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Background & Aims: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e., TIPS) to prevent further decompensation and mortality., Methods: A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year., Results: Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death., Conclusion: The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients., Impact and Implications: Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis., Methods: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD., Results: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH., Conclusions: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE., Patients and Methods: This is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation., Results: 671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients., Conclusion: pTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission., Competing Interests: Competing interests: CB has received speaker fees from GORE and is a board member in Alfa Wassemran/Norgine. VH-G, AG, JB, AA, DT and FN have received speaker fees from GORE. J-CG-P has consultant fees from GORE, and Shionogi and Cook grants from GORE and Novartis. JT has speaking and/or consulting fees from GORE, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis and Martin Pharmaceuticals. RB has received speaker fees from GORE and Grifols, unrelated to the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis., Methods: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization., Results: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9)., Conclusion: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Lay Summary: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Competing Interests: Conflicts of interest Juan Carlos Garcia-Pagan has consultant fees for GORE, Shionogi and Cook grants from GORE and Novartis. Álvaro Giráldez has served as speaker for Gore. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date., Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality., Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not., Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB., Lay Summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt., Competing Interests: Conflict of interest Christophe Bureau has received speaker fees from GORE and is a board member of Alfawassemran/Norgine. Virginia Hernández - Gea, Álvaro Giráldez, Jaume Bosch, Agustin Albillos, Dominique Thabut, Michael Praktiknjo and Frederik Nevens have received speaker fees from GORE. Juan Carlos Garcia – Pagan has received consultant fees from GORE, Shionogi and Cook grants from GORE and Novartis. Jonel Trebicka has received speaking and/or consulting fees from GORE, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical, and Rafael Bañares has received speaker fees from GORE and Grifols, unrelated to the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Patients admitted with acute variceal bleeding (AVB) and Child-Pugh C score (CP-C) or Child-Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding, and mortality. A preemptive transjugular intrahepatic portosystemic shunt (p-TIPS) has been shown to improve survival in these patients, but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. This multicenter, international, observational study included 671 patients from 34 centers admitted for AVB and high risk of treatment failure. Patients were managed according to current guidelines, and use of drugs and endoscopic therapy (D+E) or p-TIPS was based on individual center policy. p-TIPS in the setting of AVB is associated with a lower mortality in CP-C patients compared with D+E (1 year mortality 22% vs. 47% in D+E group; P = 0.002). Mortality rate in CP-B+AB patients was low, and p-TIPS did not improve it. In CP-C and CP-B+AB patients, p-TIPS reduced treatment failure and rebleeding (1-year cumulative incidence function probability of remaining free of the composite endpoint: 92% vs. 74% in the D+E group; P = 0.017) and development of de novo or worsening of previous ascites without increasing rates of hepatic encephalopathy. Conclusion: p-TIPS must be the treatment of choice in CP-C patients with AVB. Because of the strong benefit in preventing further bleeding and ascites, p-TIPS could be a good treatment strategy for CP-B+AB patients., (© 2018 by the American Association for the Study of Liver Diseases.)

