JAK2 Val617Phe Mutation Correlates with the Risk of Thrombosis in Patients with Essential Thrombocythemia.
Authors: Finazzi Guido , Guerini Vittoria , Rambaldi Alessandro , Barbui Tiziano 
Published: October 2019

Abstract
A Val617Phe mutation in the exon 12 of JAK2 gene has been recently described in about 50% of patients with Essential Thrombocythemia (ET) but it is still uncertain whether this mutation affects the risk of thrombotic complications. To tackle this issue, we evaluated the JAK2 status in 67 ET patients and its association with clinical characteristics and thrombotic complications occurring either at diagnosis or during the follow-up. We studied 25 males and 42 females (median age 50, range 10–82 years) diagnosed with ET according to the WHO criteria. Median platelet count at diagnosis was 760x109/L (range 594–1900). Fifteen patients (22%) showed a thrombotic event as the presenting symptom of ET (5 cerebral ischemia, 5 myocardial infarction, 3 splanchnic venous thrombosis, 1 deep vein thrombosis of the right leg, 1 peripheral arterial thrombosis) whereas 6 patients had a major vascular complication during a median follow-up of 4 years (range 0–19) (incidence 2.2% pt-yr) (2 cerebral ischemia, 1 myocardial infarction, 1 peripheral arterial thrombosis, 1 portal vein thrombosis, 1 pulmonary embolism). JAK2 mutation was evaluated on granulocyte DNA or RNA using an allele-specific PCR. Overall, 33 patients (49%) had the JAK2 Val617Phe mutation. There was no correlation between JAK2 mutational status and a number of clinical characteristics including gender, hemoglobin level, platelet or white blood cell count, presence of splenomegaly or duration of follow-up. However, JAK2 positive were older than JAK2 negative patients (median age 65, range 23–82 years vs. 45, range 10–78 years) and showed more thrombosis both at diagnosis (13/33, 39% vs. 2/34, 6% p<0.01) and during the follow-up (4/33, 3% pt-yr vs. 2/34, 1.5% pt-yr). In a further analysis, we evaluated separately a subgroup of 29 patients (43% of the total population) classified at high risk for thrombosis on the basis of conventional clinical risk factors, such as age >60 years and/or previous thrombotic events. The “high-risk” subgroup included 9 males and 20 females (median age 71, range 31–82 years; median platelet count at diagnosis 805x109/L, range 594–1302). The prevalence of thrombosis at diagnosis was 52% and the incidence during follow-up 4.3% pt-yr. In this group, 21 patients (72%) had the JAK2 Val617Phe mutation. Again, no correlation was found between JAK2 mutational status and gender, blood cell counts, splenomegaly or follow-up duration. At variance of the total population, median age was similar between JAK2 positive and negative “high-risk” patients (72, range 31–82 years vs. 65, range 46–78 years). However, JAK2 positive “high-risk” patients still showed more thrombosis at diagnosis (62% vs. 25% p<0.05) and a trend during the follow-up (4.8% pt-yr vs. 3.1% pt-yr) than the negative cases. In conclusion, we studied an homogenous series of ET patients diagnosed and followed at a single Institution and observed a consistent association between JAK2 mutational status and thrombotic events in different phases of disease and different subgroup of patients. These data may help to establish the prognostic role of JAK2 mutation in ET and to better define the thrombotic risk profile of patients.