R. Reati

Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis

The diagnosis of an underlying chronic myeloproliferative disorder (CMPD) is often problematic in patients with primary extrahepatic portal vein obstruction (EHPVO) or Budd‐Chiari syndrome (BCS); indeed, conventional clinical and hematological parameters usually yield insufficient information. To assess the diagnostic contribution of the gain‐of‐function mutation V617F of the JAK2 gene, 93 patients with EHPVO or BCS were investigated. JAK2 V617F was identified in 35.6% of 73 patients with EHPVO and in 40% of 20 patients with BCS. Taking the JAK2 mutation as a test with the highest positive predictive value for the diagnosis of CMPD, conventional clinical‐hematological parameters had a sensitivity for CMPD lower than 48%. Bone marrow (BM) histology provided a diagnosis of CMPD in 41/74 (55.4%) patients, with a sensitivity of 93.5%. Clonality of hematopoiesis as assessed by granulocyte X‐chromosome inactivation was present in 65.1% of 43 informative female patients, with a sensitivity of 86.6%. By resolving the sensitivity bias of the JAK2 mutation with the results of BM histology and clonality assay, CMPD was diagnosed in 53% of patients with EHPVO or BCS. In conclusion, CMPD is the major cause of primary EHPVO or BCS. JAK2 V617F is a very reliable and noninvasive molecular marker for CMPD and should be used as a first test for diagnosis. (HEPATOLOGY 2006;44:1528–1534.)

Risk factors for thrombophilia in extrahepatic portal vein obstruction

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain‐of‐function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3–7.0) and 4.4 (95% CI, 3.3–5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8–17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1–18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1–6.4) and for lower limb DVT of 7.5 (95% CI, 4.4–13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9–4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden. (HEPATOLOGY 2005;41:603–608.)

High levels of factor VIII and risk of extra-hepatic portal vein obstruction

BACKGROUND/AIMS High levels of coagulation factor VIII are a risk factor for lower-limb deep vein thrombosis (DVT). Their role in extra-hepatic portal vein obstruction (EHPVO) is not established. METHODS Factor VIII was measured in 85 patients with EHPVO (primary in 58 and complicating liver cirrhosis in 27), in 200 with lower-limb DVT, in 108 with liver cirrhosis without thrombosis and in 200 healthy controls. RESULTS Factor VIII levels were significantly higher in patients with primary EHPVO (138 IU/dL, range 86-366), EHPVO and cirrhosis (147 IU/dL, 95-242), lower-limb DVT (140 IU/dL, 64-400) and cirrhosis alone (160 IU/dL, 43-446) than in controls (112 IU/dL, 62-250, p<0.001). When factor VIII exceeded 129 IU/dL (66th percentile), the odds ratios were 10.5 (95%CI 3.3-33.4) for primary EHPVO, 6.0 (1.2-30.7) for EHPVO and cirrhosis, 5.0 (2.6-9.4) for lower-limb DVT. After exclusion of the effect of the acute phase reaction, the odds ratio for primary EHPVO was 4.2 (0.8-22.7), and was 8.7 (0.9-80.5) after exclusion also of patients with chronic myeloproliferative disorders. CONCLUSIONS High factor VIII levels are independently associated with an increased risk for EHPVO. The risk of EHPVO increased with increasing factor VIII levels and was only partially dependent on the acute phase reaction.

MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction

To the editor: The Budd-Chiari syndrome (BCS) and extrahepatic portal vein obstruction (EHPVO) are splanchnic vein thromboses (SVT) that may occur as presenting complications of undiagnosed chronic myeloproliferative disorders (CMPD). Diagnosis of the underlying CMPD may be difficult because

Primary prophylaxis of variceal bleeding in cirrhotic patients: A cohort study

BACKGROUND Current guidelines recommend beta-blockers for primary prevention of variceal haemorrhage in cirrhotic patients, and band ligation for patients with contraindications or intolerance to beta-blockers. However, it has been suggested that these patients may respond poorly to band ligation. AIM We evaluated the usefulness of a strategy in which band ligation was used to treat patients with contraindications or intolerance and patients not responding to beta-blockers identified by hepatic vein pressure gradient measurement. Haemodynamic responders and patients refusing hepatic vein pressure gradient measurement were given long-term beta-blockers. METHODS One hundred and thirty-five consecutive patients with high-risk oesophageal varices and no prior bleeding were enrolled. Twenty-five patients with contraindications (group A), 26 with intolerance to beta-blockers (group B) and 25 showing a poor haemodynamic response (Group C) underwent band ligation. Twenty-two haemodynamic responders (Group D) and 37 refusing hepatic vein pressure gradient measurement (Group E) were treated with beta-blockers. RESULTS Median follow-up was 32 months. 12/135 patients (8.9%) bled: 3/25 (12%) in group A, 1/26 (3.8%) in group B, 0/25 (0%) in group C, 0/22 (0%) in group D and 8/37 (22.2%) in group E. Mortality was 8/135 (5.9%). CONCLUSIONS Patients with contraindications, intolerance or not responding to beta-blockers treated with band ligation achieve protection from variceal bleeding comparable to that of good responders to beta-blockers.