Background & Aims: Early placement of a transjugular intrahepatic portosystemic shunts (TIPS) is considered the treatment of choice for patients with acute variceal bleeding (AVB) and cirrhosis who have a high risk of death (Child-Pugh class B with active bleeding at endoscopy or Child-Pugh class C). It has been proposed that patients of Child-Pugh class B, even with active bleeding, should not be considered high risk. Alternative criteria have been proposed for identification of high-risk patients, such as Child-Pugh class C with plasma level of creatinine of 1 mg/dL or more (ChildC-C1) and a model for end-stage liver disease (MELD) score of 19 or more. We analyzed outcomes of a large cohort of patients with AVB who received the standard of care at different centers to validate these systems of risk stratification., Methods: We performed an observational study of 915 patients with liver cirrhosis and AVB who received standard treatment (drugs, antibiotics, and endoscopic ligation, with TIPS as the rescue treatment), over different time periods between 2006 and 2014 in Canada and Europe. All patients were followed until day 42 (week 6) after index AVB or death. Child-Pugh and MELD scores were calculated at time of hospital admission. The primary outcome was mortality 6 weeks after index AVB among patients who met the early TIPS criteria (Child-Pugh class B with active bleeding at endoscopy or Child-Pugh class C), MELD19 criteria (patients with MELD scores of 19 or more), and ChildC-C1 criteria., Results: Among 915 patients with AVB, 18% died within 6 weeks. Among the 523 patients who met the early TIPS criteria, 17% died within 6 weeks. All 3 rules discriminated patients at high risk of death from those with low risk: 28.3% of the patients classified as high risk by the early TIPS criteria died whereas only 7.0% of patients classified as low risk died; 46.0% of patients classified as high risk by the MELD19 criteria died vs 8.1% of patients classified as low risk; 51.9% of patients classified as high risk by the ChildC-C1 criteria died compared with 10.9% of patients classified as low risk. Mortality was significantly lower among patients with Child-Pugh class B (11.7%) than with Child-Pugh class C (35.6%) (P ≤ .001). Mortality was similar between patients with Child-Pugh class B cirrhosis with or without active bleeding (11.7%). Patients with Child-Pugh class A cirrhosis or MELD scores of 11 or less had low mortality (2%-4%), patients with Child-Pugh class B cirrhosis or MELD scores of 12 to 18 had intermediate mortality (10%-12%), and patients with Child-Pugh class C cirrhosis or MELD scores of 19 or more had high mortality (22%-46%)., Conclusions: Patients with Child-Pugh class B cirrhosis and AVB who receive standard therapy, regardless of the presence of active bleeding, have 3-fold lower mortality than patients with Child-Pugh C cirrhosis and might not need TIPS. Patients with Child-Pugh class C and/or MELD scores of 19 or more should be considered at high risk of death. These findings might help refine criteria for early TIPS., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN., Materials and Methods: A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed., Results: In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation. The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p=0.032). The thrombosis-free survival was lower in patients with (p=0.04) or developing later MPN and the JAK2 V617F mutation (p=0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups., Conclusions: MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients., (© 2013.)

Objectives: The mortality from esophageal variceal hemorrhage in liver cirrhosis patients remains approximately 15-20%. Predictors of short-term outcomes, such as the hepatic venous pressure gradient, are often unavailable in the acute setting. Clinical variables seem to have a similar predictive performance, but some variables including active bleeding during endoscopy have not been reevaluated after the utilization of endoscopic banding as endoscopic procedure. In addition, patients with severe liver failure are often excluded from clinical trials. The aim of this study was to prospectively reevaluate the risk factors affecting a 5-day failure after acute variceal bleeding in unselected cirrhotic patients, managed with the current standard treatment using vasoactive drugs, band ligation, and antibiotics., Methods: One hundred and eighty five patients with liver cirrhosis and variceal bleeding admitted from January 2010 to July 2011 were evaluated., Results: Hepatocellular carcinoma was present in 28.1% of cases and portal vein thrombosis (PVT) was present in 17.3% of cases. Band ligation was feasible in 92.4% of cases. Five-day failure occurred in 16.8% of cases; 12 patients (6.5%) experienced failure to control bleeding or early rebleeding, and 66.7% of patients died within 5 days. The overall 5-day mortality rate was 14.6%. By multivariate analysis, we determined that Child-Pugh class C, a white blood cell count over 10 × 10(9)/l, and the presence of PVT were the only independent predictors of the 5-day failure., Conclusions: The prognosis of a consistent group of liver cirrhosis patients with variceal bleeding remains poor. The current treatment is highly effective in controlling variceal bleeding, but mortality is related mainly to the severity of liver failure.

