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Current knowledge and management of portal vein thrombosis in cirrhosis

  • Marco Senzolo
    Correspondence
    Corresponding author. Address: Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustninani 2, 35128, Padua, Italy. Tel.: +390498218726; fax +390498218727
    Affiliations
    Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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  • Guadalupe Garcia-Tsao
    Affiliations
    Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA

    Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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  • Juan Carlos García-Pagán
    Affiliations
    Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain

    Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain

    CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Spain
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  • Author Footnotes
    † Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver).
Published:April 27, 2021DOI:https://doi.org/10.1016/j.jhep.2021.04.029

      Summary

      Portal vein thrombosis (PVT) is an increasingly recognised complication of cirrhosis whose incidence increases in parallel with the severity of cirrhosis. Several risk factors have been associated with the occurrence and progression of PVT. Although the negative effect of complete PVT on the surgical outcome of liver transplant recipients is clear, its impact on cirrhosis progression remains uncertain. Treatment options include anticoagulants and interventional thrombolytic therapies, which are chosen almost on a case-by-case basis depending on the characteristics of the patient and the thrombus. In this manuscript, we review current knowledge regarding the epidemiology, risk factors, diagnosis and classification, natural history, clinical consequences and treatment of non-neoplastic PVT in cirrhosis.

      Keywords

      Introduction

      Cirrhosis, particularly at the decompensated stage, is characterised by profound and complex haemostatic alterations that are both procoagulant and anticoagulant and could theoretically lead to both thrombotic and bleeding complications.
      • Intagliata N.M.
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      • Lisman T.
      • Caldwell S.H.
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      Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference.
      Therefore, despite a low platelet count and elevated international normalised ratio (INR), patients with cirrhosis are not “auto-anticoagulated,” as previously thought, but actually have a greater propensity than patients without cirrhosis to develop thrombotic complications, the most important being portal vein thrombosis (PVT), which is defined as the presence of a thrombus in the lumen of the main portal vein that can extend into intrahepatic or extrahepatic venous branches.

      Epidemiology

      PVT is a relatively rare disease in the general population. In an autopsy study, representing 84% of all in-hospital deaths in Malmo, the lifetime cumulative prevalence of PVT was 1.0%, but 40% of these patients had cirrhosis and those with both liver disease and hepatocellular carcinoma (HCC) had the highest risk of PVT (odds ratio [OR] 17.1).
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      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      The prevalence of PVT in cirrhosis varies widely among studies and depends on the type of diagnostic approach used, the stage of cirrhosis (compensated or decompensated) and/or on the inclusion or exclusion of patients with HCC. Because HCC invasion of the portal vein (tumoral PVT) has entirely different implications than a blood clot in the portal vein, this review refers solely to non-tumoral PVT.
      The prevalence of PVT increases in parallel with the severity of cirrhosis: 10% in patients with compensated cirrhosis,
      • Tsochatzis E.A.
      • Senzolo M.
      • Germani G.
      • Gatt A.
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      Systematic review: portal vein thrombosis in cirrhosis.
      17% in patients with mostly Child-Pugh B/C cirrhosis
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      Incidence and recurrence of portal vein thrombosis in cirrhotic patients.
      and up to 26% in liver transplant (LT) candidates.
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      • Gasbarrini A.
      • Avolio A.W.
      Portal vein thrombosis and liver transplantation: implications for waiting list period, surgical approach, early and late follow-up.
      Earlier series of patients on the LT waiting list showed a lower prevalence of PVT (~7%) perhaps due to different policies regarding listing patients with PVT.
      • Montenovo M.
      • Rahnemai-Azar A.
      • Reyes J.
      • Perkins J.
      Clinical impact and risk factors of portal vein thrombosis for patients on wait list for liver transplant.
      In these studies, most PVTs are partial, but, in a study that pooled 589 patients listed for LT, occlusive PVT was observed in 44% of cases.
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      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      In prospective studies, the 1-year incidence of PVT ranges from 3.7% to 24.4% (Fig. 1),
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      • et al.
      Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.
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      De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes.
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      • et al.
      Impact of untreated portal vein thrombosis on pre and post liver transplant outcomes in cirrhosis.
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      De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the model for End-stage Liver Disease scoring system.
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      • et al.
      Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.
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      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      • Zanetto A.
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      • et al.
      Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma.
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      • Wu H.
      • Chen Y.
      • Wang L.
      • et al.
      Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B.
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      Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: a prospective study.
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      • Gilabert R.
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      Predicting portal thrombosis in cirrhosis: a prospective comprehensive study of clinical, ultrasonografic and hemostatic factors.
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      • Valadares D.
      • et al.
      Nonselective beta-blockers and the risk of portal vein thrombosis in patients with cirrhosis: results of a prospective longitudinal study.
      with a lower incidence in cohorts that included a majority of patients with compensated cirrhosis.
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      • 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.
      ,
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      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: a prospective comprehensive study of clinical, ultrasonografic and hemostatic factors.
      Figure thumbnail gr1
      Fig. 1Incidence of PVT in prospective studies.
      HCC, hepatocellular carcinoma; PVT, portal vein thrombosis.

      Risk factors

      The pathogenesis of PVT in cirrhosis is probably multifactorial and results mainly from alterations in the different components of Virchow’s triad: decreased portal vein flow, hypercoagulability and damage of the vessel wall (Box 1).
      Risk factors for PVT in cirrhosis. NASH, non-alcoholic steatohepatitis; PVT, portal vein thrombosis.
      Cryptogenic and NASH cirrhosis
      Child-Pugh class B and C
      Oesophageal varices grade ≥2
      Portal vein blood flow <15 cm/s
      Large porto systemic collaterals with high blood flow
      Non-selective beta blockers
      Local vascular damage
      Previous splanchnic vein thrombosis
      Sclerotherapy of oesophageal varices
      Splenectomy
      Partial splenic embolisation

      Altered portal venous blood flow

      A threshold portal vein flow <15 m/sec has been described as the most predictive of PVT based on both prospective and retrospective studies.
      • 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.
      ,
      • Stine J.G.
      • Wang J.
      • Shah P.M.
      • Argo C.K.
      • Intagliata N.
      • Uflacker A.
      • et al.
      Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study.
      An increase in portal blood inflow through portosystemic collaterals also seems to influence PVT development. Indeed, a large flow volume (>400 ml/min) and velocity (>10 cm/sec) in the largest porto-collateral vessel visualised by Doppler ultrasound have been shown to predict PVT.
      • Maruyama H.
      • Okugawa H.
      • Takahashi M.
      • Yokosuka O.
      De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes.
      Nevertheless, in another study,
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      reversal of portal vein blood flow, the maximal expression of increased porto-collateral blood flow, did not correlate with an increased risk of PVT. Further prospective studies evaluating the role of reduced portal blood flow velocity and/or increased porto-collateral blood flow are needed.
      Non-selective beta blockers (NSBBs), by reducing portal venous blood flow, could theoretically increase the risk of PVT, although data are conflicting and a causal relationship has not been firmly demonstrated. A recent meta-analysis of prospective and retrospective cohort studies suggested a positive association between NSBBs and the risk of PVT (OR 4.62).
      • 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.
      However, most studies were retrospective, abstracts were included and there was significant heterogeneity. In a prospective single centre cohort of 108 patients, predictors of PVT development were history of varices (grade ≥2) and use of NSBBs.
      • 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.
      However, the number of patients developing PVT was small (only 11) and the analysis was not adjusted for confounders. Given strong data demonstrating the benefits of NSBBs in cirrhosis, their use should not be limited by their unconfirmed role in facilitating PVT.

      Altered coagulation

      Haemostatic alterations associated with cirrhosis

      Patients with cirrhosis have a well-described derangement of the haemostatic balance due to a reduction of both anticoagulant and procoagulant factors, together with increased levels of several procoagulant factors such as factor VIII and von Willebrand factor (vWF).
      • Tripodi A.
      • Mannucci P.M.
      The coagulopathy of chronic liver disease.
      Overall, these alterations indicate that the homeostatic balance leans toward hypercoagulability, which would favour the development of PVT. However, the association between hypercoagulability and the development of PVT has not been well studied. Indeed, only a single retrospective study in 53 patients with cirrhosis found a significant association between thrombomodulin resistance in peripheral blood and PVT development.
      • La Mura V.
      • Tripodi A.
      • Tosetti G.
      • Cavallaro F.
      • Chantarangkul V.
      • Colombo M.
      • et al.
      Resistance to thrombomodulin is associated with de novo portal vein thrombosis and low survival in patients with cirrhosis.
      Results from larger prospective studies, including a more comprehensive panel of haemostatic alterations in patients with cirrhosis should clarify this potential mechanism.

      Inherited and acquired prothrombotic disorders

      While disorders such as prothrombin or factor V gene mutations, and protein C, S or antithrombin deficiencies play an important role in the development of PVT in patients without cirrhosis, their role in PVT in patients with cirrhosis is much less clear.
      • Ma S.D.
      • Wang J.
      • Bezinover D.
      • Kadry Z.
      • Northup P.G.
      • Stine J.G.
      Inherited thrombophilia and portal vein thrombosis in cirrhosis: a systematic review and meta-analysis.
      ,
      • Tremblay D.
      • Naymagon L.
      • Troy K.
      • Cromwell C.
      • Edwards C.
      • Schiano T.
      • et al.
      The utility of thrombophilia testing in patients with newly diagnosed portal vein thrombosis.
      Indeed, relevant studies have shown that most patients with cirrhosis and PVT do not have any of these inherited alterations. Similarly, although 1 study suggested a higher prevalence of JAK2 V617F mutations in patients with cirrhosis and PVT,
      • Saugel B.
      • Lee M.
      • Feichtinger S.
      • Hapfelmeier A.
      • Schmid R.M.
      • Siveke J.T.
      Thrombophilic factor analysis in cirrhotic patients with portal vein thrombosis.
      no JAK2 mutations were found in a cohort of 271 LT recipients irrespective of the presence of PVT.
      • Ayala R.
      • Rapado I.
      • Grande S.
      • Moreno E.
      • Martinez-Lopez J.
      JAK2 exon 12 mutations were not found in liver transplant recipients with or without pretransplant portal vein thrombosis.
      Therefore, because it is not cost-effective, screening for thrombophilia is not recommended in patients with cirrhosis and PVT.
      EASL Clinical Practice Guidelines
      Vascular diseases of the liver.
      Probably reflecting an increased prothrombotic state associated with neoplasia, a small prospective study showed a high (24.4%) 1-year incidence of non-neoplastic PVT in 41 patients with HCC.
      • Zanetto A.
      • Senzolo M.
      • Vitale A.
      • Cillo U.
      • Radu C.
      • Sartorello F.
      • et al.
      Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma.
      Similarly, another study showed an incidence of PVT of 25% over a median follow-up time of only 4.4 months from the diagnosis of HCC.
      • Connolly G.C.
      • Chen R.
      • Hyrien O.
      • Mantry P.
      • Bozorgzadeh A.
      • Abt P.
      • et al.
      Incidence, risk factors and consequences of portal vein and systemic thromboses in hepatocellular carcinoma.
      Further exploration is warranted.

      Local portal vein alterations

      In patients with cirrhosis and portal hypertension, bacterial translocation, local inflammation and endotoxemia could play a role in promoting a local hypercoagulable state in the portal venous area. In fact, a recent study in patients receiving a transjugular intrahepatic portosystemic shunt (TIPS) showed that there is a portal/systemic circulation gradient for lipopolysaccharide (LPS), vWF and factor VIII. LPS may favour a hypercoagulable state by increasing endothelial secretion of factor VIII
      • Carnevale R.
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      • Bartimoccia S.
      • Novo M.
      • Severino A.
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      Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis.
      and decreasing thrombomodulin activity
      • Kapiotis S.
      • Besemer J.
      • Bevec D.
      • Valent P.
      • Bettelheim P.
      • Lechner K.
      • et al.
      Interleukin-4 counteracts pyrogen-induced downregulation of thrombomodulin in cultured human vascular endothelial cells.
      while also increasing platelet activation.
      • Queck A.
      • Carnevale R.
      • Uschner F.E.
      • Schierwagen R.
      • Klein S.
      • Jansen C.
      • et al.
      Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS.
      Moreover, the observation of a significantly higher concentration of microparticles of endothelial origin (CD62E- MP) in the portal vein compared to the systemic circulation suggested greater endothelial damage at this level.
      • Shalaby S.
      • Simioni P.
      • Campello E.
      • Spiezia L.
      • Gavasso S.
      • Bizzaro D.
      • et al.
      Endothelial damage of the portal vein is associated with heparin-like effect in advanced stages of cirrhosis.
      Although all these arguments make it possible that local inflammatory conditions could play a role in PVT development in patients with cirrhosis, this has not been demonstrated in prospective cause-effect studies.

      Other factors associated with PVT development

      Among other risk factors for PVT in cirrhosis, endoscopic therapy for oesophageal varices (with sclerotherapy or variceal band ligation)
      • Rodriguez-Castro K.I.
      • Porte R.J.
      • Nadal E.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      and a past history of variceal bleeding seem to play a role.
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      Endothelial damage or endotoxemia following endoscopic sclerotherapy have been incriminated in PVT development,
      • Amitrano L.
      • Brancaccio V.
      • Guardascione M.A.
      • Margaglione M.
      • Iannaccone L.
      • D'Andrea G.
      • et al.
      Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.
      however other studies failed to confirm this association.
      • Politoske D.
      • Ralls P.
      • Korula J.
      Portal vein thrombosis following endoscopic variceal sclerotherapy. Prospective controlled comparison in patients with cirrhosis.
      Previous abdominal surgery, splenectomy
      • Gong C.
      • Qin X.
      • Yang J.
      • Guo T.
      The best anticoagulation strategy for cirrhotic patients who underwent splenectomy: a Network meta-analysis.
      and portosystemic shunt surgery have also been reported as determinants of PVT due to venous injury and/or by altering portal venous flow. In addition, it has been suggested that cryptogenic and NASH (non-alcoholic steatohepatitis)-related cirrhosis are associated with a higher risk of PVT than other aetiologies of cirrhosis
      • Ghabril M.
      • Agarwal S.
      • Lacerda M.
      • Chalasani N.
      • Kwo P.
      • Tector A.J.
      Portal vein thrombosis is a risk factor for poor early outcomes after liver transplantation: analysis of risk factors and outcomes for portal vein thrombosis in waitlisted patients.
      ,
      • Stine J.G.
      • Shah N.L.
      • Argo C.K.
      • Pelletier S.J.
      • Caldwell S.H.
      • Northup P.G.
      Increased risk of portal vein thrombosis in patients with cirrhosis due to nonalcoholic steatohepatitis.
      because of increased thrombin generation and hyperfibrinolysis.
      • Tripodi A.
      • Fracanzani A.L.
      • Primignani M.
      • Chantarangkul V.
      • Clerici M.
      • Mannucci P.M.
      • et al.
      Procoagulant imbalance in patients with non-alcoholic fatty liver disease.
      Both the incidence and prevalence of portal vein thrombosis (PVT) in patients with cirrhosis increase in parallel with the severity of liver disease. The pathogenesis of PVT is multifactorial but a decrease in portal vein flow seems to play the most important role.

      Diagnosis and classification

      Colour Doppler ultrasound is usually the first-line imaging method used to diagnose PVT. In most cases, the diagnosis is established in asymptomatic patients during HCC screening. At ultrasound, the thrombus appears as a hypo or iso-echoic material inside the vessel, more hyperechoic if chronic. The addition of Doppler helps to evaluate the velocity of flow in the vessels, and to detect shunts and the presence of small vessels in the extrahepatic main PV that are characteristic of a cavernoma.
      • Margini C.
      • Berzigotti A.
      Portal vein thrombosis: the role of imaging in the clinical setting.
      However, changes related to cavernous transformation of the portal vein, which have been reported to occur as early as 6–20 days after acute PVT,
      • 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.
      are far less common in patients with cirrhosis, since the pressure gradient before and after the clot is small, leading to stasis of portal vein flow which hinders the formation and dilatation of collateral channels.
      • 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.
      Ultrasound has a specificity of 92% and a sensitivity of 89% for the detection of PVT,
      • Tessler F.N.
      • Gehring B.J.
      • Gomes A.S.
      • Perrella R.R.
      • Ragavendra N.
      • Busuttil R.W.
      • et al.
      Diagnosis of portal vein thrombosis: value of color Doppler imaging.
      with a lower sensitivity (14%–50%) for partial PVT.
      • Rodriguez-Castro K.I.
      • Porte R.J.
      • Nadal E.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      The use of contrast-enhanced ultrasonography can be recommended in doubtful cases, since the sensitivity of this method is very high, exceeding 95%.
      EASL Clinical Practice Guidelines
      Vascular diseases of the liver.
      However, evaluation of the extension and occlusion of all portal vein branches (superior mesenteric and splenic veins) by Doppler ultrasound can be limited by the presence of ascites, obesity and bowel gas and is operator-dependent; therefore, the use of cross-sectional imaging (angio-CT or angio-MRI) is recommended to confirm the presence of PVT and for complete PVT staging.
      On CT, imaging features of acute PVT include increased attenuation in the portal vein on unenhanced scans and a lack of enhancement after administration of IV contrast; associated changes in hepatic perfusion may be seen with increased hepatic enhancement in the arterial phase and decreased hepatic enhancement during the portal phase.
      • Mathieu D.
      • Vasile N.
      • Grenier P.
      Portal thrombosis: dynamic CT features and course.
      MRI can be used as an alternative particularly since it is not associated with radiation exposure. However, it may have a lower specificity in small calibre vessels and may lack the spatial resolution necessary to evaluate thrombus size.
      • Jha R.C.
      • Khera S.S.
      • Kalaria A.D.
      Portal vein thrombosis: imaging the spectrum of disease with an emphasis on MRI features.
      In the presence of HCC, exclusion of tumoral invasion of the portal vein is essential. Recently, non-invasive criteria with the acronym A-VENA based on the presence of 3 or more of the following: AFP >1,000 ng/dl; Venous expansion; thrombus Enhancement; Neovascularity; and PVT Adjacent to HCC have been shown to have 100% sensitivity, 93.6% specificity, 80% positive predictive value, and 100% negative predictive value in diagnosing tumoral PVT and distinguishing it from non-tumoral PVT.
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      • Roberts J.P.
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      • Mehta N.
      Distinguishing tumor from bland portal vein thrombus in liver transplant candidates with hepatocellular carcinoma: the A-VENA criteria.
      However, these results need to be validated.
      Several different classifications, mainly based on the anatomy, extension and degree of occlusion have been proposed
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      A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation.
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      • Bauer J.
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      • Bak T.
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      • Sarin S.K.
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      • Bhangui P.
      • Lim C.
      • Levesque E.
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      (Table 1). A more recent classification also takes into account the presence of symptoms related to portal hypertension and the time of onset of thrombosis.
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      All these characteristics are not only important to address the severity of thrombosis and its possible impact on portal hypertension and liver transplantation (LT), but also in the formulation of a treatment algorithm. The severity of the underlying liver dysfunction and completeness of the occlusion, together with a delay in initiating treatment, can reduce the efficacy of anticoagulation. Current or future candidacy for liver transplantation is essential in the evaluation. In this context, the most widely used classification up to now was proposed by Yerdel et al.
      • Yerdel M.A.
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      • Mirza D.
      • Karayalcin K.
      • Olliff S.
      • Buckels J.
      • et al.
      Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.
      Its importance lies in the surgical approach employed, which is determined by the extent of thrombosis and the possibility to reconstruct a physiological portal venous inflow. Recently, a new classification system has been proposed, which could serve as a guide to multidisciplinary decision-making before and during LT in patients with diffuse PVT.
      • Bhangui P.
      • Lim C.
      • Levesque E.
      • Salloum C.
      • Lahat E.
      • Feray C.
      • et al.
      Novel classification of non-malignant portal vein thrombosis: a guide to surgical decision-making during liver transplantation.
      This classification incorporates an analysis of the presence of portosystemic collaterals, such as large gastric vein, pericholedocal varices, splenorenal or other shunts, which could be used to guarantee portal vein inflow in complex PVT.
      Classification of PVT should be treatment-oriented and include extension and grade of occlusion of thrombosis, severity of liver disease and evaluation of feasibility of physiological reconstruction of portal vein inflow at liver transplantation.
      Table 1Classifications of non-neoplastic PVT in patients with cirrhosis.
      PublicationGrade IGrade IIGrade IIIGrade IV
      Stieber
      • 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.
      (Segmental) thrombosis of the PV trunk (partial or complete)Thrombosis extension to SMV; patent SV (partial or complete)Thrombosis extension to SV (partial or complete)Diffuse, with involvement of SMV and SV, including the confluence (complete)
      Nonami
      • Stieber A.C.
      • Zetti G.
      • Todo S.
      • Tzakis A.G.
      • Fung J.J.
      • Marino I.
      • et al.
      The spectrum of portal vein thrombosis in liver transplantation.
      Thrombosis of intrahepatic PV branchesThrombosis of the right or left portal branch of the PV or at the bifurcationPartial obstruction of the PV trunkComplete obstruction of the PV trunk
      Gayowski
      • Nonami T.
      • Yokoyama I.
      • Iwatsuki S.
      • Starzl T.E.
      The incidence of portal vein thrombosis at liver transplantation.
      Partial (mural) thrombosis of the main portal trunk extending to or below the confluence with residual flowComplete thrombosis of the main portal trunk not extending to the confluence of the SMV and SVComplete thrombosis of the main portal trunk extending to the level of the confluenceComplete thrombosis of the main portal trunk with extension below the confluence
      Yerdel
      • Gayowski T.J.
      • Marino I.R.
      • Doyle H.R.
      • Echeverri L.
      • Mieles L.
      • Todo S.
      • et al.
      A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation.
      Minimally or partially thrombosed PV (thrombosis <50% of the vessel lumen) with or without minimal extension into the SMV>50% occlusion of the PV, including complete thrombosis, with or without minimal extension into the SMVComplete thrombosis of both PVT and proximal SMV; patent distal SMVComplete thrombosis of the PV and proximal and distal SMV
      Jamieson
      • Yerdel M.A.
      • Gunson B.
      • Mirza D.
      • Karayalçin K.
      • Olliff S.
      • Buckels J.
      • et al.
      Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.
      Thrombosis confined to the PV beyond the splenomesenteric confluence (partial or complete)Thrombosis extending into the proximal SMV but with a patent vessel in the mesenteryDiffuse thrombosis of the splanchnic venous system but with large accessible collateralsExtensive thrombosis of the splanchnic venous system but with only fine collaterals
      Charco
      • Jamieson N.V.
      Changing perspectives in portal vein thrombosis and liver transplantation.
      Thrombosis confined to the PV (partial or complete)Thrombosis that extends all the way to the proximal portion of the SMV with permeability of the mesenteric confluenceDiffuse thrombosis of the splanchnic system with presence of dilated collateral veinsDiffuse thrombosis with presence of fine collateral veins
      Bauer
      Refers to percentage of occlusion of the vessel (a grade is assigned to each vessel, according to the degree of occlusion).
      • Charco R.
      • Fuster J.
      • Fondevila C.
      • Ferrer J.
      • Mans E.
      • García-Valdecasas J.C.
      Portal vein thrombosis in liver transplantation.
      Occlusion <25% (PVT, SV, or SMV)Occlusion 26%-50% (PVT, SV, or SMV)Occlusion 51%-75% (PVT, SV, or SMV)Occlusion >76% (PVT, SV, or SMV)
      Sarin
      Covers also functional aspects of PVT as duration (recent or chronic ± presence of a cavernoma), presentation (asymptomatic or symptomatic). PV, portal vein; PVT, portal vein thrombosis; SMV, superior mesenteric vein; SV, splenic vein.
      • Bauer J.
      • Johnson S.
      • Durham J.
      • Ludkowski M.
      • Trotter J.
      • Bak T.
      • et al.
      The role of TIPS for portal vein patency in liver transplant patients with portal vein thrombosis.
      Thrombosis of one (type 2a) or both (2b) intrahepatic PV branches (partial or complete)Thrombosis confined to the PV trunk (type 1) (partial or complete)Thrombosis of PV trunk and branches (type 3) (partial or complete)Thrombosis of PV trunk and/or branches with involvement of SMV ± SV (partial or complete)
      Bhangui
      • Sarin S.K.
      • Philips C.A.
      • Kamath P.S.
      • Choudhury A.
      • Maruyama H.
      • Nery F.G.
      • et al.
      Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis.
      Yerdel grade 1-3Complex PVT (Yerdel grade 4, Jamieson grade 3-4 and Charco grade 3-4) in presence of spontaneous or surgical portosystemic shuntComplex PVT (Yerdel grade 4, Jamieson grade 3-4 and Charco grade 3-4) in absence of spontaneous or surgical portosystemic shunts

      Refers to percentage of occlusion of the vessel (a grade is assigned to each vessel, according to the degree of occlusion).
      ∗∗ Covers also functional aspects of PVT as duration (recent or chronic ± presence of a cavernoma), presentation (asymptomatic or symptomatic). PV, portal vein; PVT, portal vein thrombosis; SMV, superior mesenteric vein; SV, splenic vein.

