Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.

Splanchnic vein thrombosis (SVT) includes the Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). Primary BCS is characterized by thrombosis of the hepatic veins and/or the suprahepatic inferior vena cava, resulting in obstruction of the hepatic venous outflow tract.1  A distinct disorder that also includes the liver vasculature is PVT, which often occurs in association with local factors, such as liver cirrhosis or malignancy.2,3  PVT in the absence of liver cirrhosis or local malignancy is less frequently encountered and shows a considerable overlap in etiology with primary BCS. In this meta-analysis, we will focus exclusively on primary BCS and nonmalignant, noncirrhotic PVT.

Philadelphia-negative myeloproliferative neoplasms (MPNs) are the most frequent underlying prothrombotic factor in BCS and PVT, with a reported prevalence of 30%-50%4-9  and 15%-30%,2,6,10-12  respectively. Peripheral blood cell counts often remain within a normal range because of portal hypertension and its sequelae (splenomegaly, hemodilution, and iron deficiency). Despite suggestive features of an MPN, fulfillment of usual diagnostic criteria can therefore often be lacking, which is a notorious problem in MPN diagnostics in these patients. The term occult MPN has been used in the literature for patients who lack these typical hematologic features of MPN but who harbor clear features of MPN, for example, by means of bone marrow (BM) biopsy findings and growth of erythroid colonies in the absence of exogenous erythropoietin, referred to as spontaneous endogenous erythroid colonies, both of which have several limitations.12-14  BM biopsy is invasive, and the distinction between MPN and reactive BM is not unambiguous. Endogenous erythroid colony assays are performed only in specialized centers, are difficult to standardize, and offer the possibility of false positives in nonclonal causes of erythrocytosis and healthy controls.15 

The discovery of the JAK2V617F gain-of-function mutation in 2005, found in 95% of patients with polycythemia vera (PV) and in ∼ 50% of patients with essential thrombocythemia (ET) and myelofibrosis (MF), represented a crucial advance in the diagnostic approach to MPNs.16-19  The close relationship between MPNs and BCS and PVT was confirmed by the high frequency of JAK2V617F among these patients, present in 30%-45%4,9,20  and 17%-35%,11,20,21  respectively. Interestingly, JAK2V617F screening offered a new diagnostic tool to detect these so-called occult MPNs in SVT patients, as this mutation was frequently demonstrated in SVT patients without characteristic elevated peripheral blood counts.22 JAK2V617F screening has since become part of the standard diagnostic workup in SVT.

Other advances in the field of MPNs were the identification of the MPL515 mutations in the thrombopoietin receptor gene in ∼ 5% and 10% of patients with JAK2V617F-negative ET and MF, respectively, and JAK2 exon 12 mutations in < 5% of JAK2V617F-negative PV patients.23-27  Both mutations have been described in small numbers of SVT patients, but their clinical relevance has not yet been fully clarified.28,29 

The aims of this study were: (1) to assess the prevalence of MPNs and JAK2V617F in BCS and PVT patients; (2) to determine the frequency of MPN subtypes in BCS and PVT patients; (3) to determine JAK2V617F prevalence in BCS and PVT patients without typical hematologic features of MPN; and (4) to evaluate the clinical relevance of the MPL and JAK2 exon 12 mutations in BCS and PVT patients.

Search strategy and selection criteria

One of the authors (J.H.S.) searched Ovid MEDLINE and EMBASE from 1980 to August 1, 2011. The search strategy was restricted to published data and the English language using the subject headings presented in the Appendix. The search was supplemented by manually reviewing the reference list of retrieved articles and relevant reviews. Titles and abstracts of retrieved citations were screened, and potentially suitable studies were read in full by J.H.S. and F.W.G.L. Studies were selected when the following criteria were met: (1) patients were diagnosed with primary BCS or noncirrhotic, nonmalignant PVT, or patients with an underlying malignancy or cirrhosis were explicitly mentioned; (2) information on MPNs and/or JAK2V617F, JAK2 exon 12, or MPL515 was provided; (3) the cohort consisted of patients in which patients with established MPNs or other thrombophilic factors were not excluded; (4) SVT was subdivided in BCS and PVT; and (5) a minimum of 10 patients were included. Disagreements were resolved after discussion or after having collected the opinion of a third reviewer (H.L.A.J.).

Data extraction

J.H.S. extracted data on each selected study (year of publication, study design, demographics, criteria for diagnosing MPNs, number of patients included). Patients with BCS in the presence of a malignancy and PVT patients with a malignancy or cirrhosis were excluded from the analysis. Patients with combined BCS and PVT were classified as BCS according to common practice.4  MPNs were defined according to the diagnostic criteria used in the included studies. Different diagnostic criteria, mostly World Health Organization or Polycythemia Vera Study Group criteria, were used in the various studies. JAK2V617F, being discovered in 2005, was only reported in studies published after this date and was almost invariably presented as a separate entity, rather than being integrated in MPN workup as is now customary. We therefore extended MPN workup of these studies as follows. JAK2V617F was considered pathognomonic for MPN, and patients whodid not meet the diagnostic criteria for MPN but were found JAK2V617F-positive were classified as MPN. MPN subtypes were classified according to the diagnostic criteria used in each study. If high clinical suspicion based on typical hematologic features (ie, clinical, laboratory and/or morphological) of MPN existed in patients with JAK2V617F, but insufficient criteria for a specific subtype was met, the patient was classified as MPN unclassifiable. If JAK2V617F was present, but clinical, laboratory and/or morphologic data were insufficiently collected, patients were designated as solitary JAK2V617F positive MPN. Studies that did not report on JAK2V617F were only included in the MPN subtype analysis and not in the MPN prevalence analysis, as this would result in an underestimation of MPN prevalence. Corresponding authors were contacted in case essential data were not mentioned, with a reminder sent after 2 weeks.

Statistical analysis

Weighted mean proportion and 95% confidence intervals (CI) of MPNs, JAK2V617F, and MPN subtypes prevalence were calculated using a random effects model. Differences in prevalence were calculated by means of Pearson χ2. All statistical tests were 2-sided, and P < .05 was considered statistically significant. Statistical heterogeneity was evaluated using the I2 statistic, which describes the percentage of variation across studies that is the result of heterogeneity rather than chance, with P < .05 representing statistically significant heterogeneity. If heterogeneity was present, the analyses were repeated, removing one study a time to identify the source of heterogeneity. All analyses were performed with Comprehensive Meta Analysis Version 2.2 for Windows (Biostat), and the overall effects are presented as event rates with 95% CI.

Study identification and selection

We identified 822 potentially relevant publications: 256 from MEDLINE and 566 from EMBASE. A total of 109 studies were duplicate, and 665 studies were excluded after title and abstracts screening according to predefined inclusion criteria. The remaining studies were retrieved in full for detailed evaluation. Five additional studies were identified from reference lists. Figure 1 shows the study selection process.

