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Management of splanchnic vein thrombosis

  • Author Footnotes
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    Laure Elkrief
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    Affiliations
    Service d’Hépato-Gastroenterologie CHU de Tours, France
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    Audrey Payancé
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    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
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  • Aurélie Plessier
    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
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  • Louis d’Alteroche
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    Service d’Hépato-Gastroenterologie CHU de Tours, France
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  • Maxime Ronot
    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service de radiologie, Hôpital Beaujon APHP.Nord, Clichy, France
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  • Valérie Paradis
    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service d’anatomie et cytologie pathologique, Hôpital Beaujon APHP.Nord, Clichy, France
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  • Dominique Valla
    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
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  • Pierre-Emmanuel Rautou
    Correspondence
    Corresponding author. Prof. Pierre-Emmanuel Rautou, Service d’Hépatologie, Hôpital Beaujon, 100 boulevard du Général Leclerc, 92110 Clichy France, Tel: +331 40 87 50 91, Fax +331 40 87 44 35,
    Affiliations
    Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France

    Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
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Open AccessPublished:January 02, 2023DOI:https://doi.org/10.1016/j.jhepr.2022.100667

      Summary

      Splanchnic vein thromboses include Budd-Chiari syndrome and portal vein thrombosis. These disorders have common characteristics: (i) they are rare diseases; and (ii) they can cause portal hypertension and its complications. Budd-Chiari syndrome and portal vein thrombosis in the absence of underlying liver disease share many risk factors, among which myeloproliferative neoplasms represent the most common; a rapid comprehensive workup for risk factors for thrombosis is needed in these patients. Long-term anticoagulation is indicated in most patients. Portal vein thrombosis can also develop in patients with cirrhosis and in patients with portosinusoidal vascular liver disease. The presence and nature of underlying liver disease impact the management of portal vein thrombosis. Indications for anticoagulation in patients with cirrhosis are growing, while transjugular intrahepatic portosystemic shunt (TIPSS) appears as a second-line option. Due to the rarity of these diseases, studies yielding high grade of evidence are scarce. However, collaborative studies have provided new insight into the management of these patients. This article focuses on the causes, diagnosis, and management of patients with Budd-Chiari syndrome, patients with portal vein thrombosis without underlying liver disease, patients with cirrhosis and nonmalignant portal vein thrombosis.

      Keywords

      Abbreviations:

      AFP (alpha-fetoprotein), BCS (Budd Chiari syndrome), CALR (calreticulin), CT (computed tomography), DOACs (direct‐acting oral anticoagulants), JAK2 (Janus kinase 2), LMWH (low molecular weight heparin), MPN (myeloproliferative neoplasm), MRI (magnetic resonance imaging), PTA (percutaneous transluminal angioplasty), PVT (portal vein thrombosis), SVT (splanchnic vein thrombosis), TIPSS (transjugular intrahepatic portosystemic shunt), VKA (vitamin K antagonists)
      • 1.
        Patients with Budd-Chiari syndrome or portal vein thrombosis in the absence of underlying liver disease should be systematically screened for myeloproliferative neoplasm by testing the presence of V617F mutation of the JAK2 gene. Molecular profiling using next-generation sequencing is a promising tool for diagnosis and prognosis purposes.
      • 2.
        The diagnosis of Budd-Chiari syndrome or portal vein thrombosis is suspected using abdominal Doppler ultrasonography, and confirmed using contrast-enhanced computed tomography or magnetic resonance imaging. Liver biopsy is generally not necessary for a diagnosis of Budd-Chiari syndrome. In patients with portal vein thrombosis, liver stiffness measurement using transient elastography < 10 kPa rules out underlying cirrhosis.
      • 3.
        In patients with Budd-Chiari syndrome, long-term anticoagulation is recommended; prompt identification and treatment of the causal factor have a beneficial impact on patient’s outcomes.
      • 4.
        Spontaneous recanalization is exceptional in patients with portal vein thrombosis in the absence of underlying liver disease. By contrast, in patients with cirrhosis and PVT, spontaneous recanalization occurs in ≈40% of the patients, especially in those with nonocclusive PVT.
      • 5.
        In patients with portal vein thrombosis in the absence of underlying liver disease, long-term anticoagulation is generally recommended. In patients without a strong risk factor for thrombosis, a lower dose (e.g. rivaroxaban 15 mg once daily) may be sufficient to prevent recurrence of thrombosis
      • 6.
        In patients with portal vein thrombosis in the absence of underlying liver disease, preliminary data suggest that portal vein recanalization with or without TIPSS is a safe option when performed in expert centers in patients with refractory complications of portal hypertension or portal cavernoma cholangiopathy
      • 7.
        In patients with cirrhosis and portal vein thrombosis, anticoagulation is recommended in all potential candidates for liver transplantation regardless of age and the thrombus extension. In non-candidates for liver transplantation, anticoagulation is recommended in case of recent (<6 months) thrombosis, occluding > 50% of the lumen of the main portal vein
      • 8.
        In patients with cirrhosis, TIPSS can be considered as the 2nd-line option for the treatment of portal vein thrombosis, especially in case of significant concomitant complications of portal hypertension
      • 9.
        Anticoagulation of patients with splanchnic vein thrombosis used to be based on low molecular weight heparin and vitamin K antagonists. There is now growing evidence demonstrating that DOACs are as safe and effective an option. However, high-grade of evidence is still needed before making strong recommendations on the use of DOACs in patients with splanchnic vein thrombosis.

      Introduction

      Splanchnic vein thromboses (SVT) include Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). PVT can develop in patients without underlying liver disease or affect patients with cirrhosis. Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) in the absence of underlying liver disease share several similarities. First, they belong to rare disorders since they affect fewer than 1 in 2000 people in the general population
      • Jones D.E.J.
      • Sturm E.
      • Lohse A.W.
      Access to care in rare liver diseases: New challenges and new opportunities.
      . Second, they are commonly associated with risk factors for thrombosis. Third, they have portal hypertension as a common consequence. PVT can also occur in patients with cirrhosis, where it is usually non-occlusive and found in the absence of symptoms. Risk factors for thrombosis in patients PVT and cirrhosis are uncommon. However, PVT in cirrhosis carries specific challenges, especially in liver transplant candidates.
      The present review focuses on the recent findings on the management of BCS and PVT without underlying liver disease or with underlying cirrhosis. PVT occurring in patients with PSVD will not be discussed here, since it has been recently reviewed elsewhere
      • De Gottardi A.
      • Sempoux C.
      • Berzigotti A.
      Porto-sinusoidal vascular disorder.
      . Management of BCS and PVT is multidisciplinary, with a growing place for interventional radiology. Importantly, besides treating portal-hypertension-related complications, managing patients with splanchnic vein thrombosis largely depends on associated risk factors for thrombosis or extra-hepatic conditions. Indeed, the outcome and prognosis of patients with vascular liver diseases differ according to the causal factors.

      Causes of splanchnic vein thrombosis in the absence of underlying liver diseases

      Causes for SVT include general risk factors for thrombosis, namely systemic acquired prothrombotic diseases and inherited thrombophilia, and local factors. General risk factors for thrombosis are found in approximately 70% of the patients with SVT, while local factors are identified in 20% and 5% of the patients with PVT and BCS, respectively.
      A combination of two or more genetic or acquired risk factors is found in 26%-46% and 10-23% of patients with BCS or PVT, respectively
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      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
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      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
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      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
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      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      . Furthermore, 36% of the patients with PVT and a local factor also have a general risk factor for thrombosis
      • Plessier A.
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      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
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      • Guillaume M.
      • Ruidavets J.B.
      • et al.
      Central obesity is associated with non-cirrhotic portal vein thrombosis.
      . These results justify comprehensive investigations, even when predisposing or precipitating factors have already been shown (Table 1). This workup should be performed at diagnosis of SVT since control of some conditions (e.g., myeloproliferative neoplasms (MPN), Behcet’s disease, paroxysmal nocturnal hemoglobinuria (PNH)) influences patients’ outcomes
      • Chagneau-Derrode C.
      Impact of cytoreductive therapy on the outcome of patients with myeloproliferative neoplasms and hepato-splanchnic vein thrombosis.
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      • Wechsler B.
      • Resche-Rigon M.
      • et al.
      Behcet’s disease in Budd-Chiari syndrome.
      • Magaz M.
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      • et al.
      Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.
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      • Shukla A.
      • Pagan J.C.G.
      • De Raucourt E.
      • et al.
      Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.
      .
      Table 1Prevalence of risk factors for Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) in the absence of underlying liver disease and proposed diagnostic work-up and specific management (see
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      • Bureau C.
      • Laurent J.
      • Robic M.A.
      • Christol C.
      • Guillaume M.
      • Ruidavets J.B.
      • et al.
      Central obesity is associated with non-cirrhotic portal vein thrombosis.
      ,
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernández-Gea V.
      • Garcia-Pagán J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      ,
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      ).
      ConditionPrevalenceRecommended work-up
      BCSPVT
      Myeloproliferative neoplasm30-57%21-25%Systematic genetic testing of the V617F mutation of the JAK2 gene in all patients

      If negative
      • -
        genetic testing of the calreticulin gene if platelet count ≥ 200 x109/L and/or spleen height ≥ 16 cm
      • -
        discuss next-generation sequencing
      • -
        discuss bone marrow biopsy
      JAK2 V617F28-45%15-21%
      CALR mutation1-3%1-2%
      Inherited thrombophilic disordersGenetic testing
      • -
        Prothrombin G20210A gene mutation
      • -
        Factor V Leiden
      Protein S activity

      Protein C activity

      Antithrombin activity

      Dosage should be performed in the absence of VKA. Cautious interpretation of impaired liver function
      Prothrombin G20210A gene mutation12%5%
      Factor V Leiden mutation4%8%
      Antithrombin deficiency3%5%
      Protein C deficiency2%1%
      Protein S deficiency2%2%
      Acquired thrombophilic disorders
      Antiphospholipid antibody syndrome5%5%Lupus anticoagulant, Anti-cardiolipin, and Anti-beta2 glycoprotein 1 antibodies testing

      Repeat testing after 12 weeks in case of positive testing
      Paroxysmal nocturnal hemoglobinuria10%0-0.5%Flow cytometry analysis
      Behcet’s disease1-2%uncommonNo specific testing, clinical diagnosis

      Suspect Behcet's disease if: male gender, Mediterranean origin

      IVC stenosis, genital/oral ulcers, deep vein thrombosis in other sites, arterial thrombosis
      Celiac disease1.4%0.7%Anti-transglutaminase antibody +/- duodenal biopsies
      Other systemic factors

      Auto-immune disease

      Inflammatory bowel disease

      Vasculitis

      Sarcoidosis

      Connective tissue disease

      Cytomegalovirus disease
      Search clinical and/or laboratory features

      CMV IgM and CMV PCR (blood)
      Hormonal factors

      Oral contraceptive or pregnancy
      ≈ 30%≈ 20%Clinical context

      Search for introduction/modification of oral contraception within 6 months before diagnosis
      Local factors
      Pancreatitis0-3%20 %Computed tomography scan

