Uncontrolled thrombocytosis in polycythemia vera is a risk for thrombosis, regardless of JAK2V617F mutational status

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The JAK2V617F mutation is found in the vast majority of patients with polycythemia vera (PV) and this change is proposed to be one of diagnostic tools for PV,1 while the presence of idiopathic erythrocytosis with other JAK2 mutations is currently demonstrated.2 PV patients with JAK2V617F have significantly higher leukocytes and platelets, and a higher frequency of palpable splenomegaly at the time of diagnosis.3, 4 It is reported that thrombotic events in PV patients are not linked to JAK2V617F mutational status.3, 5 Moreover, although thrombosis is a major complication in PV patients,1 no hematologic parameters during followup could be shown to predict thrombosis.1, 6 We, therefore, assessed the association between thrombosis and hematologic indicators both at diagnosis and during the courses of PV patients, in combination with JAK2V617F mutational status, to find out the possible risk factor for thrombosis in PV patients.

We analyzed 33 patients with PV (followed for at least 1 year) based on the PV Study Group criteria: seven patients were non-WHO PV and the remaining 26 met the World Health Organization (WHO) criteria. The JAK2V617F mutation was determined by using the sequence-specific primer-single molecule fluorescence detection assay.3 As reported previously, PV patients with JAK2V617F (n=24) had a significantly higher leukocyte count (P<0.0001) and platelet (P<0.0001) at the time of PV diagnosis, while there was no significant difference in the frequency of thrombotic episodes (1/9 versus 5/24: P=0.5190) (Supplementary Table 1).3 None of the 33 PV patients showed MPL 515 mutation (data not shown). The frequency of thrombosis (3/17 versus 2/7: P=0.5492) and initial hematologic parameters did not show any significant difference between PV patients with heterozygous and homozygous JAK2V617F. We next compared the maximal levels of hematologic data during followup in PV patients with or without thrombotic episodes. Notably, PV patients with thrombosis (n=6) had a significantly higher platelet count during their courses (987±460 × 109/l versus 604±335 × 109/l: P=0.0349), while the initial platelet count between these two groups did not show any significant difference (P=0.3722) (Table 1). This tendency was also evident in PV patients with JAK2V617F (P=0.0612). The frequency of thrombosis was not influenced by the anti-thrombotic treatment (P=0.0742 in total PV, and P=0.2611 in PV with JAK2V617F).

Table 1 Clinical and hematologic features of polycythemia vera associated with thrombosis

The presence of JAK2V617F mutation was related to initial platelet counts in PV patients,3 but not to thrombotic episodes. In the current study, the increased amount of platelets during follow-up (delta platelets=maximal platelets during follow-up – initial platelets) correlated with thrombotic episodes (P=0.0318), but did not show any significant association with the JAK2V617F mutational status (Table 1). Five of six patients with thrombosis had additive elevated platelet counts of >250 × 109/l during the follow-up period from the base-line platelets. This aspect requires further confirmation using large cohort studies, since we encountered only 6/33 PV patients with thrombosis. Our data indicate that uncontrolled thrombocytosis, despite administration of cytoreductive chemotherapy, may be a risk factor for developing thrombosis.

Management for PV patients focused on the reduction of hematocrit level for less than 45% in men and less than 42% in women by either phlebotomy or administration of hydroxyurea.1 Although aspirin administration is recommended for PV patients,1 aspirin therapy might be insufficient to prevent thrombosis in some PV patients with prominent thrombocytosis. Moreover, the timing of thrombosis in PV patients did not coincide with the maximal platelet count during followup (data not shown), in agreement with other reports.6 Finazzi et al.7 reported that the risk of thrombosis in JAK2V617F-positive PV was 3.63-fold that of those with wild-type JAK2 essential thrombocythemia (ET), while Tefferi et al.5 found no association between JAK2V617F mutational status and bleeding or thrombotic history. Vannucchi et al.8 also confirmed the lack of any difference in the frequency of thrombosis between PV patients with heterozygous and homozygous JAK2V617F. Some JAK2V617F-positive PV cases show hematologic transformation among CMPD and tend to exhibit thrombosis or myelofibrosis during their courses;1, 3, 4 Di Nisio et al.6 did not find any association between platelet count during follow-up and thrombotic events in PV. It is recommended to control the platelet count to under 400 × 109/l even in PV patients,1 however, cytoreductive treatment sometimes fails to control platelets at any appropriate level, due to paradoxical over-reduction of red blood cells. These data indicate that control of platelet counts during followup by some approaches, for example, combination of hydroxyurea and interferon or switching to interferon, might be the next issue to examine concerning the prevention of thrombosis in PV patients, regardless of the JAK2V617F mutational status. The risk of thrombosis in PV might be linked to elevated platelet level during the course, but to neither initial platelet count nor JAK2V617F mutational status. This situation is different from ET, in which JAK2V617F mutation is a key change predictive of thrombosis. Further studies are required to clarify the candidates linking uncontrolled thrombocytosis to thrombosis in PV patients.

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Acknowledgements

We thank Professor J Patrick Barron of the International Medical Communication Center of Tokyo Medical University for his review of this manuscript and Mr K Hori and T Makino, NovusGene, Tokyo, for their technical assistance. 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.

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Correspondence to K Ohyashiki.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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