Download PDF
Thromb Haemost 2016; 115(02): 240-249
DOI: 10.1160/th15-04-0326
Review Article
Schattauer GmbH

Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment

Valerio De Stefano   #
1   Institute of Hematology, Catholic University, Rome, Italy
,
Xingshun Qi   #
2   Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
,
Silvia Betti
1   Institute of Hematology, Catholic University, Rome, Italy
,
Elena Rossi
1   Institute of Hematology, Catholic University, Rome, Italy
› Author Affiliations
Further Information

Publication History

Received: 20 April 2015

Accepted after major revision: 15 July 2015

Publication Date:
21 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Splanchnic vein thrombosis (SVT) encompasses Budd-Chiari syndrome (BCS), extrahepatic portal vein obstruction (EHPVO), and mesenteric vein thrombosis. Philadelphia-negative myeloproliferative neoplasms (MPNS) are the leading systemic cause of non-cirrhotic and non-malignant SVT and are diagnosed in 40 % of BCS patients and one-third of EHPVO patients. In SVT patients the molecular marker JAK2 V617F is detectable up to 87 % of those with overt MPN and up to 26 % of those without. In the latter, other MPN molecular markers, such as mutations in JAK2 exon 12, CALR and MPL genes, are extremely rare. Immediate anticoagulation with heparin is used to treat acute patients. Upon clinical deterioration, catheter-directed thrombolysis or a transjugular intrahepatic portosystemic shunt is used in conjunction with anticoagulation. Orthotopic liver transplantation is the only reliable option in BCS patients with a lack of a response to other treatments, without contraindication due to MPN. Long-term oral anticoagulation with vitamin K–antagonists (VKA) is recommended in all SVT patients with the MPN-related permanent prothrombotic state; the benefits of adding aspirin to VKA are uncertain. Cytoreduction is warranted in all SVT patients with an overt MPN, but its appropriateness is doubtful in those with molecular MPN without hypercythaemia.

Keywords

Budd-Chiari syndrome - extrahepatic portal vein obstruction - mesenteric vein thrombosis - Philadelphia-negative myeloproliferative neoplasms - antithrombotic treatment

# The first two authors contributed equally to this work.


 