Figure 1

Flow diagram of study selection process.

Figure 1

Flow diagram of study selection process.

Close modal

Of the 53 retrieved studies, 21 were excluded because of the following reasons: in 2 studies, patients with malignancies or liver cirrhosis were not excluded or explicitly mentioned30,31 ; 5 studies were based on selected cohorts in which patients with established MPNs or other thrombophilic factors were excluded32-36 ; one study did not differentiate SVT into BCS and PVT37 ; in 4 studies, MPN criteria were not acceptable or unclear14,38-40 ; and 2 studies included < 10 patients.29,41  In addition, 7 studies contained duplicate data.42-48  This resulted in 32 studies eligible for inclusion.

Study characteristics and quality

Tables 1 and 2 summarize the characteristics of the included studies for BCS and PVT, respectively. Study size ranged between 10 and 237 patients. Nineteen studies, including 1062 patients, reported on MPNs and/or the JAK2V617F mutation in BCS patients. Fifteen studies, including 855 patients, reported on MPNs and/or the JAK2V617F mutation in PVT patients. Three studies, including 268 patients, reported on JAK2 exon 12 mutations.20,28,49  Two studies, including 305 patients, reported on MPL515 mutations.20,28  Five studies included a healthy control population21,47,50-52 ; all other studies were essentially retrospective cohort studies. Twenty of these studies enrolled patients consecutively.2,4,5,7-9,11,12,21,28,52-61  Studied populations partly overlapped in 9 publications (ie, to some extent duplication of patients).2,5-7,9,14,20,47,62 

Table 1

Baseline characteristics of studies, including BCS patients

ReferenceYDesignMale/femaleMedian age, y (range)Median follow-up, mo (range)MPN criteriaMPN
JAK2V617F
Classification (PV/ET/MF/U/solitaryJAK2)*
No.%No.%
Smira et al58  2010 RC NA NA NA NA NA NA 14/20 70 NA 
Zahn et al61  2010 RC 4/16 34 (14-60) NA BM if MPN was suspected 6/20 30 NA NA 4/1/0/1/0 
Darwish Murad et al4  2009 RC 70/93 38 (16-83) 17 (0.1-31) WHO 2001, BM in majority of patients 56/103 39 35/121 29 27/9/2/15/3 
Xavier et al60  2009 RC 11/20 33 (17-50) 51 (1-104) WHO 2001, BM if MPN was suspected 8/31 26 8/31 26 4/2/0/0/2 
Rajani et al8  2009 RC 19/24 40 (4-80) 32 (0.5-192) BM in 79% of patients 14/36 39 NA NA 8/6/0/0 
Kiladjian et al20  2008 RC 69/35 36 (IQR 27-46) 47 (range NA) BM in nearly all patients 47/104 45 47/104 45 17/3/0/27/0 
Colaizzo et al53  2008 RC 9/23 35 (14-66) NA WHO criteria 2001 17/32 53 11/32 34 4/1/9/2/1 
Uskudar et al59  2008 RC 40/35 34 (14-72) 18 (1-30) BM if MPN was suspected 6/72 NA NA 5/1/0/0/0 
DeStefano et al63  2007 RC 4/11 NA 48 (24-108) PVSG 2000 5/15 33 5/15 33 1/3/0/0/1 
Smalberg et al9  2006 RC 14/26 28 (18-53) 7.1 ± 6.9 WHO 2001, BM in majority of patients 13/40 33 7/17 41 6/6/0/1/0 
Patel et al51  2006 RC 15/26 36 ± 13.3 49 (8-87)§ BM in all patients 27/55 49 24/41 59 6/8/0/14/0 
Primignani et al52  2006 RC 8/12 33 (19-72) NA WHO 2001, based on BM only 9/20 45 8/20 40 3/3/0/3/0 
Eapen et al62  2006 RC 22/39 36 (16-77) 52 (0-181) Not specified 17/61 28 NA NA 7/6/1/3/0 
Khuroo et al54  2005 RC 17/23 27 ± 7.3 NA BM if MPN was suspected 4/40 10 NA NA 1/3/0/0/0 
Darwish Murad et al5  2004 RC 78/159 35 (13-76) 44 (0-203) BM if MPN was suspected 54/237 23 NA NA 45/9/0/0/0 
Attwell et al74  2004 RC 7/15 24 (18-68) NA BM if MPN was suspected 11/22 50 NA NA 8/3/0/0/0 
Janssen et al47  2000 CC 16/27 40 (19-60) NA BM if MPN was suspected 12/43 28 NA NA 10/1/0/1/0 
Denninger et al6  2000 RC NA NA NA BM if MPN was suspected 12/32 38 NA NA 12/0/0/4/0 
Mahmoud et al7  1996 RC 17/27 37 (19-60) NA BM if MPN was suspected 17/42 40 NA NA 11/5/1/0/0 
ReferenceYDesignMale/femaleMedian age, y (range)Median follow-up, mo (range)MPN criteriaMPN
JAK2V617F
Classification (PV/ET/MF/U/solitaryJAK2)*
No.%No.%
Smira et al58  2010 RC NA NA NA NA NA NA 14/20 70 NA 
Zahn et al61  2010 RC 4/16 34 (14-60) NA BM if MPN was suspected 6/20 30 NA NA 4/1/0/1/0 
Darwish Murad et al4  2009 RC 70/93 38 (16-83) 17 (0.1-31) WHO 2001, BM in majority of patients 56/103 39 35/121 29 27/9/2/15/3 
Xavier et al60  2009 RC 11/20 33 (17-50) 51 (1-104) WHO 2001, BM if MPN was suspected 8/31 26 8/31 26 4/2/0/0/2 
Rajani et al8  2009 RC 19/24 40 (4-80) 32 (0.5-192) BM in 79% of patients 14/36 39 NA NA 8/6/0/0 
Kiladjian et al20  2008 RC 69/35 36 (IQR 27-46) 47 (range NA) BM in nearly all patients 47/104 45 47/104 45 17/3/0/27/0 
Colaizzo et al53  2008 RC 9/23 35 (14-66) NA WHO criteria 2001 17/32 53 11/32 34 4/1/9/2/1 
Uskudar et al59  2008 RC 40/35 34 (14-72) 18 (1-30) BM if MPN was suspected 6/72 NA NA 5/1/0/0/0 
DeStefano et al63  2007 RC 4/11 NA 48 (24-108) PVSG 2000 5/15 33 5/15 33 1/3/0/0/1 
Smalberg et al9  2006 RC 14/26 28 (18-53) 7.1 ± 6.9 WHO 2001, BM in majority of patients 13/40 33 7/17 41 6/6/0/1/0 
Patel et al51  2006 RC 15/26 36 ± 13.3 49 (8-87)§ BM in all patients 27/55 49 24/41 59 6/8/0/14/0 
Primignani et al52  2006 RC 8/12 33 (19-72) NA WHO 2001, based on BM only 9/20 45 8/20 40 3/3/0/3/0 
Eapen et al62  2006 RC 22/39 36 (16-77) 52 (0-181) Not specified 17/61 28 NA NA 7/6/1/3/0 
Khuroo et al54  2005 RC 17/23 27 ± 7.3 NA BM if MPN was suspected 4/40 10 NA NA 1/3/0/0/0 
Darwish Murad et al5  2004 RC 78/159 35 (13-76) 44 (0-203) BM if MPN was suspected 54/237 23 NA NA 45/9/0/0/0 
Attwell et al74  2004 RC 7/15 24 (18-68) NA BM if MPN was suspected 11/22 50 NA NA 8/3/0/0/0 
Janssen et al47  2000 CC 16/27 40 (19-60) NA BM if MPN was suspected 12/43 28 NA NA 10/1/0/1/0 
Denninger et al6  2000 RC NA NA NA BM if MPN was suspected 12/32 38 NA NA 12/0/0/4/0 
Mahmoud et al7  1996 RC 17/27 37 (19-60) NA BM if MPN was suspected 17/42 40 NA NA 11/5/1/0/0 