Objectives: Splanchnic vein thrombosis (SVT) affects the short-term prognosis of acute variceal bleeding in cirrhotic patients. This study evaluated whether SVT also affects the rebleeding rate of patients included in a program of secondary prophylaxis after variceal bleeding., Patients and Methods: A total of 387 patients with variceal bleeding were included from January 2001 to December 2010. Band ligation was carried out every 3-4 weeks. Follow-up included endoscopy at 1, 3, and every 6 months, Echo-Doppler, and biochemical examination every 6 months. From 2005, patients with SVT received anticoagulation with enoxaparin 200 UI/kg/day for at least 6 months. The therapy was started after variceal eradication., Results: SVT was diagnosed in 41 patients at variceal bleeding, in eight before and in 18 patients during the follow-up. Variceal eradication was achieved in 89.2 and 86.6% in no-SVT and SVT patients. Rebleeding occurred in 9.5 and 11.9% of no-SVT and SVT patients at 12 months. Varices relapsed more frequently in SVT than in no-SVT patients (25.4 vs. 14.67%, P=0.03). The rates of variceal rebleeding and relapse were similar in patients who received or did not receive anticoagulation, but mortality was significantly lower in patients who received anticoagulation., Conclusion: SVT favors the relapse of esophageal varices, but rebleeding can be effectively prevented by standard scheduled band ligations. Anticoagulation does not prevent variceal relapse. The improvement in the survival of patients treated with anticoagulation needs to be confirmed in future studies.

Background: Hypoxic hepatitis (HH) occurring after gastrointestinal bleeding in cirrhotic patients has been scarcely studied and is reported as a rare occurrence carrying a severe prognosis. The management of bleeding from esophageal varices (BEV) and similarly the prognosis has improved in the last decades., Goals: To evaluate retrospectively the incidence, clinical features, risk factors, and outcome of HH occurring in cirrhotic patients with BEV treated with the current standard therapy. Cirrhotics with BEV consecutively admitted from 2004 to 2008 were considered. Standard therapy consisted of intensive care support, somatostatin, antibiotics, and band ligation. HH was diagnosed if an elevation of alanine aminotransferase >10-fold from basal occurred., Results: Among 349 patients admitted for BEV, 24 (6.8%) had HH. Most patients were over 60 years old and had advanced liver disease; 41.7% had hepatocellular carcinoma, and 29.2% had portal vein thrombosis (PVT). Hypovolemic shock occurred in 16 (66.7%) patients, and failure to control initial bleeding in 12 (50%) patients. The 6-week mortality rate was 83.3% in HH compared with 24.6% in non-HH patients. Causes of death were massive bleeding in 4, hepatic encephalopathy in 7, and renal failure in 9. Binary logistic regression analysis showed that failure to control initial bleeding, diabetes, and PVT were factors independently associated with the development of HH., Conclusions: HH occurring in cirrhosis with gastrointestinal bleeding still carries an ominous prognosis. The severity of hemorrhage as expressed by failure to control bleeding contributes heavily to HH; in addition, the presence of PVT and diabetes further compromising the hepatic circulatory reserve may favor hypoxic damage.

