Prevalence of the Activating JAK2 Tyrosine Kinase Mutation V617F in the Budd-Chiari Syndrome.

Abstract

Budd-Chiari Syndrome (BCS) is a group of disorders resulting from obstruction to hepatic venous outflow; myeloproliferative disorder (MPD) accounts for 10–40% of cases. A number of BCS cases labelled as ‘idiopathic’ do not fulfil the accepted diagnostic criteria for MPD but have features suggestive of a latent form of MPD based on hyperplastic bone marrow and spontaneous erythroid colony progenitor cell culture studies; these cases may subsequently develop overt MPD. A clonal mutation in JAK2 tyrosine kinase (JAK2V617F) occurs in a high proportion of patients with MPD and is of potential use in the characterization of latent MPD in BCS. We studied 44 patients with BCS (female n=27, mean age 36.1 years, SD 13) presenting between 1985 and 2005. Genomic DNA obtained from archived bone marrow films was screened by allele-specific PCR for the JAK2V617F tyrosine kinase mutation. JAK2V617F was detected in 27/44 (61.4%) subjects. Fulminant hepatic failure was the presenting feature in 86.4%. 3/38 subjects had previously diagnosed Polycythemia Vera and all of these were JAK2V617F positive. Analysis for hereditary thrombophilia in 32/44 cases showed Factor V Leiden (FVL) heterozygosity (n=2) and Protein C deficiency (n=1); JAK2V617F was detected in one of the FVL cases. Screening for antiphospholipid antibodies and paroxysmal nocturnal hemoglobinuria in 31 and 30 out of 44 cases respectively proved negative. 22/44 cases had splenomegaly of which 72.2% had JAK2V617F detected. Mean hemoglobin concentration was higher in patients with JAK2V617F (12.4 g/dL, SD 2.8) compared to the wild-type allele (10.2 g/dL, SD 2.1)(p=0.005). Mean neutrophil count was similar (p=0.26) in both groups (JAK2V617F 7.8 x109/L, SD 5.5; wild-type 6.1 x109/L, SD 4.5). Mean platelet count was higher (p=0.01) in subjects with JAK2V617F (289 x109/L, SD 192) compared to wild-type (180 x109/L, SD 158). The bone marrow (BM) was hyperplastic in all lineages in 19/44 subjects of which 15 (78.9%) contained the JAK2V617F mutation. Importantly, in 25/44 subjects without hyperplastic BM, 48% had JAK2V617F detected. Clonal cytogenetic abnormalities occurred in 6/44 subjects all of which carried JAK2V617F. In 35 evaluable subjects, 10/35 (28.6%) showed endogenous erythroid colony (EEC) formation (8/10 JAK2V617F positive), and the remainder (25/35) showed no EEC formation (14/25 JAK2V617F positive). Treatment of BCS included anticoagulation (n=44), porto-systemic shunt insertion (n=26) and orthotopic liver transplantation (OLT) (n=15). Overall survival was 81.8% (median 32.5 months, range 2 days-240 months). In the 8 non-survivors, JAK2V617F was detected in 50%. 15/44 subjects underwent OLT (11/15 JAK2V617F positive) of which 14/15 are alive at a median of 36 months post transplant (1–240 months). 14/44 subjects were treated with cytoreductive treatment following diagnosis of BCS and in 92.9% of these JAK2V617F was detected. 5/15 subjects went on to receive cytoreductive treatment following OLT of which all were JAK2V617F positive. We have found a high prevalence of JAK2V617F in patients with BCS. Latent MPD was missed in 12/25 subjects on BM morphology and 14/25 subjects on BM progenitor culture. We suggest that JAK2V617F analysis should be performed in all new cases of BCS. Given their age, these patients are possible candidates for JAK2 targeted therapy.

The JAK2V617F tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis

“…Almost three-quarters of the patients had molecular evidence suggestive of a MPD, highlighting the importance of these diseases as a cause of lifethreatening intra-abdominal thrombosis even when they are clinically latent and not able to be diagnosed using conventional criteria. This observation is in accordance with other studies demonstrating a high frequency of JAK2 V617F in unselected patients with HVT/PVT (Patel et al, 2006;Primignani et al, 2000;De Stefano et al, 2007).…”

“…Causes of PVT and HVT include MPDs, such as polycythemia vera (PV) and essential thrombocythemia (ET; Denninger et al, 2000). Although older case series suggested that a significant number of PVT and HVT were idiopathic, more recent data suggest that clinically latent MPDs are an important underlying cause of these events (Patel et al, 2006;De Stefano et al, 1997). Patients may have morphologic features of a MPD in the marrow but have normal peripheral blood counts and defy diagnosis by conventional criteria, only developing overt evidence of a MPD several years after presenting with thrombosis (McNamara et al, 2002).…”

JAK2 V617F mutation and 46/1 haplotype in Chinese Budd‐Chiari syndrome patients

“…Previous studies reported JAK2V617F mutation was detected in a larger number of sporadic BCS patients, [22][23][24] and the prevalence of mutation was different. In 2006, Patel et al 8 and Primignani M et al 10 identified a high prevalence, 58.5% and 40%, respectively. Then, Regina et al 23 found that JAK2V617F was specifically associated with idiopathic splanchnic vein thrombosis, with a prevalence of 18.2% in BCS patients.…”

“…6,7 The etiology of BCS has been attributed to a variety of genetic and environmental factors while myeloproliferative neoplasms (MPNs) is considered to be the leading cause of BCS. A somatic mutation identified in 40-59% of patients with BCS, [8][9][10] and 80% of MPNs is JAK2V617F mutation providing a robust diagnostic tool. 11 The prevalence of JAK2V617F mutation in Chinese BCS and the exact role in the pathogenic mechanism is unclear.…”

Successful reduced‐intensity bone marrow transplantation in a patient with bone marrow failure associated with Seckel syndrome

“…The presence of the JAK2 V617F mutation has proved even more useful to distinguish, in patients with true polycythaemia, those with Polycythaemia Vera (PV, 90% JAK2 V617F positive) from those with Idiopathic Erythrocytosis (IE, V617F-negative) (Percy et al, 2006;unpublished observations). The JAK2 V617F mutation is also present in about half of the patients with Corresspondence ª 2008 The Authors splanchnic vein thrombosis (Patel et al, 2006), suggesting that occurrence of thrombosis in these patients is caused by an undiagnosed MPD. However, there still exists patients in whom the diagnosis of MPD is highly suspected but the absence of the JAK2 V617F mutation does not allow correct classification.…”