RC indicates retrospective cohort; CC, case-control; U, unclassifiable; solitaryJAK2, solitary JAK2-positive; NA, not available; IQR, interquartile range; and BM, bone marrow biopsy.

*

MPNs that became overt during follow-up were included in subtype analysis.

Mean age/follow-up (range) or ± SD.

Median follow-up of patients with JAK2V617F-positive MPNs without elevated blood counts.

§

Median time of diagnosis to overt MPNs.

Table 2

Baseline characteristics of studies including portal vein thrombosis patients

ReferenceYDesignMale/femaleMedian age, y (range)Median follow-up, mo, (range)MPN criteriaMPNs
JAK2V617F
Classification (PV/ET/MF/U/solitaryJAK2)*
No.%No.%
Hoekstra et al64  2011 RC 13/31 48 (18-79) 70 (5-252) WHO 2008 criteria NA NA NA NA 14/12/7/11/0 
Rajani et al57  2010 RC 80/93 57 (15-94) 30 (0-116) Not specified, BM in majority of patients 15/89 17 NA NA 10/4/0/0/0§ 
Orr et al56  2010 RC 14/21 43 (18-72) 51 (10-300) WHO 2001, BM if MPN was suspected 6/35 17 16/35 46 2/3/1/1/9§ 
Plessier et al11  2010 RC 50/52 48 (16-84) 20 (0-75) WHO 2001, BM in majority of patients 17/102 17 14/82 17 3/11/3/2/2 
Xavier et al60  2009 RC 40/37 42 (17-74) 51 (1-104) WHO 2001, BM if MPN was suspected 3/76 15/76 20 1/3/2/1/8 
Kiladjian et al20  2008 RC 77/60 42 (IQR 30-57) 66 (range NA) Not specified, BM in nearly all patients 48/137 28 47/137 34 14/8/3/23/0 
Bayraktar et al10  2008 RC 9/16 45 (24-73) NA WHO, BM if MPN was suspected 6/25 24 6/25 24 3/2/1/0/5 
DeStefano et al63  2007 RC 27/31 NA 48 (24-108) PVSG 2000 8/58 14 24/58 41 4/5/0/0/15 
McMahon et al50  2007 RC 9/1 NA NA Not specified 0/10 1/10 10 0/0/0/0/1 
Colaizzo et al21  2007 RC 44/55 41 (10-85) 41 (3-114) WHO 2001 9/99 17/99 17 3/5/5/2/5§ 
Primignani et al52  2006 RC 29/44 42 (13-66) NA WHO 2001, based on BM only 31/55 56 26/73 36 5/14/5/9/0 
Kocher et al55  2005 RC 10/10 51 (17-83) 21 (2-61) Not specified, BM if MPN was suspected 6/20 30 NA NA 2/4/0/0/0 
Janssen et al2  2001 RC NA NA 3.9 (0.1-13.1) Not specified, BM if MPN was suspected 22/82 27 NA NA 12/2/5/2/0§ 
Denninger et al6  2000 RC NA NA NA Not specified, BM if MPN was suspected 5/36 14 NA NA 5/0/0/6/0 
Valla et al12  1988 RC 14/17 NA NA Not specified, BM if MPN was suspected 7/31 23 NA NA 2/1/2/6/0 
ReferenceYDesignMale/femaleMedian age, y (range)Median follow-up, mo, (range)MPN criteriaMPNs
JAK2V617F
Classification (PV/ET/MF/U/solitaryJAK2)*
No.%No.%
Hoekstra et al64  2011 RC 13/31 48 (18-79) 70 (5-252) WHO 2008 criteria NA NA NA NA 14/12/7/11/0 
Rajani et al57  2010 RC 80/93 57 (15-94) 30 (0-116) Not specified, BM in majority of patients 15/89 17 NA NA 10/4/0/0/0§ 
Orr et al56  2010 RC 14/21 43 (18-72) 51 (10-300) WHO 2001, BM if MPN was suspected 6/35 17 16/35 46 2/3/1/1/9§ 
Plessier et al11  2010 RC 50/52 48 (16-84) 20 (0-75) WHO 2001, BM in majority of patients 17/102 17 14/82 17 3/11/3/2/2 
Xavier et al60  2009 RC 40/37 42 (17-74) 51 (1-104) WHO 2001, BM if MPN was suspected 3/76 15/76 20 1/3/2/1/8 
Kiladjian et al20  2008 RC 77/60 42 (IQR 30-57) 66 (range NA) Not specified, BM in nearly all patients 48/137 28 47/137 34 14/8/3/23/0 
Bayraktar et al10  2008 RC 9/16 45 (24-73) NA WHO, BM if MPN was suspected 6/25 24 6/25 24 3/2/1/0/5 
DeStefano et al63  2007 RC 27/31 NA 48 (24-108) PVSG 2000 8/58 14 24/58 41 4/5/0/0/15 
McMahon et al50  2007 RC 9/1 NA NA Not specified 0/10 1/10 10 0/0/0/0/1 
Colaizzo et al21  2007 RC 44/55 41 (10-85) 41 (3-114) WHO 2001 9/99 17/99 17 3/5/5/2/5§ 
Primignani et al52  2006 RC 29/44 42 (13-66) NA WHO 2001, based on BM only 31/55 56 26/73 36 5/14/5/9/0 
Kocher et al55  2005 RC 10/10 51 (17-83) 21 (2-61) Not specified, BM if MPN was suspected 6/20 30 NA NA 2/4/0/0/0 
Janssen et al2  2001 RC NA NA 3.9 (0.1-13.1) Not specified, BM if MPN was suspected 22/82 27 NA NA 12/2/5/2/0§ 
Denninger et al6  2000 RC NA NA NA Not specified, BM if MPN was suspected 5/36 14 NA NA 5/0/0/6/0 
Valla et al12  1988 RC 14/17 NA NA Not specified, BM if MPN was suspected 7/31 23 NA NA 2/1/2/6/0 

RC indicates retrospective cohort; CC, case-control; U, unclassifiable; solitaryJAK2, solitary JAK2-positive; NA, not available; IQR, interquartile range; and BM, bone marrow biopsy.