Background: The JAK2 V617F mutation is an independent risk factor for MPN and SVT. Gender-related differences in MPN distribution have been reported and, recently, variability in the JAK2 V617F allele burden between sexes has been suggested. We wondered whether gender would modulate the role of the JAK2 V617F mutation as susceptibility risk factor for SVT., Materials and Methods: In 180 patients presenting with SVT, medical history was collected. The presence of the JAK2 V617F mutation and 46/1 haplotype was determined by polymerase chain reaction followed by TaqMan SNP genotyping assays., Results: Among patients with SVT, 43 (23.9%; 95%-CI: 18.2-30.7) carried the JAK2 V617F mutation. The JAK2 V617F mutation was found more frequently in women (29/95: 30.5%; 95%-CI: 22.1-40.4) than in men (14/85: 16.5%; 95%-CI: 10.0-25.9; OR: 2.2; 95%-CI: 1.1-4.5). The distribution of 46/1 haplotype frequencies did not differ significantly between men and women. In women carrying the rs12343867 CC genotype, the frequency observed for the occurrence of the V617F mutation was significantly higher than that observed in those not carrying (60.0% [95% CI: 31.2-83.3] vs. 26.8% [95% CI: 18.4-37.4]; OR: 4.1; 95%-CI: 1.1-14.9). In men, a similar prevalence was found among carriers of the rs12343867 CC genotype (16.7% [95% CI: 3.5-46.0]) and in non carriers (16.4% [95% CI: 9.3-27.2]). The V617F allele burden was unrelated to clinical characteristics and significantly higher in carriers of the rs12343867 CC genotype., Conclusions: Present findings suggest that, in patients presenting with SVT, the JAK2 V617F mutation is frequently found in women and, possibly by interacting with the 46/1 haplotype, may represent a gender-related susceptibility allele for SVT., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Unlabelled: The antiphospholipid syndrome (APS) has been associated with portal vein thrombosis (PVT). This study explored the contribution of antiphospholipid antibodies (aPL) to PVT in cirrhotic and noncirrhotic patients., Patients and Methods: A total of 50 patients with liver cirrhosis and PVT, 50 patients with liver cirrhosis without PVT, 50 consecutive PVT without liver cirrhosis, and 50 controls. aPL tests: lupus anticoagulants (LAs), immunoglobulin G (IgG) anti-cardiolipin antibodies (aCL), IgG anti-beta-2-glycoprotein-I (β(2)GPI), and IgG β( 2)GPI-complexed with oxidized low-density lipoprotein antibodies (ox-LDL)., Results: Lupus anticoagulants were negative in all patients. A titre of IgG aCL >40 IgG phospholipid units (GPL) was present in 2% of patients with liver cirrhosis and in none of the other groups. In all, 4% of patients with PVT without cirrhosis were positive for IgG β(2)GPI in the absence of any other positive aPL and labelled as primary APS., Conclusions: aPL play no role in PVT associated with liver cirrhosis but can be tested in idiopathic PVT.

Background: Treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis is not well established., Aim: We intended to assess the safety and efficacy of low molecular weight heparin (LMWH) to treat PVT in cirrhotic patients., Study: All 39 patients diagnosed with non-neoplastic PVT and cirrhosis from June 2005 to December 2006 were evaluated for anticoagulation therapy (AT). PVT was occludent in 15.4%, partial in 64.1%, and portal cavernoma presented in 20.5%. Twenty-eight patients received 200 U/kg/d of enoxaparin for at least 6 months. In 39.3% of patients PVT was an occasional finding, in 10.7% presented with acute abdominal pain, in 50% with bleeding from gastroesophageal varices. In this last group LMWH was started after endoscopic eradication of varices by band ligation., Results: Complete recanalization of portal vein occurred in 33.3%, partial recanalization in 50% and no response in 16.7% of patients. Further 12 patients who continued AT obtained complete recanalization at a median time of 11 months (range 7 to 17 mo). Overall, a complete response was obtained in 75% of patients. No significant side effects, particularly bleeding complications, were observed during the treatment., Conclusions: LMWH demonstrated safe and effective in the treatment of PVT in patients with liver cirrhosis.

Portal vein thrombosis (PVT) not associated with hepatocellular carcinoma is considered a frequent complication of liver cirrhosis but, unlike PVT occurring in non-cirrhotic patients, very few data are available on its natural history and management. The reduced portal blood flow velocity is the main determinant of PVT but, as in other venous thromboses, multiple factors local and systemic, inherited or acquired often can concur with. PVT has a variety of clinical presentations ranging from asymptomatic to life-threatening diseases like gastroesophageal bleeding or acute intestinal ischemia. It is usually diagnosed by Doppler ultrasound but computed tomography and magnetic resonance imaging are useful to study the extent of thrombosis and the involvement of the abdominal organs. The risk of bleeding mainly determined by the presence of gastroesophageal varices and clotting alterations causes concern for the treatment of PVT in cirrhotic patients. To date, anticoagulant therapy seems to be indicated only in patients awaiting liver transplantation. This review focuses on the definition of the subgroups of patients with cirrhosis that might benefit from treatment of PVT and examines the pros and cons of the available treatments in terms of efficacy, monitoring and safety, providing also perspectives for future studies.