      Natural history of PVT

      While spontaneous recanalisation of PVT is rare in a non-cirrhotic population, it can occur in patients with cirrhosis. In a recent meta-analysis comparing anticoagulated vs. non-anticoagulated patients (excluding the study by Wang et al. that included patients treated with TIPS in both arms
      • Wang Z.
      • Jiang M.S.
      • Zhang H.L.
      • Weng N.N.
      • Luo X.F.
      • Li X.
      • et al.
      Is post-TIPS anticoagulation therapy necessary in patients with cirrhosis and portal vein thrombosis? A randomized controlled trial.
      ), 12% of patients had complete spontaneous PVT recanalisation while 48% had thrombosis progression.
      • 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.
      The largest study included in the meta-analysis was performed by Nery et al. on 1,243 patients with mostly compensated cirrhosis (70% Child-Pugh A) of whom 101 developed PVT, which showed that thrombi disappearance occurred at an unexpectedly high rate of 70%. Nevertheless, thrombi reappeared in 19 of these 70 patients.
      • 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.
      It is important to mention that most PVTs in this study were partial and disappearance of thrombi was assessed by ultrasound and not confirmed by CT. In another study using CT scanning, PVT was also shown to improve (but not resolve) in 45% of patients. Contrary to the study by Nery et al., these patients were mostly decompensated, as 67% had ascites.
      • Luca A.
      • Caruso S.
      • Milazzo M.
      • Marrone G.
      • Mamone G.
      • Crino F.
      • et al.
      Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis.
      A much lower percentage of spontaneous recanalisation (ranging from 5% to 19%) has been reported in patients with decompensated cirrhosis and/or those listed for liver transplantation, with higher rates of progression than regression.
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      ,
      • Senzolo M.
      • Sartori T.M.
      • Rossetto V.
      • Burra P.
      • Cillo U.
      • Boccagni P.
      • et al.
      Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis.
      ,
      • Hidaka H.
      • Kokubu S.
      • Sato T.
      • Katsushima S.
      • Izumi N.
      • Igura T.
      • et al.
      Antithrombin III for portal vein thrombosis in patients with liver disease: a randomized, double-blind, controlled trial.
      Therefore, although spontaneous resolution of PVT may occur, especially if non-occlusive and in compensated cirrhosis, PVT is more likely to progress. Further prospective studies on well-characterised patient populations are required to identify predictors of PVT regression or progression.

      Clinical consequences of PVT in cirrhosis

      Impact of PVT on complications/outcomes in patients with cirrhosis

      The extent to which PVT influences outcomes in patients with cirrhosis is still a matter of debate. Development of PVT, especially if complete, would exert a further increase in resistance to portal blood flow, resulting in worsening portal hypertension (proximal to the thrombus). However, in patients with extensive porto-collateral circulation and very low or absent hepatopetal portal blood flow, the development of PVT may be of no consequence.
      Few studies describe the impact of untreated PVT on the natural history of cirrhosis and all include very heterogeneous populations in terms of underlying liver disease and thrombus characteristics. Although the prospective study by Nery et al. in mostly compensated patients showed that the presence of varices and a prolonged INR predicted PVT, development of PVT did not predict liver disease progression or decompensation.
      • 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.
      In a large retrospective cohort of patients with cirrhosis admitted with a decompensating event, PVT was not associated with 1-year mortality. In this study, causes of PVT were heterogeneous (1/3 being related to splenectomy or partial splenic embolisation) and liver disease was significantly less severe in the PVT group.
      • 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.
      In another prospective study there was no correlation between development of PVT and variceal bleeding or mortality but progressive PVT did correlate with worsening ascites.
      • Maruyama H.
      • Okugawa H.
      • Takahashi M.
      • Yokosuka O.
      De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes.
      The fact that, at time of diagnosis, PVT is often asymptomatic
      • Ageno W.
      • Riva N.
      • Schulman S.
      • Beyer-Westendorf J.
      • Bang S.M.
      • Senzolo M.
      • et al.
      Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry.
      has also been used as an argument against a major role of PVT in worsening outcomes in cirrhosis.
      Other studies provide arguments that support a deterioration of cirrhosis with PVT development. In a study by Amitrano et al., among 79 patients with cirrhosis and newly diagnosed PVT, 39% presented with an episode of portal hypertension-related gastrointestinal bleeding.
      • Amitrano L.
      • Guardascione M.A.
      • Brancaccio V.
      • Iannaccone L.
      • Ames P.R.
      • Balzano A.
      Portal and mesenteric venous thrombosis in cirrhotic patients.
      Similarly, in the previously mentioned large retrospective cohort of 2,597 patients admitted with acute decompensation, patients with PVT were more likely to have been admitted with variceal haemorrhage compared to those without PVT.
      • 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.
      Moreover, in patients with variceal bleeding, PVT was found to be independently associated with a higher risk of failure to control acute variceal bleeding, re-bleeding and short-term mortality
      • Amitrano L.
      • Guardascione M.A.
      • Martino R.
      • Manguso F.
      • Menchise A.
      • Balzano A.
      Hypoxic hepatitis occurring in cirrhosis after variceal bleeding: still a lethal disease.
      • Amitrano L.
      • Guardascione M.A.
      • Manguso F.
      • Bennato R.
      • Bove A.
      • DeNucci C.
      • et al.
      The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors.
      • D'Amico G.
      • De Franchis R.
      Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators.
      Further arguments on the issue come from studies that have correlated the response of PVT to treatment, mostly anticoagulation, and patient outcome. In this regard, it has been shown that successful treatment of PVT decreases variceal pressure
      • De Santis A.
      • Moscatelli R.
      • Catalano C.
      • Iannetti A.
      • Gigliotti F.
      • Cristofari F.
      • et al.
      Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: a pilot study.
      and may reduce the risk of decompensation.
      • Senzolo M.
      • Sartori T.M.
      • Rossetto V.
      • Burra P.
      • Cillo U.
      • Boccagni P.
      • et al.
      Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis.
      ,
      • Senzolo M.
      • Riva N.
      • Dentali F.
      • Sartori M.T.
      • Ageno W.
      Portal vein thrombosis in decompensated cirrhosis: rationale for treatment.
      • 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.
      • 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.
      Moreover, in a recent study, patients who achieved spontaneous or treatment-associated portal vein recanalisation (partial or complete) had better survival than a group of patients matched by severity of cirrhosis who had stable or progressive thrombosis. This effect was especially marked in patients with more advanced liver disease (Child-Pugh B and C vs. A).
      • Senzolo M.
      • Riva N.
      • Dentali F.
      • Rodriguez-Castro K.
      • Sartori M.T.
      • Bang S.M.
      • et al.
      Long-term outcome of splanchnic vein thrombosis in cirrhosis.
      Moreover, Luca et al. reported increased mortality in patients who had a stable or progressive thrombus (39.1%) vs. those in whom PVT improved (15.8%).
      • Luca A.
      • Caruso S.
      • Milazzo M.
      • Marrone G.
      • Mamone G.
      • Crino F.
      • et al.
      Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis.
      It is important to point out that, while longer complication-free survival was only observed in patients in whom PVT resolved with anticoagulation in the study by La Mura et al.,
      • 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.
      this was not the case in the study by Pettinari et al., where a beneficial effect of anticoagulation was observed irrespective of resolution (or not) of PVT.
      • Pettinari I.
      • Vukotic R.
      • Stefanescu H.
      • Pecorelli A.
      • Morelli M.
      • Grigoras C.
      • et al.
      Clinical impact and safety of anticoagulants for portal vein thrombosis in cirrhosis.
      A similar beneficial effect on survival was observed in the study by Villa et al. who used prophylactic heparin in patients with cirrhosis without PVT.
      • 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.
      Anticoagulation has been shown to exert a beneficial effect on portal hypertension and fibrosis in different experimental models of cirrhosis
      • Cerini F.
      • Vilaseca M.
      • Lafoz E.
      • García-Irigoyen O.
      • García-Calderó H.
      • Tripathi D.M.
      • et al.
      Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats.
      ,
      • Vilaseca M.
      • García-Calderó H.
      • Lafoz E.
      • García-Irigoyen O.
      • Avila M.A.
      • Reverter J.C.
      • et al.
      The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells.
      and also in epidemiological studies of a large cohort of patients with cirrhosis anticoagulated for atrial fibrillation.
      • Serper M.
      • Weinberg E.M.
      • Cohen J.B.
      • Reese P.P.
      • Taddei T.H.
      • Kaplan D.E.
      Mortality and hepatic decompensation in patients with cirrhosis and atrial fibrillation treated with anticoagulation.
      Thus, a direct beneficial effect of anticoagulation on the natural history of cirrhosis irrespective of PVT cannot be discarded. In a recent meta-analysis, anticoagulation was associated with decreased mortality in 6/26 studies which reported this outcome.
      • Valeriani E.
      • Di Nisio M.
      • Riva N.
      • Cohen O.
      • Porreca E.
      • Senzolo M.
      • et al.
      Anticoagulant treatment for splanchnic vein thrombosis in liver cirrhosis: a systematic review and meta-analysis.
      To better understand the impact of PVT on the natural history of cirrhosis will require well-designed prospective studies on large cohorts of patients with a detailed evaluation of the severity of both liver disease and PVT.

      Impact of PVT on liver transplant outcomes

      While the impact of PVT on the course of cirrhosis is not entirely clear and does not appear to be significant, its impact on transplant and post-transplant outcomes is major. The establishment of adequate portal flow to the graft is essential, particularly during the initial postoperative period.
      In a systematic review by Rodriguez et al., the authors demonstrated that when PVT is complete (Grade III or IV according to Yerdel’s classification), 30-day and 1-year post-transplant survival rates are decreased.
      • Rodriguez-Castro K.I.
      • Porte R.J.
      • Nadal E.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      This was also confirmed in a recent meta-analysis in which complete PVT carried a 5.65-fold increase in the 1-month post-surgical risk of death.
      • Zanetto A.
      • Rodriguez-Kastro K.I.
      • Germani G.
      • Ferrarese A.
      • Cillo U.
      • Burra P.
      • et al.
      Mortality in liver transplant recipients with portal vein thrombosis - an updated meta-analysis.
      Early post-transplant re-thrombosis, observed more often in patients with advanced pre-transplant Yerdel’s grades, is associated with significant mortality, therefore anticoagulation is recommended in the postoperative period.
      • Rodriguez-Castro K.I.
      • Porte R.J.
      • Nadal E.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      PVT increases the risk of acute variceal bleeding and recurrence of bleeding, although its impact on mortality has mostly been shown in the post-transplant setting.
      In fact, in the case of complete obstruction of the portal vein with extension into the superior mesenteric vein preventing the performance of a physiological portal-to-portal vein anastomosis during LT, several different technical approaches have been proposed, such as portacaval hemi-transposition. However, most of these techniques are unable to resolve the portal hypertensive state, which complicates the postoperative course (with variceal bleeding or persistent ascites) in approximately 50% of patients.
      • Ravaioli M.
      • Zanello M.
      • Grazi G.L.
      • Ercolani G.
      • Cescon M.
      • Del Gaudio M.
      • et al.
      Portal vein thrombosis and liver transplantation: evolution during 10 years of experience at the University of Bologna.
      Azoulay et al. proposed a left renal vein to graft portal vein anastomosis in patients with spontaneous or surgical spleno renal shunts (reno-portal anastomosis) as a successful strategy in patients for whom portal-to-portal anastomosis was not possible.
      • Bhangui P.
      • Lim C.
      • Levesque E.
      • Salloum C.
      • Lahat E.
      • Feray C.
      • et al.
      Novel classification of non-malignant portal vein thrombosis: a guide to surgical decision-making during liver transplantation.
      All these strategies highlight the need to discuss all potential means of achieving portal vein reconstruction in patients with PVT before deeming them non-transplant candidates.

