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Management of portal vein thrombosis inliver cirrhosis

Xingshun Qi, Guohong Han and Daiming Fan
Abstract | Portal vein thrombosis (PVT) is a fairly common complication of liver cirrhosis. Importantly, occlusive PVT might influence the prognosis of patients with cirrhosis. Evidence from a randomized controlled trial has shown that anticoagulation can prevent the occurrence of PVT in patients with cirrhosis without prior PVT. Evidence from several case series has also demonstrated that anticoagulation can achieve portal vein recanalization in patients with cirrhosis and PVT. Early initiation of anticoagulation therapy and absence of previous portal hypertensive bleeding might be positively associated with a high rate of portal vein recanalization after anticoagulation. However, the possibility of spontaneous resolution of partial PVT questions the necessity of anticoagulation for the treatment of partial PVT. In addition, a relatively low recanalization rate of complete PVT after anticoagulation therapy suggests its limited usefulness in patients with complete PVT. Successful insertion of a transjugular intrahepatic portosystemic shunt (TIPS) not only recanalizes the thrombosed portal vein, but also relieves the symptomatic portal hypertension. However, the technical difficulty of TIPS potentially limits its widespread application, and the risk and benefits should be fully balanced. Notably, current recommendations regarding the management of PVT in liver cirrhosis are insufficient owing to low-quality evidence.
Qi, X. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 1 April 2014; doi:10.1038/nrgastro.2014.36

Introduction
Portal vein thrombosis (PVT) is characterized by the formation of a thrombus within the portal vein trunk and intrahepatic portal branches.1,2 Evolution of PVT mainly includes the degree (that is, partial occlusion, complete occlusion and fibrotic cord), stage (fresh thrombus, recent or old thrombus, and portal cavernoma), and extension (portal vein alone or extension into the splenic and/or superior mesenteric vein).35 A classification system proposed by Yerdel is frequently used, as follows: grade 1, <50% PVT with or without minimal obstruction of the superior mesenteric vein; grade 2, >50% PVT with or without minimal obstruction of the superior mesenteric vein; grade 3, complete portal vein and proximal superior mesenteric vein thrombosis; and grade 4, complete portal vein and entire superior mesenteric vein thrombosis.6 In contrast to other classifications,79 this system considers both the degree and extension of PVT. PVT is frequently encountered in the setting of liver cirrhosis, especially at the decompensated or advanced stage. 10,11 However, the prevalence and incidence of PVT often varies among different studies owing to heterogeneous diagnostic methods and target populations (reviewed in detail elsewhere 10). In a large case series including 701 patients with cirrhosis but without hepatocellular carcinoma who were undergoing routine Doppler ultrasonography, the prevalence of PVT was 11.2% (79 patients).12 In another study, the
Competing interests The authors declare no competing interests.

Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 17 West Changle Road, Xian, 710032China (X.Q., G.H., D.F.). Correspondence to:D.F. fandaim@fmmu.edu.cn; G.H. guohhan@126.com

prevalence of PVT was 8.4% (21 of 251 patients) at the time of listing for liver transplantation, and the incidence ofdenovo PVT in transplant recipients was 7.4% (17 of 230 patients) during a mean follow-up of 12.1months.13 Results of a prospective study demonstrated that the incidence of denovo PVT in liver cirrhosis was 16.4% (12 of 73 patients) within 1year.14 Similarly, a retrospective study shows that the 1year and 5year cumulative incidence of denovo PVT is 12.8% and 20.0%, respectively, in virus-related cirrhosis. 15 However, several inconsistencies and drawbacks in the design and data analysis of these studiesincluding splenic vein thrombosis alone falsely classified as PVT, uneven distribution of incidence of PVT during follow-up, and difficulty of using Doppler ultrasonography in the regular evaluation of PVTraise questions about the reliability of these findings.16 In 2011, a pre-planned satellite study (using data from a published multicentre randomized trial in which the incidence of small hepatocellular carcinoma was compared between patients with compensated cirrhosis receiving 3month versus 6month ultrasonographic periodicities17) reported that 101 of 898 patients with compensated cirrhosis and a prior patent portal vein developed PVT during a mean follow-up time of 47months, and the 5year cumulative incidence of PVT was 11.9%.18 A large prospective Italian Venous Thrombotic Events Registry project is ongoing primarily to estimate the prevalence of PVT evaluated by power Doppler ultrasonography in a cohort of patients with liver cirrhosis of any aetiology and severity.19 Thisproject
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Key points
Portal vein thrombosis (PVT) is a fairly common complication of liver cirrhosis; occlusive PVT can be associated with poor prognosis, especially in patients with a prior history of bleeding A randomized controlled trial has shown that anticoagulation is effective for the primary prevention of PVT in liver cirrhosis, and might also improve liver function and survival Further randomized trials with a larger sample size are warranted to confirm these findings Evidence from several case series has demonstrated the efficacy and safety of anticoagulation therapy and a transjugular intrahepatic portosystemic shunt for the management of PVT in liver cirrhosis Future research should aim to weigh the benefits of various treatment modalities against the risks that they will bring and to establish their different timings and indications

