JAK2 617V&gt;F Mutation Correlates with Arterial Thrombosis in Essential Thrombocythemia.
Authors: Barry Keith , Frantz Christine , Mirbolooki Mohammadreza , Mant Michael , Clarke Gwendolyn , Mirza Imran 
Published: April 2020

Background: Philadelphia chromosome negative chronic myeloproliferative disorders (CMPD) are a group of hematopoietic stem cell disorders associated with elevated blood counts, abnormal bone marrow morphology, and often with coagulopathy. The JAK2 617V&gt;F mutation is reported to be present in approximately half of the CMPD classified as essential thrombocythemia (ET). The mutation is currently used in diagnosis. Its relation to prognosis is unclear.

Aim: The goal of this study was to determine the prognostic relevance of JAK2 617V&gt;F mutational status in ET patients.

Methods: A 12-year retrospective review of laboratory and medical records identified 255 cases of ET. The diagnosis was based on PVSG or WHO criteria. Peripheral blood, bone marrow, cytogenetics, and other laboratory findings at the time of diagnosis were catalogued. Clinical complications before and after diagnosis were documented. For cases where JAK2 617V&gt;F status was unknown, we used InvivoScribe RFLP kit assay utilizing polyacrylamide gel electrophoresis analysis on archived bone marrow or peripheral blood samples (5% analytical sensitivity). The associations were calculated as odds ratio (OR) with 95% confidence interval (CI). Differences in continuous variables were tested using Student’s t-test and Mann-Whitney U test. Chi-square test and Fisher’s Exact test were used to compare differences in proportions. A difference was considered significant if P &lt;0.05. Statistical analysis was performed using SPSS Version 12.0 software.

Results: Complete laboratory and clinical data were available for 227 cases of ET (male:female = 0.6; mean age, 65.9 years; mean follow up, 63.7 ± 2.5 months). 125 (55.1%) patients were heterozygous and 6 (2.6%) were homozygous positive for theJAK2 617V&gt;F mutation and 96 (42.2%) were negative. There was no significant difference in sex, age of onset survival, karyotype, or treatment rate (with hydroxyurea or anagrelide) between JAK2 617V&gt;F positive and negative groups. The presence of mutation at the time of diagnosis correlated with higher hemoglobin (141.8 ± 1.7 vs. 128.0 ± 2.3 g/L, P = &lt;0.001), WBC count (10.8 ± 0.4 vs. 9.6 ± 0.5 *109/L, P = &lt;0.05), neutrophilia (7.8 ± 0.4 vs. 6.3 ± 0.3 *109/L, P = &lt;0.02) and lower platelets (856 ± 27 vs. 954 ± 42 *109/L, P = &lt;0.02). Standard risk factors (age ≥60 and/or previous thrombosis) showed association with thrombotic events in both groups (P = &lt;0.04). Mutation positive patients displayed 2.4 fold greater risk of arterial thrombosis (95% CI 1.2-4.6). This risk was 3.3 fold greater before ET diagnosis (95% CI 1.4-7.9), but not significant afterwards. Venous thrombosis and bleeding were not different between groups and did not correlate with the leukocyte count. Mutation status did not predict transformation to myelofibrosis or acute leukemia.

Conclusion: Our data supports the reported incidence of JAK2 617V&gt;F mutation in ET (58%). Presence of the JAK2 617V&gt;F mutation in ET patients does not predict survival, gender, age of onset, karyotype, risk of venous thrombosis, or bleeding. The mutation does correlate with a higher risk of arterial thrombosis in our study population. This risk appears to be highest before diagnosis of ET and equalizes after diagnosis between mutation positive and negative patients, possibly reflecting better response to therapy in the former group.