      Colonoscopy
      Diverticulitis
      Cholecystitis
      Appendicitis
      Intra-abdominal surgery
      Hydatid cyst
      No identified factor10-29%15-40%
      Abbreviations: CMV, cytomegalovirus; IVC, inferior vena cava

      Myeloproliferative neoplasms

      MPNs represent the most common risk factor for BCS and PVT in Europe and Asia. In Europe, the reported prevalence of MPNs in patients with BCS and PVT is 30-57% and 21-25%, respectively
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      • Bureau C.
      • Laurent J.
      • Robic M.A.
      • Christol C.
      • Guillaume M.
      • Ruidavets J.B.
      • et al.
      Central obesity is associated with non-cirrhotic portal vein thrombosis.
      ,
      • Smalberg J.H.
      • Arends L.R.
      • Valla D.C.
      • Kiladjian J.-J.
      • Janssen H.L.A.
      • Leebeek F.W.G.
      Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernández-Gea V.
      • Garcia-Pagán J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      . In Asia, the prevalence of MPN among patients with BCS or PVT ranges from 5 to 28%
      • Qi X.
      • Han G.
      • Guo X.
      • De Stefano V.
      • Xu K.
      • Lu Z.
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      Review article: the aetiology of primary Budd-Chiari syndrome - differences between the West and China.
      ,
      • Fan J.
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      • Chen H.
      • Wang Z.
      • Niu J.
      • et al.
      Prevalence of prothrombotic factors in patients with Budd-Chiari syndrome or non-cirrhotic nonmalignant portal vein thrombosis: A hospital-based observational study.
      . In over 90% of the patients with SVT and MPN, Janus kinase 2 gene (JAK2) V617F mutation can be detected. Thus, routine screening for JAK2 V617F mutation should be performed in all patients with SVT. Somatic mutations of the gene encoding calreticulin (CALR) are identified in about 2% of SVT patients without JAK2 V617F mutation. CALR mutations should be searched particularly in patients with spleen height ≥16 cm, and a platelet count ≥200 x 109/L since 33-56% of the patients with this association have CALR mutations
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      ,
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernández-Gea V.
      • Garcia-Pagán J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      ,
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      . MPL exon 10 and JAK2-exon 12 mutations are even less common in patients with SVT
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      ,
      • Magaz M.
      • Alvarez-Larrán A.
      • Colomer D.
      • López-Guerra M.
      • García-Criado M.Á.
      • Mezzano G.
      • et al.
      Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.
      ,
      • Smalberg J.H.
      • Arends L.R.
      • Valla D.C.
      • Kiladjian J.-J.
      • Janssen H.L.A.
      • Leebeek F.W.G.
      Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
      . Next-generation sequencing (NGS) has recently been shown to be an interesting tool for diagnosing an underlying MPN in patients without JAK2 V617F or CALR mutations
      • Magaz M.
      • Alvarez-Larrán A.
      • Colomer D.
      • López-Guerra M.
      • García-Criado M.Á.
      • Mezzano G.
      • et al.
      Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.
      ,
      • Debureaux P.-E.
      • Cassinat B.
      • Soret-Dulphy J.
      • Mora B.
      • Verger E.
      • Maslah N.
      • et al.
      Molecular profiling and risk classification of patients with myeloproliferative neoplasms and splanchnic vein thromboses.
      ,
      • Kiladjian J.-J.
      • Debureaux P.-E.
      • Plessier A.
      • Soret-Dulphy J.
      • Valla D.
      • Cassinat B.
      • et al.
      Benefits of molecular profiling with next-generation sequencing for the diagnosis and prognosis of myeloproliferative neoplasms in splanchnic vein thrombosis.
      . Moreover, in patients with SVT, NGS molecular profiling carries prognosis information since some molecular risk factors predict the risk of thrombosis recurrence in patients without MPN
      • Magaz M.
      • Alvarez-Larrán A.
      • Colomer D.
      • López-Guerra M.
      • García-Criado M.Á.
      • Mezzano G.
      • et al.
      Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.
      and the risk of hematological transformation and poorer survival in patients with MPN
      • Debureaux P.-E.
      • Cassinat B.
      • Soret-Dulphy J.
      • Mora B.
      • Verger E.
      • Maslah N.
      • et al.
      Molecular profiling and risk classification of patients with myeloproliferative neoplasms and splanchnic vein thromboses.
      . Portal hypertension, by causing hypersplenism and hemodilution, often masks the increased blood cell counts and makes the diagnosis of MPN challenging
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      • Condat B.
      • Cazals-Hatem D.
      • Rufat P.
      • Atmani S.
      • Chaoui D.
      • et al.
      Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis.
      . Therefore, given the frequency of MPN in patients with SVT and the consequences of its diagnosis, referral to a hematologist should be systematically considered to discuss NGS and/or bone marrow biopsy (Table 1).

      Other acquired pro-thrombotic disorders

      The frequency of antiphospholipid antibodies in patients with SVT has been reported to be between 5% and 30%
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      ,
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernández-Gea V.
      • Garcia-Pagán J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      ,
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      , while in healthy individuals, these antibodies can be found in the absence of antiphospholipid syndrome in up to 5%
      • Levine J.S.
      • Branch D.W.
      • Rauch J.
      The Antiphospholipid Syndrome.
      . A meta-analysis did not show an association between antiphospholipid antibodies and BCS or PVT, except for IgG anticardiolipin antibodies
      • Qi X.
      • De Stefano V.
      • Su C.
      • Bai M.
      • Guo X.
      • Fan D.
      Associations of antiphospholipid antibodies with splanchnic vein thrombosis: a systematic review with meta-analysis.
      . Therefore, in the case of antiphospholipid antibodies at diagnosis of SVT, it is recommended to perform second testing for antiphospholipid antibodies 12 weeks after the diagnosis.
      The association between Behcet’s disease and SVT mainly concerns BCS and is especially relevant in the Mediterranean population
      • Desbois A.C.
      • Rautou P.E.
      • Biard L.
      • Belmatoug N.
      • Wechsler B.
      • Resche-Rigon M.
      • et al.
      Behcet’s disease in Budd-Chiari syndrome.
      ,
      • Sakr M.A.
      • Reda M.A.
      • Ebada H.E.
      • Abdelmoaty A.S.
      • Hefny Z.M.
      • Ibrahim Z.H.
      • et al.
      Characteristics and outcome of primary Budd-Chiari syndrome due to Behçet’s syndrome.
      . Diagnosis of Behcet’s disease should be suspected in case of inferior vena cava obstruction, oral and/or genital ulcers, male gender, deep venous thrombosis in other territories, and systemic inflammatory syndrome
      • Desbois A.C.
      • Rautou P.E.
      • Biard L.
      • Belmatoug N.
      • Wechsler B.
      • Resche-Rigon M.
      • et al.
      Behcet’s disease in Budd-Chiari syndrome.
      . Early medical therapy, including anticoagulation and immunosuppressive agents, may improve symptoms of BCS (including requirement of invasive treatments) in patients with BCS and Behcet’s disease
      • Desbois A.C.
      • Rautou P.E.
      • Biard L.
      • Belmatoug N.
      • Wechsler B.
      • Resche-Rigon M.
      • et al.
      Behcet’s disease in Budd-Chiari syndrome.
      .
      Paroxysmal nocturnal hemoglobinuria (PNH) was found in up to 10% of the patients with BCS
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Hoekstra J.
      • Leebeek F.W.G.
      • Plessier A.
      • Raffa S.
      • Darwish Murad S.
      • Heller J.
      • et al.
      Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study.
      . Conversely, PNH appears extremely rare (less than 2%) among PVT patients
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      . Still, systematic screening for PNH is recommended in all patients with SVT since specific therapies, especially eculizumab, have been shown to decrease the recurrence of thrombosis and mortality in this setting
      • Plessier A.
      • Esposito-Farèse M.
      • Baiges A.
      • Shukla A.
      • Pagan J.C.G.
      • De Raucourt E.
      • et al.
      Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.
      .
      In a cohort of 115 Algerian patients with BCS, celiac disease has been found in 11% of the patients
      • Afredj N.
      • Guessab N.
      • Nani A.
      • Faraoun S.A.
      • Ouled Cheikh I.
      • Kerbouche R.
      • et al.
      Aetiological factors of Budd-Chiari syndrome in Algeria.
      . This association is less common in European countries
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernández-Gea V.
      • Garcia-Pagán J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      .
      Cytomegalovirus disease is another recently highlighted rare (<5%) risk factor for PVT. This association should be suspected in patients with recent PVT displaying features of mononucleosis syndrome. CMV disease should not deter a complete workup since a general risk factor for thrombosis (especially G20210A prothrombin gene mutation) was found in 50% of the patients
      • De Broucker C.
      • Plessier A.
      • Ollivier-Hourmand I.
      • Dharancy S.
      • Bureau C.
      • Cervoni J.-P.
      • et al.
      Multicenter study on recent portal venous system thrombosis associated with cytomegalovirus disease.
      . CMV disease does not influence thrombosis extension or recanalization. In addition, acute SVT has been reported in patients with Sars-Cov-2 infection. Although rare, SVT may be severe in this setting, suggesting that patients with Sars-Cov-2 infection and severe gastrointestinal symptoms should be screened for SVT
      • Buso G.
      • Becchetti C.
      • Berzigotti A.
      Acute splanchnic vein thrombosis in patients with COVID-19: A systematic review.
      . Although rare cases of SVT occurring after Covid-19 vaccination were reported, the risk of thrombosis is higher after Sars-Cov-2 infection than after Covid-19 vaccination
      • Hippisley-Cox J.
      • Patone M.
      • Mei X.W.
      • Saatci D.
      • Dixon S.
      • Khunti K.
      • et al.
      Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.
      . Furthermore, since Sars-Cov-2 infection seems to be more frequent and severe in patients with vascular liver diseases than in the general population
      • Baiges A.
      • Cerda E.
      • Amicone C.
      • Téllez L.
      • Alvarado-Tapias E.
      • Puente A.
      • et al.
      Impact of SARS-CoV-2 Pandemic on Vascular Liver Diseases.
      , a history of SVT should not contraindicate Covid-19 vaccination.

