Splenomegaly and thrombosis risk in essential thrombocythemia: the mayo clinic experience
Authors: Mahnur Haider, Naseema Gangat, Curtis Hanson, Ayalew Tefferi
Journal: American Journal of Hematology (2016)

To the Editor: Essential thrombocythemia (ET) is a myeloproliferative neoplasm with a clinical course complicated by a greater than 20% risk of thrombosis 1. History of thrombosis, JAK2V617F mutation, age >60 years and cardiovascular (CV) risk factors have been identified as independent risk factors for thrombosis in ET 2, 3. Recently, Andriani et al. identified palpable splenomegaly as an independent risk factor for thrombosis in a retrospective study of 1,297 patients with ET (diagnosed by time-specific conventional criteria) from 12 hematologic centers in Italy 4. They reported palpable splenomegaly in 172 (13.3%) patients, including 162 whose spleen was palpable at ≤5 cm below the costal margin. Their patients with splenomegaly, compared to those without palpable splenomegaly, were significantly younger and more likely to display male gender, higher platelet count, lower prevalence of CV risk factors and higher JAK2V617F allele burden. In the particular Italian study, 124 (9.6%) patients developed thrombosis during follow up and the rate of thrombosis was significantly higher in patients with splenomegaly (15.7% versus 8.6%, P = 0.003); multivariable analysis identified splenomegaly (HR 1.73, CI 1.08–2.79; P = 0.023), male gender (HR 1.46, CI 1.00–2.15; P = 0.048), leukocyte count above the mean (HR 1.52, CI 1.03–2.22; P = 0.032) and history of thrombosis (HR 1.74, CI 1.13–2.67; P = 0.011) to be independently predictive of future vascular events. In the current study, which was approved by the Mayo Foundation Institutional Review Board, 560 Mayo Clinic patients with WHO-defined ET and spleen size evaluated at diagnosis were studied. Collected data at diagnosis included age, sex, JAK2V617F mutational status and presence or absence of palpable splenomegaly, CV risk factors (smoking, hypertension, and diabetes mellitus) and thromboembolic events before and after diagnosis. Thrombosis-free survival (TFS) was estimated using the Kaplan–Meier product-limit method. Cox proportional hazards regression was applied to carry out multivariable analysis. A two tailed P ≤ 0.05 was considered statistically significant. A total of 560 ET patients (median age at diagnosis 56 years, females 61%) were followed for a median of 105 months. At least one CV risk factor was present in 53% of the patients; the JAK2V617F mutation was present in 54% and 13.8% had a previous history of thrombosis before or at diagnosis. The median peripheral blood counts at diagnosis were as follows: platelet count 861 × 109/l, hemoglobin level 13.6 g/dl and leukocyte count 8.6 × 109/l. Of the 560 study patients, 35 (6.3%) had palpable splenomegaly at diagnosis; of these 35 patients, 28 (80%) displayed a spleen size of <5 cm below the left costal margin. There was no significant difference between patients with and without splenomegaly in terms of platelet count (P = 0.456), hemoglobin level (P = 0.322), leukocyte count (P = 0.5164), prevalence of CV risk factors (P = 0.827) or JAK2V617F mutational status (P = 0.274). However, patients with splenomegaly were predominantly male (P = 0.008) and showed a trend toward younger age (P = 0.06). During follow up, 68 (12%) patients experienced thromboembolic events. Despite similar median follow-up period, patients with splenomegaly developed thrombosis earlier (median 22 months) compared to those without splenomegaly (median 64 months; P = 0.05). However, the cumulative TFS at 50 and 100 months were not significantly different: 83.9% ± 6.6 and 79.9% ± 7.4, respectively, in patients with splenomegaly and 94.3% ± 1.1 and 89.7% ± 1.6 in patients without splenomegaly (P = 0.54). Table 1 outlines the results of univariate and multivariable analysis of risk factors for developing thrombosis; in univariate analysis risk factors for the development of thrombosis after diagnosis were history of thrombosis, JAK2V617F, CV risk factors, older age, and leukocyte count. In multivariable analysis, history of thrombosis, JAK2V617F mutation and CV risk factors retained their significance. The current study did not identify splenomegaly at diagnosis as a risk factor for thrombosis in ET, either by univariate or multivariable analysis, although patients with splenomegaly experienced thrombotic complications earlier than their counterparts without splenomegaly. The incidence of palpable splenomegaly was higher in the Italian study (13.3%) 4, compared to the current study (6.3%), and the difference might have been contributed by the difference in diagnostic criteria and the inadvertent inclusion of patients with prefibrotic myelofibrosis in the Italian study 4. The difference in diagnostic criteria might have also been responsible for the aforementioned discrepancies in the two studies, including the difference in identified risk factors for thrombosis 4. In this regard, our study corroborated most of the risk factors included in the International Prognostic Score for thrombosis (IPSET-thrombosis) which was developed to risk stratify for thrombosis in WHO defined ET 2, 3. Conversely, in both studies, patients with splenomegaly were more likely to be males and be younger. Additional studies in WHO-defined ET are needed to confirm the similar findings in the two studies and reconcile their differences. Mahnur Haider,1 Naseema Gangat,1 Curtis Hanson,2 Ayalew Tefferi1 1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; 2Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota