Skip to main content
SpringerLink
Log in

The impact of JAK2V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia: a meta-analysis

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

To assess the effect of JAK2V617F on different thrombotic risks in essential thrombocythemia (ET) patients, we identified eligible studies from several databases including Pubmed, Embase, and Cochrane Central Register of Controlled Trials (up to November 2014). Twenty-two studies of 2922 ET patients were included in exploring the relationship between JAK2V617F and the risk of thrombosis. Compared to JAK2V617F-negative ET patients, JAK2V617F-positive ET patients had higher odd risks (ORs) of arterial thrombosis [OR = 2.59 (1.84–3.65)] and venous thrombosis [OR = 2.10 (1.53–2.88)]. The JAK2V617F-positive group was also more prone to increased risk of microcirculatory disturbances [OR = 1.50 (0.97–2.32)]. Moreover, JAK2V617F may indicate increased risk of either arterial [OR = 1.71 (1.22–2.39)] or venous thrombosis [OR = 2.90 (1.54–5.46)] before diagnosis of ET. During follow-up, JAK2V617F might not be related to arterial thrombosis [OR = 1.90 (0.90–2.08)], but rather venous thrombosis [OR = 1.95 (1.08–3.53)]. In conclusion, JAK2V617F increased the risk of arterial and venous thrombosis in ET patients, while understanding its role in microcirculatory disturbances will require further studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Hsiao HH, Yang MY, Liu YC, Lee CP, Yang WC, Liu TC, et al. The association of JAK2V617F mutation and leukocytosis with thrombotic events in essential thrombocythemia. Exp Hematol. 2007;35:1704–7.

    Article  CAS  PubMed  Google Scholar 

  3. Lee HS, Park LC, Lee EM, Lee SJ, Shin SH, Im H, et al. Incidence rates and risk factors for vascular events in patients with essential thrombocythemia: a multicenter study from Korea. Clin Lymphoma Myeloma Leuk. 2012;12:70–5.

    Article  PubMed  Google Scholar 

  4. Cetin G, Ozkan T, Turgut S, Ali CM, Cem AM, Ayer M, et al. Evaluation of clinical and laboratory findings with JAK2 V617F mutation as an independent variable in essential thrombocytosis. Mol Biol Rep. 2014;41:6737–42.

    Article  CAS  PubMed  Google Scholar 

  5. Rudzki Z, Sacha T, Stoj A, Czekalska S, Wojcik M, Skotnicki AB, et al. The gain-of-function JAK2 V617F mutation shifts the phenotype of essential thrombocythemia and chronic idiopathic myelofibrosis to more “erythremic” and less “thrombocythemic”: a molecular, histologic, and clinical study. Int J Hematol. 2007;86:130–6.

    Article  CAS  PubMed  Google Scholar 

  6. Alvarez-Larran A, Cervantes F, Bellosillo B, Giralt M, Julia A, Hernandez-Boluda JC, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia. 2007;21:1218–23.

    Article  CAS  PubMed  Google Scholar 

  7. Speletas M, Katodritou E, Daiou C, Mandala E, Papadakis E, Kioumi A, et al. Correlations of JAK2-V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. Leuk Res. 2007;31:1053–62.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang S, Qiu H, Fischer BS, Li W, Duan L, Sun X, et al. JAK2V617F patients with essential thrombocythemia present with clinical features of polycythemia vera. Leuk Lymphoma. 2008;49:696–9.

    Article  CAS  PubMed  Google Scholar 

  9. Palandri F, Ottaviani E, Salmi F, Salmi F, Catani L, Polverelli N, et al. JAK2V617F 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 

  10. Ziakas PD. Effect of JAK2V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain. Haematologica. 2008;93:1412–4.

    Article  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. Murphy S, Peterson P, Iland H, Laszlo J. Experience of the polycythemia vera study group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol. 1997;34:29–39.

    CAS  PubMed  Google Scholar 

  14. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–302.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology/the Education Program of the American Society of Hematology. Am Soc Hematol Educ Program. 2012;2012:571–81.

    Google Scholar 

  17. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non randomised studies in meta-analyses (2015). http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

  18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.

    CAS  PubMed  Google Scholar 

  19. Mantel N. Chi-square tests with one degree of freedom: extensions of the Mantel–Haenszel procedure. J Am Stat Assoc. 1963;58:690–700.