      Inherited thrombophilia

      Factor V Leiden and G21020 prothrombin gene mutations have been reported in 12% and 4% of the patients with BCS, respectively. In patients with PVT, the prevalence of Factor V Leiden and G21020 prothrombin gene mutations are 5% and 8%, respectively
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      ,
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      . Compared to healthy individuals, Factor V Leiden mutation is associated with an increased risk of both BCS and PVT, whereas G21020 prothrombin gene is associated with PVT but not with BCS
      • Qi X.
      • Ren W.
      • De Stefano V.
      • Fan D.
      Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis.
      .
      Prevalence of deficiency in antithrombin, protein C or protein S is 3%, 2% and 2% in BCS, and 5%, 1% and 2% in those with PVT
      • Poisson J.
      • Plessier A.
      • Kiladjian J.-J.
      • Turon F.
      • Cassinat B.
      • Andreoli A.
      • et al.
      Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
      ,
      • Plompen E.P.C.
      • Valk P.J.M.
      • Chu I.
      • Darwish Murad S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic Calreticulin Mutations in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.
      . Diagnosis of inherited deficiencies in antithrombin, protein C, and protein S may be difficult to establish because liver dysfunction can induce a nonspecific decrease in those natural anticoagulants, as recently highlighted with antithrombin deficiency
      • Fisher N.C.
      • Wilde J.T.
      • Roper J.
      • Elias E.
      Deficiency of natural anticoagulant proteins C, S, and antithrombin in portal vein thrombosis: a secondary phenomenon?.
      ,
      • Baiges A.
      • de la Morena-Barrio M.E.
      • Turon F.
      • Miñano A.
      • Alberto Ferrusquía J.
      • Magaz M.
      • et al.
      Congenital antithrombin deficiency in patients with splanchnic vein thrombosis.
      . Although not widely available, genetic testing might be considered in cases of rethrombosis, family history of deep vein thrombosis or doubtful interpretation of antithrombin, protein C, and protein S concentrations.
      Hyperhomocysteinemia and/or homozygous C677T methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism has been found in 22% of the patients with BCS
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      and 11% of those with PVT
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      . However, the role of hyperhomocysteinemia as a risk factor for SVT is difficult to assess because homocysteine levels are highly influenced by diet and by vitamin B6, B12, or B9 deficiencies. The role of homozygous C677T MTHFR mutation as a risk factor for BCS seems more relevant in Asia than in Europe
      • Qi X.
      • Han G.
      • Guo X.
      • De Stefano V.
      • Xu K.
      • Lu Z.
      • et al.
      Review article: the aetiology of primary Budd-Chiari syndrome - differences between the West and China.
      ,
      • Qi X.
      • Yang Z.
      • De Stefano V.
      • Fan D.
      Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta-analysis of observational studies.
      . The prevalence of C677T MTHFR mutation does not differ between PVT patients and healthy individuals
      • Qi X.
      • Yang Z.
      • De Stefano V.
      • Fan D.
      Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta-analysis of observational studies.

      Hormonal factors

      Pregnancy and oral contraceptives have been associated with BCS. Up to 74% of western women with BCS have been using oral contraceptive agents and a temporal link between pregnancy and BCS has been described
      • Denninger M.H.
      • Chaït Y.
      • Casadevall N.
      • Hillaire S.
      • Guillin M.C.
      • Bezeaud A.
      • et al.
      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
      ,
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Bissonnette J.
      • Durand F.
      • de Raucourt E.
      • Ceccaldi P.-F.
      • Plessier A.
      • Valla D.
      • et al.
      Pregnancy and vascular liver disease.
      . Local or other general pro-thrombotic factors are commonly associated with pregnancy or oral contraceptives in women with BCS. Regarding PVT, exposure to female hormones does not appear to cause PVT, as illustrated by the absence of female predominance among patients with PVT contrary to BCS
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • van Der Meer F.J.
      • 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.
      ,
      • Rajani R.
      • Björnsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      .

      Local factors

      Local risk factors for SVT include abdominal surgery and infectious or inflammatory conditions involving splanchnic organs, such as cancer or inflammatory bowel disease
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      (Table 1). Certain local factors can be identified on the CT scan performed at SVT diagnosis. In PVT, colonoscopy is recommended to screen for colon cancer or inflammatory bowel disease, although level of evidence is low
      • Soret J.
      • Debray D.
      • Fontbrune FS de
      • Kiladjian J.-J.
      • Saadoun D.
      • Latour RP de
      • et al.
      Risk factors for vascular liver diseases: Vascular liver diseases: position papers from the francophone network for vascular liver diseases, the French Association for the Study of the Liver (AFEF), and ERN-rare liver.
      . PVT associated with alcoholic pancreatitis has some specificity since it does not seem to be favored by general risk factors for thrombosis, so the interest in a comprehensive workup for risk factors for thrombosis is questionable in this setting
      • Rebours V.
      • Boudaoud L.
      • Vullierme M.-P.
      • Vidaud D.
      • Condat B.
      • Hentic O.
      • et al.
      Extrahepatic portal venous system thrombosis in recurrent acute and chronic alcoholic pancreatitis is caused by local inflammation and not thrombophilia.
      . Visceral adipose tissue might also promote PVT. Indeed, in a retrospective case control study gathering 79 patients with PVT and 79 healthy individuals, features of the metabolic syndrome were more frequent in patients with “idiopathic PVT” (i.e. no risk factor for PVT identified) than in those with either secondary PVT (i.e. risk factor for PVT identified) or healthy individuals. Especially, increased waist circumference was found in ≈75% of the patients with “idiopathic PVT” versus ≈30% of the patients with either secondary PVT or healthy individuals, pointing to visceral adipose tissue as a potential risk factor for PVT.
      • Bureau C.
      • Laurent J.
      • Robic M.A.
      • Christol C.
      • Guillaume M.
      • Ruidavets J.B.
      • et al.
      Central obesity is associated with non-cirrhotic portal vein thrombosis.
      . Confirmatory studies addressing the link between visceral obesity and PVT are needed.
      In patients with BCS, local factor appears to be rare. However, in countries with a high prevalence of Echinococcus granulosus, liver hydatid cysts have been associated with BCS in up to 4% of the patients
      • Afredj N.
      • Guessab N.
      • Nani A.
      • Faraoun S.A.
      • Ouled Cheikh I.
      • Kerbouche R.
      • et al.
      Aetiological factors of Budd-Chiari syndrome in Algeria.
      .

      Budd-Chiari syndrome

      BCS is caused by hepatic venous outflow tract obstruction, from the small hepatic veins to the entrance of the inferior vena cava into the right atrium. BCS is usually caused by thrombosis. Heart failure, constrictive pericarditis, and sinusoidal obstruction syndrome/veno-occlusive disease are differential diagnoses of BCS.

      Diagnosis

      BCS should be considered in patients with any acute or chronic liver disease. Clinical presentation of BCS varies from asymptomatic (3% of the cases) to severe portal hypertension or liver insufficiency. In most patients, clinical manifestations include abdominal pain and ascites
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      .
      The diagnosis of BCS is based on radiological findings on Doppler ultrasonography and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Because BCS diagnosis can be difficult, radiologists should be experienced and aware of the clinical suspicion of BCS. Radiological features of BCS include (i) direct arguments of obstruction, including solid non-enhancing endoluminal material or transformation of the veins into a cord devoid of flow signal, and (ii) indirect arguments of outflow obstruction, including dilatation of the vein upstream to the obstruction, inter-hepatic venous collateral or inverted venous flow, atrophy/hypertrophy of affected/unaffected segments
      • Van Wettere M.
      • Bruno O.
      • Rautou P.-E.
      • Vilgrain V.
      • Ronot M.
      Diagnosis of Budd-Chiari syndrome.
      . “Classical” forms of BCS do not require liver biopsy for diagnosis, whereas it can be helpful in the rare form of small hepatic veins BCS where large hepatic veins are patent. Location of obstruction varies according to geographic areas: 62% of BCS in Western countries are pure hepatic vein obstruction, whereas membranous obstruction of the inferior vena cava is more common in Asia
      • Valla D.-C.
      Budd-Chiari syndrome/hepatic venous outflow tract obstruction.
      . The difficulty of BCS diagnosis is illustrated by a French epidemiological study where the duration between first clinical manifestations and diagnosis of primary BCS exceeded 6 months in 15% of the patients and one year in 6% of the patients
      • Ollivier-Hourmand I.
      • Allaire M.
      • Goutte N.
      • Morello R.
      • Chagneau-Derrode C.
      • Goria O.
      • et al.
      The epidemiology of Budd-Chiari syndrome in France.
      .

      Management

      BCS requires referral to centers with expertise in managing patients with vascular liver diseases and having access to interventional radiology and liver transplantation. The approach should be multidisciplinary, including specialists in hemostasis, hematology, diagnostic and interventional radiology, and liver transplantation. For more than 15 years, a stepwise treatment strategy, according to response to previous therapy (from less to more invasiveness), has been proposed and is now largely used worldwide
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.-H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      • Northup P.G.
      • Garcia‐Pagan J.C.
      • Garcia‐Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . With this strategy, patients’ outcome has dramatically improved, with 5-year overall survival ranging from 77% to 87%
      • Eapen C.E.
      • 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.
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      • Tripathi D.
      • Macnicholas R.
      • Kothari C.
      • Sunderraj L.
      • Al-Hilou H.
      • Rangarajan B.
      • et al.
      Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd-Chiari syndrome.
      . Among patients alive at 5 year, around 30% are controlled with medical therapy alone, 35% with interventional radiology and 10% with liver transplantation
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      . The exact timing for further intervention is not stated. Improvement with no need of further intervention is considered in the presence of the combination of several of the following features: decreasing rate of ascites formation, decreasing serum bilirubin, decreasing serum creatinine and decreasing INR (or increasing factor V in patients receiving vitamin K antagonists)
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Several prognostic indices have been proposed for all patients with BCS (Child-Pugh score, MELD, Clichy prognostic index, Rotterdam BCS index, New Clichy prognostic index) and one for BCS patients in whom TIPS is considered as a therapeutic option (BCS-TIPS). These prognostic indices are accurate to assess transplant-free survival and invasive therapy-free survival. However, because i) they derived from retrospective cohorts constituted over several decades with drastically different therapeutic options and outcomes, and ii) they had low prognostic accuracy in most recent studies, they are considered insufficiently accurate to base the management of individual BCS patients
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Rautou P.-E.
      • Moucari R.
      • Escolano S.
      • Cazals-Hatem D.
      • Denié C.
      • Chagneau-Derrode C.
      • et al.
      Prognostic indices for Budd-Chiari syndrome: valid for clinical studies but insufficient for individual management.
      • Garcia-Pagán J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      EASL Clinical Practice Guidelines: Vascular diseases of the liver.
      .