  • References

  • 1 Janssen HL. et al. Budd-Chiari syndrome: a review by an expert panel. J Hepatol 2003; 38: 364-371.
    Google Scholar
  • 2 Sarin SK. et al. Consensus on extra-hepatic portal vein obstruction. Liver Int 2006; 26: 512-519.
    CrossrefPubMedGoogle Scholar
  • 3 Valla D. Hepatic venous outflow tract obstruction etiopathogenesis: Asia versus the West. J Gastroenterol Hepatol 2004; 19: 204-211.
    CrossrefPubMedGoogle Scholar
  • 4 Almdal TP, Sorensen TI. Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver. Hepatology 1991; 13: 650-655.
    CrossrefPubMedGoogle Scholar
  • 5 Rajani R. et al. Budd-Chiari syndrome in Sweden: eidemiology, clinical characteristics and survival - an 18-year experience. Liver Int 2009; 29: 253-259.
    CrossrefPubMedGoogle Scholar
  • 6 Acosta S. et al. Epidemiology, risk and prognostic factors in mesenteric venous thrombosis. Br J Surg 2008; 95: 1245-1251.
    CrossrefPubMedGoogle Scholar
  • 7 Ogren M. et al. Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23, 796 consecutive autopsies. World J Gastroenterol 2006; 12: 2115-2119.
    CrossrefPubMedGoogle Scholar
  • 8 De Stefano V, Martinelli I. Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med 2010; 05: 487-494.
    CrossrefPubMedGoogle Scholar
  • 9 Qi X. et al. Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies. J Gastroenterol Hepatol 2013; 28: 432-442.
    CrossrefPubMedGoogle Scholar
  • 10 Plessier A. et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicentre follow-up study. Hepatology 2009; 51: 210-218.
    PubMedGoogle Scholar
  • 11 Martinelli I. et al. High levels of factor VIII and risk of extra-hepatic portal vein obstruction. J Hepatol 2009; 50: 916-922.
    CrossrefPubMedGoogle Scholar
  • 12 Dentali Fet al. Inherited thrombophilic abnormalities and risk of portal vein thrombosis. A meta-analysis. Thromb Haemost 2008; 99: 675-682.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Qi X. et al. Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 12: 1801-1812.
    CrossrefPubMedGoogle Scholar
  • 14 Janssen HL. 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; 96: 2364-2368.
    PubMedGoogle Scholar
  • 15 Darwish Murad S. et al. Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Intern Med 2009; 151: 167-175.
    CrossrefPubMedGoogle Scholar
  • 16 Janssen HL. et al. Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut 2001; 49: 720-724.
    CrossrefPubMedGoogle Scholar
  • 17 Denninger MH. et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 2000; 31: 587-591.
    CrossrefPubMedGoogle Scholar
  • 18 De Stefano V. et al. 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; 23: 411-418.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Smalberg JH. et al. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012; 120: 4921-4928.
    CrossrefPubMedGoogle Scholar
  • 20 Sekhar M. et al. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013; 162: 730-747.
    CrossrefPubMedGoogle Scholar
  • 21 Patrono C. et al. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood 2013; 121: 1701-1711.
    CrossrefPubMedGoogle Scholar
  • 22 Barbui T. et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European Leuke-miaNet. J Clin Oncol 2011; 29: 761-770.
    CrossrefPubMedGoogle Scholar
  • 23 Gangat N. et al. Leukocytosis at diagnosis and the risk of subsequent thrombosis in patients with low-risk essential thrombocythemia and polycythemia vera. Cancer 2009; 115: 5740-5745.
    CrossrefPubMedGoogle Scholar
  • 24 Bazzan M. et al. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Haematol 1999; 78: 539-543.
    CrossrefPubMedGoogle Scholar
  • 25 Gangat N. et al. Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications. Eur J Haematol 2006; 77: 327-333.
    CrossrefPubMedGoogle Scholar
  • 26 Passamonti F. et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica 2008; 93: 1645-1651.
    CrossrefPubMedGoogle Scholar
  • 27 De Stefano V. et al. JAK2 V617F mutational frequency in essential thrombo-cythemia associated with splanchnic or cerebral vein thrombosis. Am J Haema-tol 2011; 86: 526-528.
    CrossrefPubMedGoogle Scholar
  • 28 De Stefano V. et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93: 372-3780.
    CrossrefPubMedGoogle Scholar
  • 29 Passamonti F. et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leu-kemic disease transformation and vascular complications. Leukemia 2010; 24: 1574-1579.
    CrossrefPubMedGoogle Scholar
  • 30 DeLeve LD. et al. Vascular disorders of the liver. Hepatology 2009; 49: 1729-1764.
    CrossrefPubMedGoogle Scholar
  • 31 Tait C. et al. Guidelines on the investigation and management of venous thrombosis at unusual sites. Br J Haematol 2012; 159: 28-38.
    CrossrefPubMedGoogle Scholar
  • 32 Chait Y. et al. Relevance of the criteria commonly used to diagnose myelopro-liferative disorder in patients with splanchnic vein thrombosis. Br J Haematol 2005; 129: 553-560.
    CrossrefPubMedGoogle Scholar
  • 33 Jones C. et al. Elevated serum erythropoietin in a patient with polycythaemia vera presenting with Budd-Chiari syndrome. BMJ Case Rep.. 2014 2014. pii: bcr2014205663.
    PubMedGoogle Scholar
  • 34 Kiladjian JJ. 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: 4922-4929.
    CrossrefPubMedGoogle Scholar
