|Year : 2018 | Volume
| Issue : 3 | Page : 371-374
|Association of JAK2V617F mutation with thrombosis in Indian patients with Philadelphia negative chronic myeloproliferative neoplasms
Kanwaljeet Singh, Sudha Sazawal, Sunita Chhikara, Manoranjan Mahapatra, Renu Saxena
Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
Click here for correspondence address and email
|Date of Web Publication||13-Jul-2018|
| Abstract|| |
Background: It is still a matter of debate regarding the association of JAK2V617F mutation with thrombosis in BCR-ABL negative CMPN patients. The role of JAK2V617F mutation in increasing the thrombotic risk in CMPNs is yet unequivocal. Aims: To clarify the contribution of JAK2V617F mutation in thrombosis in CMPN patients. Settings and Design: This retrospective study was done to evaluate role of JAK2V617F mutation in thrombosis in CMPNs. Materials and Methods: 65 CMPN patients (PV, ET and PMF) were analyzed for JAK2V617F mutation using ARMS-PCR and detailed history of thrombosis was recorded in these patients. Statistical Analysis: P values were 2 tailed, and statistical significance was set at P < 0.05. Results: 46/65 were males and 19/65 were females [M: F: 2.4:1] with median age 46 years [range, 14-80 years]. Patients had median Hb 15.6 g/dl [range, 5.1-20.3], median TLC 10.7 × 109/l [range 2.4-216] and platelet count 360 × 109/l [range, 20-1859]. 32 were JAK2V617F positive and 33 were negative for this mutation. On comparing the prevalence of thrombosis in JAK2V617F positive patients with JAK2V617F negative patients, we observed that 20/32 (62.5%) JAK2V617F positive patients had thrombosis as compared to 16/33 (48%) in JAK2V617F negative patients (P = 0.04). We observed significant association of JAK2V617F mutation with thrombosis, however no association of this mutation with thrombosis was observed among the JAK2V617F negative patients. Conclusion: Our study suggests that JAK2V617F mutation may increase the risk of thrombosis in CMPNs. This finding could lead to risk stratification, setting up the treatment strategy in CMPNs.
Keywords: Chronic myeloproliferative neoplasms, JAK2V617F mutation, thrombosis
|How to cite this article:|
Singh K, Sazawal S, Chhikara S, Mahapatra M, Saxena R. Association of JAK2V617F mutation with thrombosis in Indian patients with Philadelphia negative chronic myeloproliferative neoplasms. Indian J Pathol Microbiol 2018;61:371-4
|How to cite this URL:|
Singh K, Sazawal S, Chhikara S, Mahapatra M, Saxena R. Association of JAK2V617F mutation with thrombosis in Indian patients with Philadelphia negative chronic myeloproliferative neoplasms. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Jul 23];61:371-4. Available from: https://www.ijpmonline.org/text.asp?2018/61/3/371/236630
| Introduction|| |
Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic myeloproliferative neoplasms (CMPN) characterized by clonal proliferation of abnormal hematopoietic stem cells. The understanding of the CMPN pathogenesis significantly improved after the discovery of JAK2V617F mutation in exon 14, which involves 95% of PV and 50% to 60% of ET and PMF patients, respectively., Clinical manifestations of these CMPNs are characterized by thrombotic and hemorrhagic complications and propensity to transform into acute leukemia. Thrombosis remains the leading cause for morbidity and mortality in myeloproliferative disorder representing the initial presentation for 12%–39% of patients subsequently diagnosed with PV and 11%–25% for those given the diagnosis of ET and PMF.
Current management recommendations for these disorders emphasize the importance of prognostic stratification, especially with regard to thrombotic risk, in determining the treatment strategy. Well-described risk factors for thrombosis identified in CMPN patients include increasing age, a prior thrombotic event, raised hematocrit, and in vitro occurrence of spontaneous megakaryocyte colony formation.,,,,, One of the potential novel risk factors for thrombosis which are currently being explored include JAK2V617F mutation. JAK2V617F mutation has been reported to be associated with leukocytosis and platelet activation which may be a possible explanation underlying the increased risk of thrombosis in CMPN patients.,,
There is still a diagnostic dilemma and mixed opinions regarding the associative role of JAK2V617F mutation in increasing the risk of thrombosis in CMPNs.,,,,,,,,
To the best of our knowledge, there is paucity regarding the role of JAK2V617F mutation in augmenting the risk of thrombosis in CMPN patients in India. In view of this, we conducted this study to access the possible role of JAK2V617F mutation in increasing the thrombotic risk in CMPNs.