      Medical therapy

      Prompt identification of MPN, PNH, or Behcet’s disease associated with BCS is essential since targeting the underlying condition positively influences patients’ outcomes
      • Chagneau-Derrode C.
      Impact of cytoreductive therapy on the outcome of patients with myeloproliferative neoplasms and hepato-splanchnic vein thrombosis.
      • Desbois A.C.
      • Rautou P.E.
      • Biard L.
      • Belmatoug N.
      • Wechsler B.
      • Resche-Rigon M.
      • et al.
      Behcet’s disease in Budd-Chiari syndrome.
      • Magaz M.
      • Alvarez-Larrán A.
      • Colomer D.
      • López-Guerra M.
      • García-Criado M.Á.
      • Mezzano G.
      • et al.
      Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.
      • Plessier A.
      • Esposito-Farèse M.
      • Baiges A.
      • Shukla A.
      • Pagan J.C.G.
      • De Raucourt E.
      • et al.
      Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.
      . Anticoagulation should be started at BCS diagnosis, even in absence of identified prothrombotic disorder. Despite the absence of randomized study comparing anticoagulation vs. no treatment, long-term anticoagulation therapy is currently recommended for all BCS patients. This recommendation is based on the comparison of survival between historical studies not using anticoagulation and studies after using anticoagulation
      • Zeitoun G.
      • Escolano S.
      • Hadengue A.
      • Azar N.
      • El Younsi M.
      • Mallet A.
      • et al.
      Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting.
      . Only a few cases of anticoagulation interruption have been described in BCS patients in whom the prothrombotic factor was treated
      • Denninger M.H.
      • Chaït Y.
      • Casadevall N.
      • Hillaire S.
      • Guillin M.C.
      • Bezeaud A.
      • et al.
      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
      ,
      • Al-Jafar H.A.
      • AlDallal S.M.
      • Askar H.A.
      • Aljeraiwi A.M.
      • Al-Alansari A.
      Long Standing Eculizumab Treatment without Anticoagulant Therapy in High-Risk Thrombogenic Paroxysmal Nocturnal Hemoglobinuria.
      . However, there is no clear or sufficient argument currently to stop anticoagulation once BCS is stabilized and causal factor adequately treated. Because of a high rate of heparin-induced thrombocytopenia, mainly observed with unfractionated heparin (15%), low-molecular-weight heparin (LMWH) is currently recommended
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.-H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      ,
      • Randi M.L.
      • Tezza F.
      • Scapin M.
      • Duner E.
      • Scarparo P.
      • Scandellari R.
      • et al.
      Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis.
      ,
      • Zaman S.
      • Wiebe S.
      • Bernal W.
      • Wendon J.
      • Czuprynska J.
      • Auzinger G.
      Increased prevalence of heparin-induced thrombocytopenia in patients with Budd-Chiari syndrome: a retrospective analysis.
      . LMWH is usually substituted with VKA in patients with stable disease, targeting an INR between 2 and 3. Although the experience is limited, direct oral anticoagulants (DOACs) seem safe and effective in BCS patients, but larger prospective studies are needed
      • De Gottardi A.
      • Trebicka J.
      • Klinger C.
      • Plessier A.
      • Seijo S.
      • Terziroli B.
      • et al.
      Antithrombotic treatment with direct-acting oral anticoagulants (DOACs) in patients with splanchnic vein thrombosis and cirrhosis.
      ,
      • Semmler G.
      • Lindorfer A.
      • Schaefer B.
      • Bartl S.
      • Hametner-Schreil S.
      • Gensluckner S.
      • et al.
      Outcome of Budd-Chiari Syndrome (BCS) Patients Treated With Direct Oral Anticoagulants (DOACs) - An Austrian Multicenter Study.
      (Table 2). A recent retrospective case-control study found that dabigatran was associated with similar stent patency and complications rates after endovascular intervention as VKAs
      • Sharma S.
      • Kumar R.
      • Rout G.
      • Gamanagatti S.R.
      • null Shalimar
      Dabigatran as an oral anticoagulant in patients with Budd-Chiari syndrome post-percutaneous endovascular intervention.
      . DOACs are currently not recommended in patients with antiphospholipid syndrome as they have been associated with an increased risk of recurrent arterial thrombosis
      • Dufrost V.
      • Wahl D.
      • Zuily S.
      Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials.
      . Ascites, gastrointestinal bleeding, infections, renal failure, and encephalopathy should be treated as recommended for patients with cirrhosis, due to absence of specific data in the BCS population. Severe bleeding related to paracentesis have been reported in these patients receiving anticoagulation. A brief interruption of anticoagulation could be considered before paracentesis
      • Rautou P.-E.
      • Douarin L.
      • Denninger M.-H.
      • Escolano S.
      • Lebrec D.
      • Moreau R.
      • et al.
      Bleeding in patients with Budd–Chiari syndrome.
      .
      Table 2Considerations for the choice of anticoagulant to treat splanchnic vein thrombosis and suggestion of doses (adapted from
      • Steffel J.
      • Collins R.
      • Antz M.
      • Cornu P.
      • Desteghe L.
      • Haeusler K.G.
      • et al.
      2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation.
      .
      ConsiderationsLow molecular weight heparinVitamin K antagonistsDirect oral anticoagulants
      ApixabanRivaroxabanEdoxabanDabigatran
      Liver function
      Child-Pugh class ANo action neededNo action needed

      Target INR 2-3
      No action needed

      5 mg twice a day
      No action needed

      20 mg once a day
      No action needed

      60 mg once a day
      No action needed

      150 mg twice a day
      Child-Pugh class BNo action neededPossible

      Target INR 2-3
      Use with caution

      2.5 mg twice a day
      Use with caution

      15 mg once a day
      Use with caution

      30 mg once daily
      Use with caution

      110 mg twice a day
      Child-Pugh class CNo action neededPossible

      Target INR 2-3
      Contra-indicatedContra-indicatedContra-indicatedContra-indicated
      Renal function
      eGFR 30-50 mL/minNo action neededPossible

      Target INR 2-3
      No action needed

      5 mg twice a day
      Use with caution

      15 mg once a day
      Use with caution

      30 mg once daily
      Use with caution

      110 mg twice a day
      eGFR < 30 mL/minUse with cautionPossible

      Target INR 2-3
      Use with caution

      2.5 mg twice a day
      Use with caution

      15 mg once a day
      Use with caution

      30 mg once daily
      Contra-indicated
      eGFR < 15 mL/minContra-indicatedPossible

      Target INR 2-3
      Contra-indicatedContra-indicatedContra-indicatedContra-indicated
      Other considerations
      Drug-drug interaction

      Other medication with P-gp protein or Cytochrome 3A4 metabolism
      No action neededNo action needed

      Target INR 2-3
      No action neededUse with caution

      15 mg once a day
      No action neededUse with caution

      110 mg twice a day
      History of peptic ulcer disease with or without gastrointestinal bleedingNo action neededUse with caution

      Consider 15 mg once a day
      No action neededUse with caution

      Consider 110 mg twice a day
      Specific considerationMonitoring may be difficult in patients with liver insufficiency

      Factor II concentration may be useful in this setting
      Contraindicated in patients with antiphospholipid syndrome

      No data on pharmacokinetics after TIPSS placement
      Abbreviations: eGFR, estimated glomerular filtration rate, P-gp, Permeability glycoprotein

      Interventional radiology

      Short-length hepatic vein stenosis should be systematically searched for to re-establish the physiological drainage of the portal and sinusoidal blood. When identified, i.e., in ≈15% of the patients, percutaneous transluminal angioplasty (PTA) of accessible stenosis should be performed since this procedure has good efficacy and low morbidity
      • Valla D.-C.
      Budd-Chiari syndrome/hepatic venous outflow tract obstruction.
      ,
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.-H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ,
      • Eapen C.E.
      • 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.
      ,
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Mukund A.
      • Sarin S.K.
      Budd–Chiari syndrome: a focussed and collaborative approach.
      . In a recent Chinese randomized controlled trial including 88 patients with BCS and short-length stenosis, stent placement improved hepatic vein patency and reduced symptom recurrence over PTA alone
      • Wang Q.
      • Li K.
      • He C.
      • Yuan X.
      • Luo B.
      • Qi X.
      • et al.
      Angioplasty with versus without routine stent placement for Budd-Chiari syndrome: a randomised controlled trial.
      .
      Transjugular intrahepatic portosystemic shunt (TIPSS) has become the standard of care for patients with BCS and incomplete response to medical therapy and/or angioplasty
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Tripathi D.
      • Macnicholas R.
      • Kothari C.
      • Sunderraj L.
      • Al-Hilou H.
      • Rangarajan B.
      • et al.
      Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd-Chiari syndrome.
      ,
      • Garcia-Pagán J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      . TIPSS is currently needed in 40% of the patients with BCS, persistent ascites being the most common indication
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      . The technical success rate exceeds 90% in expert centers and the 10-year liver transplantation-free survival reaches 76%. Long term anticoagulation therapy should be maintained after TIPSS placement
      • Eapen C.E.
      • 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.
      . TIPSS dysfunction occurs in 42% and was mostly due to re-thrombosis of the stent which can be managed with TIPSS revision leading to a secondary patency rate close to 100%. The incidence of late hepatic encephalopathy is 25% in these patients, mostly transient encephalopathy, easily medically controlled with no reappearance
      • Hayek G.
      • Ronot M.
      • Plessier A.
      • Sibert A.
      • Abdel-Rehim M.
      • Zappa M.
      • et al.
      Long-term Outcome and Analysis of Dysfunction of Transjugular Intrahepatic Portosystemic Shunt Placement in Chronic Primary Budd-Chiari Syndrome.
      .

      Surgery

      Surgical portosystemic shunt in BCS has now been almost completely abandoned because of high perioperative mortality, averaging 25%
      • Langlet P.
      • Valla D.
      Is surgical portosystemic shunt the treatment of choice in Budd-Chiari syndrome?.
      and a high rate of shunt dysfunction due to early or late thrombosis or late stenosis, reaching 30% in series with long-term follow-up
      • Bachet J.-B.
      • Condat B.
      • Hagège H.
      • Plessier A.
      • Consigny Y.
      • Belghiti J.
      • et al.
      Long-term portosystemic shunt patency as a determinant of outcome in Budd-Chiari syndrome.
      .

      Liver transplantation

      Despite medical therapy and interventional radiology, liver transplantation is necessary for ≈10% of BCS patients. Previous TIPSS does not compromise the results of liver transplantation
      • Segev D.L.
      • Nguyen G.C.
      • Locke J.E.
      • Simpkins C.E.
      • Montgomery R.A.
      • Maley W.R.
      • et al.
      Twenty years of liver transplantation for Budd-Chiari syndrome: A national registry analysis.
      .

      Specific issues

      Pregnancy

      Pregnancy is not contra-indicated in BCS women with controlled disease. Three retrospectives studies, including 55 pregnancies carried out between 1985 and 2015, reported no maternal death
      • Rautou P.-E.
      • Angermayr B.
      • Garcia-Pagan J.-C.
      • Moucari R.
      • Peck-Radosavljevic M.
      • Raffa S.
      • et al.
      Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes.
      • Khan F.
      • Rowe I.
      • Martin B.
      • Knox E.
      • Johnston T.
      • Elliot C.
      • et al.
      Outcomes of pregnancy in patients with known Budd-Chiari syndrome.
      • Shukla A.
      • Sadalage A.
      • Gupta D.
      • Gupte A.
      • Mahapatra A.
      • Mazumder D.
      • et al.
      Pregnancy outcomes in women with Budd Chiari Syndrome before onset of symptoms and after treatment.
      . Liver-related complications were rare in women with BCS known and treated before pregnancy. Bleeding events occurred in women receiving anticoagulation and were unrelated to portal hypertension. The reported rate of miscarriages or ectopic pregnancies before the 20th week of pregnancy was about 30%, higher than in healthy women of similar age. On the other hand, after 20 weeks of pregnancy, 93% of children were healthy, but the prematurity rate was high. Practical management of pregnancy in women with vascular liver diseases is described in Table 3. All VKAs must be switched to LMWH before the 6th weeks of gestation as VKAs cross placenta and can cause fetal hemorrhage and fetal vitamin K antagonist syndrome, especially between 6 to 12 weeks of gestation
      • Bates S.M.
      • Greer I.A.
      • Middeldorp S.
      • Veenstra D.L.
      • Prabulos A.-M.
      • Vandvik P.O.
      • et al.
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      .
      Table 3Practical management of pregnancy in patients with vascular liver diseases.
      Before conceptionEarly counseling should always be proposed before conception.