*

MPNs that became overt during follow-up were included in subtype analysis.

Mean age/follow-up (range) was reported.

Median follow-up of patients with JAK2V617F-positive MPNs without elevated blood counts.

§

In each of these studies, also one patient with chronic myeloid leukemia was reported.

MPNs and JAK2V617F in BCS

A total of 1062 BCS patients were included in the analysis (Figure 2). Of these patients, 440 underwent a complete diagnostic workup for MPN, including clinical, laboratory, and/or morphologic features of MPN as well as JAK2V617F mutation analysis. MPN was present in 40.9% (95% CI, 32.9%-49.5%) of these patients. Of the MPN patients, 80.3% were JAK2V617F-positive (95% CI, 63.5%-90.5%). The JAK2V617F mutation was present in 159 of 401 tested patients, for a mean prevalence of 41.1% (95% CI, 32.3%-50.6%). JAK2V617F screening in patients without typical hematologic features of MPN yielded diagnosis of MPN in 17.1% (95% CI, 7.9%-33.3%). Distribution of MPN subtypes was as follows: PV, ET, MF, unclassifiable MPNs, and solitary JAK2V617F-positive MPNs in 52.9% (95% CI, 42.2%-63.4%), 24.6% (95% CI, 18.0%-32.5%), 6.7% (95% CI, 3.7%-11.9%), 17.0% (95% CI, 9.8%-27.9%), and 6.5% (95% CI, 2.4%-16.3%), respectively (supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article).

Figure 2

Forest plots. (A) MPNs in patients with BCS. (B) JAK2V617F in patients with BCS.

Figure 2

Forest plots. (A) MPNs in patients with BCS. (B) JAK2V617F in patients with BCS.

Close modal

Four studies made a distinction between diagnosis of MPN before or simultaneous to BCS, in which 13 of 50 patients were diagnosed with MPN before BCS, whereas BCS was the presenting symptom of MPN in 37 of 50 patients.7,9,53,60  Follow-up of JAK2V617F-positive MPNs without typical hematologic MPN features was provided in 3 publications, in which 11 of 28 patients (41%) developed characteristic laboratory or morphologic features of MPN, ranging from 0.7 to 7 years after diagnosis of BCS.51,60,63 

MPNs and JAK2V617F in PVT

A total of 855 PVT patients were included in the analysis (Figure 3). MPNs were present in 188 of 615 or 31.5% (95% CI, 25.1%-38.8%) of the patients who underwent complete diagnostic workup for MPNs, including clinical, laboratory, and/or morphologic features of MPN as well as JAK2V617F mutation analysis. Of the MPN patients, 86.6% were JAK2V617F-positive (95% CI, 73.1%-93.9%). The JAK2V617F mutation was present in 166 of 595 tested patients, for a mean prevalence of 27.7% (95% CI, 20.8%-35.8%). JAK2V617F mutation analysis yielded diagnosis of MPN in 15.4% (95% CI, 7.9%-33.3%) of screened PVT patients without characteristic hematologic features of MPNs, which would otherwise have been undiagnosed. Distribution of MPN subtypes was as follows: PV, ET, MF, unclassifiable MPNs, and solitary JAK2V617F-positive MPNs in 27.5% (95% CI, 19.0%-38.1%), 26.2% (95% CI, 19.1%-34.8%), 12.8% (95% CI, 8.0%-19.9%), 17.7% (95% CI, 9.9%-29.7%), and 24.0% (95% CI, 11.5%-43.3%), respectively (supplemental Figure 1).

Figure 3

Forest plots. (A) MPNs in patients with PVT. (B) JAK2V617F in patients with PVT.

Figure 3

Forest plots. (A) MPNs in patients with PVT. (B) JAK2V617F in patients with PVT.

Close modal

Five studies differentiated between diagnosis of MPN before or simultaneous to PVT diagnosis, showing that 17 of 64 patients were diagnosed with MPN before PVT, whereas PVT was the presenting symptom of MPN in 47 of 64 patients.10,14,56,60,64  Follow-up of JAK2V617F-positive MPNs without typical MPN features counts was provided in 4 publications in which 6 of 48 patients (13%) developed characteristic laboratory or morphologic features of MPN, ranging from 1-10 years after diagnosis of PVT.21,56,60,63  One study described the long-term follow-up of 44 PVT patients with an underlying MPN.64  Five PV and 2 ET patients developed secondary MF, 3 patients with MF progressed to end-stage MF, and 4 patients developed acute myeloid leukemia after a median period of 9.7 years (range, 1-17 years) after MPN diagnosis. A total of 29% and 18% of the deaths in this cohort were attributable to end-stage MF and progression to acute myeloid leukemia, respectively.

JAK2 exon 12 and MPL515 mutations in SVT

A total of 268 SVT patients (ratio BCS/PVT unknown) were tested for JAK2 exon 12 and 305 for MPL515 mutations. Three of these patients were found to carry MPLW515K mutation. The JAK2 exon 12 mutation was not present in any of these patients.

Differences between BCS and PVT

Prevalence of JAK2V617F and MPNs was higher in BCS than in PVT (P = .03 and P = .09, respectively). With regards to the subtype analysis, prevalence of PV and MF was higher in BCS than in PVT patients (P = .001 and P = .09, respectively). Prevalence of solitary JAK2V617F-positive MPNs was higher in PVT compared with BCS (P = .03). There was no difference between the prevalence of ET and MPNs unclassifiable (P = .77 and P = .92, respectively). There was no difference in identification rate of MPNs without typical features by means of JAK2V617F between the 2 disorders (17.1% vs 15.4%, P = .68). All analyses were repeated, including only publications since 2005 and excluding papers with potentially duplicated inclusion of patients, which showed the same results (data not shown).

I2 and heterogeneity among studies

A considerable heterogeneity among the studies was observed (P < .05). We therefore performed an additional analysis in which we excluded one study per analysis. This analysis showed that no single study significantly affected the point estimate of MPNs, JAK2V617F, and its subtypes in both BCS and PVT.

In this meta-analysis, we assessed the role of MPNs in the etiology of primary BCS and nonmalignant, noncirrhotic PVT. The results showed a higher prevalence of MPNs and JAK2V617F in BCS compared with PVT patients. Interestingly, our results indicate a difference in the distribution of underlying MPN subtype between BCS and PVT patients, PV being the most frequent MPN in BCS. Finally, MPL515 mutations were present in < 1% of BCS and PVT series, whereas JAK2 exon 12 mutations have never been published so far in SVT patients.

