High prevalence of the JAK2 V617F mutation in patients with extrahepatic portal vein thrombosis
Authors: Valerio De Stefano, Alessia Fiorini, Elena Rossi, Tommaso Za, Patrizia Chiusolo, Simona Sica, Giuseppe Leone
Journal: Hepatology (2007)

Thrombosis of splanchnic veins is a typical presentation of chronic myeloproliferative diseases (CMD); overt CMD can be diagnosed in about 40% of the patients with hepatic vein thrombosis (HVT) and 25% of the patients with extrahepatic portal vein thrombosis (PVT).1-4 Yet the criteria to suspect polycythemia vera (PV) or essential thrombocythemia (ET) may be altered because of the presence of hypersplenism and increased plasma volume which can mask erythrocytosis or thrombocytosis.1-4 Recently the acquired JAK2V617F mutation has been recognized as closely related with CMD, providing a robust diagnostic tool.5 We read with interest the article by Primignani et al.,6 who found the JAK2 mutation in 40% of 20 HVT patients and 36% of 73 PVT patients. We retrospectively investigated for the presence of the JAK2 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 benefit-risk 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. Valerio De Stefano*, Alessia Fiorini*, Elena Rossi*, Tommaso Za*, Patrizia Chiusolo*, Simona Sica*, Giuseppe Leone*, * Institute of Hematology, Catholic University, Rome, Italy.