      Pregnancy should be planned when the liver disease and the prothrombotic condition are well-controlled.

      Cytoreductive therapy for myeloproliferative neoplasm should be stopped before conception as they are teratogenic.
      AnticoagulationVKA must be switched to LMWH before the 6th week of amenorrhea, as they cross placenta and can cause fetal warfarin syndrome or warfarin embryopathy. LMWH are then continued during the whole pregnancy.

      DOACs are contraindicated during the whole pregnancy.
      Portal hypertensionGastroesophageal varices should ideally be investigated in the year before conception or during the second trimester of pregnancy.

      Variceal hemorrhage occurring during pregnancy should be prevented and managed as in non-pregnant patients
      DeliveryVaginal delivery should be preferred even in case of portal hypertension. Caesarian section reserved only for obstetrical indications.

      Platelet count > 20 x109/L and > 50 x109/L considered as safe for vaginal delivery and caesarean section respectively.

      Platelet counts > 75 x109/L are considered safe for epidural anesthesia and over 50 x109/L for spinal anesthesia. Stop anticoagulation therapy 24h before epidural analgesia
      Post-partumEstrogen-derived oral contraceptives are contraindicated.

      Breastfeeding is possible with beta-blockers therapy and warfarin but not with other VKA molecules or DOACs.
      Abbreviations: VKA, vitamin K antagonists; DOACs, direct oral anticoagulants, LMWH, low molecular weight heparin

      Liver nodules

      Early decrease in portal perfusion associated with a compensatory increase in hepatic arterial perfusion is thought to contribute to the development of liver nodules in chronic BCS. Most liver nodules are benign regenerative nodules, also called focal nodular hyperplasia-like (FNH-like) nodules, but hepatocellular adenomas or hepatocellular carcinoma (HCC) can also arise
      • Moucari R.
      • Rautou P.-E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      • Gwon D.
      • Ko G.-Y.
      • Yoon H.-K.
      • Sung K.-B.
      • Kim J.H.
      • Lee S.S.
      • et al.
      Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE.
      • Sempoux C.
      • Balabaud C.
      • Paradis V.
      • Bioulac-Sage P.
      Hepatocellular nodules in vascular liver diseases.
      • Vilgrain V.
      • Paradis V.
      • Van Wettere M.
      • Valla D.
      • Ronot M.
      • Rautou P.-E.
      Benign and malignant hepatocellular lesions in patients with vascular liver diseases.
      • Van Wettere M.
      • Purcell Y.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • Rautou P.-E.
      • et al.
      Low specificity of washout to diagnose hepatocellular carcinoma in nodules showing arterial hyperenhancement in patients with Budd-Chiari syndrome.
      . The cumulative incidence of HCC is about 4%
      • Moucari R.
      • Rautou P.-E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      ,
      • Paul S.B.
      • null Shalimar
      • Sreenivas V.
      • Gamanagatti S.R.
      • Sharma H.
      • Dhamija E.
      • et al.
      Incidence and risk factors of hepatocellular carcinoma in patients with hepatic venous outflow tract obstruction.
      , similar to that reported in other chronic liver diseases. So, screening for liver nodules every 6 months can be proposed likewise
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . When liver nodules are detected, MRI is the imaging procedure of choice, ideally with the injection of hepatobiliary contrast agent, to distinguish malignant from benign nodules. The vast majority of nodules show arterial phase hyper-enhancement
      • Van Wettere M.
      • Purcell Y.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • Rautou P.-E.
      • et al.
      Low specificity of washout to diagnose hepatocellular carcinoma in nodules showing arterial hyperenhancement in patients with Budd-Chiari syndrome.
      ,
      • Van Wettere M.
      • Paulatto L.
      • Raynaud L.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • et al.
      Hepatobiliary MR contrast agents are useful to diagnose hepatocellular carcinoma in patients with Budd-Chiari syndrome.
      . Washout is observed in 75% of HCC vs. 29% of benign lesions and is thus not specific for HCC. Additional features are helpful to differentiate benign nodules from HCC, including serum alpha-fetoprotein (AFP) > 15 ng/ml, fat content, capsule, hypointensity on T1-weighted sequence, hyper-intensity on T2-weighted sequence, hyper-intensity on high b value diffusion-weighted imaging, or hypo-intensity on hepatobiliary phase
      • Moucari R.
      • Rautou P.-E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      ,
      • Van Wettere M.
      • Purcell Y.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • Rautou P.-E.
      • et al.
      Low specificity of washout to diagnose hepatocellular carcinoma in nodules showing arterial hyperenhancement in patients with Budd-Chiari syndrome.
      ,
      • Van Wettere M.
      • Paulatto L.
      • Raynaud L.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • et al.
      Hepatobiliary MR contrast agents are useful to diagnose hepatocellular carcinoma in patients with Budd-Chiari syndrome.
      . Association of a hyper-enhanced nodule with washout and one of these features reaches a specificity between 88 and 100%
      • Van Wettere M.
      • Purcell Y.
      • Bruno O.
      • Payancé A.
      • Plessier A.
      • Rautou P.-E.
      • et al.
      Low specificity of washout to diagnose hepatocellular carcinoma in nodules showing arterial hyperenhancement in patients with Budd-Chiari syndrome.
      . A liver biopsy is required in case of suspicion of HCC (Figure 1). Management of hepatocellular adenoma and HCC should be discussed case by case in specialized centers. Ablation, transarterial chemoembolization, and liver transplantation can be considered
      • Moucari R.
      • Rautou P.-E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      ,
      • Gwon D.
      • Ko G.-Y.
      • Yoon H.-K.
      • Sung K.-B.
      • Kim J.H.
      • Lee S.S.
      • et al.
      Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE.
      .
      Figure thumbnail gr1
      Figure 1Management of liver nodules in patients with Budd-Chiari syndrome.

      Portal vein thrombosis in patients without underlying cirrhosis

      Diagnosis

      Recent PVT refers to the recent formation (<6 months) of a thrombus within the portal vein and/or its branches and/or radicles. Abdominal pain is the most frequent clinical feature (91%); high leukocyte count and C-reactive protein levels are common
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      . Conversely, signs of peritoneal irritation, organ failure, clinical ascites, and/or high lactate levels are rare and should raise suspicion of PVT complicated with intestinal necrosis, i.e., a complication requiring emergency surgery (see below)
      • Nuzzo A.
      • Maggiori L.
      • Ronot M.
      • Becq A.
      • Plessier A.
      • Gault N.
      • et al.
      Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.
      .
      Diagnosis of recent PVT is based on imaging. Ultrasound coupled with Doppler is usually the first-line approach, allowing the direct detection of the thrombus in the portal vein and the absence of flow in case of complete PVT. Contrast-enhanced CT or MRI is recommended to (i) confirm the diagnosis of PVT, showing a hyperattenuating (hyperintense) thrombus on unenhanced CT (MRI) and a lack of enhancement of the lumen in contrast-enhanced portal venous phase; enlargement of the portal vein can be observed when PVT is complete; (ii) determine the extension of the thrombus to splenic and mesenteric veins; (iii) identify potential local factors and (iv) search for complications including signs of acute mesenteric ischemia and intestinal necrosis
      • Berzigotti A.
      • García-Criado Á.
      • Darnell A.
      • García-Pagán J.-C.
      Imaging in clinical decision-making for portal vein thrombosis.
      . Bowel wall thickening, mesenteric fat stranding, and ascites are common both in patients without acute mesenteric ischemia, with acute mesenteric ischemia and with intestinal necrosis
      • Nuzzo A.
      • Maggiori L.
      • Ronot M.
      • Becq A.
      • Plessier A.
      • Gault N.
      • et al.
      Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.
      ,
      • Elkrief L.
      • Corcos O.
      • Bruno O.
      • Larroque B.
      • Rautou P.-E.
      • Zekrini K.
      • et al.
      Type 2 diabetes mellitus as a risk factor for intestinal resection in patients with superior mesenteric vein thrombosis.
      . By contrast, decreased bowel wall enhancement (especially of the mucosa) is more suggestive of intestinal necrosis
      • Nuzzo A.
      • Maggiori L.
      • Ronot M.
      • Becq A.
      • Plessier A.
      • Gault N.
      • et al.
      Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.
      .
      Chronic extrahepatic portal vein obstruction (EHPVO) in the absence of underlying liver disease refers to incomplete resolution of the portal vein obstruction 6 months after recent PVT or to portal cavernoma (Figure 2). Portal cavernoma is a network of porto-portal collaterals that develop following portal vein obstruction. Obstruction leading to cavernoma is mainly related to thrombosis in adults but less likely so in children and young adults
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . The main signs of EHPVO include gastroesophageal varices (80%), splenomegaly (70%), and thrombocytopenia (30%)
      • Noronha Ferreira C.
      • Seijo S.
      • Plessier A.
      • Silva-Junior G.
      • Turon F.
      • Rautou P.-E.
      • et al.
      Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis.
      . Diagnosis of EHPVO is based on contrast-enhanced CT or MRI, showing a lack of visualization of the portal vein, usually associated with a cavernoma enhancing after contrast injection
      • De Gaetano A.M.
      • Lafortune M.
      • Patriquin H.
      • De Franco A.
      • Aubin B.
      • Paradis K.
      Cavernous transformation of the portal vein: patterns of intrahepatic and splanchnic collateral circulation detected with Doppler sonography.
      . A liver biopsy is needed when an underlying chronic liver disease (cirrhosis or porto-sinusoïdal vascular liver disorder (PSVD)) is suspected based on abnormal liver morphology and/or increased liver stiffness measurement. Liver stiffness measurement <10 kPa can rule-out underlying cirrhosis in this setting
      • Sharma P.
      • Mishra S.R.
      • Kumar M.
      • Sharma B.C.
      • Sarin S.K.
      Liver and spleen stiffness in patients with extrahepatic portal vein obstruction.
      .
      Figure thumbnail gr2
      Figure 2Example of acute portal vein thrombosis with progressive development of a cavernous transformation.
      A female patient presented with abdominal pain. Contrast-enhanced CT (all portal venous phase, axial view) showed a complete occlusion of an enlarged portal trunk and intrahepatic portal branches by nonenhancing and hypoattenuating material (arrow) consistent with an acute portal vein thrombosis. Note the heterogeneous enhancement of the hepatic parenchyma with central hypoenhancement relative to the liver periphery (zonal perfusion, *). Over time, CT shows the progressive development of numerous tortuous veins in the hepatic pedicle and the hepatic hilum corresponding to a cavernous transformation of the portal vein (dashed arrows). Note the absence of recanalization of the portal veins and the progressive enlargement of the cavernoma, with progressive extension to the pancreas. No bile duct dilatation was noted.