  • 35 Tefferi A, Pardanani A. Genetics: CALR mutations and a new diagnostic algorithm for MPN. Nat Rev Clin Oncol 2014; 11: 125-126.
    CrossrefPubMedGoogle Scholar
  • 36 Tefferi A. et al. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 2014; 28: 1407-1413.
    CrossrefPubMedGoogle Scholar
  • 37 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Haematol 2015; 90: 162-173.
    CrossrefPubMedGoogle Scholar
  • 38 Dentali F. et al. JAK2V617F mutation for the early diagnosis of Ph-myeloprolife-rative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009; 113: 5617-5623.
    CrossrefPubMedGoogle Scholar
  • 39 Qi X. et al. Meta-analysis: the significance of screening for JAK2V617F mutation in Budd-Chiari syndrome and portal venous system thrombosis. Aliment Pharmacol Ther 2011; 33: 1087-103.
    CrossrefPubMedGoogle Scholar
  • 40 Sozer S. et al. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood 2009; 113: 5246-5249.
    CrossrefPubMedGoogle Scholar
  • 41 Rosti V. et al. Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation. Blood 2013; 121: 360-368.
    CrossrefPubMedGoogle Scholar
  • 42 Qi X. et al. Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study. J Gas-troenterol Hepatol 2012; 27: 1036-1043.
    CrossrefPubMedGoogle Scholar
  • 43 Cheng D. et al. Clinical features and etiology of Budd-Chiari syndrome in Chinese patients: a single-centre study. J Gastroenterol Hepatol 2013; 28: 1061-1067.
    CrossrefPubMedGoogle Scholar
  • 44 Wang H. et al. JAK2 V617F mutation and 46/1 haplotype in Chinese Budd-Chiari syndrome patients. J Gastroenterol Hepatol 2014; 29: 208-214.
    CrossrefPubMedGoogle Scholar
  • 45 Qi X. et al. Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature. Thromb Hae-most 2013; 109: 878-884.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Qi X. et al. Scientific publications on portal vein thrombosis and Budd-Chiari syndrome: a global survey of the literature. J Gastrointestin Liver Dis 2014; 23: 65-71.
    PubMedGoogle Scholar
  • 47 Qi X. et al. Thrombotic risk factors in Chinese nonmalignant and noncirrhotic patients with portal vein thrombosis: an observational study with a systematic review of the literature. Eur J Gastroenterol Hepatol 2015; 27: 77-83.
    CrossrefPubMedGoogle Scholar
  • 48 Turon F. et al. Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis. J Hepatol 2015; 62: 72-74.
    CrossrefPubMedGoogle Scholar
  • 49 Marzac C. et al. CALR somatic mutations in a prospective cohort of 308 patients with splanchnic vein thrombosis. J Hepatol 2015; 62: S230.
    PubMedGoogle Scholar
  • 50 Haslam K, Langabeer SE. Incidence of CALR mutations in patients with splanchnic vein thrombosis. Br J Haematol 2015; 168: 459-460.
    CrossrefPubMedGoogle Scholar
  • 51 Roques M. et al. Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis. Br J Haematol 2015; 169: 601-603.
    CrossrefPubMedGoogle Scholar
  • 52 Castro N. et al. CALR mutations screening should not be studied in splanchnic vein thrombosis. Br J Haematol 2015; 170: 588-589.
    CrossrefPubMedGoogle Scholar
  • 53 Iurlo A. et al. Molecular analyses in the diagnosis of myeloproliferative neoplasm-related splanchnic vein thrombosis. Ann Haematol 2015; 94: 881-882.
    CrossrefPubMedGoogle Scholar
  • 54 Plompen EP. et al. Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis. Haematologica 2015; 100: e226-228.
    CrossrefPubMedGoogle Scholar
  • 55 Colaizzo D. et al. Clinical utility of screening for CALR gene exon 9 mutations in patients with splanchnic venous thrombosis. Thromb Haemost 2015; 113: 1381-1382.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Westbrook RH. et al. Prevalence and clinical outcomes of the 46/1 haplotype, Janus kinase 2 mutations, and ten-eleven translocation 2 mutations in Budd-Chiari syndrome and their impact on thrombotic complications post liver transplantation. Liver Transpl 2012; 18: 819-827.
    CrossrefPubMedGoogle Scholar
  • 57 Fiorini A. et al. Absence of the JAK2 exon 12 mutations in patients with splanchnic venous thrombosis and without overt myeloproliferative neoplasms. Am J Haematol 2009; 84: 126-127.
    CrossrefPubMedGoogle Scholar
  • 58 Bergamaschi GM. et al. MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction. Blood 2008; 111: 4418.
    CrossrefPubMedGoogle Scholar
  • 59 Jones AV. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 2009; 41: 446-449.
    CrossrefPubMedGoogle Scholar
  • 60 Kilpivaara O. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 2009; 41: 455-459.
    CrossrefPubMedGoogle Scholar
  • 61 Olcaydu D. et al. A common JAK2 haplotype confers susceptibility to myelopro-liferative neoplasms. Nat Genet 2009; 41: 450-454.
    CrossrefPubMedGoogle Scholar
  • 62 Colaizzo D. et al. The JAK2 rs12343867 CC genotype frequently occurs in patients with splanchnic venous thrombosis without the JAK2V617F mutation: a retrospective study. J Thromb Haemost 2010; 08: 413-416.
    CrossrefPubMedGoogle Scholar
  • 63 Smalberg JH. et al. The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis. Blood 2011; 117: 3968-3973.
    CrossrefPubMedGoogle Scholar
  • 64 Villani L. et al. JAK2 46/1 haplotype predisposes to splanchnic vein thrombosis-associated BCR-ABL negative classic myeloproliferative neoplasms. Leuk Res 2012; 36: e7-9.
    CrossrefPubMedGoogle Scholar