Myeloproliferative diseases represent a major risk factor for Budd-Chiari syndrome. In 32 patients with Budd-Chiari syndrome, the JAK2 V617F mutation was detected, in heterozygous state, in 11 individuals (34.4%; 95% confidence interval: 18.6-53.2). Eight patients with (72.7%; 95% confidence interval: 39.0-94.0) and six without (28.6%; 95% confidence interval: 11.3-52.2) the JAK2 V617F mutation had a diagnosis of myeloproliferative diseases before or at the occurrence of the venous thrombotic event. In three patients carrying the JAK2 V617F mutation, a myeloproliferative disease was not detected. Determination of the JAK2 V617F mutation may be useful to recognize patients with Budd-Chiari syndrome with or at risk for the subsequent development of overt myeloproliferative diseases.

Objectives and Methods: Splanchnic vein thrombosis (SVT), not associated with cancer or liver cirrhosis, is a rare event and scanty data are available on its natural history, long-term prognosis, and treatment. In this study 121 SVT patients consecutively seen from January 1998 to December 2005 were included and 95 of them were followed up for a median time of 41 months. Screening for thrombophilic factors was performed in 104 patients. New thrombotic or bleeding episodes were registered and anticoagulant therapy was performed according to preestablished criteria., Results: SVT was an incidental finding in 34 (28.1%) patients; 34 (28.1%) presented with abdominal infarction; 39 (32.2%) had bowel ischemia or acute portal vein thrombosis; 14 (11.6%) had bleeding from portal hypertensive sources. Survival rates at 1, 3, and 7 yr were 95%, 93.3%, and 89.6%, respectively; 87.5% of deaths occurred at onset of SVT as complications of intestinal infarction. Patients with isolated portal vein thromboses had symptoms and intestinal infarction in 16/41 (39%) and 0/41 (0%) of the cases, respectively, whereas superior mesenteric vein thromboses, isolated or not, were associated with symptoms and intestinal infarction in 69/75 (92%) and 34/75 (45%), respectively. During the follow-up 14 (14.7%) suffered from 39 episodes of gastrointestinal bleeding with no deaths. A previous gastrointestinal bleed was associated with new hemorrhagic events during follow-up. New venous thrombotic episodes occurred in 10 of 95 patients (10.5%), of which 73% were in the splanchnic area. Seven out of these 10 patients had a chronic myeloproliferative disease (MPD) and none was on anticoagulation., Conclusions: Anticoagulant therapy was effective to obtain recanalization of acute SVT in 45.4% of patients and preserved patients from recurrent thrombosis when given lifelong.

Background: Myeloproliferative disorders (MPDs) represent a risk factor for thrombosis in the portal, mesenteric, and hepatic districts., Objective: We aimed to assess whether the Janus kinase 2 (JAK2) V617F mutation, an acquired mutation that occurs in MPD patients, is a risk factor for portal and mesenteric venous thrombosis (PMVT) independently of the presence of overt MPDs., Patients and Methods: The medical histories of 99 patients presenting with PMVT were obtained. The presence of the JAK2 V617F and VHL 598C > T mutations was determined by polymerase chain reaction followed by restriction enzyme analysis and direct cycle sequence analysis., Results: Over a 10-year period of observation, of the 99 patients presenting with PMVT, the JAK2 V617F mutation was detected in heterozygous state in 17 individuals [17.2%; 95% confidence interval (95% CI) 10.9-25.9]. None of the patients presenting with the JAK2 V617F mutation carried an inherited thrombophilic risk factor. Seven patients with (43.8%; 95% CI 19.8-70.1) and two without (2.4%; 95% CI 0.3-8.4) the JAK2 V617F mutation had a diagnosis of MPD at the occurrence of the venous thrombotic event. After a median follow-up of 41 months (range 3-114 months), three out of the 10 patients carrying the JAK2 V617F mutation were then diagnosed as having idiopathic myelofibrosis (n = 2) or polycythemia vera (n = 1), whereas in seven patients a MPD was not detected. Two of the 83 patients without the JAK2 V617F mutation went on to develop MPDs., Conclusions: Determination of the JAK2 V617F mutation may contribute to the search for genetic determinants of PMVT and may be useful to recognize patients who should be carefully observed for the subsequent development of overt MPDs.