will provide more solid data by recruiting 1,100 patients between December 2011 and December 2014. Decreased portal flow velocity and increased flow volume in the largest collateral vessel were considered to be independent factors predicting the development of PVT in three studies (Supplementary Table1online).14,15,20 In addition, increased severity of liver cirrhosis is positively associated with the reduction of portal vein flow velocity, 21 thereby potentially leading to the development of PVT.14 However, it should be noted that the statistical significance of liver dysfunction on the development of PVT disappears in multivariate analysis.14 Other local factors associated with the development of PVT include portal venous endothelial injury (for example, splenectomy, hepatectomy, surgical shunt, and other intra-abdominal surgery) and inflammation (pancreatitis, cholecystitis, appendicitis, and other intra-abdominal infections). Systemic thrombotic risk factors, which are more frequently observed in patients with cirrhosis and PVT than in those without PVT, include factor V Leiden mutation, prothrombin G20210Amutat ion, methylenetetrahydrofolate reductase C677T mutation, hypofibrinolysis, positive anticardiolipin antibodies, and positive lupus anticoagulant (Supplementary Table1online).20,2230 A meta-analysis of observational studies performed by our group showed that decreased levels of antithrombin and protein C and S are not significantly associated with the development of PVT in liver cirrhosis.31 This finding has been further supported by the findings of our casecontrol study.32 Another meta-analysis by Dentali suggests that prothrombin G20210A mutation, but not factor V Leiden mutation, might contribute to the pathogenesis of PVT in liver cirrhosis.28 Evidence regarding the effect of PVT on the prognosis of patients with cirrhosis is complex and contro versial.6,13,15,3343 The heterogeneous results of these studies might be attributable to discrepancies in the selection of the target population (for example compensated or decompensated cirrhosis), degree and extension of PVT (partial or complete, and mesenteric venous involvement or not), study design (retrospective or prospective), sample size (small or large), and follow-up length (shortterm or long-term). For example, by using the Scientific
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Registry of Transplant Recipients data, Englesbe etal. did not identify any significant effect of PVT on mortality on the waiting list for liver transplantation.36 However, in another study in which the same investigators stratified data from the University of Michigan according to the degree of PVT, they found that the presence of occlusive PVT was an independent predictor of mortality from the time of liver transplant evaluation.35 Indeed, several studies have reported that post-transplantation mortality is similar between patients with a patent portal vein and those with partial PVT, but is significantly increased in patients with complete or more-extensive PVT.6,1337,38 Systematic reviews have also confirmed that occlusive or complete PVT affects survival after liver transplantation.44,45 Furthermore, whether or not the physiological portal inflow is re-established in patients with complete PVT during transplantation surgery also influences the prognosis.46 However, in this Review, we do not repeat previous reports of work regarding the effect of PVT on the survival of liver transplantation recipients,44,45 but instead attempt to collect evidence regarding the effect of PVT on the prognosis of patients with cirrhosis who have had a prior variceal bleed (SupplementaryTable2online). An Italian, multicentre, prospective, cohort study identified PVT as an important predictor of 5day treatment failure for variceal bleeding (defined as un controlled bleeding, rebleeding, or death) in patients with liver cirrhosis.47 This conclusion is also in line with the results of a prospective study from 2012.48 Moreover, the presence of PVT might increase the incidence of early rebleeding,49,50 but the relationship between PVT and late occurrence of rebleeding is not unanimous.5154 Except for the results of two studies,52,55 most studies suggest that PVT substantially effects the short-term and long-term mortality of patients with cirrhosis and variceal bleeding.50,5356 Collectively, complete PVT could be considered a clinical marker for the severity of liver cirrhosis.45 The clinical significance of PVT in liver cirrhosis prompts clinicians to explore different treatment modal ities. However, recommendations from current practice guidelines and consensus statements are insufficient owing to limited data and poor-quality evidence. 57,58 Herein, we discuss the current evidence regarding the management of PVT in liver cirrhosis and attempt to propose an exploratory and preliminary algorithm.

Primary prophylaxis of PVT

Several large casecontrol studies have shown a high risk of venous thromboembolism (that is, deep vein thrombosis and pulmonary embolism) in patients with liver cirrhosis in spite of an elevated international normalized ratio (INR) and/or low platelet count.5963 In addition, experimental studies demonstrate the hypercoagulability of plasma from patients with cirrhosis.64,65 These findings potentially suggest the necessity of primary prevention of venous thromboembolism in patients with cirrhosis.66,67 A historical casecontrol study further confirms that the prophylactic use of anticoagulation for deep vein thrombosis is safe in hospitalized patients with cirrhosis who do not have active bleeding, and does not increase the
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a
100 90 80 Total events (%) 70 60 50 40 30 20 10 0 During the year of active treatment At the end of follow-up During the year of active treatment At the end of follow-up At the end of follow-up De novo portal vein thrombosis

New hepatic decompensation

Overall death

Enoxaparin group No enoxaparin group

Figure 1 | Benefits of anticoagulation in patients with cirrhosis. Improvement in a | the primary prophylaxis of portal vein thrombosis, b | prevention of hepatic decompensation, and c | survival.

