Oxidative Stress Levels, JAK2V617F Mutational Status and Thrombotic Complications in Patients with Essential Thrombocythemia

Cornel Moisa,Mihnea Alexandru Gaman,Amelia Maria Gaman,Camelia Cristina Diaconu

doi:10.37358/rc.19.8.7435

Abstract

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm associated with thrombotic and haemorrhagic complications. Reactive oxygen species (ROS) overexpression induces a growth advantage to JAK2V617F-positive clones and, in association with a higher number of immature platelets, leukocytosis, and additional cardiovascular risk factors, leads to an increased risk for thrombotic events. We evaluated oxidative stress by measuring ROS levels and the total antioxidant capacity (TAC) in 62 ET patients and investigated the relationship between oxidative stress, JAK2V617F mutational status and the development of thrombotic events. We found higher oxidative stress levels in JAK2V617F-positive vs. JAK2V617F-negative ET cases with no significant differences between homozygous and heterozygous genotypes. Increased ROS levels and thrombotic events were more frequent in ET patients with old age at diagnosis, higher haematocrit levels or leukocytosis.

Highlights

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by altered proliferation and differentiation of hematopoietic stem cells, persistent thrombocytosis > 450.000/mmc independent of thrombopoietin levels, excessive proliferation of bone marrow megakaryocytes with large, mature morphology, hyperlobulated nuclei and minor reticulin fibrosis
The JAK2V617F mutation was detected in 36 ET patients (58.06%), whereas 26 ET patients (41.94%) were JAK2V617F-negative
The percentages are similar to those found in other publications that estimate that 23-57% of ET cases are JAK2V617F-positive [1]

Summary

Introduction

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by altered proliferation and differentiation of hematopoietic stem cells, persistent thrombocytosis > 450.000/mmc independent of thrombopoietin levels, excessive proliferation of bone marrow megakaryocytes with large, mature morphology, hyperlobulated nuclei and minor reticulin fibrosis. Other mutations can be discovered in JAK2V617Fnegative patients: JAK2 exon 12 mutations, mutations of the calreticulin gene (CALR 19p13.2) associated with altered activation of the JAK-STAT5 signalling pathway, or mutations in the exon 10 of the c-MPL gene (which codes for the thrombopoietin receptor) that lead to a permanent activation of the receptor and JAK-STAT pathway [5-9]. Several studies have revealed that oxidative stress, via increased levels of reactive oxygen species (ROS), is associated with chronic inflammation and is involved in atherogenesis, obesity, neurodegenerative disorders, carcinogenesis and disease progression in myeloproliferative neoplasms through the activation of the NFkB and NF-E2 pro-inflammatory pathways [14-20]. Informed consent was obtained from all patients and the study protocol was carried out in accordance with the standards imposed by the Declaration of Helsinki and with the approval of the Ethics Committee of the University of Medicine and Pharmacy of Craiova (approval no. 79/23.02.2017)

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