The liver has a central role in the clotting process and an altered haemostasis is common in advanced liver disease. Nevertheless, recent studies have questioned the historical belief that impaired haemostasis in liver disease means an increased risk of bleeding. Coagulation and anticoagulation mechanisms are still balanced but are set at a lower level. Platelet function and number also play a role. The prevalence of thrombotic events is similar in both cirrhotic patients and in the general population but the cirrhotic patients have an increased risk for thrombosis in the splanchnic area. Portal blood flow stasis is the main underlying change favouring thrombosis even if other local, systemic, congenital and acquired factors are present. The onset of portal vein thrombosis strongly affects the prognosis of liver cirrhosis, worsening both portal hypertension and liver function. Some of the known risk factors for venous thrombosis--G20210A mutation of prothrombin, factor V Leiden, endoscopic treatment of esophageal varices and abdominal surgery--have a specific role in the development of splanchnic thrombosis in cirrhotic patients. The knowledge of the pathophysiological aspects of portal vein thrombosis and clotting alterations in liver disease will allow determination of the indication, duration and timing of anticoagulation therapy.

It was the aim of the present study to investigate factor II levels in liver cirrhosis (LC) patients with portal vein thrombosis (PVT) carrying the heterozygous G20210A prothrombin (PT) mutation. Plasma concentrations of factor II, VII, X, V, protein C (PC) total protein S (tPS) antithrombin (AT) and D-dimers (DD) were measured in 13 LC patients with PVT heterozygous for PT G20210A, in 13 LC patients with PVT without PT G20210A and in 13 LC controls matched by age, sex and Child-Pugh score. Crude factor II and factor II/DD ratio were highest in LC patients with PVT heterozygous for PT G20210A (p = 0.03 and p = 0.02 respectively). The factor II/PC ratio, expression of a procoagulant/anticoagulant imbalance was highest in the same group (p = 0.0008). Plasma factor II levels are elevated in LC patients heterozygous for PT G20210A and may favour PVT.

Budd-Chiari syndrome is a rare disease due to occlusion of the hepatic veins often presenting with acute liver failure. Common causes of Budd-Chiari syndrome are chronic myeloproliferative disorders, while acute leukemia has been associated with hepatic vein thrombosis in only two cases in the literature to date. We report a case of Budd-Chiari syndrome complicating a non-promyelocytic acute myelogenous leukemia leading to fulminant hepatic failure.

Background/aims: The role of model for end stage liver disease (MELD) and the presence of hepatocellular carcinoma (HCC) as risk factors of short-term mortality in patients bleeding from oesophageal varices were evaluated., Methods: From February 2002 to August 2003, 172 cirrhotic patients admitted for the first episode of bleeding from oesophageal varices received vasoactive and endoscopic therapy. Patients' survival was evaluated at 6 weeks and 3 months. The role of MELD and HCC as independent risk factors of mortality was evaluated., Results: In the 172 patients, the overall mortality was 21.5% at 6 weeks and 30.2% at 3 months. MELD score resulted a good predictor of mortality either at 6 weeks or 3 months. Fifty-four patients (31.3%) had HCC. The presence of advanced HCC was an independent risk factor of mortality at 3 months. Patients with MELD score>15 and advanced HCC had a significantly worse survival than patients with MELD