| Materials and Methods|| |
This is a retrospective study conducted at the All India Institute of Medical Sciences, New Delhi, India, during the year 2014–2016. A total of 65 CMPN patients (PV, PMF, and ET) were available for this study and these patients were diagnosed as per the WHO criteria. Chronic myeloid leukemia cases were excluded from the study. Five milliliter peripheral blood sample was collected in 1.6% ethylenediaminetetraacetic acid solution. DNA was extracted from peripheral blood sample using commercially available DNA extraction kit. All the samples were screened for JAK2V617F mutation using amplification refractory mutational system-polymerase chain reaction, and results were analyzed using 3% agarose gel [Figure 1]. Detailed history of thrombosis was recorded in these patients for correlation with JAK2V617F mutation. Ethical approval for the study protocol was obtained and written informed consent was taken from all patients.
|Figure 1: JAK2V617F mutation was detected by amplification refractory mutational system-polymerase chain reaction on 3% agarose gel. Lane 1: 100 bp ladder, Lane 2–5: Heterozygous for JAK2V617F mutation, Lane 6–10: negative for JAK2V617F, Lane 11: blank|
Click here to view
Statistical analysis was performed using Stata 11. P values were two-tailed, and statistical significance was set at P < 0.05. Comparison between categorical variables was performed using Chi-square test except where numbers <5 were encountered in which case Fisher's exact test was used.
| Results|| |
Baseline characteristics and hematological parameters of the patients are summarized in [Table 1]. Forty-six were male and 19 were female (M: F: 2.4:1) with median age of 46 years (range, 14–80 years). Among hematological parameters, median Hb was 15.6 g/dl (range, 5.1–20.3), median TLC was 10.7 × 109/L (range 2.4–216), and platelet count was 360 × 109/L (range, 20–1859). Out of 65 patients, 32 were JAK2V617F positive and 33 were negative for JAK2V617F mutation. Out of 32 JAK2V617F-positive cases, 20 (62.5%) patients had thrombosis and 12 (37.5%) patients had no history of thrombosis. Out of 33 JAK2V617F negative cases, 16 (48%) patients had thrombosis and 17 (52%) patients had no history of thrombosis. On comparing the prevalence of thrombosis in JAK2V617F-positive patients with JAK2V617F-negative patients, we observed that 20/32 (62%) JAK2V617F-positive patients had thrombosis as compared to 16/33 (48%) in JAK2V617F-negative patients (P = 0.04) [Table 2]. Splanchnic vein thrombosis, portal vein thrombosis, deep vein thrombosis, cavernous sinus thrombosis, and stroke/myocardial infarction (MI) were most predominant manifestations of thrombosis. Among the patients with thrombosis, 26 had splanchnic vein thrombosis, 9 had portal vein thrombosis, 3 had deep vein thrombosis, 4 had cavernous sinus thrombosis, and 8 had transient ischemic attacks/MI.
|Table 1: Baseline characteristics of chronic myeloproliferative neoplasms patients|
Click here to view
|Table 2: Correlation of JAK2V617F mutation with thrombosis in chronic myeloproliferative neoplasms|
Click here to view
| Discussion|| |
PV, ET, and PMF are Philadelphia-negative CMPNs with cardinal features of an increased red cell mass in PV, raised platelet count in ET, and bone marrow fibrosis in PMF with thrombosis, hemorrhage, and acute leukemic transformation as major complications., JAK2V617F point mutation is usually identified in most patients with PV (95%) and in significant proportion of patients with ET (50%–60%) and PMF (50%–60%).
In the era of a better molecular understanding of CMPNs, much attention has been focused on whether the presence of JAK2V617F has any bearing on thrombotic risk. Several hypothetical mechanisms exist, i.e., JAK2 mutation augments thrombotic risk by increasing Hb and TLC, platelet activation and hyperresponsiveness through impairment of cMPL signal transduction, and elevated platelet-WBC aggregates through increased P-selectin expression.,,, There are mixed views regarding the association of JAK2V617F mutation with thrombosis in CMPNs. Some studies have depicted the possible role of this mutation in thrombosis while others have contrary opinion [Table 3].,,,,,,
|Table 3: Association of JAK2V617F mutation with thrombosis in different populations|
Click here to view
In our study, we observed thrombosis in 62.5% of JAK2V617F-positive patients as compared to 48% of JAK2V617F-negative patients, and this difference was found to be statistically significant (P = 0.04). These results are suggestive of the associative role of JAK2V617F in thrombosis, which is in concordance with studies from Switzerland, China, Italy, and Japan conducted by Kralovics et al., Cheung et al., Hsiao et al., Finazzi et al., and Ohyashiki et al., respectively. However, studies from New York and Manchester, USA, by Wolanskyj et al. and Tefferi et al. showed nonsignificant association of thrombosis with JAK2V617F mutation [Table 3].,,,,,,
| Conclusion|| |
Our study suggests that JAK2V617F mutation may increase the thrombotic risk in CMPN patients. This finding could further lead to risk stratification, setting up the treatment strategy in these patients. However, more randomized studies in larger subset of patients are required to confirm our findings.