Two meta-analyses have previously evaluated the impact of the JAK2V617F mutation in SVT patients. In 2009, Dentali et al assessed the role of JAK2V617F in patients with various venous thrombosis, including SVT, deep vein thrombosis of the lower extremities or pulmonary embolism, cerebral vein thrombosis, and retinal vein thrombosis.65  In this study, a remarkable high prevalence of JAK2V617F in SVT was reported, whereas its prevalence in other forms of VTE was similar to that of the general population. SVT was not subdivided into BCS and PVT, which impedes comparison of MPNs and JAK2V617F prevalence between the 2 disorders. Qi et al calculated the prevalence of JAK2V617F in BCS and PVT separately and assessed its prevalence after exclusion of cases with preexisting MPNs.66  In contrast to those previously published studies, we set out to provide a complete overview of MPNs in the etiology of BCS and PVT. This included assessment of the prevalence of MPNs and JAK2V617F as well as the prevalence of MPN subtypes. In addition, we have compared BCS and PVT for each of these variables, as it is increasingly recognized that, despite several similarities, risk profiles are different between these patients.67  To achieve this goal, we have assessed all the publications regarding MPNs in SVT since 1980.

The results of this meta-analysis indicate a high prevalence of MPNs in patients with SVT. The strong relation between MPNs and SVT is confirmed by the high prevalence of JAK2V617F in these patients. Interestingly, JAK2V617F and MPNs were more prevalent in BCS compared with PVT patients, the latter showing a statistical trend rather than a significant difference. This difference may be partially explained by the more prominent role of local risk factors, such as focal inflammatory lesions and injury to the portal venous system, in the development of PVT.68  This might contribute to the relatively limited role of general prothrombotic conditions reported in the etiology of PVT. Why MPNs and JAK2V617F are so strongly related to thrombosis of the splanchnic veins remains an unresolved issue. Further research is needed to identify associated factors that could be involved in the pathogenesis of thrombosis at these specific sites. In this respect, it has been speculated that endothelial cells of the splanchnic veins may interact with activated platelets and/or leukocytes and increased microparticles, which are characteristic features of MPNs.69  In addition, these endothelial cells have been shown to carry the JAK2V617F mutation and could be part of the malignant process.70 

We observed a marked difference between BCS and PVT patients regarding the distribution of MPN subtypes. PV was clearly more common in BCS compared with PVT. The prothrombotic effect of high hematocrit values in PV is well established.71  Under low-shear conditions, such as in the venous circulation, a high hematocrit has a more important impact on blood viscosity and causes a major disturbance to blood flow.72,73  This mechanism may be mediated by the interaction between adhesion molecules and red blood cells. Wautier et al described an increased adhesiveness of red blood cells in PV to human umbilical vein endothelial cells and elegantly showed that adhesion was inversely related to increasing shear stress (ie, adhesion proved particularly increased at low shear rates).9  It is possible that variability in the expression of these molecules along the vascular tree along with differences in flow conditions might contribute to the site specificity of thrombosis, as suggested by these authors.9  Indeed, the low-flow state in the hepatic veins compared with the portal venous system may participate in the higher frequency of PV in BCS. We also observed a statistical trend toward increased frequency of MF in PVT compared with BCS. Such difference could be the result of the frequent presence of splenomegaly in MF, which may lead to external compression of the portal venous system and subsequent stasis of blood flow. Finally, solitary JAK2V617F-positive MPNs were more frequent in PVT than in BCS patients. These are new findings that deserve further evaluation in future studies.

This meta-analysis, for the first time, systematically assessed the diagnostic yield of JAK2V617F screening in SVT patients without typical hematologic MPN features. JAK2V617F screening identified MPN in 17.1% and 15.4% of these BCS and PVT patients, respectively, which would have remained undetected before the JAK2V617F era. JAK2V617F was associated with subsequent development of MPNs with typical hematologic MPN features in 41% and 14% of these BCS and PVT patients, respectively. These findings clearly substantiate inclusion of JAK2V617F in the routine diagnostic workup of all SVT patients, regardless of the absence of MPN hallmarks, such as elevated peripheral blood cell counts. Whether MPN specific treatment should be initiated in these patients, such as cytoreductive therapies or addition of aspirin to oral anticoagulant treatment, is a question that remains to be answered. One study described the long-term outcome of PVT patients with an underlying MPN.64  Twenty-nine and 18% of the deaths in this cohort were attributable to end-stage MF and progression to acute myeloid leukemia, respectively, indicating that risk of MPN progression is a clinical significant issue in these patients.

MPL515 mutations were reported in < 1% of SVT patients, whereas the JAK2 exon 12 could not be found at all. The JAK2 exon 12 mutation has been described only once in both a PVT and BCS patient, but this was a case study.29  These results indicate that both mutations are infrequent in SVT patients, in agreement with their low frequency in MPNs compared with the JAK2V617F mutation.23-27  We therefore conclude that, unlike JAK2V617F, screening for these mutations is dispensable in the routine diagnostic approach of SVT patients.

Our analysis has several potential limitations. First, because of the rarity of both diseases, only observational studies have been published and could be included in this analysis, with their inherent risks of bias. However, a prospective design for rare thrombotic manifestations as PVT and BCS is probably unachievable. Second, a considerable heterogeneity among the included studies was noticed. We therefore performed all analyses using a random-effects model, thereby accounting for between-study variance, next to within-study variance. In addition to the random-effects analysis, which generates a conservative estimate, we performed an analysis in which we excluded one study at a time to assess its individual impact on the results. This analysis showed that none of the included studies significantly affected the estimated prevalence of MPNs, JAK2V617F, and its subtypes in both BCS and PVT. Third, diagnostic criteria for MPNs were not similar across studies. Notably, BM biopsy was not always routinely performed, which may have resulted in an underestimation of the prevalence of MPNs. Because this applies to both BCS and PVT series, the effect on the comparison between these 2 groups is presumably small, if at all present. Lastly, since the discovery of JAK2V617F in 2005, an increase in larger and better quality studies was observed. We therefore repeated all analyses, including only publications from that time point. In addition, we excluded papers with potential overlap of patients. The same differences between BCS and PVT were observed.

In conclusion, this meta-analysis shows a high prevalence of MPNs and JAK2V617F in SVT patients. Prevalence of JAK2V617F and MPNs in BCS is higher compared with PVT, and differences in underlying MPN subtypes between these disorders exist. JAK2V617F screening identifies MPNs in patients without typical hematologic MPN features and should be included the routine diagnostic workup of SVT. On the contrary, JAK2 exon 12 and MPL515 mutations are extremely rare in SVT and should not be used in the routine diagnostic approach of SVT patients. Altogether, our results are in line with the advancing insight that, despite well-established similarities, marked differences in the etiology of BCS and PVT do exist.