    Google Scholar 

  20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  21. Higgins JPT, Green S. Chapter 9: analysing data and undertaking meta-analyses. Cochrane hand book for systematic reviews of interventions version 5.1.0. 2011.

  22. Tobias A. Assessing the influence of a single study in the meta-analysis estimate. Stata Techn Bull. 1999;8:15–7.

    Google Scholar 

  23. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  24. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61:991–6.

    Article  PubMed  Google Scholar 

  26. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63.

    Article  CAS  PubMed  Google Scholar 

  27. Palmer TM, Peters JL, Sutton AJ, et al. Contour-enhanced funnel plots for meta-analysis. Stata J. 2008;8:242–54.

    Google Scholar 

  28. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005;366:1945–53.

    Article  CAS  PubMed  Google Scholar 

  29. Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol. 2006;132:244–5.

    Article  CAS  PubMed  Google Scholar 

  30. Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica. 2007;92:135–6.

    Article  PubMed  Google Scholar 

  31. Antonioli E, Guglielmelli P, Poli G, Bogani C, Pancrazzi A, Longo G, et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica. 2008;93:41–8.

    Article  CAS  PubMed  Google Scholar 

  32. Larsen TS, Pallisgaard N, Moller MB, Hasselbalch HC. High prevalence of arterial thrombosis in JAK2 mutated essential thrombocythaemia: independence of the V617F allele burden. Hematology. 2008;13:71–6.

    Article  PubMed  Google Scholar 

  33. Moreno MJ, Lozano ML, Roldan V, Bellosillo B, García-Barberá N, Rivera J, et al. JAK2 V617F, hemostatic polymorphisms, and clinical features as risk factors for arterial thrombotic events in essential thrombocythemia. Ann Hematol. 2008;87:763–5.

    Article  PubMed  Google Scholar 

  34. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, Colomer D, Villamor N, Bellosillo B, et al. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol. 2009;84:102–8.

    Article  CAS  PubMed  Google Scholar 

  35. Patriarca A, Pompetti F, Malizia R, Iuliani O, Di Marzio I, Spadano A, et al. Is the absence of JAK2 mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients. Blood Transfus. 2010;8:21–7.

    PubMed Central  PubMed  Google Scholar 

  36. De Stefano V, Rossi E, Za T, Ciminello A, Betti S, Luzzi C, et al. JAK2 V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. Am J Hematol. 2011;86:526–8.

    Article  PubMed  Google Scholar 

  37. Pich A, Riera L, Beggiato E, Nicolino B, Godio L, Campisi P, et al. JAK2V617F mutation and allele burden are associated with distinct clinical and morphological subtypes in patients with essential thrombocythaemia. J Clin Pathol. 2012;65:953–5.

    Article  CAS  PubMed  Google Scholar 

  38. Coucelo M, Caetano G, Sevivas T, Almeida Santos S, Fidalgo T, Bento C, et al. JAK2V617F allele burden is associated with thrombotic mechanisms activation in polycythemia vera and essential thrombocythemia patients. Int J Hematol. 2014;99:32–40.

    Article  CAS  PubMed  Google Scholar 

  39. Ohyashiki K, Ito Y, Hori K, Sato K, Makino T, Ohyashiki JH. Thrombosis can occur at any phase of essential thrombocythemia with JAK2(V617F) mutation: a single institutional study in Japan. Leukemia. 2007;21:1570–1.

    Article  CAS  PubMed  Google Scholar 

  40. Wong RS, Cheng CK, Chan NP, Cheng SH, Wong WS, Lau KM, et al. JAK2 V617F mutation is associated with increased risk of thrombosis in Chinese patients with essential thrombocythaemia. Br J Haematol. 2008;141:902–4.

    Article  PubMed  Google Scholar 

  41. Cho YU, Chi HS, Lee EH, Jang S, Park CJ, Seo EJ. Comparison of clinicopathologic findings according to JAK2 V617F mutation in patients with essential thrombocythemia. Int J Hematol. 2009;89:39–44.

    Article  CAS  PubMed  Google Scholar 

  42. Chim CS, Sim JP, Chan CC, Kho BC, Chan JC, Wong LG, et al. Impact of JAK2V617F mutation on thrombosis and myeloid transformation in essential thrombocythemia: a multivariate analysis by Cox regression in 141 patients. Hematology. 2010;15:187–92.

