Bleeding and thrombotic complications in philadelphia-negative classic chronic myeloproliferative neoplasms: Prevelance, clinical risk factors and the role of JAK2V617F mutation

Philadelphia chromosome-negative classic chronic myeloproliferative neoplasms (MPNs) are clonal diseases of hematopoietic stem cells characterized by proliferation of one or more myeloid series in the bone marrow and classified as polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These diseases share common clinical characteristics such as splenomegaly, thrombotic complications, and risk of conversion to leukemia. Bleeding and thrombosis are common complications of myeloproliferative neoplasms and are associated with severe organ damage and high mortality. PV is characterized by increased red cell mass as a result of uncontrolled erythrocyte production due to neoplastic proliferation of hematopoietic progenitor cells and increased leukocyte and platelet production, usually due to simultaneous stimulation of myeloid and megakaryocytic cell lineages. ET is a clonal myeloproliferative disease characterized by excessive platelet production and often accompanying thrombotic or hemorrhagic symptoms. PMF is mainly characterized by bone marrow fibrosis, extramedullary hematopoiesis, and shortened lifespan. After the discovery of the JAK2V617F mutation in 2005, the underlying molecular occurrence was understood in more than 95% of cases with PV and about 50-60% of cases with ET or PMF. In this study, a total of 951 Ph-negative MPNs (413 ET, 358 PV, 180) from the Department of Internal Medicine, Istanbul Faculty of Medicine (ITF), the Polyclinic of the Department of Hematology and Istanbul Bakırköy University of Health Sciences Doctor Sadi Konuk Education and Research Hospital Hematology Clinic. The association between bleeding, the frequency and localization of thromboembolic events, cardiovascular risk factors and genetic mutations, the impact of these complications on recovery and predictive parameters were studied in a patient diagnosed with PMF. 951 Ph-Negative MPN cases (413 ET, 358 PV, 180 PMF) that met the 2016 World Health Organization (WHO) criteria were included in the study. In addition to demographic characteristics, clinical and laboratory data of the cases, OS was also examined. Parameters that included clinical and laboratory data were uploaded to the SPSS statistics program. Results with a p-value of < 0.05 were considered statistically significant. Survival curves in PMF, ET, and PMF were constructed to calculate OS using the "Kaplan-Meier" analysis, and comparisons of survival rates between groups were performed using the log-rank test. In addition, survival analysis in PMF was conducted in order to calculate leukemia-independent survival (LFS). Among 951 Ph (-) MPN cases included in the study, 413 were diagnosed with ET, 358 with PV, and 180 with PV. Of all cases, 477 were male and 474 were female. Of the cases with ET, 263 were female, 150 were male, 100 of the cases with PMF were female and 80 were male, and 247 of the cases with PV were male and 111 were female. The mean age at diagnosis was 53.25 (SS 15.37). Splenomegaly was found in 35.2 % (n = 335) of all groups. 18.1% (n = 173) of cases were complicated by bleeding and 32.7% (n = 311) by thrombosis. The incidence of arterial thrombosis was higher than that of venous thrombosis in all 3 diagnostic groups. However, the rate of venous thrombosis in patients with ET was statistically significant higher in patients with JAK2V617F mutation than in the group without mutation (p = 0.014). In the overall cohort, thrombosis was found to be significantly more frequent in the PV group and bleeding in the PMF group (p = 0.05 and p = 0.001, respectively). In addition, the thrombosis group showed a statistically significant higher rate of male gender (p=0.005). When comparing the groups with and without thrombosis in terms of bleeding complications, bleeding was significantly higher in the thrombotic group (respectively 23.1 % vs. 15.8 %; p = 0.006). In our study, the JAK2V617F mutation was found to be positive in 70.1% (n = 667). The JAK2V617F mutation was positive in 61.7 % (n = 255) of cases with ET, 75 % (n = 135) of cases with PMF and 77.4 % (n = 277) of cases with PV. The incidence of total thrombosis was 35.4% (n = 236) in the group with positive JAK2V617F mutation, 26.8% (n = 76), in the group with negative JAK2V617F mutation and was statistically significantly higher in the group with positive JAK2V617F mutation (p = 0.01). There was no significant difference in bleeding between the positive and negative JAK2V617F mutation groups (p = 0.159). Splenectomy was performed in a total of 21 cases (2.2 %). Allo-SCT was performed in 0.9 % (n = 9) of cases and all of these cases were diagnosed with PMF. In 1.7 % (n=16) of all cases it was converted into leukaemia. 14.4 % (n=137) of patients died. Both complications were significantly more frequent in the PMF group than in ET and PV (p = 0.001; p = 0.001). Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) share common clinical characteristics such as thrombotic and haemorrhagic complications and the risk of conversion to leukaemia. Bleeding and thrombosis are common complications of myeloproliferative neoplasms and are associated with severe organ damage and high mortality. After the JAK2V617F mutation in Ph-Negative myeloproliferative neoplasms (MPN) was identified in 2005, there were major developments in the pathophysiology of the disease and the diagnostic criteria were revised by the WHO following the discovery of this mutation. Although high age, high platelet count and increased haematocrit are considered risk factors for thromboembolic events and bleeding, the significance of these parameters has not been proven by clinical studies and the lack of a large-scale study with the planned number of patients in the literature review on the research subject has made this study necessary. In our study, the incidence of thrombosis was found to be higher in MPN than haemorrhage, so in case of unexplained thrombosis, investigation should be done in relation to MPN, yet haemorrhage is non-negligible.