incidence of gastrointestinal bleeding or overall death.68 However, a meta-analysis did not find any decreased risk of venous thromboembolism in patients with cirrhosis receiving thromboprophylaxis, although the use of heparin was not associated with an increased rate of bleeding.69 Certainly, these studies do not accurately identify the effect of thromboprophylaxis in patients with cirrhosis who are at an increased risk of developing venous thromboembolism. In 2012, an Italian, single-centre, randomized controlled trial (RCT) for the first time explored the benefit of enoxaparin in the primary prevention of PVT in patients with cirrhosis.70 During an enrolment period of 31months, 70 patients with cirrhosis and a ChildPugh score of 710 points and without ascites, portal hypertensive bleeding, high-risk varices or a platelet count of <10,000/mm3 were randomly allocated to enoxaparin (n=34) or non-anticoagulation (n=36) group. As for the primary end point, the incidence of PVT during the periods of active treatment and follow-up was significantly lower in patients in the enoxaparin group than in those not receiving the drug (P=0.025 for the period of active treatment, P=0.048 for the end of follow-up; Figure1a). Notably, no patients receiving enoxaparin developed PVT during the period of active treatment. In addition, no anticoagulant-related bleeding episode was recorded. As for the secondary end point, the probabilities of developing hepatic decompensation and death were significantly lower in the enoxaparin group than in the non-anticoagulation group (hepatic decompensation: P<0.0001 for the period of active treatment, P<0.0001 for the end of follow-up; death: P=0.02by log-rank test) (Figure1b,c). Cox regression multivariate analysis further confirmed enoxaparin treatment as the independent predictor for reducing the development of PVT, hepatic decompensation and death.70 As well as demonstrating the efficacy of anticoagulation for the primary prophylaxis of PVT, this trial reveals that anticoagulation can improve liver function and survival of patients with cirrhosis. Similarly, an earlier, Chinese, RCT also showed that total bilirubin and alanine aminotransferase levels were significantly decreased in patients with HBV-related liver cirrhosis
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receiving low molecular weight heparin (LMWH), but not in those who did not receive LMWH.71 Furthermore, a case report demonstrated that anticoagulation could improve the biochemical test results of liver function and portal hypertension complications in two sister patients who had both primary biliary cirrhosis and heterozygous factor V Leiden mutation.72 These impressive findings might be explained by the role of coagu lation disorders in the progression of liver disease.73 One or more thrombotic risk factors are frequently detected in patients with liver disease of various aetiologies (for example, 68% of patients with chronic viral hepatitis have one or more thrombotic risk factors, and 3746% of patients with NAFLD have one or more thrombotic risk factors).7476 More importantly, histological studies suggest a positive association between the presence of one or more thrombotic risk factors and more advanced hepatic fibrosis.7476 On the other hand, the rationale of anticoagulation is potentially supported by the contribution of intrahepatic microvascular occlusion to the extent of liver fibrosis and worsening of liver function.77 A UK phaseII multicentre study 78 (ISRCTN 12504151) is attempting to explore the role of warfarin anticoagulation for the reduction of liver fibrosis in patients transplanted for HCV-related diseases. However, before the prophylactic use of anticoagulants is recommended in patients with cirrhosis who do not have pre-existent PVT, several inherent limitations ofthe Italian RCT should be clearly recognized.79.80 First, the benefit of preventing the development of PVT and occurrence of hepatic decompensation disappear after the discontinuation of anticoagulants.80 Second, the investigators did not evaluate whether or not the occurrence of PVT influences liver function, hepatic decompensation, and survival. If not, primary prophylaxis of PVT might not be necessary. Third, the investigators analysed the data before the completion of patient enrolment.81 However, no interim analysis or early stopping rule was planned in their study. Accordingly, this conduct of looking at the data ahead of schedule introduces the possibility of falsely rejecting the null hypothesis (that is, a typeI error).82 The way to offset this problem is to reduce the P value for statisticalsignificance.83 If so, the
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Table 1 | Outcomes for untreated patients with liver cirrhosis and portal vein thrombosis. Study Type of study Target population No. patients
70 42 42 21 10

Diagnostic methods

Follow-up

Spontaneous recanalization or improvement

22 (31.4%) 20 (47.6%) 19 (45%) 1 (5%) 0 (0%)

No. thrombus extensions

3 (4.3%) 3 (7.2%) 20 (48%) 15 (71.4%) 6 (60%)

John et al. (2013)34 Maruyama etal. (2013)15 Luca et al. (2012)86 Senzolo et al. (2012)96 Francoz et al. (2005)13 De Santis etal. (2003)87

Single-centre, prospective Single-centre, retrospective Single-centre, retrospective Single-centre, prospective Single-centre, retrospective Single-centre

LC, awaiting LT, and PVT (occlusive n=32) LC with PVT LC with nonmalignant partial PVT LC with PVT (CTPV n=3, complete n=4, partial n=14) LC, awaiting LT, andpartial PVT LC with PVT but without HCC

Ultrasonography with CT orMRI Ultrasonography Multi-detector CT Dopplerultrasonography and CT Doppler ultrasonography and CT & MRI Ultrasonography

>6months in allpatients MeanSD: 65.239.6months Mean: 27months Mean: 22.53months N/A

21

N/A

7 (33%)

N/A

Abbreviations: CTPV, cavernous transformation of the portal vein; HCC, hepatocellular carcinoma; LC, liver cirrhosis; N/A, not available; PVT, portal vein thrombosis; SD, standard deviation.

difference in the development of PVT and improvement of liver function and overall survival might not be statistically significant between enoxaparin and control groups. Fourth, the multi variate analysis was performed using two different methods (logistic regression in two previous abstracts81,84 and Cox regression in the full-text 70). Importantly, the conclusions are remarkably different (the degree of portal hypertension as the significant factor for developing PVT in two previous abstracts,81,84 but enoxaparin treatment as the independent factor in the full-text 70). Indeed, these methodological issues should have been decided before the trial was started. Further confirmative studies are warranted owing to the fairly small number of patients and a large proportion of patients with alcoholic liver cirrhosis. 85 In addition, subgroup analyses are necessary to identify patients who should receive anticoagulants for the primary prevention of PVT in liver cirrhosis.