Appendix: Medline search strategy

August 1, 2011

Database: Medline.

Limits: English, limits publication date January 1, 1980 to August 1, 2011:

  1. Myeloproliferative disorders [Mesh]: 23 690

  2. Myeloproliferative neoplasms: 2798

  3. Janus kinase 2 [Mesh]: 2880

  4. MPL protein, human [substance name]: 503

  5. Colony-forming units assay: 13111

  6. Budd-Chiari syndrome [Mesh]: 1539

  7. Hepatic vein thrombosis: 2885

  8. Hepatic venous thrombosis: 1544

  9. Hepatic outflow obstruction: 295

  10. Vascular liver disease: 11915

  11. Thrombosis [Mesh] AND vena cava, inferior [Mesh]: 1784

  12. Portal system [Mesh] AND thrombosis [Mesh]: 2535

  13. Portal vein thrombosis: 3158

  14. Portal venous thrombosis: 2015

  15. Splanchnic vein thrombosis: 206

  16. Splanchnic venous thrombosis: 163

  17. Abdominal vein thrombosis: 2091

  18. Abdominal venous thrombosis: 1587

  19. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18: 19 561

  20. 1 and 19: 214

  21. 2 and 19: 45

  22. 3 and 19: 57

  23. 4 and 19: 3

  24. 5 and 19: 12

  25. 20 or 21 or 22 or 23 or 24: 255

The search was supplemented by manually reviewing the reference list of retrieved articles.

The online version of this article contains a data supplement.

Contribution: J.H.S. conceived and designed the study, collected, assembled, and interpreted the data, and wrote the manuscript; L.R.A. performed data analysis; J.-J.K. and D.C.V. interpreted the data and critically revised the article for important intellectual content; H.L.A.J. assisted in study selection and analysis of results and critically revised the article for important intellectual content; and F.W.G.L. designed the study, selected included studies, analyzed the results, and assisted with writing the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Frank W. G. Leebeek, Department of Hematology, University Medical Center Rotterdam, Room L-438, PO Box 2040, 3000 CA Rotterdam, The Netherlands; e-mail: f.leebeek@erasmusmc.nl.

1
Janssen
 
HL
Garcia-Pagan
 
JC
Elias
 
E
, et al. 
Budd-Chiari syndrome: a review by an expert panel.
J Hepatol
2003
, vol. 
38
 
3
(pg. 
364
-
371
)
2
Janssen
 
HL
Wijnhoud
 
A
Haagsma
 
EB
, et al. 
Extrahepatic portal vein thrombosis: aetiology and determinants of survival.
Gut
2001
, vol. 
49
 
5
(pg. 
720
-
724
)
3
Ogren
 
M
Bergqvist
 
D
Bjorck
 
M
Acosta
 
S
Eriksson
 
H
Sternby
 
NH
Portal vein thrombosis. Prevalence, patient characteristics and lifetime risk: a population study based on 23 796 consecutive autopsies.
World J Gastroenterol
2006
, vol. 
12
 
13
(pg. 
2115
-
2119
)
4
Darwish Murad
 
S
Plessier
 
A
Hernandez-Guerra
 
M
, et al. 
Etiology, management, and outcome of the Budd-Chiari syndrome.
Ann Intern Med
2009
, vol. 
151
 
3
(pg. 
167
-
175
)
5
Darwish Murad
 
S
Valla
 
DC
de Groen
 
PC
, et al. 
Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome.
Hepatology
2004
, vol. 
39
 
2
(pg. 
500
-
508
)
6
Denninger
 
MH
Chait
 
Y
Casadevall
 
N
, et al. 
Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
Hepatology
2000
, vol. 
31
 
3
(pg. 
587
-
591
)
7
Mahmoud
 
AE
Mendoza
 
A
Meshikhes
 
AN
, et al. 
Clinical spectrum, investigations and treatment of Budd-Chiari syndrome.
QJM
1996
, vol. 
89
 
1
(pg. 
37
-
43
)
8
Rajani
 
R
Melin
 
T
Bjornsson
 
E
, et al. 
Budd-Chiari syndrome in Sweden. Epidemiology, clinical characteristics and survival: an 18-year experience.
Liver Int
2009
, vol. 
29
 
2
(pg. 
253
-
259
)
9
Smalberg
 
JH
Darwish Murad
 
S
Braakman
 
E
Valk
 
PJ
Janssen
 
HL
Leebeek
 
FW
Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome.
Haematologica
2006
, vol. 
91
 
12
(pg. 
1712
-
1713
)
10
Bayraktar
 
Y
Harmanci
 
O
Buyukasik
 
Y
, et al. 
JAK2V617F mutation in patients with portal vein thrombosis.
Dig Dis Sci
2008
, vol. 
53
 
10
(pg. 
2778
-
2783
)
11
Plessier
 
A
Darwish-Murad
 
S
Hernandez-Guerra
 
M
, et al. 
Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
Hepatology
2010
, vol. 
51
 
1
(pg. 
210
-
218
)
12
Valla
 
D
Casadevall
 
N
Huisse
 
MG
, et al. 
Etiology of portal vein thrombosis in adults: a prospective evaluation of primary myeloproliferative disorders.
Gastroenterology
1988
, vol. 
94
 
4
(pg. 
1063
-
1069
)
13
De Stefano
 
V
Teofili
 
L
Leone
 
G
Michiels
 
JJ
Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis.
Semin Thromb Hemost
1997
, vol. 
23
 
5
(pg. 
411
-
418
)
14
Valla
 
D
Casadevall
 
N
Lacombe
 
C
, et al. 
Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome.
Ann Intern Med
1985
, vol. 
103
 
3
(pg. 
329
-
334
)
15
Spivak
 
JL
Polycythemia vera: myths, mechanisms, and management.
Blood
2002
, vol. 
100
 
13
(pg. 
4272
-
4290
)
16
Baxter
 
EJ
Scott
 
LM
Campbell
 
PJ
, et al. 
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
Lancet
2005
, vol. 
365
 
9464
(pg. 
1054
-
1061
)
17
Campbell
 
PJ
Green
 
AR
The myeloproliferative disorders.
N Engl J Med
2006
, vol. 
355
 
23
(pg. 
2452
-
2466
)
18
James
 
C
Ugo
 
V
Le Couedic
 
JP
, et al. 
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
Nature
2005
, vol. 
434
 
7037
(pg. 
1144
-
1148
)
19
Kralovics
 
R
Passamonti
 
F
Buser
 
AS
, et al. 
A gain-of-function mutation of JAK2 in myeloproliferative disorders.
N Engl J Med
2005
, vol. 
352
 
17
(pg. 
1779
-
1790
)
20
Kiladjian
 
JJ
Cervantes
 
F
Leebeek
 
FW
, et al. 
The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases.
Blood
2008
, vol. 
111
 