      Management

      Medical therapy

      In patients with recent PVT, immediate initiation of anticoagulation therapy is recommended because it has been associated with the prevention of thrombus extension and a decreased incidence of intestinal infarction to only 2%, compared with 30% in patients not receiving anticoagulant
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Acosta S.
      • Alhadad A.
      • Svensson P.
      • Ekberg O.
      Epidemiology, risk and prognostic factors in mesenteric venous thrombosis.
      . In a study gathering 67 patients with acute mesenteric ischemia (arterial and venous), administration of oral antibiotics (gentamicin 80 mg/day + metronidazole 1.5 g/day) was associated with a decreased incidence of intestinal necrosis
      • Nuzzo A.
      • Maggiori L.
      • Paugam-Burtz C.
      • Cazals-Hatem D.
      • Ronot M.
      • Huguet A.
      • et al.
      Oral Antibiotics Reduce Intestinal Necrosis in Acute Mesenteric Ischemia: A Prospective Cohort Study.
      .
      Recanalization of the thrombosed veins is achieved in ≈30% of the patients treated with anticoagulation and takes place within the first six months of therapy
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Condat B.
      • Pessione F.
      • Helene Denninger M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      ,
      • Turnes J.
      • García-Pagán J.C.
      • González M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      . Spontaneous recanalization is uncommon
      • Condat B.
      • Pessione F.
      • Helene Denninger M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      . Factors associated with recanalization include the site of thrombosis (splenic or superior mesenteric veins having a higher rate of recanalization than main portal vein) and early anticoagulation (<15 days after first symptoms)
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Condat B.
      • Pessione F.
      • Helene Denninger M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      . By contrast, in patients with recent PVT, ascites, an occluded splenic vein, and underlying prothrombotic disorders have been associated with failure to recanalize the portal vein
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      . Accordingly, initial anticoagulation therapy should last for at least six months in patients with recent PVT
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . In most studies, anticoagulation therapy was based on unfractionated heparin or low molecular weight heparin within the first weeks and then substituted for VKAs targeting an INR between 2 and 3
      • Plessier A.
      • Darwish-Murad S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Rajani R.
      • Björnsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      . Unfractionated heparin should be avoided because of the high risk (up to 20%) of heparin-induced thrombocytopenia, especially in patients with MPNs
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      ,
      • Randi M.L.
      • Tezza F.
      • Scapin M.
      • Duner E.
      • Scarparo P.
      • Scandellari R.
      • et al.
      Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis.
      . Although mostly derived from small retrospective unselected cohort studies, DOACs are now part of the therapeutic arsenal in patients with recent PVT. Despite the absence of direct comparison between LMWH or VKA and DOACs, the rates of PVT recanalization seem similar, without a higher risk of bleeding. Dedicated studies are still needed to assess the efficacy and safety of each DOAC in patients with PVT in the absence of underlying liver disease. The choice of anticoagulant therapy in PVT should be individualized, considering comorbidities and risk factors for PVT (table 2).
      In patients with past PVT (i.e. who achieved recanalization after 6 months of anticoagulation) or in patients with chronic EHPVO, long-term anticoagulation is indicated in most cases since it decreases the incidence of recurrent thrombosis
      • Valeriani E.
      • Di Nisio M.
      • Riva N.
      • Cohen O.
      • Garcia-Pagan J.-C.
      • Magaz M.
      • et al.
      Anticoagulant therapy for splanchnic vein thrombosis: A systematic review and meta-analysis.
      ,
      • Plessier A.
      • Goria O.
      • Cervoni J.P.
      • Ollivier-Hourmand I.
      • Bureau C.
      • Poujol-Robert A.
      • et al.
      GS-613 Prophylaxis of recurrent thrombosis by rivaroxaban in patients with non-cirrhotic chronic portal vein thrombosis (PVT): a multicentre randomized controlled study testing rivaroxaban vs no anticoagulation.
      . Recent Baveno VII consensus conference recommended adapting the dosage of anticoagulant therapy according to the etiologic workup (grade B recommendation). In patients with a permanent and strong risk factor for thrombosis (MPN, PNH, Behcet’s diseases, antiphospholipid syndrome, personal or 1st-degree familial history of spontaneous venous thrombosis or a history of intestinal necrosis due to mesenteric ischemia), full-dose long-term oral anticoagulation should be maintained
      • Northup P.G.
      • Garcia‐Pagan J.C.
      • Garcia‐Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
      ,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . VKA targeting an INR between 2 and 3 have been long used in this situation
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Although solid data are still lacking, DOACs at therapeutic dosage (e.g., Rivaroxaban 20 mg once a day or apixaban 5 mg twice a day) appear an attractive alternative in patients without antiphospholipid syndrome
      • Dufrost V.
      • Wahl D.
      • Zuily S.
      Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials.
      ,
      • Valeriani E.
      • Di Nisio M.
      • Riva N.
      • Cohen O.
      • Garcia-Pagan J.-C.
      • Magaz M.
      • et al.
      Anticoagulant therapy for splanchnic vein thrombosis: A systematic review and meta-analysis.
      . In patients without underlying permanent and strong risk factors for thrombosis, the recent RIPORT randomized controlled trial found that rivaroxaban at the dose of 15 mg per day decreased the incidence of recurrent thrombosis from 19/100 patients-years to 0 patients-years. Of note, in this trial, plasma D-dimers concentration <500 ng/mL 1 month after interruption of anticoagulation was predictive of a low risk of recurrence
      • Plessier A.
      • Goria O.
      • Cervoni J.P.
      • Ollivier-Hourmand I.
      • Bureau C.
      • Poujol-Robert A.
      • et al.
      GS-613 Prophylaxis of recurrent thrombosis by rivaroxaban in patients with non-cirrhotic chronic portal vein thrombosis (PVT): a multicentre randomized controlled study testing rivaroxaban vs no anticoagulation.
      . Furthermore, recurrence of thrombosis was uncommon in patients with an isolated transient local factor for PVT. Therefore, in patients with no general risk factor for thrombosis and a transient local factor, anticoagulation might be discontinued, with D-dimer monitoring one month later to determine whether or not to resume anticoagulation
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      (Figure 3A).
      Figure thumbnail gr3
      Figure 3Proposed algorithm for anticoagulant therapy in patients with portal vein thrombosis (A) without cirrhosis and (B) with cirrhosis.
      In patients with recent PVT or chronic EHPVO, endoscopy should be performed within the first months after diagnosis to screen for gastroesophageal varices. In patients with recent PVT, varices develop mainly during the first year of follow-up
      • Turnes J.
      • García-Pagán J.C.
      • González M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      , so endoscopy should be repeated one year after PVT diagnosis
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Noninvasive methods, including transient elastography, are not accurate in rule-out large varices
      • Sharma P.
      • Mishra S.R.
      • Kumar M.
      • Sharma B.C.
      • Sarin S.K.
      Liver and spleen stiffness in patients with extrahepatic portal vein obstruction.
      . In patients with chronic EHPVO, a study gathering 178 patients showed that the course of gastroesophageal varices is similar to that in patients with cirrhosis. Therefore, primary prophylaxis is usually based on nonselective beta-blockers or endoscopic band ligation, and secondary prophylaxis on the association of both
      • Noronha Ferreira C.
      • Seijo S.
      • Plessier A.
      • Silva-Junior G.
      • Turon F.
      • Rautou P.-E.
      • et al.
      Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis.
      . A study of 471 endoscopies showed that endoscopic band ligation is safe in patients with EHPVO treated with VKA
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      ,
      • Guillaume M.
      • Christol C.
      • Plessier A.
      • Corbic M.
      • Péron J.-M.
      • Sommet A.
      • et al.
      Bleeding risk of variceal band ligation in extrahepatic portal vein obstruction is not increased by oral anticoagulation.
      . This suggests that oral anticoagulation can be maintained in patients undergoing scheduled endoscopic variceal band ligation.

      Radiology

      In patients with recent PVT, invasive strategy including transjugular or transhepatic thrombus-aspiration, local fibrinolysis, and/or TIPSS has been proposed in the first weeks after PVT diagnosis in highly selected patients, namely those with PVT and extension to the superior mesenteric vein, particularly when features predicting intestinal necrosis are present
      • Hernández-Gea V.
      • De Gottardi A.
      • Leebeek F.W.G.
      • Rautou P.-E.
      • Salem R.
      • Garcia-Pagan J.C.
      Current knowledge in pathophysiology and management of Budd-Chiari syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis.
      ,
      • Benmassaoud A.
      • AlRubaiy L.
      • Yu D.
      • Chowdary P.
      • Sekhar M.
      • Parikh P.
      • et al.
      A stepwise thrombolysis regimen in the management of acute portal vein thrombosis in patients with evidence of intestinal ischaemia.
      . However, further studies are needed to clarify indications and patients’ outcomes.
      In patients with chronic EHPVO, portal vein recanalization with or without TIPSS can be considered in patients with portal-hypertensive related bleeding not controlled with endoscopic treatment or in patients with symptomatic portal cavernoma cholangiopathy. Various approaches have been reported, including transjugular, transhepatic and transsplenic route. This procedure is technically successful in more than 80% of the cases when performed in expert centers if intrahepatic portal branches are patent
      • Marot A.
      • Barbosa J.V.
      • Duran R.
      • Deltenre P.
      • Denys A.
      Percutaneous portal vein recanalization using self-expandable nitinol stents in patients with non-cirrhotic non-tumoral portal vein occlusion.
      . The usefulness of long-term anticoagulation after portal vein recanalization is unknown. Maintaining anticoagulation seem reasonable, especially in patients with risk factors for thrombosis. The clinical outcome seems favorable. Recent data suggest successful portal vein recanalization is associated with increased muscle mass and decreased spleen volume
      • Marot A.
      • Barbosa J.V.
      • Duran R.
      • Deltenre P.
      • Denys A.
      Percutaneous portal vein recanalization using self-expandable nitinol stents in patients with non-cirrhotic non-tumoral portal vein occlusion.
      • Fanelli F.
      • Angeloni S.
      • Salvatori F.M.
      • Marzano C.
      • Boatta E.
      • Merli M.
      • et al.
      Transjugular intrahepatic portosystemic shunt with expanded-polytetrafuoroethylene-covered stents in non-cirrhotic patients with portal cavernoma.
      • Knight G.M.
      • Clark J.
      • Boike J.R.
      • Maddur H.
      • Ganger D.R.
      • Talwar A.
      • et al.
      TIPS for Adults Without Cirrhosis With Chronic Mesenteric Venous Thrombosis and EHPVO Refractory to Standard-of-Care Therapy.
      • Artru F.
      • Vietti-Violi N.
      • Sempoux C.
      • Vieira Barbosa J.
      • Becce F.
      • Sah N.
      • et al.
      Portal vein recanalisation alone to treat severe portal hypertension in non-cirrhotic patients with chronic extrahepatic portal vein obstruction.
      . However, these results are mainly based on small, retrospective mostly single-center unselected cohort studies. Dedicated comparative studies are needed to evaluate the impact of portal vein recanalization on long-term outcome and to determine the best technical approach.

      Surgery

      In patients with acute mesenteric ischemia, emergency surgery is indicated in case of signs suggesting intestinal necrosis to assess bowel viability. Patients should be transfer to a referral center, enabling a multidisciplinary approach
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Shunt surgery to treat portal-hypertension related complications has lost ground to radiological portal vein recanalization.

