2009;50:247–53.

    Article  CAS  PubMed  Google Scholar 

  41. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999;77:527–43.

    Article  CAS  PubMed  Google Scholar 

  42. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  CAS  PubMed  Google Scholar 

  43. Cacciola RR, Di Francesco E, Giustolisi R, Cacciola E. Elevated serum vascular endothelial growth factor levels in patients with polycythemia vera and thrombotic complications. Haematologica. 2002;87:774–5.

    CAS  PubMed  Google Scholar 

  44. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7:575–83.

    Article  CAS  PubMed  Google Scholar 

  45. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994;269:25646–54.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grant from Medical University of Łódź No: 503-1093-1.

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Authors and Affiliations

  1. Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Ciolkowskiego 2, 93-510, Lodz, Poland

    Jacek Treliński, Agnieszka Wierzbowska, Anna Krawczyńska, Tadeusz Robak & Krzysztof Chojnowski

  2. Department of Medical Biotechnology, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland

    Agata Sakowicz & Tadeusz Pietrucha

  3. Department of Experimental Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Ciolkowskiego 2, 93-510, Lodz, Poland

    Piotr Smolewski

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  1. Jacek Treliński
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Correspondence to Jacek Treliński.

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Treliński, J., Wierzbowska, A., Krawczyńska, A. et al. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int J Hematol 91, 792–798 (2010). https://doi.org/10.1007/s12185-010-0596-7

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  • DOI: https://doi.org/10.1007/s12185-010-0596-7

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