10
(pg. 
4922
-
4929
)
21
Colaizzo
 
D
Amitrano
 
L
Tiscia
 
GL
, et al. 
The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis.
J Thromb Haemost
2007
, vol. 
5
 
1
(pg. 
55
-
61
)
22
Janssen
 
HL
Leebeek
 
FW
JAK2 mutation: the best diagnostic tool for myeloproliferative disease in splanchnic vein thrombosis?
Hepatology
2006
, vol. 
44
 
6
(pg. 
1391
-
1393
)
23
Pardanani
 
AD
Levine
 
RL
Lasho
 
T
, et al. 
MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.
Blood
2006
, vol. 
108
 
10
(pg. 
3472
-
3476
)
24
Pikman
 
Y
Lee
 
BH
Mercher
 
T
, et al. 
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
PLoS Med
2006
, vol. 
3
 
7
pg. 
e270
 
25
Scott
 
LM
Beer
 
PA
Bench
 
AJ
Erber
 
WN
Green
 
AR
Prevalence of JAK2 V617F and exon 12 mutations in polycythaemia vera.
Br J Haematol
2007
, vol. 
139
 
3
(pg. 
511
-
512
)
26
Scott
 
LM
Tong
 
W
Levine
 
RL
, et al. 
JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.
N Engl J Med
2007
, vol. 
356
 
5
(pg. 
459
-
468
)
27
Tefferi
 
A
Skoda
 
R
Vardiman
 
JW
Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics.
Nat Rev Clin Oncol
2009
, vol. 
6
 
11
(pg. 
627
-
637
)
28
Bergamaschi
 
GM
Primignani
 
M
Barosi
 
G
, et al. 
MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction.
Blood
2008
, vol. 
111
 
8
pg. 
4418
 
29
Colaizzo
 
D
Amitrano
 
L
Tiscia
 
GL
Grandone
 
E
Guardascione
 
MA
Margaglione
 
M
A new JAK2 gene mutation in patients with polycythemia vera and splanchnic vein thrombosis.
Blood
2007
, vol. 
110
 
7
(pg. 
2768
-
2769
)
30
McCarthy
 
N
McCarron
 
SL
Langabeer
 
SE
Prevalence of the JAK2 V617F and MPL mutations in stroke, abdominal and peripheral venous thrombosis.
Acta Haematol
2010
, vol. 
124
 
3
(pg. 
160
-
161
)
31
Yoo
 
EH
Jang
 
JH
Park
 
KJ
, et al. 
Prevalence of overt myeloproliferative neoplasms and JAK2 V617F mutation in Korean patients with splanchnic vein thrombosis.
Int J Lab Hematol
2011
, vol. 
33
 
5
(pg. 
471
-
476
)
32
Boissinot
 
M
Lippert
 
E
Girodon
 
F
, et al. 
Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis.
Blood
2006
, vol. 
108
 
9
(pg. 
3223
-
3224
)
33
Goulding
 
C
Uttenthal
 
B
Foroni
 
L
, et al. 
The JAK2(V617F) tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis.
Int J Lab Hematol
2008
, vol. 
30
 
5
(pg. 
415
-
419
)
34
Rossi
 
D
Cresta
 
S
Destro
 
T
, et al. 
JAK2V617F in idiopathic venous thromboembolism occurring in the absence of inherited or acquired thrombophilia.
Br J Haematol
2007
, vol. 
138
 
6
(pg. 
813
-
814
)
35
Shetty
 
S
Kulkarni
 
B
Pai
 
N
Mukundan
 
P
Kasatkar
 
P
Ghosh
 
K
JAK2 mutations across a spectrum of venous thrombosis cases.
Am J Clin Pathol
2010
, vol. 
134
 
1
(pg. 
82
-
85
)
36
Tondeur
 
S
Boutruche
 
S
Biron-Andreani
 
C
Schved
 
JF
Prevalence of the JAK2 V617F mutation associated with splanchnic vein thrombosis: a 10-year retrospective study.
Thromb Haemost
2009
, vol. 
101
 
4
(pg. 
787
-
789
)
37
Regina
 
S
Herault
 
O
D'Alteroche
 
L
Binet
 
C
Gruel
 
Y
JAK2 V617F is specifically associated with idiopathic splanchnic vein thrombosis.
J Thromb Haemost
2007
, vol. 
5
 
4
(pg. 
859
-
861
)
38
Averbuch
 
M
Aderka
 
D
Winer
 
Z
Levo
 
Y
Budd-Chiari syndrome in Israel: predisposing factors, prognosis, and early identification of high-risk patients.
J Clin Gastroenterol
1991
, vol. 
13
 
3
(pg. 
321
-
324
)
39
Brown
 
KM
Kaplan
 
MM
Donowitz
 
M
Extrahepatic portal venous thrombosis: frequent recognition of associated diseases.
J Clin Gastroenterol
1985
, vol. 
7
 
2
(pg. 
153
-
159
)
40
Cardin
 
F
Graffeo
 
M
McCormick
 
PA
McIntyre
 
N
Burroughs
 
A
Adult “idiopathic” extrahepatic venous thrombosis: importance of putative “latent” myeloproliferative disorders and comparison with cases with known etiology.
Dig Dis Sci
1992
, vol. 
37
 
3
(pg. 
335
-
339
)
41
P'ng
 
S
Carnley
 
B
Baker
 
R
Kontorinis
 
N
Cheng
 
W
Undiagnosed myeloproliferative disease in cases of intra-abdominal thrombosis: the utility of the JAK2 617F mutation.
Clin Gastroenterol Hepatol
2008
, vol. 
6
 
4
(pg. 
472
-
475
)
42
Amitrano
 
L
Guardascione
 
MA
Scaglione
 
M
, et al. 
Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
Am J Gastroenterol
2007
, vol. 
102
 
11
(pg. 
2464
-
2470
)
43
Chait
 
Y
Condat
 
B
Cazals-Hatem
 
D
, et al. 
Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis.
Br J Haematol
2005
, vol. 
129
 
4
(pg. 
553
-
560
)
44
Colaizzo
 
D
Amitrano
 
L
Iannaccone
 
L
, et al. 
Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.
J Med Genet
2007
, vol. 
44
 
6
(pg. 
412
-
416
)
45
De Stefano
 
V
Fiorini
 
A
Rossi
 
E
, et al. 
High prevalence of the JAK2 V617F mutation in patients with extrahepatic portal vein thrombosis.
Hepatology
2007
, vol. 
45
 
3
(pg. 
831
-
832
author reply 832-833
46
Harmanci
 
O
Ersoy
 
O
Gurgey
 
A
, et al. 
The etiologic distribution of thrombophilic factors in chronic portal vein thrombosis.
J Clin Gastroenterol
2007
, vol. 
41
 
5
(pg. 
521
-
527
)
47
Janssen
 
HL
Meinardi
 
JR
Vleggaar
 
FP
, et al. 
Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
Blood
2000
, vol. 
96
 