      Specific issues

      Pregnancy

      Pregnancy is not contraindicated in women with stable chronic EHPVO. The best information stems from three series of patients, two Indian and one European, including 104 pregnancies
      • Bissonnette J.
      • Durand F.
      • de Raucourt E.
      • Ceccaldi P.-F.
      • Plessier A.
      • Valla D.
      • et al.
      Pregnancy and vascular liver disease.
      ,
      • Aggarwal N.
      • Chopra S.
      • Raveendran A.
      • Suri V.
      • Dhiman R.K.
      • Chawla Y.K.
      Extra hepatic portal vein obstruction and pregnancy outcome: largest reported experience.
      • Mandal D.
      • Dattaray C.
      • Sarkar R.
      • Mandal S.
      • Choudhary A.
      • Maity T.K.
      Is pregnancy safe with extrahepatic portal vein obstruction? An analysis.
      • Hoekstra J.
      • Seijo S.
      • Rautou P.E.
      • Ducarme G.
      • Boudaoud L.
      • Luton D.
      • et al.
      Pregnancy in women with portal vein thrombosis: results of a multicentric European study on maternal and fetal management and outcome.
      . Anticoagulation was administered on a case-by-case basis. Rates of miscarriage and preterm birth were 14% and 14%, respectively. Fetal and maternal outcomes were favorable for most pregnancies. Only five episodes of variceal hemorrhage happened, including three among patients without adequate prophylaxis for portal hypertension-related bleeding. This highlights the importance of upper gastrointestinal endoscopy before conception or during the second trimester of pregnancy in women not receiving beta-blockers (Table 2). Thrombotic events occurred in two patients.

      Portal cavernoma cholangiopathy

      ‘‘Portal cavernoma cholangiopathy’’ refers to abnormalities of the biliary tract in patients with chronic EHPVO
      • Dhiman R.K.
      • Saraswat V.A.
      • Valla D.C.
      • Chawla Y.
      • Behera A.
      • Varma V.
      • et al.
      Portal cavernoma cholangiopathy: consensus statement of a working party of the Indian national association for study of the liver.
      . These abnormalities are due to the pressure of dilated collaterals on the bile ducts or their lumen and ischemic damage to the biliary tree
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      ,
      • Puri P.
      Pathogenesis of Portal Cavernoma Cholangiopathy: Is it Compression by Collaterals or Ischemic Injury to Bile Ducts During Portal Vein Thrombosis?.
      . Magnetic resonance cholangiography coupled with MR angiography is the reference technique for diagnosing portal cavernoma cholangiopathy
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      ,
      • Condat B.
      • Vilgrain V.
      • Asselah T.
      • O’Toole D.
      • Rufat P.
      • Zappa M.
      • et al.
      Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study.
      . MR cholangiography shows bile duct changes, including stenoses, upstream dilatation, and irregularities in the caliber of bile ducts; MR angiography shows cavernomatous veins in the vicinity of stenoses
      • Condat B.
      • Vilgrain V.
      • Asselah T.
      • O’Toole D.
      • Rufat P.
      • Zappa M.
      • et al.
      Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study.
      ,
      • Malkan G.H.
      • Bhatia S.J.
      • Bashir K.
      • Khemani R.
      • Abraham P.
      • Gandhi M.S.
      • et al.
      Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications.
      . At MRI, bile duct changes are common, found in 80% of patients.
      • Condat B.
      • Vilgrain V.
      • Asselah T.
      • O’Toole D.
      • Rufat P.
      • Zappa M.
      • et al.
      Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study.
      • Malkan G.H.
      • Bhatia S.J.
      • Bashir K.
      • Khemani R.
      • Abraham P.
      • Gandhi M.S.
      • et al.
      Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications.
      • Llop E.
      • Juan C de
      • Seijo S.
      • García-Criado Á.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      . However, the clinical impact is much more limited than morphologic changes: moderate liver enzyme abnormalities are observed in 50% of the patients
      • Malkan G.H.
      • Bhatia S.J.
      • Bashir K.
      • Khemani R.
      • Abraham P.
      • Gandhi M.S.
      • et al.
      Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications.
      ; severe biliary complications, including cholangitis, pancreatitis, jaundice, and pruritus, occur in ≈10% of the patients
      • Condat B.
      • Vilgrain V.
      • Asselah T.
      • O’Toole D.
      • Rufat P.
      • Zappa M.
      • et al.
      Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study.
      • Malkan G.H.
      • Bhatia S.J.
      • Bashir K.
      • Khemani R.
      • Abraham P.
      • Gandhi M.S.
      • et al.
      Cholangiopathy associated with portal hypertension: diagnostic evaluation and clinical implications.
      • Llop E.
      • Juan C de
      • Seijo S.
      • García-Criado Á.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      . Such complications were described only in patients with grade III cholangiopathy (namely strictures with dilations), in whom the risk was 41%
      • Llop E.
      • Juan C de
      • Seijo S.
      • García-Criado Á.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      .
      Treatment of portal cavernoma cholangiopathy should be discussed on individual basis at referral centers. Specific treatments of portal cavernoma cholangiopathy include endoscopic retrograde cholangiopancreatography (ERCP) and portal vein recanalization. These treatments should be considered only in patients with cholangitis, pancreatitis, jaundice, or pruritus. ERCP allows bile stones extraction and temporary stenting of biliary strictures
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      . The risk of bleeding from bile duct varices should be kept in mind. Treatment with ursodesoxycholic acid following endoscopic therapy was associated with a reduction of symptoms in ≈ 50% of the patients
      • Condat B.
      • Vilgrain V.
      • Asselah T.
      • O’Toole D.
      • Rufat P.
      • Zappa M.
      • et al.
      Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study.
      ,
      • Llop E.
      • Juan C de
      • Seijo S.
      • García-Criado Á.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      . Portal vein recanalization may also be helpful in this setting
      • Artru F.
      • Vietti-Violi N.
      • Sempoux C.
      • Vieira Barbosa J.
      • Becce F.
      • Sah N.
      • et al.
      Portal vein recanalisation alone to treat severe portal hypertension in non-cirrhotic patients with chronic extrahepatic portal vein obstruction.
      . Bilio-enteric by-pass in the absence of portal decompression is not recommended because it is associated with high morbidity and mortality
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      .

      Non-malignant portal vein thrombosis in patients with cirrhosis

      Cirrhosis accounts for ≈ 40% of unselected cases of PVT
      • Rajani R.
      • Björnsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      . The prevalence of PVT increases in parallel with the severity of cirrhosis: 10% in patients with compensated cirrhosis, 17% in patients with decompensated cirrhosis, and up to 26% in liver transplants (LT) candidates
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      . Longitudinal studies reported an incidence of PVT ranging from 11% at 5 years in patients with compensated cirrhosis
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      to 24% per year in patients awaiting liver transplantation
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      ,
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      .

      Causes

      In patients with cirrhosis and PVT, systematic screening for factor V Leiden and G20210A prothrombin gene mutation is not systematically recommended because their prevalence is low in this setting
      • Qi X.
      • Ren W.
      • De Stefano V.
      • Fan D.
      Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis.
      ,
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.
      ,
      • Fortea J.I.
      • Carrera I.G.
      • Puente Á.
      • Cuadrado A.
      • Huelin P.
      • Tato C.Á.
      • et al.
      Portal Thrombosis in Cirrhosis: Role of Thrombophilic Disorders.
      . Features of metabolic syndrome, including higher body mass index
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      , obesity
      • Ayala R.
      • Grande S.
      • Bustelos R.
      • Ribera C.
      • García-Sesma A.
      • Jimenez C.
      • et al.
      Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients.
      and diabetes
      • Ayala R.
      • Grande S.
      • Bustelos R.
      • Ribera C.
      • García-Sesma A.
      • Jimenez C.
      • et al.
      Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients.
      ,
      • Abdel-Razik A.
      • Mousa N.
      • Elhelaly R.
      • Tawfik A.
      De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the Model for End-stage Liver Disease scoring system.
      have been associated with the occurrence of PVT, although the impact of these features on PVT development might be limited. Local risk factors, such as abdominal surgery, have also been reported
      • Mangia A.
      • Villani M.R.
      • Cappucci G.
      • Santoro R.
      • Ricciardi R.
      • Facciorusso D.
      • et al.
      Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors.
      .
      The main risk factors for PVT are features reflecting the severity of portal hypertension, including large esophageal varices and low platelet count
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      ,
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.
      ,
      • Abdel-Razik A.
      • Mousa N.
      • Elhelaly R.
      • Tawfik A.
      De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the Model for End-stage Liver Disease scoring system.
      ,
      • Zocco M.A.
      • Di Stasio E.
      • De Cristofaro R.
      • Novi M.
      • Ainora M.E.
      • Ponziani F.
      • et al.
      Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.
      . Low portal vein flow velocity (<15 cm/sec) has also been reported in several large studies, although not systematically
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      ,
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.
      ,
      • Zocco M.A.
      • Di Stasio E.
      • De Cristofaro R.
      • Novi M.
      • Ainora M.E.
      • Ponziani F.
      • et al.
      Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.
      . The link between nonselective beta-blockers and PVT occurrence remains debated
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.
      ,
      • Nery F.
      • Correia S.
      • Macedo C.
      • Gandara J.
      • Lopes V.
      • Valadares D.
      • et al.
      Nonselective beta-blockers and the risk of portal vein thrombosis in patients with cirrhosis: results of a prospective longitudinal study.
      ,
      • Xu X.
      • Guo X.
      • De Stefano V.
      • Silva-Junior G.
      • Goyal H.
      • Bai Z.
      • et al.
      Nonselective beta-blockers and development of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis.
      . The only study evaluating the association between beta-blockers and PVT occurrence by time-dependent analysis did not find any association between beta-blockers and with PVT occurrence
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.
      .

      Diagnosis

      In patients with cirrhosis, PVT is usually found in the absence of symptoms on the occasion of imaging performed as part of the screening for HCC or when a decompensation of cirrhosis occurs
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      ,
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      . Although PVT is generally recognized in US, CT or MR angiography are recommended to assess the degree and extent of obstruction. Contrasting with the findings in patients without cirrhosis, non-occlusive PVT is the predominant form in patients with cirrhosis, accounting for around 70% of cases
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      . Recent recommendations concur for considering that the following characteristics need to be provided as part of the description of PVT: time course (recent, i.e., < 6 months or chronic, i.e., ≥ 6 months), degree of occlusion (minimally occlusive, i.e., <50% of the lumen obstructed, partially occlusive, i.e., ≥ 50% of the lumen obstructed or completely occlusive, i.e., no persistent lumen), and response to treatment or interval change (progression, stability or regression)
      • Northup P.G.
      • Garcia‐Pagan J.C.
      • Garcia‐Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases.
      ,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Patients with HCC are at risk of tumoral invasion of the portal vein but also at higher risk of nontumoral PVT since HCC may tilt the hemostatic balance towards hypercoagulability
      • Zanetto A.
      • Campello E.
      • Pelizzaro F.
      • Farinati F.
      • Burra P.
      • Simioni P.
      • et al.
      Haemostatic alterations in patients with cirrhosis and hepatocellular carcinoma: laboratory evidence and clinical implications.
      .
      The presence of three or more features among serum AFP concentrations >1,000 μg/L, venous expansion, thrombus enhancement at arterial phase, neovascularity, and PVT adjacent to HCC have a 100% sensitivity and 94% specificity for the diagnosis of tumoral invasion of the portal vein
      • Sherman C.B.
      • Behr S.
      • Dodge J.L.
      • Roberts J.P.
      • Yao F.Y.
      • Mehta N.
      Distinguishing Tumor From Bland Portal Vein Thrombus in Liver Transplant Candidates With Hepatocellular Carcinoma: the A-VENA Criteria.
      . In the absence of these specific features, fine needle ultrasound-guided biopsy of the thrombi may be safe and useful to obtain a definitive diagnosis
      • Dodd G.D.
      • Carr B.I.
      Percutaneous biopsy of portal vein thrombus: a new staging technique for hepatocellular carcinoma.
      .