Background/aims: Portal vein thrombosis in patients with liver cirrhosis is usually associated to hepatocellular carcinoma. Clinical presentation of non-neoplastic portal vein thrombosis (PVT) in cirrhotic patients has not been specifically studied and risk factors of PVT in this group of patients are still poorly understood., Methods: We studied all patients with PVT and liver cirrhosis admitted to our Unit from January 1998 to December 2002. They were paired (by gender, age and Child-Pugh score) to a group of cirrhotic patients without PVT and screened for acquired and inherited thrombophilic risk factors. These factors together with the site of thrombosis and the severity of the liver disease were correlated to the clinical presentation of PVT., Results: Out of a total of 701 cirrhotic patients admitted to our hospital and routinely screened with Doppler ultrasound, 79 (11.2%) were found to have PVT. Of these, 34 (43%) were asymptomatic and 45 (57%) were symptomatic (31 presented with portal hypertensive bleed and 14 with abdominal pain, 10 of whom had intestinal infarction). Mesenteric vein involvement was never asymptomatic and lead to intestinal ischemia or infarction. Most patients were in class Child-Pugh B and C. Among thrombophilic risk factors studied only the mutation 20210 of the prothrombin gene resulted independently associated to PVT., Conclusions: Portal vein thrombosis may be completely asymptomatic in patients with liver cirrhosis; however in more than half of cases presents with life-threatening complications such as gastrointestinal haemorrhage and intestinal infarction. Cirrhotic patients with PVT usually have an advanced liver disease and the presence of the mutation 20210 of the prothrombin gene increases more than fivefold the risk of PVT.

The contribution of pro-thrombotic factors towards the development of arterial disease (AD) and splanchnic vein thrombosis (SVT) was retrospectively evaluated in 79 patients (39M, 40F, mean age 55 +/- 16 years) with myeloproliferative disorders (MPD) (essential thrombocythemia [n = 26], primary proliferative polycythemia [n = 27], and idiopathic myelofibrosis [n = 26]). Of these, 18 had AD and 17 SVT, the remaining 44 were non-thrombotic (NT). Plasma concentrations of natural anticoagulants, plasma homocysteine (HC), IgG anticardiolipin antibodies (aCL), and thrombophilic genotypes (methylenetetrahydrofolate reductase C(677)T, factor V Leiden, prothrombin G(20210)-->A) were determined. Isolated protein C deficiency was found in 23% of patients from the SVT group, in 5% from the AD group, in 6.8% from the NT group, and in 1% of historical controls (P = 0.0001). The prevalence of thrombophilic genotypes and that of the other natural anticoagulants did not differ across the groups. The proportion of patients with elevated plasma HC was 66% in the AD group, 27% in the non-thrombotic group, 12% in the SVT group and 4.5% in the control group (P < 0.0001). Patients with AD had higher plasma HC (24.4 +/- 23 micromol/L) than NT patients (12.3 +/- 7.7 micromol/L), SVT patients (9 +/- 4.9 micromol/L), and healthy controls (7.9 +/- 3 micromol/L) (P < 0.0001). In a logistic regression model lower protein C was independently associated with SVT, whereas elevated plasma HC was independently associated with AD. Measurement of plasma HC and protein C in MPD may identify patients more likely to suffer arterial disease and splanchnic vein thrombosis and who may require plasma HC lowering in the former case., (Copyright 2003 Wiley-Liss, Inc.)

Background and Study Aims: Portal vein thrombosis is a rare event in patients with liver cirrhosis in the absence of a related neoplasm. Endoscopic sclerotherapy of esophageal varices has been anecdotally associated with the development of portal vein thrombosis. We tested the hypothesis that genetic thrombophilia plays a role in the development of portal vein thrombosis in patients with liver cirrhosis undergoing endoscopic sclerotherapy., Patients and Methods: From June 1998 to December 1999, 61 consecutive patients underwent multiple sessions of endoscopic sclerotherapy for bleeding esophageal varices. Doppler ultrasound of the portal vein was performed before sclerotherapy and every 3 months thereafter. Antiphospholipid antibodies, factor V Leiden (FVL) mutation, prothrombin mutation G20210A (PTHRA20210) and mutation TT677 of methylenetetrahydrofolate reductase (MTHFR C677T) were evaluated in all patients., Results: Portal vein thrombosis developed in 16 % of the patients (10 of 61) after a mean follow-up period of 16 months. A genetic cause for thrombosis was found in 70 % of patients with liver cirrhosis who developed portal vein occlusion, but only in 8 % of patients without this complication., Conclusions: Endoscopic sclerotherapy of esophageal varices may represent a trigger factor for portal vein thrombosis in cirrhotic patients with genetic thrombophilia.

