The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia

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Recently, several groups have identified a single point mutation in the JAK2 gene in the Philadelphia-negative myeloproliferative disorders, including polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis with myeloid metaplasia (MMM) (Baxter et al, 2005; James et al, 2005; Jones et al, 2005; Kralovics et al, 2005; Levine et al, 2005). A G → T transversion results in the substitution of valine by phenylalanine at codon 617 (V617F) within the pseudokinase autoinhibitory centre with overall constitutive activation of the tyrosine kinase. The presence of this mutation has been detected in high frequency in patients with PV (65–97%), ET (23–57%) and MMM (35–57%) and suggests that it may have a fundamental role in the pathogenesis of these disorders. Most studies have shown no differences in the clinical phenotype of patients with or without the JAK2 mutation. However, a longer disease duration was associated with the ‘homozygous’ status (Levine et al, 2005) and the mutation correlated with an older age, greater requirement for cytoreductive therapy, and higher frequency of thrombotic, haemorrhagic and fibrotic complications (Kralovics et al, 2005) in myeloproliferative disorders. Only one group have investigated ET patients independently, and they demonstrated a higher haemoglobin and haematocrit in ET patients with the mutation (Antonioli et al, 2005). To address these clinical findings further, we investigated 60 patients with ET for the presence of the JAK2 mutation and possible phenotypic associations. Patient notes were examined for their diagnostic blood counts and thrombotic histories. Thrombotic complications included major thromboses as well as microvascular disturbances. The clinical characteristics for the patients are shown in Table I. We used the previously published allele-specific polymerase chain reaction (PCR) method (Baxter et al, 2005) on whole blood DNA to detect qualitatively the presence or absence of the JAK2 V617F mutation and designed a second allele-specific PCR to confirm the findings independently. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) software, version 11.5, using Wilcoxon's rank sum for continuous variables, Fisher's exact test for nominal variables and binary logistic regression for multivariate analysis with all tests being two-sided and significance taken for values P < 0·05. The JAK2 mutation was identified in 48% of our ET population, which is a similar frequency to those reported by others. There was no difference in age at diagnosis, gender or disease duration between those with and those without the mutation. The proportion of patients receiving some form of cytoreductive therapy was also similar in both the groups. However, we found a significantly higher haemoglobin concentration at diagnosis in ET patients with the mutation (median 14·2 ± 1·5 g/dl vs. 13 ± 1·7 g/dl, P = 0·0426) although no differences were seen in the packed cell volume, white cell or platelet counts. Thrombotic complications were more common in patients with the JAK2 mutation; 18 (62%) vs. 8 (26%), P = 0·009. Although arterial events were more common, overall there was no statistical difference between the two groups, as defined by JAK2 mutational status, for either the type or timing of the thrombotic event. Our data therefore suggests that the presence of the JAK2 mutation in ET defines a subgroup of patients with both a polycythaemic and thrombotic tendency, confirming the results of recent studies. The ease of screening for the V617F mutation makes it a very attractive tool for diagnostic purposes but its role in risk stratification for therapy remains to be further evaluated. Shire Pharmaceuticals for an educational fellowship for Betty Cheung; Special Haematology and Molecular Diagnostics, St Thomas' Hospital for their technical support.