The JAK2V617F mutation is an activating kinase that is constitutively expressed in the vast majority of patients with polycythemia vera and approximately half of those with essential thrombocythemia (ET).1 The significance of the association between JAK2V617F mutation in ET and thrombosis is still controversial: we have shown that ET patients with JAK2V617F had more frequent thrombotic episodes compared with those with wild-type JAK2, whereas the platelet count at the initial ET diagnosis did not differ between wild-type ET and JAK2V617F-positive ET.2 On the basis of this evidence, we retrospectively sought and evaluated thrombotic episodes in ET patients to obtain more insight into the risk factors of thrombosis in ET patients.
We used the JAK2 mutational status database in 49 patients with ET in our institute. The JAK2V617F mutation was determined using by the semiquantitative sequence-specific primer single-molecule fluorescence detection (SSP-SMPD) assay. As reported previously, ET patients with JAK2V617F showed a significantly higher incidence of thrombotic episodes (10/31 versus 1/18: P=0.0308), high leukocyte count (P=0.0092) and hemoglobin level (P=0.0044) than those with wild-type JAK2.2 ET patients with thrombosis had higher hemoglobin (14.5±1.5 versus 13.3±1.5 g/dl: P=0.0283) at initial diagnosis, whereas no significant differences were noted in leukocyte count (P=0.140), hematocrit level (P=0.0801) or platelet count (P=0.0877) (Supplementary Information 1). Of the ET patients with JAK2V617F mutation (n=31), no significant differences were noted in hematologic parameters regardless of whether they developed thrombosis or not.
In ET patients followed for at least 1 year, we found 11 patients who suffered thrombosis (Table 1): two patients at intermediate risk, and nine at high risk, according to the thrombotic risk.3 Six ET cases were initially diagnosed by thrombosis, and the remaining five had thrombotic events during stable phase of the disease. Hematologic parameters at the time of initial ET diagnosis in these two groups did not significantly differ, including leukocyte count (P=0.2703), hemoglobin concentration (P=0.1306), hematocrit level (P=0.4472) or platelet count (P=0.9662). Except for one patient (JAK2_0050), all ET patients with thrombotic episodes had JAK2V617F. Five patients with thrombotic events during the stable phase had platelet counts ranging from 389 × 109/l to 706 × 109/l (mean=529.2 × 109/l) at the time of thrombosis: two of them received prophylactic anticoagulant agents, as well (Table 1). Although the number of patients in our study is too small to provide significant odds ratio, ET patients with JAK2V617F frequently have thrombotic episodes. Some ET patients are given a diagnosis owing to thrombotic events at the first manifestation. However, the remaining ET patients with JAK2V617F may develop thrombosis even during hematologically stable condition, indicating that there is a risk of thrombosis in ET patients at any phase of the disease, but especially in those with JAK2V617F mutation.
Antonioli et al.4 did not find a high incidence of thrombosis in JAK2V617F-positive ET, whereas JAK2V617F-positive ET had a significantly high hemoglobin level and hematocrit with low platelet count, in comparison with ET with wild-type JAK2. Wolanskyj et al.5 also reported no higher frequency of thrombotic events in JAK2V617F-positive ET, whereas an increased risk of thrombotic complications in JAK2V617F-positive ET has been reported by some investigators,1, 6, 7 in agreement with our observations. It is also reported that an increased leukocyte count, but not JAK2V617F mutational status, in ET patients is associated with thrombosis, and it is speculated that an association with JAK2V617F in ET and thrombosis might be an indirect effect from leukocytes.8 Carobbio et al.8 showed that cytoreductive chemotherapy reduced the association between leukocytosis and thrombosis. Our data indicate that JAK2V617F-positive ET can develop thrombosis at any time, and propose the importance of a prospective study to determine whether prophylactic anticoagulant therapy could prevent thrombotic events in JAK2V617F-positive ET patients.
We thank Professor JP Barron for his review of this manuscript. This work was supported in part by the ‘High-Tech Research Center’ Project from the Ministry of Education, Culture, Sports and Technology (MEXT) and by the ‘University-Industry Joint Research Project’ from MEXT.