Impact of portal vein thrombosis on the efficacy of endoscopic variceal band ligation

BACKGROUND Influence of portal vein thrombosis on efficacy of endoscopic variceal banding in patients with cirrhosis or extrahepatic portal vein obstruction has never been evaluated. Aim of the study was to assess influence of thrombosis on rate and time to eradication in cirrhosis and extrahepatic portal vein obstruction undergoing banding, compared to cirrhotic patients without thrombosis. METHODS Retrospective analysis of 235 consecutive patients (192 with cirrhosis without thrombosis, 22 cirrhosis and thrombosis and 21 extrahepatic portal vein obstruction) who underwent banding. Banding was performed every 2-3 weeks until eradication; endoscopic follow-up was performed at 1, 3, 6 months, then annually. RESULTS Eradication was achieved in 233 patients. Median time to eradication in cirrhotic patients with portal vein thrombosis vs. cirrhotic patients without thrombosis was 50.9 days (12-440) vs. 43.4 days (13-489.4); log-rank: 0.04; patients with extrahepatic portal vein obstruction vs. cirrhotic patients without thrombosis 63.9 days (31-321.6) vs. 43.4 days (13.0-489.4); log-rank: 0.008. Thrombosis was shown to be the only risk factor for longer time to eradication. CONCLUSIONS Portal vein thrombosis per se appears to be the cause of a longer time to achieve eradication of varices but, once eradication is achieved, it does not influence their recurrence.

JAK2 mutation [reply letter]

mutation 76 adult patients (greater than 18 years old) with PVT or isolated mesenteric vein thrombosis (MVT) (39 men, 37 women, median age at thrombosis 49 years, range 25-78 years). They had been consecutively referred to our center for screening of thrombophilia (deficiency of natural anticoagulants, factor V Leiden, prothrombin G20210A, hyperhomocysteinemia, antiphospholipids); a preliminary evaluation had ruled out patients with overt cancer or liver cirrhosis. Among the 17 MVT patients, 7 (41%) had inherited or acquired thrombophilia and none carried the JAK2 mutation. Out of the 59 PVT patients, 19 developed thrombosis after a provoking circumstance (oral contraception in 9, surgery in 6, puerperium in 3, and trauma in 1). Twenty-two (37%) had thrombophilia and 24 (41%) the JAK2 mutation; 9 of them (15%) carried both. Eight patients, all with the JAK2 mutation, met the conventional criteria for diagnosis of PV (n 4) or ET (n 4) at the time of thrombosis. Two additional patients developed overt ET and myelofibrosis 8 and 4 years after thrombosis, respectively; the ET patient was JAK2-mutated. Therefore, JAK2 mutation allowed strong suspicion of CMD in 15 of the remaining 49 patients (31%). In our series, no difference in the prevalence of the mutation was found in respect to the presence of thrombophilia (P 1.0) or a provoking circumstance (P 0.16), in agreement with Primignani et al.6 However, among the patients without thrombophilia or overt CMD the rate of the mutation was 43% (9 of 21) in those with unprovoked thrombosis and 9% in those with provoked thrombosis (1 of 11). In the series of Primignani et al.6 the mutation was present in 71% of the patients with a bone marrow (BM) biopsy diagnostic for CMD; conversely, the BM biopsy was diagnostic in 93% of the mutated patients. Thus, BM biopsy was the only sign of CMD in 16% of the patients with HVT or PVT, in line with other reports.3,4 They conclude that BM biopsy is warranted in patients with splanchnic vein thrombosis either JAK2-mutated (in order to precise diagnosis of CMD and to exclude myelofibrosis) or JAK2 wild-type (in order to assist diagnosis of JAK2-negative CMD); this is in line with the recent consideration of BM biopsy as a positive tool for diagnosis of CMD, as established by the WHO criteria.7 Yet in our opinion such recommendation should be tempered. The adverse events associated with BM biopsy are rare (about 1 per 1000 procedures) but can be serious; moreover, diagnosis of CMD is a risk factor for hemorrhagic complications even in the absence of antiplatelet agents.8 Finally, most of the PVT patients are on anticoagulant therapy, so that biopsy needs special care. Therefore, the indication to BM biopsy in this particular setting should be balanced with the clinical utility and to the likelihood that the procedure will modify treatment. In adult patients with nonmalignant, noncirrhotic PVT anticoagulant therapy has a favorable benefitrisk ratio9 and in patients with a prothrombotic state life-long oral anticoagulant treatment has been recommended.10 However the assumption that the presence of JAK2 mutation or a BM biopsy suggestive for CMD should be considered per se a prothrombotic state is to date quite premature and should not influence decision for life-long anticoagulation. In our patients without overt CMD, none had significant splenomegaly and the median values were 12.6 g/l (range 9.6-16.4 g/l) for Hb, 6.84 109/l (range 2.50-20.40) for WBC count, 199 109/l (range 93-400) for platelet count, in agreement with those reported by Primignani et al.;6 although such values are obviously in part affected by hypersplenism and increased plasma volume, indication to cytoreductive treatment seems remote even in the presence of JAK2 mutation or a BM biopsy suggestive for CMD. As suggested by others, in such patients without clinical or haematological evidence of an active CMD a watchful-waiting attitude is recommended, reserving cytoreduction in the presence of usual haematological symptoms of CMD.4 At present, the indication to BM biopsy should be given on an individual basis and the routine use of procedures that are invasive and not well-standardized should be necessarily validated by further prospective controlled trials, aimed to improve the diagnostic flow-sheet in such patients.