JAK2 V617F Mutation Status Predicts Thrombotic Complications, Including Arterial Thrombosis, in Patients with Essential Thrombocytosis (ET).
Authors: Weston Helen , Bird Robert , Griffiths Vanessa , Jones Mark , Grimmett Karen , Saal Russell , Mills Anthony K. , Gill Devinder , Marlton Paula , Mollee Peter 
Published: April 2020

Abstract
Background: ET carries a significant risk of thrombotic complications which are difficult to predict, with a past history of thrombosis being the main predictor of subsequent events. The JAK2V617F mutation (JAK2) and spontaneous erythroid colony growth (SEC) have been inconsistently associated with increased thrombosis in these patients. We aimed to assess the predictive value of these assays for the development of thrombotic events post-diagnosis in patients with ET.
Methods: A retrospective review of consecutive patients with ET diagnosed according to WHO criteria between January 1998 and August 2006 was performed. Data was abstracted from the medical record regarding baseline demographic characteristic, vascular risk factors, therapy, occurrence of thrombo-haemorrhagic events, and transformation to AML or myelofibrosis. Thrombotic events were defined as arterial or venous events occurring at or 12 months prior to diagnosis (prior thrombosis) and at any time post diagnosis of ET (subsequent thrombosis). Investigators were blinded to JAK2 and SEC results at the time of data collection. SECs were performed at the time of diagnosis in 53 patients. JAK2 analysis was performed by an allele specific PCR method on peripheral whole blood (n=32) or archived bone marrow samples (n=29).
Results: 62 patients with ET were identified: median age 60yrs; 53% female; median platelet count at diagnosis 873 × 109/L; 10,8 and 44 being low, intermediate and high clinical risk, respectively. 67% (41/61) had a positive JAK2 test and 47% (25/53) had a positive SEC assay. 8 (13%) and 6 (10%) had a history of prior arterial and venous thrombotic complications. Median follow up was 39 months (range, 1 to 137 months). At diagnosis JAK2 positive patients had higher white cell counts (12.3 vs 8.9 ×109/L, p=0.01) and neutrophil counts (9.1 vs 5.7 ×109/L, p=0.01), and a trend to older age (62 vs 57yrs, p=0.3) and higher haemoglobin (139 vs 133 g/L, p=0.12), but not platelet count (870 vs 892 ×109/L, p=0.8). There was a trend for increased rates of prior thrombosis among JAK2 positive patients (27% vs 5%, p=0.08). Survival was not affected by JAK2 status (5yr OS 71% vs 72%, p=0.7). The presence of the JAK2 mutation predicted for the development of subsequent thrombosis (5yr event rate 32% vs 0%, p=0.01) which persisted when the analysis was stratified for a prior history of thrombosis (p=0.01). Further analysis demonstrated the JAK2 mutation to predict subsequent arterial thrombosis (5yr event rate 22% vs 0%, p=0.05) but not venous thromboembolism (5yr event rate 11% vs 0%, p=0.18). The increased risk of arterial thrombosis in JAK2 positive patients persisted when corrected for a prior history of vascular events (p=0.04). The SEC assay was not found to be predictive of any thrombotic events.
Conclusions: Patients with ET who are JAK2 positive are at increased risk of thrombotic complications, particularly arterial thrombosis. This increased risk persists after correction for a history of prior thrombosis.