Thisstudy also showed that the diameter and flow volume in the largest collateral vessel at the time of the thrombus detection were considerably smaller in patients with spon taneous improvement than in those without. Accordingly, evaluating the characteristics of the largest collateral vessel might be helpful to identify candidates who are in no need of any treatment. Taken together, anticoagulation or other treatment modalities might be unnecessary in a proportion of patients with liver cirrhosis and partial PVT.88 However, before more solid evidence is provided, we recommend that treatment should be given to avoid the possibility of thrombus extension into the mesenteric veins and its related complications. Current treatment modalities for PVT mainly include anticoagulation, systemic and local thrombolysis, percutaneous portal vein recanalization, and transjugular intrahepatic po rtosystemic shunt (TIPS).57,8991

Treatment of PVT
Spontaneous improvements Traditionally, it is deemed unusual for PVT to spon tane ously recanalize. However, such a dogma should be re appraised owing to the emerging evidence that 3050% of patients with cirrhosis and partial PVT can achieve this spontaneous improvement.15,33,86,87 (Table1). In an Italian, single-centre, retrospective, observational study, 42 patients with liver cirrhosis and partial PVT were enrolled and untreated.86 Follow-up evaluations by multidetector CT demonstrated that PVT spon taneously decreased in 45% of patients (n=19). However, the investigators did not find any predictors associated with spontaneous portal vein recanalization. Similarly, a prospective cohort study from the USA also showed that a third of patients with cirrhosis and untreated PVT had a recanalization or spontaneous resolution of thrombus while awaiting liver transplantation.34 In addition, a Japanese, single-centre, retrospective study demonstrated that spontaneous improvement of PVT was observed in 47.6% of patients with cirrhosis. 15
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Anticoagulation Anticoagulants are readily available and inexpensive drugs widely used for the treatment of venous thromboembolic diseases. 92,93 However, clinicians usually hesitate to initiate anticoagulation therapy for PVT in patients with liver cirrhosis owing to their tendency to bleed.94 Evidence from several case series has shown the safety and efficacy of anticoagulation for the treatment of PVT in patients with liver cirrhosis (Table2), 13,95105 although it should be noted that the majority of published studies are retrospective and have small sample sizes. First, anti coagulation therapy is safe with a low rate of complication (Table3). Notably, all but three studies96,97,99 do not report any severe adverse effects, especially bleeding events, related to anticoagulation therapy. This finding might be explained by the strict selection of patients. Before anticoagulation is initiated, endoscopic variceal ligation should be performed to eradicate high-risk varices and to control active variceal bleeding. Indeed, oral anticoagulation might not increase the risk or severity of upper gastrointestinal bleeding in patients with PVT treated with endoscopic variceal
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Table 2 | Anticoagulation for the treatment of portal vein thrombosis in patients with liver cirrhosis Study
Takatori et al. (2013)104 Copaci etal. (2013)105 Werner etal (2013)99 Senzolo et al. (2012)96* Delgado et al. (2012)97

Type of study
Single-centre, prospective, comparative Single-centre, retrospective Single-centre, retrospective

Target population
LC with PVT

No. patients
28

Characteristics of PVT
N/A

Varices and variceal bleeding

N/A

Outcome
Effective (defined as >50% reduction of thrombus size in diameter) (n=26) Complete recanalization (n=5); partial recanalization (n=8); no response (n=8) Complete resolution (n=11); stability with partial resolution (n=12); no change (n=5); thrombus extension (n=0) Complete recanalization (n=12); partial response (n=9); unchanged (n=7); progression of thrombosis (n=5) Complete recanalization (n=25); partial response (n=8); norecanalization (n=22)

LC with PVT

21

Degree: complete (n=6); partial (n=15)

Bleeding from gastro-esophageal varices (n=11) Large esophageal varices (n=14); previous variceal bleeding (n=0) Varices: N/A; previous variceal bleeding (n=8) Varices: N/A; previous variceal bleeding (n=24)

LC, awaiting LT, and PVT LC with PVT

28

N/A

Single-centre, prospective

33

Degree: CTPV (n=2); complete (n=7); partial (n=24) Stage: <6months (n=19); 612months (n=6); >12months (n=8) Degree: CTPV (n=0); complete (n=14); partial (n=41) Stage: acute or sub-acute (n=31) Extension: PV or PV branches (n=25); PV+SV (n=2); PV+SMV (n=13); PV+SV+SMV (n=12); SMV (n=2); SV (n=1) Extension: MPV (n=3); PV branches (n=1); SV (n=1)

Multicentre, retrospective

LC with PVT

55

Maruyama et al. (2012)98

Single-centre, prospective

LC with PVT

Small varices (n=1); medium/large varices (n=4); red colour sign (n=5); previous variceal bleeding (n=5) N/A

Complete recanalization (n=5)

Bento etal. (2011)103 Amitrano et al. (2010)95

Single-centre, retrospective Single-centre, retrospective

LC with chronic PVT LC with PVT

28

Degree: complete (n=18); partial (n=10) Extension: MPV and/or PV branches (n=19); SMV (n=2); MPV+SMV/SV (n=7) Degree: CTPV (n=0); complete (n=5); partial (n=23) Extension: concomitant mesenteric involvement (n=15); SV (n=5) Degree: CTPV (n=0); complete (n=3); partial (n=21)

Complete recanalization (n=13); partial response (n=5) Complete recanalization (n=21); partial response (n=2); noresponse (n=3); progressioninto mesenteric vein (n=1) or CTPV (n=1) Repermeation (n=15 in partial PVT; n=0 in complete PVT); norepermeation (n=6 in partial PVT; n=3 in complete PVT) Complete recanalization (n=7 in partial PVT; n=1 in complete PVT); unchanged (n=10); thrombus extension (n=1)

28

Varices: N/A; previous variceal bleeding (n=9)

Francoz etal. (2008)100 Francoz etal. (2005)13

Single-centre, prospective

LC, awaiting LT, and PVT LC, awaiting LT, and PVT

24

N/A

Single-centre, retrospective

19

Degree: complete (n=1); partial (n=18) Stage: denovo thrombosis (n=6) Extension: MPV (n=8); RPV (n=9); LPV(n=1)||