The liver plays a central role in the clotting process, and acute and chronic liver diseases are invariably associated with coagulation disorders due to multiple causes: decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation. The bleeding tendency accounts for increased risk of morbidity and mortality in patients with liver disease undergoing diagnostic or therapeutic invasive procedures. Peculiar coagulation disorders are prevalent in patients with acute fatty liver of pregnancy or undergoing liver transplantation. Emerging evidence shows that sepsis further impairs hemostasis in patients with liver cirrhosis bleeding from esophageal varices. Thrombotic events, even if rare in cirrhotic patients, occur mainly in the portal and mesenteric veins. The therapeutic approach to coagulative disorders is also discussed.

Myeloproliferative disorders are the main cause of Budd-Chiari syndrome in western countries. Inherited or acquired thrombophilic factors have also been implicated. A novel mutation of the prothrombin gene (G-->A20210) has only been described in a few cases of Budd-Chiari syndrome so far. Venous thrombosis is often the result of multiple concomitant thrombophilic factors. We report the case of a patient with essential thrombocythemia and Budd-Chiari syndrome in which heterozygosity for both factor V Leiden and the mutation G20210A of the prothrombin gene were identified.

Objectives: Mesenteric vein thrombosis is a rare but severe abdominal emergency, often requiring intestinal resection. New genetic prothrombotic defects such as factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype have been described in association with venous thrombosis. Our goal was to assess prevalence and clinical significance of genetic thrombophilia in mesenteric vein thrombosis., Methods: Twelve patients with acute mesenteric vein thrombosis were compared with 431 healthy people from the same geographical area. The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype were identified by polymerase chain reaction and restriction analysis., Results: A thrombophilic genotype was present in 9 patients (75%): the methylenetetrahydrofolate reductase TT677 genotype was present in 6 (50%), the factor V Leiden in 3 (25%), and the prothrombin transition G20210A in 3 (25%). Combined mutations were present in 4 (33%) patients., Conclusions: The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype are important predisposing factors in the pathogenesis of mesenteric vein thrombosis. Their identification bears strong clinical implications for management of patients with mesenteric vein thrombosis.

Background/aim: Aim of the present study is to assess, according to the guidelines of the Maastricht Consensus Conference, the appropriateness and diagnostic yield of upper gastrointestinal endoscopy in an open-access endoscopy system, in order to evaluate the diffusion of knowledge about Helicobacter pylori among different types of physicians., Methods: Patients undergoing endoscopy because of dyspeptic symptoms were prospectively considered in 21 endoscopy services of Campania during two different 1-week periods in 1998 and 2001. The following data were recorded: age, sex, symptoms, history of peptic ulcer with regard to previous endoscopic or radiographic examinations and treatment, endoscopic diagnosis, and H. pylori status. The indication for endoscopy was evaluated according to Maastricht guidelines and current medical knowledge., Results: In the two periods, 1998 and 2001, 706 and 520 patients were, respectively, considered. The two series were matched for demographic characteristics, symptoms, and endoscopic diagnosis. Endoscopy was considered not indicated in 398 patients (56.4%) in 1998 and in 265 patients (50.9%) in 2001 (p = NS). The majority of them, 288/398 (72.3%) in 1998 and 162/265 (61.1%) in 2001 (p = 0.001), had recently undergone endoscopy or radiology and empiric antisecretory treatment or eradication. They had been referred to endoscopy because of recurrence of symptoms or to assess healing. In 110 cases in 1998 (27.6%) and in 103 cases in 2001 (38.9%; p = 0.001) endoscopy was performed in dyspeptic patients younger than 45 years without alarm symptoms., Conclusions: 4 years after the Maastricht Conference, a large number of endoscopic examinations are not indicated and could be avoided following the Maastricht guidelines. In 2001, in comparison to 1998, a larger number of physicians are likely to investigate and treat correctly the H.-pylori-related diseases, but there are still some problems with the application of the 'test-and-treat policy'., (Copyright 2001 S. Karger AG, Basel)