      Treatment of PVT in cirrhosis

      Anticoagulation

      Efficacy

      Several cohort studies have investigated the efficacy and safety of anticoagulation for the treatment of PVT in patients with cirrhosis
      • Cui S.B.
      • Shu R.H.
      • Yan S.P.
      • Wu H.
      • Chen Y.
      • Wang L.
      • et al.
      Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B.
      ,
      • Noronha Ferreira C.
      • Marinho R.T.
      • Cortez-Pinto H.
      • Ferreira P.
      • Dias M.S.
      • Vasconcelos M.
      • et al.
      Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: a prospective study.
      ,
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      ,
      • Senzolo M.
      • Sartori T.M.
      • Rossetto V.
      • Burra P.
      • Cillo U.
      • Boccagni P.
      • et al.
      Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis 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.
      • 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.
      • Senzolo M.
      • Riva N.
      • Dentali F.
      • Rodriguez-Castro K.
      • Sartori M.T.
      • Bang S.M.
      • et al.
      Long-term outcome of splanchnic vein thrombosis in cirrhosis.
      • Pettinari I.
      • Vukotic R.
      • Stefanescu H.
      • Pecorelli A.
      • Morelli M.
      • Grigoras C.
      • et al.
      Clinical impact and safety of anticoagulants for portal vein thrombosis in cirrhosis.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Menchise A.
      • Martino R.
      • Scaglione M.
      • Giovine S.
      • et al.
      Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis.
      • 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.
      • Werner K.T.
      • Sando S.
      • Carey E.J.
      • Vargas H.E.
      • Byrne T.J.
      • Douglas D.D.
      • et al.
      Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation.
      • Chen H.
      • Liu L.
      • Qi X.
      • He C.
      • Wu F.
      • Fan D.
      • et al.
      Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis.
      • Scheiner B.
      • Stammet P.R.
      • Pokorny S.
      • Bucsics T.
      • Schwabl P.
      • Brichta A.
      • et al.
      Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function.
      • Kwon J.
      • Koh Y.
      • Yu S.J.
      • Yoon J.H.
      Low-molecular-weight heparin treatment for portal vein thrombosis in liver cirrhosis: efficacy and the risk of hemorrhagic complications.
      • Zhang Z.H.
      • Zhang J.W.
      • He P.
      • Zhou Y.
      • Sun C.Y.
      Fondaparinux is effective for acute portal vein thrombosis in decompensated cirrhotic patients.
      • Tripodi A.
      • Primignani M.
      • Braham S.
      • Chantarangkul V.
      • Clerici M.
      • Moia M.
      • et al.
      Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists.
      • Chung J.W.
      • Kim G.H.
      • Lee J.H.
      • Ok K.S.
      • Jang E.S.
      • Jeong S.H.
      • et al.
      Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis.
      • Hayashi T.
      • Takatori H.
      • Horii R.
      • Nio K.
      • Terashima T.
      • Iida N.
      • et al.
      Danaparoid sodium-based anticoagulation therapy for portal vein thrombosis in cirrhosis patients.
      • Naeshiro N.
      • Aikata H.
      • Hyogo H.
      • Kan H.
      • Fujino H.
      • Kobayashi T.
      • et al.
      Efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis in patients with liver cirrhosis.
      • Bergère M.
      • Erard-Poinsot D.
      • Boillot O.
      • Valette P.J.
      • Guillaud O.
      • Chambon-Augoyard C.
      • et al.
      Portal vein thrombosis and liver cirrhosis: long-term anticoagulation is effective and safe.
      • Artaza T.
      • Lopes M.
      • Romero M.
      • Gómez A.Z.
      • de la Cruz G.
      • Sánchez J.J.
      • et al.
      Efficacy and safety of anticoagulation in non-malignant portal vein thrombosis in patients with liver cirrhosis.
      (Table S1). However, most studies are retrospective with different inclusion criteria and coagulation regimens. Two separate meta-analyses summarise published studies.
      • 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.
      • Dai J.
      • Jia J.
      • Ren W.
      • Yang M.
      • Li H.
      • et al.
      Association between portal vein thrombosis and survival of liver transplant recipients: a systematic review and meta-analysis of observational studies.
      The most recent includes data from 8 studies, comprising 353 patients. Excluding the study by Wang et al. that enrolled patients who underwent TIPS placement,
      • Wang Z.
      • Jiang M.S.
      • Zhang H.L.
      • Weng N.N.
      • Luo X.F.
      • Li X.
      • et al.
      Is post-TIPS anticoagulation therapy necessary in patients with cirrhosis and portal vein thrombosis? A randomized controlled trial.
      a significantly higher proportion of patients treated with anticoagulants experienced some degree of PVT recanalisation compared to those who did not receive anticoagulants (63% vs. 22%, respectively). In addition, in 5 studies (comprising 217 patients) that described the rate of complete PVT recanalisation, it was significantly higher in patients on anticoagulation (42%) vs. those not on anticoagulation (12%). Meta-regression analysis suggests that low molecular weight heparin (LMWH) could be more effective than warfarin.
      • 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.
      Among several published cohorts, pretreatment predictive factors of anticoagulant treatment efficacy were analysed in 6 studies, demonstrating a relatively strong correlation between early anticoagulation and likelihood of recanalisation. Initiation of anticoagulation less than 6 months after the diagnosis of PVT is the most important factor predicting recanalisation.
      • 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.
      ,
      • 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.
      Other factors, such as involvement of mesenteric veins and/or the severity of baseline liver disease, have also been proposed as possible predictive factors.
      • Cui S.B.
      • Shu R.H.
      • Yan S.P.
      • Wu H.
      • Chen Y.
      • Wang L.
      • et al.
      Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B.
      ,
      • Chen H.
      • Liu L.
      • Qi X.
      • He C.
      • Wu F.
      • Fan D.
      • et al.
      Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis.
      However, not all studies are in agreement.
      • 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.
      ,
      • 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.
      There is evidence that suggests that PVT is more likely to resolve when the thrombus is partial than when it is complete, although the difference (22%) was not significantly different, perhaps because of the small number of patients with complete PVT.
      • 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.
      In 1 study, a model developed to predict successful anticoagulation in 65 patients correlated the lack of efficacy of anticoagulation with more severe liver disease, complete vs. partial PVT, age of the thrombus, and time from treatment start (>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.
      Interestingly, in this study, no case of recanalisation was observed in patients with Child-Pugh C cirrhosis (only 5 patients).
      • Pettinari I.
      • Vukotic R.
      • Stefanescu H.
      • Pecorelli A.
      • Morelli M.
      • Grigoras C.
      • et al.
      Clinical impact and safety of anticoagulants for portal vein thrombosis in cirrhosis.
      Mean time to recanalisation ranges from 5.5 to 8 months and ACG and AISF guidelines suggest a treatment course of 6 months
      • Simonetto D.A.
      • Singal A.K.
      • Garcia-Tsao G.
      • Caldwell S.H.
      • Ahn J.
      • Kamath P.S.
      ACG clinical guideline: disorders of the hepatic and mesenteric circulation.
      ,
      • Senzolo M.
      • Riggio O.
      • Primignani M.
      Vascular disorders of the liver: recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee.
      ; however, these recommendations are based on data that can be biased given the very different schedule of follow-up imaging. It has been suggested that some patients may achieve recanalisation with extension of anticoagulation to up to 1 year,
      • Amitrano L.
      • Guardascione M.A.
      • Menchise A.
      • Martino R.
      • Scaglione M.
      • Giovine S.
      • et al.
      Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis.
      however, few patients will respond after 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.
      It has also been suggested that recanalisation is more likely to occur in patients with partial PVT compared to those with complete PVT.
      • 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.
      ,
      • 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.
      Independent of length of anticoagulation therapy, it is important to mention that recurrence of thrombosis is frequent, ranging from 27% to 38% of cases.
      • 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.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Menchise A.
      • Martino R.
      • Scaglione M.
      • Giovine S.
      • et al.
      Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis.
      ,
      • Rodríguez-Castro K.I.
      • Senzolo M.
      • Sartori M.T.
      Optimal length of anticoagulant therapy in cirrhotic patients with portal vein thrombosis.
      The time elapsed between discontinuation of anticoagulation therapy and recurrence of thrombosis ranges between 2 and 5 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.
      ,
      • Rodríguez-Castro K.I.
      • Senzolo M.
      • Sartori M.T.
      Optimal length of anticoagulant therapy in cirrhotic patients with portal vein thrombosis.
      Therefore, in order to prevent re-thrombosis, particularly in patients listed for LT, long-term anticoagulation should be considered.
      EASL Clinical Practice Guidelines
      Vascular diseases of the liver.

      Types of anticoagulation

      LMWH is the initial treatment of choice. One study investigated 2 separate doses of LMWH (1.5 mg/kg daily and 1 mg/kg twice daily) showing a similar rate of recanalisation with fewer bleeding complications in the twice daily dosage group.
      • Cui S.B.
      • Shu R.H.
      • Yan S.P.
      • Wu H.
      • Chen Y.
      • Wang L.
      • et al.
      Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B.
      In 1 study, reducing the LMWH dose by 30% for patients with a platelet count lower than 50,000/ul did not significantly decrease the efficacy of anticoagulation.
      • 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.
      It should be noted that basing LMWH dosing on anti-Xa activity could inadvertently lead to higher than expected anticoagulant levels because of the innate decrease in antithrombin associated with liver synthetic dysfunction.
      • Bechmann L.P.
      • Sichau M.
      • Wichert M.
      • Gerken G.
      • Kröger K.
      • Hilgard P.
      Low-molecular-weight heparin in patients with advanced cirrhosis.
      This effect is especially pronounced at higher Child-Pugh stages and can lead to bleeding complications.
      • Senzolo M.
      • Rodriguez-Castro K.I.
      • Rossetto V.
      • Radu C.
      • Gavasso S.
      • Carraro P.
      • et al.
      Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis.
      Therefore, anti-Xa activity assays should not be used as a LMWH dosing guide in patients with cirrhosis. In the presence of renal dysfunction, LMWH requires dose reduction. Fondaparinux (FPX) exerts its function primarily through selective binding to antithrombin, causing rapid inhibition of activated factor X
      • Zhang Y.
      • Zhang M.
      • Tan L.
      • Pan N.
      • Zhang L.
      The clinical use of Fondaparinux: a synthetic heparin pentasaccharide.
      ; it can be prescribed in fixed dosages once a day with comparable or even greater efficacy than LMWH. Furthermore, unlike unfractionated heparin and LMWH, FPX does not bind to platelet factor IV and the risk of heparin-induced thrombocytopenia is rare.
      • Lobo B.
      • Finch C.
      • Howard A.
      • Minhas S.
      Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia.
      Although reports on its use for the treatment of PVT are scarce its efficacy appears not to be inferior to LMWH.
      • Senzolo M.
      • Piano S.
      • Shalaby S.
      • Tonon M.
      • Tonello S.
      • Zanetto A.
      • et al.
      Comparison of fondaparinux and low molecular weight heparin in the treatment of portal vein thrombosis in cirrhosis.
      Given the parenteral administration of LMWH, the compliance and quality of life of patients can be an issue, therefore vitamin K antagonists (VKAs) can be used for long-term treatment. However, in patients with baseline alterations in INR, the therapeutic range of VKA can be difficult to maintain.
      In the last decade, direct oral anticoagulants (DOACs) have emerged as a safe alternative to VKAs when long-term anticoagulation treatment is needed in patients with atrial fibrillation or venous thromboembolism. Underlying liver dysfunction severely affects the pharmacokinetics of DOACs because of plasmatic binding protein, cytochrome p450-mediated metabolism, biliary excretion and renal clearance.
      • Turco L.
      • de Raucourt E.
      • Valla D.C.
      • Villa E.
      Anticoagulation in the cirrhotic patient.
      For this reason, the FDA and EMA do not recommend the use of these agents in patients with Child-Pugh C cirrhosis, while they recommend caution in patients with Child-Pugh B cirrhosis and no restrictions for those with Child-Pugh A cirrhosis. However, there are no specific data on safety in these populations.
      Data on the use of DOACs in the clinical context of PVT in liver disease derives from small cohorts and 1 RCT.
      • Hanafy A.S.
      • Abd-Elsalam S.
      • Dawoud M.M.
      Randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis.
      • De Gottardi A.
      • Trebicka J.
      • Klinger C.
      • Plessier A.
      • Seijo S.
      • Terziroli B.
      • et al.
      Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis.
      • Yang H.
      • Kim S.R.
      • Song M.J.
      Recurrent acute portal vein thrombosis in liver cirrhosis treated by rivaroxaban.
      • Intagliata N.M.
      • Henry Z.H.
      • Maitland H.
      • Shah N.L.
      • Argo C.K.
      • Northup P.G.
      • et al.
      Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation.
      • Nagaoki Y.
      • Aikata H.
      • Daijyo K.
      • Teraoka Y.
      • Shinohara F.
      • Nakamura Y.
      • et al.
      Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis.
      From these studies, it seems that DOACs could have at least the same efficacy as VKAs and similar side effects, but with much simpler administration because no monitoring is required. More studies are needed to identify the specific role of DOACs and the most appropriate one for the treatment of PVT in patients with cirrhosis.

