TY - JOUR
AU - Koutroubakis, Ioannis E.
AB - To the Editor: Recently Janus kinase 2 (JAK2) mutations have been described in several Philadelphia-negative myeloproliferative disorders (MDP) as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis, conditions complicated by thrombosis.1 The point mutation in JAK2 encodes a valine-to-phenylalanine change at position 617 (JAK2 V617F) and confers constitutive tyrosine kinase activity.2 It has been suggested that thrombosis in MPD may be due to JAK2 mutation. Moreover, screening for JAK2 V617F has been carried out in a series of splanchnic, cerebral, and leg deep vein thromboses (DVTs) without overt MDP.3,4 Results from these studies indicate that the JAK2 V617F mutation in the absence of overt MDP is highly associated with splanchnic vein thrombosis and sporadically with cerebral thrombosis. Thromboembolism is a disease-specific extraintestinal manifestation of inflammatory bowel disease (IBD)5 that develops as the result of multiple interactions between acquired and genetic risk factors. Arterial and venous thromboembolism is the most important complication, representing a significant cause of morbidity and mortality in IBD patients. The most commonly detected risk factors for thrombophilia in this disease are factor V R506Q (Leiden) mutation, plasminogen activator inhibitor gene polymorphism, hyperhomocysteinemia, and antiphospholipid antibodies. However, the prevalence of these factors does not differ between patients with IBD associated with vascular complications and those with thrombosis without IBD.6 Different cytokines stimulate the JAK and signal transducer and activator of transcription (JAK/STAT) pathway. JAK2 is also important in vascular diseases, such as atherosclerosis in which inflammation plays an important role.7 The aim of our study was to investigate the frequency of the JAK2 V617F mutation, which is the most common mutation described in MPD, in a group of 48 thrombotic IBD patients (22 with CD, 26 with UC) from Argentina (n = 23) and Crete (n = 25). The clinical characteristics of patients included in this study are reported in Table 1. No case had overt MPD, whereas some cases (n = 4) had a history of more than 1 thrombotic event. The diagnosis of vascular complications was defined by typical clinical characteristics and diagnostic instrumental investigation (Doppler ultrasonography, computed tomography, magnetic resonance imaging, or angiography). Table 1. Clinical characteristics and JAK2 V617F mutation status in IBD patients with vascular complications     View Large Table 1. Clinical characteristics and JAK2 V617F mutation status in IBD patients with vascular complications     View Large Genomic DNA was isolated from peripheral blood according to an in-house DNAzol extraction procedure (Invitrogen, Breda, The Netherlands). Forty-eight patients with IBD varying in age of onset of IBD from 2 to 65 years (median 37.5 years) presented with different thrombotic events (Table 1). A semiquantitative Taqman assay was used to determine the percentage of the JAK2 V617F mutation among wild-type DNA. No JAK2 V617F mutation was found in the 48 IBD patients with thrombotic complications. JAK2 V617F mutation has been found associated with elevated hemoglobin levels and leukocytosis, which may be directly associated with the increased thrombotic risk in MPD. On the other hand, thromboembolism in IBD is not associated with elevated hemoglobin levels and leukocytosis. The finding of the absence of the JAK2 V617F mutation in the thrombotic IBD patients suggests that other mechanisms play an important role in the pathogenesis of thrombosis in IBD. The small number of cases with splanchnic vein thrombosis in our series (but also in other IBD series), which is mainly associated JAK2 V617F mutation, could also be an explanation of this finding. Because recent studies in MPD have found other mutations in the gene coding for JAK2 (chromosome 9p24) such as JAK2 exon 12 mutations,8 further study of IBD patients with these serious complications is being undertaken. References 1. Levine RL, Wadleigh M, Cools J, et al.   Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell.  2005; 7: 387– 397. CrossRef Search ADS PubMed  2. Cools J, DeAngelo DJ, Gotlib J, et al.   A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med.  2003; 348: 1201– 1214. CrossRef Search ADS PubMed  3. Boissinot M, Garand R, Hamidou M, et al.   The JAK2–V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood.  2006; 108: 1781– 1782. CrossRef Search ADS PubMed  4. De Stefano V, Fiorini A, Rossi E, et al.   Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost.  2007; 5: 708– 714. CrossRef Search ADS PubMed  5. Miehsler W, Reinisch W, Valic E, et al.   Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? Gut.  2004; 53: 542– 548. CrossRef Search ADS PubMed  6. Koutroubakis IE, Sfiridaki A, Tsiolakidou G, et al.   Genetic risk factors in patients with inflammatory bowel disease and vascular complications: case-control study. Inflamm Bowel Dis.  2007; 13: 410– 415. CrossRef Search ADS PubMed  7. Burova E, Vassilenko K, Dorosh V, et al.   Interferon gamma-dependent transactivation of epidermal growth factor receptor. FEBS Lett.  2007; 581: 1475– 1480. CrossRef Search ADS PubMed  8. Rothlisberger B, Huber A, Bargetzi M, et al.   JAK2 exon 12 mutation in JAK2V617F-negative polycythemia vera. Leuk Lymphoma.  2008; 49: 586– 588. CrossRef Search ADS PubMed  Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
TI - JAK2 V617F mutation is not involved in thromboembolism in IBD
JF - Inflammatory Bowel Diseases
DO - 10.1002/ibd.20471
DA - 2008-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/jak2-v617f-mutation-is-not-involved-in-thromboembolism-in-ibd-2m2eSwAMsT
SP - 1606
EP - 1607
VL - 14
IS - 11
DP - DeepDyve
ER -