Varices:gradeI(n=5); grade II (n=8); grade III (n=4); previous variceal bleeding (n=14)

*Results are partially published in the study by Senzolo etal.101 Anticoagulation was started and continued throughout the study period in 33/35 patients, anticoagulation was not indicated in 2/35 patients. Transjugular intrahepatic portosystemic shunt was performed in 7/35 patients. The data from the abstract by Bento et al. might be included into the study by Delgado et al.97 ||A total of 19 patients were included in this study, but information regarding extension of PVT could only be obtained for 18 patients. Abbreviations: CTPV, cavernous transformation of the portal vein; INR, international normalized ratio; LC, liver cirrhosis; LVP , left portal vein; LT, liver transplantation; MPV, main portal vein trunk; N/A, not available; PV, portal vein; PVT, portal vein thrombosis; RPV, right portal vein; SMV, superior mesenteric vein; SV, splenic vein.

ligation.106 In addition, oral anticoagulation might not affect the rate or delay of oesophageal variceal eradication.106 Second, anticoagulation therapy is effective with a high rate of portal vein recanalization (42100%) and a low rate ofthrombus extension (015%) (Figure2).13,95105 Notably, most of the patients included in the studies above presented with partial PVT, a small proportion of patients with complete PVT, and few patients with portal cavernoma, which might suggest the potentially limited efficacy of anticoagulants in patients with complete PVT or portalcavernoma. Compared with those not receiving any treatment, patients with cirrhosis and PVT who receive
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anticoagulation therapy have a markedly higher portal vein recanalization rate; in an Italian, prospective, casecontrol study, the rate of portal vein recanalization was 5% (1/21) in untreated patients, and 64% (21/33) in patients treated with anticoagulants.96 In a French retro spective study, the proportion of partial or complete recanalization was 42% (8/19) and 0% (0/10) in patients who received anticoagulation and those who did not, respectively.13 An Indian, randomized, blinded, controlled trial has been registered to further compare the portal vein recanalization rate in patients with cirrhosis and PVT who receive enoxaparin combined with acenocoumarol or placebo.107
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Table 3 | Type, dose, and complications of anticoagulants in patients with portal vein thrombosis Study
Takatori et al. (2013)
104

Type and dose of anticoagulants

Intravenous injection of danaparoid sodium (1,250 units twice daily for 14days) with or without antithrombin-III infusion (1,500 units on days 15 and 812) Sulodexidum 2tablets daily Warfarin dose started at 1mg daily by mouth and adjusted targeting an INR of 23 Therapeutic dose: nadroparin (95 anti-Xa U/kg body weight twice daily) Therapy initiated with LMWH or VKA; LMWH shifted to VKA. Target INR on VKA of 23 LMWH 75IU/kg daily LMWH (enoxaparin, therapeutic doses) for 15days, followed by LMWH (prophylactic doses, 40mg daily) oracenocoumarol for 6months LMWH (enoxaparin, 200U/kg daily) subcutaneously for6months N/A Nadroparin (5,700IU daily subcutaneously) followed byVKA (acenocoumarol), INR >2.0

Complications of anticoagulation
Severe adverse effects, including bleeding (n=0) Significant adverse effects, particularly bleeding (n=0) Vaginal bleeding (n=1); gastrointestinal bleeding (n=0) Epistaxis (n=1); haematuria (n=1); cerebral haemorrhage (n=1); HIT (n=1) Bleeding complications probably related to anticoagulation (n=5) Complications due to anticoagulation (n=0) Haemorrhagic complications (n=0); platelets counts below baseline values (n=0) Severe adverse effect of anticoagulants (n=0) Bleeding episode related to anticoagulants (n=0) Adverse effect of anticoagulants (n=0)

Copaci et al. (2013)105 Werner et al. (2013)99 Senzolo et al. (2012)96 Delgado et al. (2012)97 Maruyama et al. (2012)98 Bento et al. (2011)103

Amitrano et al. (2010)95 Francoz et al. (2008)100 Francoz et al. (2005)13

Abbreviations: HIT, heparin induced thrombocytopenia; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonist.

Three studies have confirmed that early initiation of anticoagulation after the diagnosis of PVT is positively associated with portal vein recanalization in univariate analysis.96,97,105 However, the optimal interval between the diagnosis of PVT and initiation of anticoagulation should be 6months according to the study by Senzolo,96 but 14days in the other two studies by Delgado97 and Copaci. 105 Absence of previous portal hypertensive bleeding is also identified as a significant factor associated with portal vein recanalization in the study by Senzolo,96 but not in the study by Delgado.97 Moreover, Francoz and colleagues suggest the limited usefulness of anticoagulation therapy for complete PVT in patients with liver cirrhosis.100 By contrast, Senzolo etal.96 did not find any difference in portal vein recanalization rates between partial and complete PVT. Therefore, additional well-designed studies should be performed to explore the role of anticoagulation in the treatment of complete PVT. LMWH and vitamin K antagonists (VKA) were the two main kinds of anticoagulants used in these studies. The reasons for use of LMWH, but not unfractionated heparin, are the reduced incidence of bleeding and h e parin-induced-thrombocytopenia associated with LMWH, and the once-daily dosing (unfractionated heparin must be taken three times daily). Anticoagulation-related bleeding complications were analysed in a multicentre study by Delgado and colleagues, 97 in which five bleeding events probably related to anticoagulation were reported. Importantly, all of these events occurred in patients treated with VKA alone, and no bleeding event was observed in any patients treated with LMWH alone or those with LMWH followed by VKA. Thus, the safety of LMWH might be
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superior to that of VKA.108 The main dis advantage of LMWH is the need for long-term sub cutaneous injections, which substantially reduces patients compliance in clinical practice; for example, in the study by Delgado, anticoagulation therapy was initiated with LMWH in 47 patients, and was later switched to VKA in 45% of these patients.97 By comparison, VKA can be administered orally. In addition, a target INR of 23 should be maintained to ensure adequate anticoagulation in patients treated with VKA. This recommendation primarily originates from the consensus that a low INR increases the risk of recurrent venous thromboembolism, and a high INR increases the risk of major bleeding.109,110 Owing to the difficulty of maintaining the INR in the therapeutic range throughout the course of treatment, the actual proportion of time spent within the INR target range (ITTR) might be more reasonable to assess the clinical outcome.111 Notably, regular laboratory monitoring of INR for dosage adjustment is necessary, but inconvenient. At present, direct thrombin inhibitors and inhibitors of activated factor X overcome these above-mentioned disadvantages of LMWH and VKA, because they dont require laboratory monitoring.112114 Certainly, the inadequacy of INR in monitoring the effect of VKA should be clarified. First, both pro-coagulant and anticoagulant factors are decreased in liver cirrhosis and the haemostatic balance is set at a lower point. However, INR does not account for the decrease in the procoagulant factors. Second, INR is often elevated above 2 in patients with end-stage liver diseases who receive no anticoagulation. Furthermore, evidence from Bechmann and Lisman has revealed the potential limitation of traditional anti-Xa assays in monitoring the effect of LMWH
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Proportion of portal vein recanalization after anticoagualtion (%) 100 90 80 70 60 50 40 30 20 10 0