      Complications of anticoagulation

      Anticoagulation does not seem to lead to a higher rate of bleeding complications in patients with cirrhosis compared to anticoagulation in patients without cirrhosis. According to the meta-analysis by Loffredo et al. no difference in the risk of bleeding was found between LMWH and VKA.
      • 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.
      In patients treated with VKA, a study showed that patients with a platelet count <50,000/ul had a greater bleeding risk.
      • 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.
      However, this cut-off value has not been confirmed in other studies. In settings other than PVT in cirrhosis, it has been proposed to reduce the dose of anticoagulant (i.e. LMWH) in patients with a platelet count below 50,000/ul and to consider discontinuation in patients with platelet counts below 30,000/ul.
      • Leader A.
      • Ten Cate V.
      • Ten Cate-Hoek A.J.
      • Beckers E.A.M.
      • Spectre G.
      • Giaccherini C.
      • et al.
      Anticoagulation in thrombocytopenic patients with hematological malignancy: a multinational clinical vignette-based experiment.
      Reducing the LMWH dose by 30% for patients with a platelet count below 50,000/ul did not result in a reduction in bleeding complications in a single study,
      • 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.
      therefore data are lacking to make firm recommendations in this respect.
      Anticoagulation should be attempted for at least 6 months using low molecular weight heparin or acenocumarol. Direct oral anticoagulants can be used in special situations, but evidence is still lacking regarding their safety and efficacy. Monitoring and interpretation of standard markers of anticoagulation is challenging given alterations at baseline in cirrhosis.
      According to a meta-analysis by Loffredo et al. that included 4 studies describing the rate of acute variceal bleeding,
      • Cui S.B.
      • Shu R.H.
      • Yan S.P.
      • Wu H.
      • Chen Y.
      • Wang L.
      • et al.
      Efficacy and safety of anticoagulation therapy with different doses of enoxaparin for portal vein thrombosis in cirrhotic patients with hepatitis B.
      ,
      • Senzolo M.
      • Sartori T.M.
      • Rossetto V.
      • Burra P.
      • Cillo U.
      • Boccagni P.
      • et al.
      Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis.
      ,
      • Chung J.W.
      • Kim G.H.
      • Lee J.H.
      • Ok K.S.
      • Jang E.S.
      • Jeong S.H.
      • et al.
      Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis.
      the risk of portal hypertensive bleeding was actually reduced in the anticoagulated group and this was confirmed in 2 subsequent studies.
      • 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.
      ,
      • Senzolo M.
      • Riva N.
      • Dentali F.
      • Rodriguez-Castro K.
      • Sartori M.T.
      • Bang S.M.
      • et al.
      Long-term outcome of splanchnic vein thrombosis in cirrhosis.
      On the contrary, patients with cirrhosis receiving anticoagulation for indications other than PVT seem to have a higher risk of variceal bleeding than matched cohorts of non-anticoagulated patients with cirrhosis
      • Lee S.R.
      • Lee H.J.
      • Choi E.K.
      • Han K.D.
      • Jung J.H.
      • Cha M.J.
      • et al.
      Direct oral anticoagulants in patients with atrial fibrillation and liver disease.
      ,
      • Sasso R.
      • Rockey D.C.
      Anticoagulation therapy in patients with liver cirrhosis is associated with an increased risk of variceal hemorrhage.
      Management of oesophageal varices (primary and secondary prophylaxis) must differ from that recommended for patients without PVT and should follow the Baveno and AASLD guidelines.
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ,
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      Recent evidence suggests that band ligation can be performed without the need for peri-procedure withdrawal of anticoagulation as there are no differences in bleeding risk from post banding ulcers.
      • Bianchini M.
      • Cavani G.
      • Bonaccorso A.
      • Turco L.
      • Vizzutti F.
      • Sartini A.
      • et al.
      Low molecular weight heparin does not increase bleeding and mortality post-endoscopic variceal band ligation in cirrhotic patients.
      • Ponthus S.
      • Spahr L.
      • Casini A.
      • Berney T.
      • Frossard J.L.
      • Majno P.
      • et al.
      Safety of variceal band ligation in patients with cirrhosis and portal vein thrombosis treated with anticoagulant therapy: a retrospective study.
      • Guillaume M.
      • Christol C.
      • Plessier A.
      • Corbic M.
      • Peron J.M.
      • Sommet A.
      • et al.
      Bleeding risk of variceal band ligation in extrahepatic portal vein obstruction is not increased by oral anticoagulation.
      However, the number of patients included in these studies was small and therefore a formal recommendation cannot be made.

      Thrombolysis

      Systemic or local thrombolysis using streptokinase, urokinase or tissue plasminogen activator with concomitant administration of LMWH has been attempted in a few cases
      • De Santis A.
      • Moscatelli R.
      • Catalano C.
      • Iannetti A.
      • Gigliotti F.
      • Cristofari F.
      • et al.
      Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: a pilot study.
      to treat recent PVT but cannot be recommended because of a high rate of bleeding complications and a lack of evidence showing it to be superior to anticoagulation alone.

      Transjugular intrahepatic portosystemic shunt (TIPS)