Authors wish to acknowledge Mr Rajender Chhoker and Mr Arun Dalsus for technical assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tefferi A, Vainchenker W. Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011;29:573-82.
Cross NC. Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011; 2011:208-14.
Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005;128:275-90.
Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 1999; 93:417-24.
Niittyvuopio R, Juvonen E, Kekomäki R, Oksanen K, Anttila P, Ruutu T, et al.
The predictive value of megakaryocytic and erythroid colony formation and platelet function tests on the risk of thromboembolic and bleeding complications in essential thrombocythaemia. Eur J Haematol 2004; 72:245-51.
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 Clinic Proceedings 2006; 81:159-66.
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.
De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, et al.
Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: Incidence, risk factors, and effect of treatments. Haematologica 2008; 93:372-80.
Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R, et al.
Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109:2446-52.
Arellano-Rodrigo E, Alvarez-Larrà n A, Reverter JC. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2V617F mutational status. Haematologica 2006; 91:169-75.
Marchetti M, Castoldi E, Spronk HM, van Oerle R, Balducci D, Barbui T, et al.
Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112:4061-8.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al.
A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352:1779-90.
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.
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.
Finazzi G, low-dose aspirin in polycythemia (ECLAP). A prospective analysis of thrombotic events in the European collaboration study on low-dose aspirin in polycythemia (ECLAP). Pathol Biol (Paris) 2004; 52:285-8.
Ohyashiki K, Ito Y, Hori K, Sato K, Makino T, Ohyashiki JH, et al.
Thrombosis can occur at any phase of essential thrombocythemia with JAK2(V617F) mutation: A single institutional study in japan. Leukemia 2007; 21:1570-1.
Tefferi A, Lasho TL, Schwager SM, Strand JS, Elliott M, Mesa R, et al.
The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 2006; 106:631-5.
Vannucchi AM, Guglielmelli P, Tefferi A. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin 2009; 59:171-91.
Campbell PJ, Green AR. Mechanisms of diseases: The myeloproliferative disorders. N Engl J Med 2006; 355:2452-66.
Perea G, Remacha A, Besses C, Jiménez M, Florensa L, Cervantes F, et al.
Is polycythemia vera a serious disease in young adults? Haematologica 2001; 86:543-4.
Wautier MP, El Nemer W, Gane P, Rain JD, Cartron JP, Colin Y, et al.
Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and lu/BCAM. Blood 2007; 110:894-901.
Royer Y, Staerk J, Costuleanu M, Courtoy PJ, Constantinescu SN. Janus kinases affect thrombopoietin receptor cell surface localization and stability. J Biol Chem 2005; 280:27251-61.
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 V6I7F status, clonality, and antiphospholipid antibodies. J Thromb Haemost 2007; 5:1679-85.
Alvarez-Larran A, Arellano-Rodrigo E, Reverter JC, Domingo A, Villamor N, Colomer D, et al
. Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis. Ann Hematol 2008; 87:269-76.
Department of Hematology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Molecular analysis of V617F mutation in Janus kinase 2 gene of breast cancer patients
| ||Sajjad Karim,Imran Riaz Malik,Quratulain Nazeer,Ahmad Zaheer,Muhammad Farooq,Nasir Mahmood,Arif Malik,Muhammad Asif,Asim Mehmood,Abdul Rehman Khan,Abdul Jabbar,Muhammad Arshad,Qudsia yousafi,Abrar Hussain,Zeenat Mirza,Muhammad Atif Iqbal,Mahmood Rasool |
| ||Saudi Journal of Biological Sciences. 2019; |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||2791 |
| Printed||41 |
| Emailed||0 |
| PDF Downloaded||162 |
| Comments ||[Add] |
| Cited by others ||1 |