  • 65 Li SL. et al. The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies. Ann Haematol 2014; 93: 1845-1852.
    CrossrefPubMedGoogle Scholar
  • 66 Solary E. et al. The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 2014; 28: 485-496.
    CrossrefPubMedGoogle Scholar
  • 67 Primignani M. et al. Role of the JAK2 mutation in the diagnosis of chronic mye-loproliferative disorders in splanchnic vein thrombosis. Hepatology 2006; 44: 1528-1534.
    CrossrefPubMedGoogle Scholar
  • 68 Wilkins BS. et al. Bone marrow pathology in essential thrombocythemia: inter-observer reliability and utility for identifying disease subtypes. Blood 2008; 111: 60-70.
    CrossrefPubMedGoogle Scholar
  • 69 Alvarez-Larrán A. et al. WHO-histological criteria for myeloproliferative neoplasms: reproducibility, diagnostic accuracy and correlation with gene mutations and clinical outcomes. Br J Haematol 2014; 166: 911-919.
    CrossrefPubMedGoogle Scholar
  • 70 Sharma S. et al. Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature. J Hepatol 2004; 40: 172-180.
    PubMedGoogle Scholar
  • 71 Smalberg JH. et al. Risks and benefits of transcatheter thrombolytic therapy in patients with splanchnic venous thrombosis. Thromb Haemost 2008; 100: 1084-1088.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Liu FY. et al. Interventional treatment for symptomatic acute-subacute portal and superior mesenteric vein thrombosis. World J Gastroenterol 2009; 15: 5028-5034.
    CrossrefPubMedGoogle Scholar
  • 73 Ageno W. et al. Antithrombotic treatment of splanchnic vein thrombosis: results of an international registry. Semin Thromb Hemost 2014; 40: 99-105.
    PubMedGoogle Scholar
  • 74 Kearon C. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 454S-545S.
    CrossrefPubMedGoogle Scholar
  • 75 Oldakowska-Jedynak U. et al. Myeloproliferative neoplasms and recurrent thrombotic events in patients undergoing liver transplantation for Budd-Chiari syndrome: a single-centre experience. Ann Transplant 2014; 19: 591-597.
    CrossrefPubMedGoogle Scholar
  • 76 Potthoff A. et al. Long-term outcome of liver transplant patients with Budd-Chiari syndrome secondary to myeloproliferative neoplasms. Liver Int. 2015 Epub ahead of print.
    PubMedGoogle Scholar
  • 77 Chinnakotla S. et al. Long-term follow-up of liver transplantation for Budd-Chiari syndrome with antithrombotic therapy based on the etiology. Transplantation 2011; 92: 341-345.
    CrossrefPubMedGoogle Scholar
  • 78 Colaizzo D. et al. Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: a role for the JAK2 V617F mutation re-evaluation. Thromb Res 2013; 132: e99-e104.
    CrossrefPubMedGoogle Scholar
  • 79 Qi X. et al. Survival and prognostic indicators of Budd-Chiari syndrome: a systematic review of 79 studies. Expert Rev Gastroenterol Hepatol 2015; 09: 865-875.
    CrossrefPubMedGoogle Scholar
  • 80 Thatipelli MR. et al. Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol 2010; 08: 200-205.
    CrossrefPubMedGoogle Scholar
  • 81 Darwish Murad S. et al. Determinants of survival and the effect of portosys-temic shunting in patients with Budd-Chiari syndrome. Hepatology 2004; 39: 500-508.
    CrossrefPubMedGoogle Scholar
  • 82 Zeitoun G. et al. Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatol-ogy 1999; 30: 84-89.
    CrossrefPubMedGoogle Scholar
  • 83 Garcia-Pagán JC. et al. TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients. Gastroenterology 2008; 135: 808-815.
    CrossrefPubMedGoogle Scholar
  • 84 Smalberg JH. et al. Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome. Haematologica 2006; 91: 1712-1713.
    PubMedGoogle Scholar
  • 85 Spaander MC. et al. Ascites in patients with noncirrhotic nonmalignant extrahe-patic portal vein thrombosis. Aliment Pharmacol Ther 2010; 32: 529-534.
    CrossrefPubMedGoogle Scholar
  • 86 Hoekstra J. et al. Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms. J Thromb Haemost 2011; 09: 2208-2214.
    CrossrefPubMedGoogle Scholar
  • 87 Spaander MC. et al. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J Thromb Haemost 2013; 11: 452-459.
    CrossrefPubMedGoogle Scholar
  • 88 Ageno W. et al. Long-term clinical outcomes of splanchnic vein thrombosis. Results of an International Registry. JAMA Intern Med 2015; 175: 1474-1480.
    CrossrefPubMedGoogle Scholar
  • 89 Condat B. et al. Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology 2001; 120: 490-497.
    CrossrefPubMedGoogle Scholar
  • 90 Amitrano L. et al. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007; 102: 2464-2470.
    CrossrefPubMedGoogle Scholar
  • 91 Riva N. et al. Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicentre cohort study. J Thromb Haemost 2015; 13: 1019-1027.
    CrossrefPubMedGoogle Scholar
  • 92 de Franchis R. Baveno VI Faculty. Expanding Consensus in portal hypertension. Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-752.
    CrossrefPubMedGoogle Scholar
  • 93 De Stefano V. et al. Recurrences after splanchnic venous thrombosis: risk factors and effect of different treatments in a retrospective monocentre cohort of 154 patients. Haematologica 2015; 100 (Suppl. 01) 621.
    PubMedGoogle Scholar
  • 94 Barosi G. et al. Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper. Leuk Res 2014; 38: 155-160.
    CrossrefPubMedGoogle Scholar