No change or thrombus extension Complete or partial recanalization

Figure 2 | Outcome of anticoagulation for the treatment of portal vein thrombosis in patients with cirrhosis.

Percutaneous portal vein recanalization Scattered case reports show the safety and feasibility of percutaneous portal vein recanalization in patients with cirrhosis and PVT. Two Korean studies reported that three patients with liver cirrhosis developed complete obstruction of the portal trunk after living donor liver transplantation.123,124 Portal vein recanalization was successful in two patients with balloon angioplasty and/or stent placement after percutaneous transhepatic puncture of the intrahepatic portal vein, but failed in one patient after percutaneous trans-splenic puncture of the perihilar splenic vein. Another study from China showed that PVT was successfully recanalized by the placement of covered stents in five patients with cirrhosis.125 In addi tion, g astro-oesophageal variceal embolization can be performed during the procedure of portal vein recanalization.125 Importantly, procedure-related bleeding complications can be life-threatening, and patients should be kept under rigorous surveillance. TIPS Theoretically, the advantages of TIPS for the treatment of PVT in liver cirrhosis are to effectively recanalize the thrombosed portal vein using endovascular techniques (balloon angioplasty, stent-placement, thrombectomy, and thrombolysis), and to simultaneously resolve symptomatic portal hypertension and prevent the thrombus recurrence or extension by the creation of a porto systemic shunt.126,127 However, the technical difficulty of TIPS limits its widespread application, and the risks and benefits from creating a TIPS should be fully balanced. To date, >50 case reports or series from 16 countries have reported the outcome of about 500 patients with PVT treated with TIPS insertions.90 The main technical strategies include: one, TIPS placement followed by portal vein recanalization via the portosystemic shunt; two, portal vein recanalization via percutaneous approaches followed by TIPS placement; and three, TIPS insertion between a hepatic vein and a large collateral vessel without main portal vein recanalization (Figure3). The technical success rate for TIPS is relatively high in experienced hands (range: 67100%).9,128134 The TIPS procedure is feasible in the presence of portal cavernoma, but not in the setting of an obliterated main portal vein or fibrotic cord if no large collateral vessel is present.129 The combination of transhepatic, trans-splenic, and transmesenteric approaches to access the portal vein can facilitate the TIPS procedure.129,135 Notably, these percutaneous approaches are risky if the intrahepatic portal vein branch is thrombosed.136 The rate of portal vein recanalization after successful TIPS insertions is up to 80%.128 In addition, it should be noted that the degree of PVT is often more severe (>50% of lumen occupancy and complete occlusion) in patients treated with TIPS insertion than in those treated with anticoagulation. By summarizing the results of TIPS for the treatment of PVT in patients with cirrhosis,9,128131,133,134, the procedure-related complication rate varies from 017% (Supplementary Table3online). Fatal complications rarely occur. In two studies, two patients died of TIPS-related
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at (2 ori 01 et 3 a Co ) 104 l. pa (2 ci 01 et 3) 1 al W 05 . er ne (2 r e 0 t Se 13) 9 al. 9 nz o (2 lo e 0 t De 12) 9 al. 6 lg ad (2 o e 0 M ar 12 t al. )9 uy am 7 (2 a e 01 t 2 al Be ) 98 . (2 nto 0 e Am 11) 1t al. 03 itr an o (2 e 01 t 0 al Fr an ) 95 . co (2 z 00 et al Fr 8) 100 . an co z (2 e 00 t 5) 1 al. 3

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in patients with cirrhosis, probably because of the low anti-thrombinlevels caused by the reduced hepatic synthesis.115,116 In these settings, global coagulation assays, such as the thrombin generation test with or without thrombomodulin to evaluate the balance between procoagulant and anticoagulant factors, might be considered for monitoring the anticoagulation effect in patients with advanced livercirrhosis.117 Collectively, we suggest that these preliminary studies support the use of anticoagulants in patients with cirrhosis and PVT. However, many unresolved problems deserve further research,118 such as the choice of anticoagu lant, optimal dosage of anticoagulant, and c andidates for anticoagulation therapy.

