LETTERS TO THE EDITOR

 

The role of JAK2 gene mutations in the etiologic diagnosis of splanchnic vein thrombosis

Importancia de la detección de las mutaciones en el gen JAK2 en el diagnóstico etiológico de las trombosis esplácnicas

 

 

---

Key words: Splanchnic vein thrombosis. JAK2 gene mutations.

Palabras clave: Trombosis renal esplácnica. Mutaciones del gen JAK2.

---

 

Dear Editor,

Two clinical reports, both related to the association of a portal or mesenteric vein thrombosis and an hereditary thrombophilic disorder, have been recently published in this journal (1,2). Both suggest the need, in this clinical setting, of performing a thrombophilic study including G20210A factor II gene mutation, factor V Leyden mutation, activated protein C resistance, lupus anticoagulant, anticardiolipin antibodies, protein C and S deficiencies, antithrombin deficiency and plasmatic homocysteine.

Nevertheless, the most frequent cause of splanchnic thrombosis, either portal thrombosis (PT) or Budd-Chiari syndrome (BCS), is not the existence of one of those thrombophilic factors, but the presence of an underlying myeloproliferative disorder (MPD). This entity does not seem to have been taken into account in any of the two clinical cases. The MPD, identified using conventional criteria, is present in about 30% of the cases of PT and 50% of BCS, being this percentage at least similar to that of the whole group of the aforementioned thrombophilic disorders (3). The identification of a MPD in these patients is of paramount importance since the management of this disease is completely different to that of the patients with an abdominal thrombosis without a MPD. However, in this clinical setting the clinical suspicion of a MPD is hampered since the splenomegaly and the anemia induced by hemorrhage may induce normal values in blood cellular counts. This might have been the situation in the case report presented by Chirinos et al. (1) in which hemorrhagic phenomena were the main clinical feature. Thus, it is necessary to routinely evaluate patients with splanchnic thrombosis to rule out an "occult" MPD.

An association between MPD and point mutations in the JAK2 tyrosine kinase gene has recently been described (4,5). The first mutation to be described, the JAK2V617F, has been identified in 90% of patients with polycitemia vera (PV) and in 50% of those with essential thrombocytemia or idiopathic myelofibrosis (6). If the recently described exon 12 mutations are considered, JAK2 gene mutations are present in virtually all patients with PV, thus constituting a sensitive diagnostic marker of the disease. This has led to a proposal for the modification of the WHO MPD diagnostic criteria, in order to include JAK2 mutations as major diagnostic criteria (8).

Patients with a MPD and the JAK2V617F mutation have an increased risk of thrombosis compared to those without the mutation (6). The JAK2 mutation even seems to confer some additional risk specifically for the development of splanchnic thrombosis, but not for the rest of locations (9). This mutation has been described in 40-50% of patients with BCS and in 17-36% of patients with PT (10,11). A recent study about patients that had developed a massive abdominal thrombosis leading to a visceral transplantation (liver or bowel) showed a 17% prevalence of the JAK2 mutation (12). Therefore, in the clinical setting of a patient with splanchnic thrombosis, the detection of JAK2 mutation may help to the identification of an occult MPD. For instance, in the study of Patel et al. (13) in patients with BCS, the JAK2 mutation was positive in 24 out of 41 patients, none of them fulfilling the classical MPD diagnostic criteria.

The presence of another thrombophilic factor, as it occurs in these case reports, does not exclude the possibility of finding an associated MPD. In the report by Kiladjian et al. (14), 11% of patients with PT and JAK2 mutation had an antiphospholipid antibody associated, 8% a protein S deficiency and 5% a factor II G20210A mutation. In the Prigminani et al. report (11), 32.3% of patients with a JAK2 mutation had another associated thrombophilic disorder. Our group has also described a patient with a BCS who presented an association of the JAK2V617F mutation and a factor V Leyden mutation (15).

In conclusion, nowadays, in the etiologic diagnostic work-up of a splanchnic thrombosis, the detection of JAK2 mutations and mainly the JAK2V617F, should be included, even in the presence of other possible etiologic factors and despite there is not any other laboratory parameter to suspect the presence of a MPD (14-16).

 

G. Plumé G, M. Bustamante-Balén M.¹ and A. Vayá

Unit of Thrombosis and Hemostasia. Department of Clinical Biopathology. University Hospital La Fe. Valencia, Spain.
¹Service of Digestive Medicine. Hospital Ribera. Alzira. Valencia, Spain

 

References

1. Chirinos Vega JA, Muñoz Gomez R, Amo Peláez M, Ibarrola de Andrés C, Solís Herruzo JA. Trombosis portal y mesentérica asociada a déficit de proteína S. Rev Esp Enferm Dig 2009; 100; 104-7.        [ Links ]

2. Calvo Romero JM. Trombosis venosa portal y mesentérica asociada a mutación del gen de la protrombina. Rev Esp Enferm Dig 2008; 100: 245-6.        [ Links ]

3. Denninger MH, Chaït Y, Casadevall N, Hillarie S, Guillin MC, Bezeaud A, et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 2000; 31: 587-91.        [ Links ]

4. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-61.        [ Links ]

5. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779-90.        [ Links ]

6. Schafer AI. Molecular basis of the diagnosis and treatment of polycitemia vera and essential thrombocytemia. Blood 2006; 107: 4214-22.        [ Links ]

7. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycitemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459-68.        [ Links ]

8. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Curtis A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycithemia vera, essential thrombocytopenia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007; 110: 1092-7.        [ Links ]

9. Colaizzo D, Amitrano L, Iannaccone L, Vergura P, Cappucci F, Grandone E, et al. Gain of function gene mutations and venous thromboembolism: distinct roles in different clinical settings. J Med Genet 2007;44: 412-6.        [ Links ]

10. Colaizzo D, Amitrano L, Tiscia GL, Scenna G, Grandone E, Guardascione MA, et al. The JAK2V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost 2007; 5: 55-61.        [ Links ]

11. Primignani M, Barosi G, Bergamaschi G, Gianelli U, Fabris F, Reati R, et al. Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis. Hepatology 2006; 44: 1528-34.        [ Links ]

12. McMahon C, Abu-Elmagd K, Bontempo FA, Kant JA, Swerdlow SH. JAK2V617F mutation in patients with catastrophic intra-abdominal thromboses. Am J Clin Pathol 2007; 127: 736-43.        [ Links ]

13. Patel RK, Lea NC, Heneghan MA, Westwood NB, Milojkovic D, Thanigaikumar M, et al. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 2006; 130: 2031-8.        [ Links ]

14. Kiladjian JJ, Cervantes F, Leebeek FWG, Marzac C, Cassinat B, Chevret S, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008; 111: 4922-9.        [ Links ]

15. Plumé G, Vayá A, Ferrando F, Mira Y, Orbis F. JAK2V617F mutation as a marker of a latent myeloproliferative disorder in a patient with Budd-Chiari syndrome and factor V Leiden mutation. Thromb Haemost 2007; 98: 681-2.        [ Links ]

16. Hernández-Guerra M, García-Pagán JC, y el Grupo Europeo para el Estudio de las Enfermedades Vasculares Hepáticas (ENVie). Gastroenterol Hepatol 2004; 27: 473-9.        [ Links ]