7
(pg. 
2364
-
2368
)
48
Primignani
 
M
Martinelli
 
I
Bucciarelli
 
P
, et al. 
Risk factors for thrombophilia in extrahepatic portal vein obstruction.
Hepatology
2005
, vol. 
41
 
3
(pg. 
603
-
608
)
49
Fiorini
 
A
Chiusolo
 
P
Rossi
 
E
, et al. 
Absence of the JAK2 exon 12 mutations in patients with splanchnic venous thrombosis and without overt myeloproliferative neoplasms.
Am J Hematol
2009
, vol. 
84
 
2
(pg. 
126
-
127
)
50
McMahon
 
C
Abu-Elmagd
 
K
Bontempo
 
FA
Kant
 
JA
Swerdlow
 
SH
JAK2 V617F mutation in patients with catastrophic intra-abdominal thromboses.
Am J Clin Pathol
2007
, vol. 
127
 
5
(pg. 
736
-
743
)
51
Patel
 
RK
Lea
 
NC
Heneghan
 
MA
, et al. 
Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.
Gastroenterology
2006
, vol. 
130
 
7
(pg. 
2031
-
2038
)
52
Primignani
 
M
Barosi
 
G
Bergamaschi
 
G
, et al. 
Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
Hepatology
2006
, vol. 
44
 
6
(pg. 
1528
-
1534
)
53
Colaizzo
 
D
Amitrano
 
L
Tiscia
 
GL
, et al. 
Occurrence of the JAK2 V617F mutation in the Budd-Chiari syndrome.
Blood Coagul Fibrinolysis
2008
, vol. 
19
 
5
(pg. 
459
-
462
)
54
Khuroo
 
MS
Al-Suhabani
 
H
Al-Sebayel
 
M
, et al. 
Budd-Chiari syndrome: long-term effect on outcome with transjugular intrahepatic portosystemic shunt.
J Gastroenterol Hepatol
2005
, vol. 
20
 
10
(pg. 
1494
-
1502
)
55
Kocher
 
G
Himmelmann
 
A
Portal vein thrombosis (PVT): a study of 20 non-cirrhotic cases.
Swiss Med Wkly
2005
, vol. 
135
 
25
(pg. 
372
-
376
)
56
Orr
 
DW
Patel
 
RK
Lea
 
NC
, et al. 
Prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto-splenomesenteric venous thrombosis.
Aliment Pharmacol Ther
2010
, vol. 
31
 
12
(pg. 
1330
-
1336
)
57
Rajani
 
R
Bjornsson
 
E
Bergquist
 
A
, et al. 
The epidemiology and clinical features of portal vein thrombosis; a multicentre study.
Aliment Pharmacol Ther
2010
, vol. 
32
 
9
(pg. 
1154
-
1162
)
58
Smira
 
G
Gheorghe
 
L
Iacob
 
S
Coriu
 
D
Gheorghe
 
C
Budd Chiari syndrome and V617F/JAK 2 mutation linked with the myeloproliferative disorders.
J Gastrointest Liver Dis
2010
, vol. 
19
 
1
(pg. 
108
-
109
)
59
Uskudar
 
O
Akdogan
 
M
Sasmaz
 
N
Yilmaz
 
S
Tola
 
M
Sahin
 
B
Etiology and portal vein thrombosis in Budd-Chiari syndrome.
World J Gastroenterol
2008
, vol. 
14
 
18
(pg. 
2858
-
2862
)
60
Xavier
 
SG
Gadelha
 
T
Pimenta
 
G
, et al. 
JAK2V617F mutation in patients with splanchnic vein thrombosis.
Dig Dis Sci
2010
, vol. 
55
 
6
(pg. 
1770
-
1777
)
61
Zahn
 
A
Gotthardt
 
D
Weiss
 
KH
, et al. 
Budd-Chiari syndrome: long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt.
BMC Gastroenterol
2010
, vol. 
10
 pg. 
25
 
62
Eapen
 
CE
Velissaris
 
D
Heydtmann
 
M
Gunson
 
B
Olliff
 
S
Elias
 
E
Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
Gut
2006
, vol. 
55
 
6
(pg. 
878
-
884
)
63
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
, vol. 
5
 
4
(pg. 
708
-
714
)
64
Hoekstra
 
J
Bresser
 
EL
Smalberg
 
JH
Spaander
 
MC
Leebeek
 
FW
Janssen
 
HL
Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms.
J Thromb Haemost
2011
, vol. 
9
 
11
(pg. 
2208
-
2214
)
65
Dentali
 
F
Squizzato
 
A
Brivio
 
L
, et al. 
JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.
Blood
2009
, vol. 
113
 
22
(pg. 
5617
-
5623
)
66
Qi
 
X
Yang
 
Z
Bai
 
M
Shi
 
X
Han
 
G
Fan
 
D
Meta-analysis: the significance of screening for JAK2V617F mutation in Budd-Chiari syndrome and portal venous system thrombosis.
Aliment Pharmacol Ther
2011
, vol. 
33
 
10
(pg. 
1087
-
1103
)
67
Smalberg
 
JH
Kruip
 
MJ
Janssen
 
HL
Rijken
 
DC
Leebeek
 
FW
de Maat
 
MP
Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences.
Arterioscler Thromb Vasc Biol
2011
, vol. 
31
 
3
(pg. 
485
-
493
)
68
DeLeve
 
LD
Valla
 
DC
Garcia-Tsao
 
G
, et al. 
Vascular disorders of the liver.
Hepatology
2009
, vol. 
49
 
5
(pg. 
1729
-
1764
)
69
Aird
 
WC
Vascular bed-specific thrombosis.
J Thromb Haemost
2007
, vol. 
5
 
suppl 1
(pg. 
283
-
291
)
70
Sozer
 
S
Fiel
 
MI
Schiano
 
T
Xu
 
M
Mascarenhas
 
J
Hoffman
 
R
The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome.
Blood
2009
, vol. 
113
 
21
(pg. 
5246
-
5249
)
71
Pearson
 
TC
Wetherley-Mein
 
G
Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia.
Lancet
1978
, vol. 
2
 
8102
(pg. 
1219
-
1222
)
72
Landolfi
 
R
Di Gennaro
 
L
Falanga
 
A
Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation.
Leukemia
2008
, vol. 
22
 
11
(pg. 
2020
-
2028
)
73
Landolfi
 
R
Rocca
 
B
Patrono
 
C
Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment.
Crit Rev Oncol Hematol
1995
, vol. 
20
 
3
(pg. 
203
-
222
)
74
Attwell
 
A
Ludkowski
 
M
Nash
 
R
Kugelmas
 
M
Treatment of Budd-Chiari syndrome in a liver transplant unit, the role of transjugular intrahepatic porto-systemic shunt and liver transplantation.
Aliment Pharmacol Ther
2004
, vol. 
20
 
8
(pg. 
867
-
873
)

Supplemental data