      Natural history of PVT and impact on patients’ outcome

      Spontaneous regression or even recanalization of PVT may occur in ≈ 40 % of the patients, mainly in those with non-occlusive PVT and compensated cirrhosis
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      ,
      • Loffredo L.
      • Pastori D.
      • Farcomeni A.
      • Violi F.
      Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: a Systematic Review and Meta-Analysis.
      ,
      • Qi X.
      • Guo X.
      • Yoshida E.M.
      • Méndez-Sánchez N.
      • De Stefano V.
      • Tacke F.
      • et al.
      Transient portal vein thrombosis in liver cirrhosis.
      . By contrast, the rate of spontaneous recanalization is very low in patients with occlusive PVT
      • Francoz C.
      • Belghiti J.
      • Vilgrain V.
      • Sommacale D.
      • Paradis V.
      • Condat B.
      • et al.
      Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.
      . In patients with cirrhosis with recent PVT and extension to the superior mesenteric vein, acute mesenteric ischemia or intestinal necrosis can occur but remains uncommon
      • Amitrano L.
      • Guardascione M.A.
      • Brancaccio V.
      • Margaglione M.
      • Manguso F.
      • Iannaccone L.
      • et al.
      Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.
      .
      The link between PVT and decompensation of cirrhosis has been analyzed in several studies
      • Maruyama H.
      • Okugawa H.
      • Takahashi M.
      • Yokosuka O.
      De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes.
      • Luca A.
      • Caruso S.
      • Milazzo M.
      • Marrone G.
      • Mamone G.
      • Crinò F.
      • et al.
      Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis.
      • Zhang Y.
      • Xu B.-Y.
      • Wang X.-B.
      • Zheng X.
      • Huang Y.
      • Chen J.
      • et al.
      Prevalence and Clinical Significance of Portal Vein Thrombosis in Patients With Cirrhosis and Acute Decompensation.
      , including a large prospective study gathering over 1,200 patients with compensated cirrhosis: occurrence of PVT was not associated with subsequent decompensation of cirrhosis
      • Nery F.
      • Chevret S.
      • Condat B.
      • de Raucourt E.
      • Boudaoud L.
      • Rautou P.-E.
      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
      , suggesting that PVT is a marker but not a direct cause of the progression of liver disease. By contrast, the impact of PVT in the context of liver transplantation is significant. Pre-transplantation PVT has been associated with an increased post-transplant short-term mortality and graft failure in large databases
      • Englesbe M.J.
      • Schaubel D.E.
      • Cai S.
      • Guidinger M.K.
      • Merion R.M.
      Portal vein thrombosis and liver transplant survival benefit.
      . However, in the latter studies, the link between the size and extent of PVT and post-transplant outcomes was not evaluated. The impact of PVT appears to depend on the possibility of restoring physiologic portal perfusion to the graft using anatomical (physiological) procedures. Good results are obtained when the superior mesenteric vein is patent. By contrast, an irremovable thrombus occluding the superior mesenteric vein requires left renal to portal vein anastomosis, or portocaval hemi-transposition. These interventions that do not relieve portal hypertension and do not restore graft perfusion with portal blood are associated with a high rate of failure or complications
      • Hibi T.
      • Nishida S.
      • Levi D.M.
      • Selvaggi G.
      • Tekin A.
      • Fan J.
      • et al.
      When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases.
      . Thus, in patients awaiting liver transplantation, persistent complete extensive thrombosis may preclude liver transplantation.

      Management

      Medical therapy

      In patients with cirrhosis and PVT, potential candidates for liver transplantation - meaning those without definitive contraindication to liver transplantation - the main objective of anticoagulation therapy is to maintain or obtain a patent portal vein trunk to allow liver transplantation. The efficacy of anticoagulation therapy in this setting has been evaluated in several cohort studies, mostly retrospective
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      . In a meta-analysis of eight studies involving 353 patients, PVT progression was observed in 9% of treated patients compared to 33% of untreated patients. Portal vein recanalization was achieved in 71% of treated patients compared to 42% of untreated patients
      • Loffredo L.
      • Pastori D.
      • Farcomeni A.
      • Violi F.
      Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: a Systematic Review and Meta-Analysis.
      . A detailed analysis of the structure and composition of portal vein thrombi showed that portal vein obstruction consists of intimal fibrosis with an additional fibrin-rich thrombus in only one-third of cases, which may account for the unsystematic recanalization observed after anticoagulation
      • Driever E.G.
      • von Meijenfeldt F.A.
      • Adelmeijer J.
      • de Haas R.J.
      • van den Heuvel M.C.
      • Nagasami C.
      • et al.
      Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.
      (Figure 4). Likewise, factors associated with recanalization in patients receiving anticoagulant therapy include recent PVT and duration between PVT diagnosis and treatment initiation shorter than 6 months
      • Rodriguez-Castro K.I.
      • Vitale A.
      • Fadin M.
      • Shalaby S.
      • Zerbinati P.
      • Sartori M.T.
      • et al.
      A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis.
      . Less severe liver disease and a non-occlusive PVT are also associated with a higher rate of recanalization
      • Rodriguez-Castro K.I.
      • Vitale A.
      • Fadin M.
      • Shalaby S.
      • Zerbinati P.
      • Sartori M.T.
      • et al.
      A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis.
      .
      Figure thumbnail gr4
      Figure 4Correlation between radiological findings and pathology
      A. Recent portal vein thrombosis in a 59 years old man with viral cirrhosis. Contrast-enhanced CT (coronal view, portal venous phase) shows partially occlusive non-enhancing material corresponding to the clot in the lumen of the portal trunk (arrows). The downstream venous branches are patent.B. HES staining. Low magnification. Recent portal vein partial thrombosis
      C. HES staining. Higher magnification. Recent portal vein thrombi composed of fibrinous deposits associated with red blood cells
      D. Chronic portal vein thrombosis in a 52 years old man with alcohol-related cirrhosis. Contrast-enhanced CT (coronal view, portal venous phase) shows minimally occlusive non-enhancing material corresponding to the incorporation of the clot in the wall of the portal trunk and the superior mesenteric vein (arrows)
      E. HES staining. Low magnification. Non-malignant chronic portal vein thrombi
      F. HES staining. Higher magnification. Chronic portal vein thrombi with fibro-oedematous intimal thickening with numerous siderophagous and neovessels partially repermeabilizing the luminen
      In patients with cirrhosis and PVT not candidates for liver transplantation, the beneficial effect of anticoagulation might go beyond its impact on PVT. A landmark prospective randomized controlled trial gathering 70 patients with cirrhosis without PVT showed that treatment with 4000 IU/day enoxaparin for 48 weeks effectively prevented PVT occurrence and, more importantly, decreased decompensation of cirrhosis and death
      • Villa E.
      • Cammà C.
      • Marietta M.
      • Luongo M.
      • Critelli R.
      • Colopi S.
      • et al.
      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      . In a large individual patient data meta-analysis gathering 5 studies and 500 patients with cirrhosis and PVT, anticoagulation increased overall survival, and the beneficial effect was independent of portal vein recanalization
      • Guerrero A.
      • DelCampo L.
      • Piscaglia F.
      • Reiberger T.
      • Han G.
      • Violi F.
      • et al.
      OS-1544 Anticoagulation improves overall survival through portal vein recanalization in patients with cirrhosis and portal vein thrombosis: Individual patient data meta-analysis (IMPORTAL study).
      . Based on those data, the recent Baveno VII consensus conference recommended initiating anticoagulation (i) in all patients with cirrhosis and PVT potentially candidates for liver transplantation, independently of the degree of occlusion and extension and (ii) in patients with cirrhosis and recent (<6 months) completely or partially occlusive (>50%) thrombosis of the portal vein trunk even if not a candidate to liver transplantation
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . Recanalization is usually achieved within 6 months
      • Delgado M.G.
      • Seijo S.
      • Yepes I.
      • Achécar L.
      • Catalina M.V.
      • García-Criado A.
      • et al.
      Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis.
      . Therefore, anticoagulation therapy should be maintained until portal vein recanalization or for a minimum of 6 months
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      • Abraldes J.G.
      • et al.
      BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION.
      . After that, the decision for maintaining anticoagulation depends on the response to therapy and the project or not of liver transplantation. Anticoagulation is generally maintained until liver transplantation, except if a TIPSS is performed in potential candidates for liver transplantation. In other patients, the continuation of anticoagulation should be considered in patients without complete PVT with a regular evaluation balancing the benefits and risks of anticoagulation (Figure 3B).
      Bleeding events not related to portal hypertension occur in ≈10% of the patients with cirrhosis receiving anticoagulation
      • Loffredo L.
      • Pastori D.
      • Farcomeni A.
      • Violi F.
      Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: a Systematic Review and Meta-Analysis.
      . This rate does not seem to be higher than that observed in patients with cirrhosis and PVT not receiving anticoagulation nor in patients without cirrhosis receiving anticoagulation
      • Loffredo L.
      • Pastori D.
      • Farcomeni A.
      • Violi F.
      Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: a Systematic Review and Meta-Analysis.
      ,
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA Technical Review on Coagulation in Cirrhosis.
      . In patients with cirrhosis treated with VKAs, platelet count < 50x 109/L was predictive of bleeding
      • Delgado M.G.
      • Seijo S.
      • Yepes I.
      • Achécar L.
      • Catalina M.V.
      • García-Criado A.
      • et al.
      Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis.
      . Data obtained in the setting of atrial fibrillation suggest that VKAs are associated with a higher risk of major bleeding events than DOACs in patients with cirrhosis
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA Technical Review on Coagulation in Cirrhosis.
      . Bleeding events related to portal hypertension are less frequent in patients receiving anticoagulation than in those without anticoagulation, possibly due to a beneficial effect of anticoagulation on intrahepatic vascular resistance
      • Loffredo L.
      • Pastori D.
      • Farcomeni A.
      • Violi F.
      Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis: a Systematic Review and Meta-Analysis.
      ,
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA Technical Review on Coagulation in Cirrhosis.
      ,
      • La Mura V.
      • Braham S.
      • Tosetti G.
      • Branchi F.
      • Bitto N.
      • Moia M.
      • et al.
      Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.