Thrombolysis Evidence regarding the use of thrombolytics for the treatment of PVT in patients with cirrhosis is extremely scarce. In an Italian, single-centre, prospective study, nine patients with cirrhosis and recent PVT were treated with systemic thrombolysis (continuous intravenous infusion of recombinant tissue plasminogen activator) combined with anticoagulation.119 Follow-up evaluations by colour Doppler ultrasonography showed complete recanalization (n=4), partial recanalization (n=4), and no recanalization (n=1). No clinically significant adverse effects were observed in these patients. However, considering that systemic thrombolysis potentially induces a general and uncontrolled fibrinolysis state, it must be used with caution, especially in asymptomatic patients. Such treatment should be reserved for thrombus extension into the superior mesenteric vein and its secondary intestinal ischaemia only. In addition, thrombolytics can be indirectly infused into the superior mesenteric artery through the femoral or radical artery, or directly infused into the portal vein through the percutaneous transhepatic or transjugular intrahepatic approach.120122 Given the small sample size and heterogeneous population of each study, the safety and efficacy of thrombolysis needs to be further ascertained.

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a
Stent

RHV Stent LCV

LCV CTPV Trans-splenic catheterization

MPV GEV PSV

DSV

CTPV GEV

SMV

Figure 3 | Insertion of a TIPS into a large collateral vessel in a patient with complete portal vein obstruction. a | Direct portography. b | Schematic diagram. The images are from a 44-year-old patient with HBV-related cirrhosis with variceal rebleeding unresponsive to medical and endoscopic therapy. A previous surgical portosystemic shunt was occluded. Diffuse thrombosis within the portal venoussystem and cavernous transformation was found by imaging. Direct splenoportography via a percutaneous trans-splenic approach clearly showed the location of the targeted collateral vein to facilitate TIPS. A stent was successfully placed between a large collateral vein and right hepatic vein. The portosystemic pressure gradient was reduced from 23mmHg to 11mmHg. Abbreviations: CTPV,cavernous transformation of portal vein; DSV, distal splenic vein; GEV, gastroepiploic vein; LCV, large collateral vein around portal vein; MPV, main portal vein; PSV, ligated proximal splenic vein; RHV, right hepatic vein; SMV, superior mesenteric vein; TIPS, transjugular intrahepatic portosystemic shunt.

PVT in liver cirrhosis

No symptomatic portal hypertension

Symptomatic portal hypertension

<50% thrombus, no SMV extension

>50% thrombus, SMV extension

Controlled by ET, LVP and/or drug therapy

Uncontrolled by ET, LVP and/or drug therapy

The study by Perarnau showed that these postoperative complications were not significantly different between cirrhotic patients with or without PVT.130 The overall incidence of shunt dysfunction and hepatic encephalopathy after TIPS is 732% and 050%, respectively.90 The incidence of shunt dysfunction has been reduced by theuse of covered stents;137,138 in the study by Luca etal. the incidence of shunt dysfunction at 12 and 24months was 38% and 85% in the bare stent group, and 21% and 29% in the covered stent group.128 Timing of TIPS insertion in patients with cirrhosis and PVT is another major concern. In patients with cirrhosis without PVT, TIPS has been recommended as the secondline treatment option for recurrent variceal bleeding and refractory ascites.139 Whether or not these recommendations should be extrapolated to patients with cirrhosis and PVT deserves further exploration, because the presence of PVT potentially changes the natural history of liver cirrhosis. An RCT140 is being conducted at our centre to compare the incidence of variceal rebleeding, progression of PVT, and survival between cirrhotic patients with PVT who are receiving TIPS and those receiving endoscopic and drug therapy.141,142 A total of 50 patients wereestimated to be needed for this trial. All patientswere enrolled between June 4, 2011 and January 25, 2014, and are being followed-up. Unless this trial confirms the superiority of TIPS, conventional therapy will remain the first-line treatment of choice for the prevention of variceal re-bleeding in patients with cirrhosis and PVT.142 It might be reasonable that TIPS should be performed in the case of thrombus extension despite adequate anticoagulation96 However, if the thrombus has progressed to complete occlusion or even fibrotic cord, the technical difficulty of TIPS insertion will be substantially increased. Therefore, further studies are warranted to explore the time when a nticoagulation therapy should be switched to TIPS.

Wait and see Improved or stable Follow-up

Progressed

Anticoagulation (or RCT) Progressed TIPS, or symptomatic treatment if unavailable or failed

Potential algorithm for treatment of PVT

Given that the progression of PVT might be positively associated with treatment failure,52,100,129,143 the selection of treatment options is primarily dependent onthepresence of symptomatic portal hypertension and the stage anddegree of PVT. On the basis of this considerationand results of existing studies, we propose an exploratory andpreliminary algorithm for the management of PVT in liver cirrhosis (Figure4). However, we acknowledge that this algorithm is not evidence-based owing to the absence of RCTs, and many controversies regarding theindications of each treatment option still exist. First, patients with a ChildPugh score of 710, no ascites, no high-risk varices or previous history of variceal bleeding, and a platelet count >10,000/mm3 have been considered as the target population for a randomized controlled trial to explore the role of anticoagulation in the primary prophylaxis of PVT.70 However, whether or not patients with a ChildPugh score of 56, ascites, high-risk varices, and/or a platelet count <10,000/mm3 should receive the prophylactic use of anticoagulants remains uncertain. Furthermore, it seems logical that patients with cirrhosis and risk factors for PVT (SupplementaryTable1online;
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Figure 4 | Algorithm for the treatment of portal vein thrombosis in liver cirrhosis. Symptomatic portal hypertension mainly represents variceal bleeding and/or ascites. Abbreviations: ET, endoscopic therapy; LVP, large volume paracentesis; PVT, portal vein thrombosis; RCT, randomized controlled trial; SMV, superior mesenteric vein; TIPS, transjugular intrahepatic portosystemic shunt.