      In previous decades, PVT had been considered a contraindication to TIPS placement. However, since the first reports in the early 1990s,
      • Radosevich P.M.
      • Ring E.J.
      • LaBerge J.M.
      • Peltzer M.Y.
      • Haskal Z.J.
      • Doherty M.M.
      • et al.
      Transjugular intrahepatic portosystemic shunts in patients with portal vein occlusion.
      • Walser E.M.
      • NcNees S.W.
      • DeLa Pena O.
      • Crow W.N.
      • Morgan R.A.
      • Soloway R.
      • et al.
      Portal venous thrombosis: percutaneous therapy and outcome.
      • Stein M.
      • Link D.P.
      Symptomatic spleno-mesenteric-portal venous thrombosis: recanalization and reconstruction with endovascular stents.
      the cumulative evidence – derived from non-controlled and retrospective cohort series – shows that TIPS can be performed successfully in 75%–100% of patients. In a recent meta-analysis, TIPS was able to reduce clot burden with partial recanalisation in 84% of patients with complete recanalisation in 73%.
      • Rodrigues S.G.
      • Sixt S.
      • Abraldes J.G.
      • De Gottardi A.
      • Klinger C.
      • Bosch J.
      • et al.
      Systematic review with meta-analysis: portal vein recanalisation and transjugular intrahepatic portosystemic shunt for portal vein thrombosis.
      Overall, 95% of patients with complete recanalisation after TIPS maintained patency of the portal vein. If portal vein flow is ensured after the procedure, anticoagulation is not mandatory.
      • Wang Z.
      • Jiang M.S.
      • Zhang H.L.
      • Weng N.N.
      • Luo X.F.
      • Li X.
      • et al.
      Is post-TIPS anticoagulation therapy necessary in patients with cirrhosis and portal vein thrombosis? A randomized controlled trial.
      However, when discussing the potential role of TIPS in PVT treatment, the characteristics of the thrombus should be considered.
      • Tripathi D.
      • Stanley A.J.
      • Hayes P.C.
      • Travis S.
      • Armstrong M.J.
      • Tsochatzis E.A.
      • et al.
      Transjugular intrahepatic portosystemic stent-shunt in the management of portal hypertension.
      TIPS is feasible in a patient with partial or even occlusive PVT,
      • Luca A.
      • Miraglia R.
      • Caruso S.
      • Milazzo M.
      • Sapere C.
      • Maruzzelli L.
      • et al.
      Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis.
      ,
      • Han G.
      • Qi X.
      • He C.
      • Yin Z.
      • Wang J.
      • Xia J.
      • et al.
      Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis.
      provided that the portal vein can still be identified. The presence of portal cavernoma or an inability to identify the intrahepatic portal trunk or intrahepatic portal vein branches markedly increases the technical difficulties of TIPS creation. These procedures are technically challenging and radiation intensive
      • Miraglia R.
      • Maruzzelli L.
      • Cannataci C.
      • Gerasia R.
      • Mamone G.
      • Cortis K.
      • et al.
      Radiation exposure during transjugular intrahepatic portosystemic shunt creation in patients with complete portal vein thrombosis or portal cavernoma.
      ; despite this, an increasing number of these patients have undergone successful TIPS placement as familiarity with this procedure grows. In patients with cavernoma, the recanalisation of the portal vein remnant should be preferred to the placement of a stent in a collateral vessel as the latter poses an increased risk of haemoperitoneum and is less effective for portal system decompression. In the case of chronic complete/occlusive PVT or portal cavernoma the absence of an appropriate landing zone at the distal end of the portal vein or at the spleno-mesenteric confluence should be considered as a relative contraindication to TIPS creation.
      • Han G.
      • Qi X.
      • He C.
      • Yin Z.
      • Wang J.
      • Xia J.
      • et al.
      Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis.
      The reported technical success rate of TIPS placement in patients with PVT in highly specialised centres is 75%–98%, with a major complication rate of 10%.
      • Rodrigues S.G.
      • Sixt S.
      • Abraldes J.G.
      • De Gottardi A.
      • Klinger C.
      • Bosch J.
      • et al.
      Systematic review with meta-analysis: portal vein recanalisation and transjugular intrahepatic portosystemic shunt for portal vein thrombosis.
      In cases of very extensive portal vein thrombus, mechanical thrombolysis during the TIPS procedure may help to achieve portal vein recanalisation.
      • Chamarthy M.R.
      • Anderson M.E.
      • Pillai A.K.
      • Kalva S.P.
      Thrombolysis and transjugular intrahepatic portosystemic shunt creation for acute and subacute portal vein thrombosis.
      In most of the reported studies, most patients in whom TIPS was placed still had an identifiable portal vein and the indication for TIPS was not the PVT itself but the treatment of a portal hypertension-related complication (ascites, variceal haemorrhage) in which PVT was present. In this regard, 2 RCTs in patients with cirrhosis, variceal bleeding and PVT demonstrate that TIPS is more effective than ligation combined with propranolol and anticoagulation in preventing re-bleeding and achieving PVT resolution without increasing the risk of hepatic encephalopathy or adverse events. However, this benefit did not translate into an improvement in survival.
      • Lv Y.
      • Qi X.
      • He C.
      • Wang Z.
      • Yin Z.
      • Niu J.
      • et al.
      Covered TIPS versus endoscopic band ligation plus propranolol for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: a randomised controlled trial.
      ,
      • Luo X.
      • Wang Z.
      • Tsauo J.
      • Zhou B.
      • Zhang H.
      • Li X.
      Advanced cirrhosis combined with portal vein thrombosis: a randomized trial of TIPS versus endoscopic band ligation plus propranolol for the prevention of recurrent esophageal variceal bleeding.
      TIPS can be considered for the treatment of PVT in the case of an absolute contraindication to anticoagulation or in the case of no response after a maximum of 6 months of anticoagulation treatment.
      • Fagiuoli S.
      • Bruno R.
      • Debernardi Venon W.
      • Schepis F.
      • Vizzutti F.
      • Toniutto P.
      • et al.
      Consensus conference on TIPS management: techniques, indications, contraindications.
      In LT candidates, the indications for TIPS placement are identical to those recommended for non-listed patients. A specific aim of TIPS in candidates for LT is to guarantee patency of the portal vein, if the risk of progression to grade 3-4 Yerdel is high or already present. To ensure physiological portal vein reconstruction in cases with occlusive PVT, portal vein recanalisation using a trans-splenic TIPS procedure has been shown to be successful in 98% of cases in a single cohort study, with portal vein patency obtained in 92% of patients.
      • Thornburg B.
      • Desai K.
      • Hickey R.
      • Hohlastos E.
      • Kulik L.
      • Ganger D.
      • et al.
      Pretransplantation portal vein recanalization and transjugular intrahepatic portosystemic shunt creation for chronic portal vein thrombosis: final analysis of a 61-patient cohort.
      Only 1 RCT showed no advantage of anticoagulation in maintaining portal vein patency after TIPS placement.
      • Wang Z.
      • Jiang M.S.
      • Zhang H.L.
      • Weng N.N.
      • Luo X.F.
      • Li X.
      • et al.
      Is post-TIPS anticoagulation therapy necessary in patients with cirrhosis and portal vein thrombosis? A randomized controlled trial.
      However, this will probably depend on post-TIPS haemodynamics and no definitive recommendations can be provided at this point.
      A transjugular intrahepatic portosystemic shunt (TIPS) with or without thrombectomy is feasible in most cases and may reduce the burden of thrombosis. The use of TIPS is generally reserved for patients who do not respond to 6 months of anticoagulation. However, it could be considered first line in the presence of significant complications of portal hypertension, old thrombus in a transplant candidate or contraindications to anticoagulation.

      Suggested treatment algorithm

      Patients with thrombosis of the main portal vein or intrahepatic branches involving less than 50% of the lumen of the vessels can be followed-up every 3 months to scan for progression of thrombosis unless the patient is on the LT waiting list or there is involvement of the superior mesenteric vein which is, per se, an indication for anticoagulation. Potential LT candidates or those patients with progressive or occlusive PVT with more than 50% occlusion of the main portal vein branch or both intrahepatic branches should be treated. Anticoagulation is the first choice if the main portal vein can be identified and there is no cavernoma. The use of TIPS is generally reserved for patients who do not respond to 6 months of anticoagulation. However, it could be considered first line in the following circumstances: a) presence of significant complications of portal hypertension (e.g. variceal haemorrhage, difficult to treat ascites) that would also require TIPS; b) identification of an old thrombus (>6 months), unlikely to respond to anticoagulation, in a transplant candidate; and c) contraindications to anticoagulation (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Approach to the patient with cirrhosis and PVT.
      ∗In patients who do not meet these criteria, a Doppler ultrasound should be performed every 3 months and anticoagulation is not recommended; ∗∗Provided screening for varices/CSPH and measures to prevent variceal haemorrhage are in place; if procedures are foreseen (e.g. EVL, LVP) in the near future, start with LMWH and then transition to VKA/DOAC; ∗∗∗In the presence of PV remnant or splenic vein access, experienced interventionalists may attempt portal vein recanalisation plus TIPS. DOAC, direct oral anticoagulant; EVL, endoscopic variceal ligation; LMWH, low molecular weight heparin; LVP, large volume paracentesis; PVT, portal vein thrombosis; PV, portal vein; SMV, superior mesenteric vein; TIPS, transjugular intrahepatic portosystemic shunt; VKA, vitamin K antagonist.

      Abbreviations

      DOACs, direct oral anticoagulants; FPX, fondaparinux; HCC, hepatocellular carcinoma; JAK, Janus kinase; LMWH, low molecular weight heparin; MP, microparticle; NSBBs, non-selective beta blockers; OR, odds ratio; PVT, portal vein thrombosis; SMV, superior mesenteric vein; TIPS, transjugular intraheptic portosystemic shunt; VKA, vitamin K antagonist; vWf, von Willebrand factor.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      MS, GGT and JCGP study concept and design, review of the literature, writing of article.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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