    Article  CAS  PubMed  Google Scholar 

  43. Takata Y, Seki R, Kanajii T, Nohara M, Koteda S, Kawaguchi K, et al. Association between thromboembolic events and the JAK2 V617F mutation in myeloproliferative neoplasms. Kurume Med J. 2014;60:89–97.

    Article  PubMed  Google Scholar 

  44. Heller PG, Lev PR, Salim JP, Goette NP, Chazarreta CD, Glembotsky AC, et al. JAK2V617F mutation in platelets from essential thrombocythemia patients: correlation with clinical features and analysis of STAT5 phosphorylation status. Eur J Haematol. 2006;77:210–6.

    Article  CAS  PubMed  Google Scholar 

  45. Pemmaraju N, Moliterno AR, Williams DM, Rogers O, Spivak JL. The quantitative JAK2 V617F neutrophil allele burden does not correlate with thrombotic risk in essential thrombocytosis. Leukemia. 2007;21:2210–2.

    Article  CAS  PubMed  Google Scholar 

  46. Basquiera AL, Soria NW, Ryser R, Salguero M, Moiraghi B, Sackmann F, et al. Clinical significance of V617F mutation of the JAK2 gene in patients with chronic myeloproliferative disorders. Hematology. 2009;14:323–30.

    Article  CAS  PubMed  Google Scholar 

  47. Gangat N, Wassie E, Lasho T, Finke C, Ketterling RP, Hanson CA, et al. Mutations and thrombosis in essential thrombocythemia: prognostic interaction with age and thrombosis history. Eur J Haematol. 2015;94(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  48. Stevenson WS, Hoyt R, Bell A, Guipponi M, Juneja S, Grigg AP, et al. Genetic heterogeneity of granulocytes for the JAK2 V617F mutation in essential thrombocythaemia: implications for mutation detection in peripheral blood. Pathology. 2006;38:336–42.

    Article  CAS  PubMed  Google Scholar 

  49. Weston H, Cowell V, Grimmett K, Saal R, Jones M, Mills T, et al. Prognostic utility of spontaneous erythroid colony formation and JAK2 mutational analysis for thrombotic events in essential thrombocythaemia. Intern Med J. 2011;41:408–15.

    Article  CAS  PubMed  Google Scholar 

  50. Tefferi A, Wassie EA, Lasho TL, Finke C, Belachew AA, Ketterling RP, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia. 2014;28:2300–3.

    Article  CAS  PubMed  Google Scholar 

  51. Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117:5857–9.

    Article  CAS  PubMed  Google Scholar 

  52. Montanaro M, Latagliata R, Cedrone M, Spadea A, Rago A, Di Giandomenico J, et al. Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients. Am J Hematol. 2014;89:542–6.

    Article  PubMed  Google Scholar 

  53. Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost. 2013;11:1215–27.

    Article  CAS  PubMed  Google Scholar 

  54. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128–33.

    Article  CAS  PubMed  Google Scholar 

  55. Carobbio A, Antonioli E, Guglielmelli P, Vannucchi AM, Delaini F, Guerini V, et al. Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol. 2008;26(16):2732–6.

    Article  CAS  PubMed  Google Scholar 

  56. Cheng YJ, Liu ZH, Yao FJ, Zeng WT, Zheng DD, Dong YG, et al. Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis. PLoS Med. 2013;10(9):e1001515.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Vaya A, Suescun M. Hemorheological parameters as independent predictors of venous thromboembolism. Clin Hemorheol Microcirc. 2013;53(1–2):131–41.

    PubMed  Google Scholar 

  58. Yang Y, Wang X, Wang C, Qin Y. A meta-analysis comparing clinical characteristics and outcomes in CALR-mutated and JAK2V617F essential thrombocythaemia. Int J Hematol. 2015;101(2):165–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declared that they had no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Hematology, Shanghai Jiao Tong University Affiliated Shanghai General Hospital, No.100 Haining Rd, Shanghai, 200080, People’s Republic of China

    Youwen Qin, Xiaorui Wang, Chuxian Zhao, Chun Wang & Yining Yang

Authors
  1. Youwen Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaorui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuxian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yining Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yining Yang.

Additional information

Y. Qin and X. Wang are the co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 396 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qin, Y., Wang, X., Zhao, C. et al. The impact of JAK2V617F mutation on different types of thrombosis risk in patients with essential thrombocythemia: a meta-analysis. Int J Hematol 102, 170–180 (2015). https://doi.org/10.1007/s12185-015-1808-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1808-y

Keywords

Search

Navigation