complications (one died of an intravascular disseminated coagulopathy after TIPS, and another died of intraabdominal bleeding caused by hepatic capsule perforation during the TIPS procedure).129,130 In the second case, the investigators clearly acknowledged that they did not fully recognize the risk of hepatic capsule perforation before the lethal event.129 However, with the improvement of TIPS techniques and peri-operative management, severe procedural complications might be gradually reduced. Shunt dysfunction and hepatic encephalopathy still represent the biggest clinical challenge for the management of patients with cirrhosis who are undergoing TIPS.
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especially those with portal flow velocity <15cm/s), should receive anticoagulation to prevent the occurrence of PVT. Second, spontaneous resolution of partial PVT is not infrequent in patients with cirrhosis, which questions the necessity of anticoagulation therapy in all patients with partial PVT. In addition, the portal vein recanalization rate is low in patients with complete PVT after anticoagulation therapy, which suggests the limited usefulness of anticoagulation in such patients.144 Thus, a therapeutic anticoagulation window seems to exist, but we cannot yet identify the candidates who should or shouldnt be treated with anticoagulation therapy. Third, not all patients with complete PVT achieve portal vein recanalization after TIPS insertion, especially if the thrombus is extended into the superior mesenteric vein. Further studies are necessary to identify the conditions in which TIPS insertion is clinically ineffective and inappropriate. Fourth, this proposed algorithm does not spell out a different strategy for complete versus partial PVT. However, a step-wise strategy might be considered that TIPS is used if anticoagulation is ineffective or inappropriate. To maximize the benefit of various treatment modalities, further studies should explore their respective target population. Fifth, the algorithm does not point out any approaches for the treatment of gastric varices in patients with cirrhosis and PVT, owing to the absence of relevant evidence. Notably, an RCT regarding repeated gastric variceal obtura tion with or without nonselective beta-blockers for the secondary prevention of gastric variceal bleeding demonstrated that PVT was an independent predictor of either re-bleeding or mortality.53 The discrepancy in the prognosis between cirrhotic patients with and without PVT suggests that the treatment modalities should be altered in patients with PVT.
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Conclusions
Collectively, an increasing significance of PVT in liver cirrhosis has been recognized. Anticoagulation can prevent the occurrence of PVT in liver cirrhosis, and might also improve liver function and survival. Several case series have demonstrated the efficacy and safety of anticoagulation therapy and TIPS for the management of PVT in liver cirrhosis. However, the current evidence regarding the management of PVT in liver cirrhosis is of relatively poor quality so that any firm conclusions cannot be achieved. Especially considering that the risk of various treatment modalities might potentially foster the development of severe iatrogenic complications, high-level evidence is warranted and urgently needed.
Review criteria
Several search strategies were employed to ensure a comprehensive overview in this field. First, the PubMed, EMBASE, and Cochrane library databases (from the database inception to November 12, 2012) were searched to identify all relevant papers regarding portal vein thrombosis in a recently published study (Qi, X. etal. PLoS ONE 8, e71838). Second, the PubMed, EMBASE, and ScienceDirect databases were re-searched with the search items of portal vein thrombosis and liver cirrhosis in October 2013. Third, further relevant papers were identified by searching the PubMed database with the search term of portal vein every day since 2012. Fourth, the reference lists of relevant papers, clinical trial registration websites, and AASLD and EASL conference abstracts were manually searched. The publication status (in press or formally published), type (full text or abstract), and language (English or others) were not restricted for the present review. However, owing to space limitations, not all relevant references could be cited.

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not only unblocking a pipe. J. Hepatol. 55, 945946 (2011). 137. Bureau, C. etal. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver Int. 27, 742747 (2007). 138. Yang, Z. etal. Patency and clinical outcomes oftransjugular intrahepatic portosystemic shuntwith polytetrafluoroethylene-covered stents versus bare stents: a meta-analysis. J.Gastroenterol. Hepatol. 25, 17181725 (2010). 139. Rssle, M. TIPS: 25years later. J. Hepatol. 59, 10811093 (2013). 140. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT01326949?term=NCT01326949&rank=1. 141. Qi, X. etal. Transjugular intrahepatic portosystemic shunt for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: study protocol for a randomised controlled trial. BMJ Open 3 (2013). 142. Qi, X. etal. Transjugular intrahepatic portosystemic shunt may be superior to conservative therapy for variceal rebleeding in cirrhotic patients with non-tumoral portal vein thrombosis: a hypothesis. Med. Sci. Monit. 18, HY37HY41 (2012). 143. Qi, X., Han, G. & Fan, D. Degree of portal veinthrombosis might be associated withrecanalization during anticoagulation. Clin.Gastroenterol. Hepatol. 10, 820 (2012). 144. Francoz, C., Valla, D. & Durand, F. Portal vein thrombosis, cirrhosis, and liver transplantation. J. Hepatol. 57, 203212 (2012). Acknowledgements We are indebted to the peer-reviewers elaborative review and constructive comments for the improvement of our manuscript, especially the adequacy and appropriateness of the treatment algorithm. In addition, we greatly appreciate the help of R. Xia (Educational Technology Center, Fourth Military Medical University, Xian, China) in drawing the original schematic graphs of Figure3b. Author contributions X.Q. researched data for the article, contributed to discussion of content, wrote and reviewed/edited the manuscript. D.F. and G.H. contributed to discussion of content and reviewing/editing the manuscript before submission. All authors contributed equally to this work. Supplementary information is linked to the online version of the paper at www.nature.com/nrgastro.

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