Impact of Jak2V617F Mutational Status on Essential Thrombocythemia: An Assessment of Thrombotic Risk Factors on 218 Patients

Abstract 3072

Thromboembolic disease (TE) is a major cause of morbidity and mortality in Essential Thrombocythemia (ET). Recently JAK2V617 mutational status and allele burden seem to add prognostic significance to standard risk factors; furthermore it was reported an interesting but not confirmed association between baseline leukocytosis and thrombosis. The aim of the study was to evaluate such factors in a series of patients with ET.

Study subjects were recruited from the Ancona Hematology Clinic database of ET patients; clinical and laboratory data were collected at time of diagnosis and correlated with the occurrence of TE. In addition, qualitative and quantitative PCR for JAK2V617F was performed on stored samples of peripheral blood or bone marrow in a subset of study patients. Qualitative JAK2V617F analysis was done according to standard PCR-based methods and quantitative JAK2V617F was determined with a commercially available Taqman assay. Standard statistical methods were applied to test significance of associations between thrombosis and other variables.

A total of 218 ET patients were included in the study (median age 59, range 18–90; 71 males and 147 females). At diagnosis the median of platelets, hemoglobin and leukocytes were 776×10⁹/L, 13.9g/dL, and 8.4 ×10⁹/L respectively. At diagnosis a history of remote thrombosis was recorded in 27 patients (12,4%).

Of the 122 patients analysed for JAK2 mutational status, 70 (57.4%) were JAK2 wild-type and 52 (42.6%) were JAK2V617F positive. Quantitative analysis was carried out in 48 cases: 6 patients (11.5%) were homozygotic and 42 (80.8%) were heterozygotic.

At diagnosis, a total of 17 patients (7.8%) had TE: 8 (3.7%) arterial thrombosis (AT) and 9 (4.1%) venous thrombosis (VT). the AT included acute coronary syndromes (ACS; n=4), transient ischemic attack/cerebrovascular accidents (TIA/CVA; n=3), and peripheral arterial thrombosis (PAT; n=1). The VT included deep vein thrombosis/pulmonary embolism (DVT/PE; n= 4), abdominal vein thrombosis (AVT; n=4) and dural sinus thrombosis (n=1). During follow-up 25 patients experienced TE: 13 VT (6%) and 12 AT (5.5%). Post diagnosis VT included.: DVT/PE (n= 4), AVT (n=4), superficial vein thrombosis (TVS; n=3), retinal vein thrombosis (n=1) and dural sinus thrombosis (n=1). Post diagnosis AT included TIA/CVA (n=6), ACS (n=3) and PAT (n=3).

Gender, age, hemoglobin, platelets, leucocyte count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and common vascular risk factors did not affect the probability of thrombotic events at diagnosis and during follow-up. On univariate analysis a significant increase of thrombosis as presenting manifestations, was registered in patients with a history of remote thrombosis (OR= 10.0, 95% CI 4,1-24,5; p<0,001) and in those with JAK2V617F mutation (OR=3.73, 95% CI 1.06–13.05; p=0.032). Considering JAK2 wild-type ET as a reference group, the risk of thrombosis was 1.14 (95% CI 0.97–1.33; p=0.07) and 1.42 (95% CI 0.80–2.51; p=0.06) for JAK2V617F heterozygous and homozygous patients respectively.

Subjects with both JAK2 mutation and a history of remote thrombosis have a OR of 24.44 (95% CI 3.07–194.66; p=0.01) in comparison with wild-type patients without a history of thrombosis.

During follow-up, the probability of vascular events was predicted only by a history of remote thrombosis (OR=2.3, 95% CI 1.01–5.35; p=0.05), and neither by JAK2V617F mutational status (OR=1.24, 95% CI 0.43–3.62; p=0.76). The present analysis suggests that the thrombotic risk is higher in JAK2V617F positive patients and is further increased by a past history of thrombosis. The opportunity of combine such criteria must be defined in prospective trials.