Outcome of Budd-Chiari Syndrome Patients Treated With Direct Oral Anticoagulants: An Austrian Multicenter Study.

BACKGROUND AND AIMS: Direct oral anticoagulants (DOACs) may simplify management of Budd-Chiari syndrome (BCS). Here, we report our experience with off-label use of DOACs for anticoagulation in BCS. METHODS: The safety of DOAC vs vitamin K antagonist treatment as well as associated clinical outcomes were retrospectively assessed in 47 BCS patients treated at 6 Austrian centers. RESULTS: Mean age at study inclusion was 37.9 ± 14.0 years and mean Model for End-Stage Liver Disease was 13.1 ± 5.1. Overall, 63.8% (n = 30) of patients had decompensated liver disease, and 87.2% (n = 41) showed clinical signs of portal hypertension. During a median follow-up of 82.5 (interquartile range, 43.1-121.8) months, 43 (91.5%) patients received anticoagulation alone or following interventional treatment, including 22 (46.8%) patients treated with DOACs (edoxaban: 10, apixaban: 4, rivaroxaban: 3, dabigatran: 3, more than one DOAC sequentially: 2) for a median of 24.4 (interquartile range, 5.7-35.1) months. While 72.7% (n = 16 of 22) of patients were switched from low-molecular-weight heparin (n = 12) or vitamin K antagonist (n = 4) to DOAC after disease stabilization or improvement, 27.3% (n = 6 of 22) of BCS patients were initially treated with DOAC. Complete response (European Association for the Study of the Liver criteria) was achieved or maintained in 14 (63.6%) of 22 patients, with ongoing response in 2 patients, while disease progressed in 6 patients (including 2 patients with hepatocellular carcinoma). Four major spontaneous bleedings (18.2%; incidence rate 8.8 per 100 patient-years; n = 2 upper gastrointestinal bleeding, n = 1 lower gastrointestinal bleeding, n = 1 hepatocellular carcinoma rupture), 7 minor bleedings, and 1 major procedure-related bleeding (4.5%; 2.2 per 100 patient-years) occurred during DOAC therapy. Overall transplant-free survival was 91.6% at 5 years. CONCLUSIONS: DOACs seem to be effective and safe for long-term anticoagulation in patients with BCS, but confirmation by larger prospective studies is needed.

Postreperfusion Syndrome Presenting as Posttransplant Portal Hypertension due to Prolonged Elevation of Pulmonary Vascular Resistance and the Role of Nitroglycerin in Diagnosis and Treatment: A Case Report of Budd-Chiari Syndrome.

Postreperfusion syndrome is one of the responsible mechanisms of portal hypertension in patients undergoing liver transplantation. And post-transplant portal hypertension causes graft dysfunction. Postreperfusion syndrome is characterized by a decrease in arterial pressure and cardiac output, and an increase in central venous pressure, pulmonary artery pressure, and pulmonary vascular resistance that occurs after the release of the portal vein clamp. Although early recovery from postreperfusion syndrome is desired, there is a little medication therapy such as the administration of calcium chloride, sodium bicarbonate, and beta-agonist for postreperfusion syndrome. We present a case of postreperfusion syndrome manifested as post-transplant portal hypertension and reversed after nitroglycerin administration. A 49-year-old Asian woman was scheduled for liver transplantation because of Budd-Chiari syndrome. After portal vein reperfusion, she experienced severe postreperfusion syndrome. Administration of ephedrine and calcium restored arterial pressure; however, pulmonary artery pressure, pulmonary vascular resistance, and central venous pressure elevations were sustained, causing right ventricular overload. This condition did not improve after hepatic artery reperfusion, and caused post-transplant portal hypertension. After nitroglycerin administration, pulmonary vascular resistance and central venous pressure decreased, mean arterial pressure increased, right heart contractility recovered, and portal hypertension disappeared. Hemodynamic improvement by nitroglycerin administration helped in diagnosing postreperfusion syndrome and avoiding unnecessary splenectomy. If portal vein pressure increases after liver transplantation, the change in hemodynamic parameters by nitroglycerin administration should be assessed, which will lead to accurate diagnosis and appropriate treatment. Furthermore, postreperfusion syndrome should be listed as a differential diagnosis of post-transplant portal hypertension.

From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms.

Thrombotic and hemorrhagic complications are prevalent in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis. Given the impact on morbidity and mortality, reducing the risk of thrombosis and/or hemorrhage is a major therapeutic goal. Historically, patients have been risk stratified on the basis of traditional factors, such as advanced age and thrombosis history. However, multiple factors contribute to the thrombotic tendency, including gender, mutational profile, inflammatory stress, and abnormal cell adhesion. Management includes cardiovascular risk reduction and use of antiplatelet therapy, depending on myeloproliferative neoplasm subtype and mutational status. Anticoagulation is a mainstay of therapy for those with venous thrombosis, but practice patterns remain heterogeneous. Cytoreduction is indicated for higher-risk patients, but efficacy may depend on the involved vascular bed. Management of special situations, such as unusual site thrombosis, bleeding, the perioperative period, and pregnancy, are especially challenging. In this article, risk factors and treatment strategies for myeloproliferative neoplasm thrombosis and bleeding, including special situations, are reviewed. Insights gained from recent studies may lead to the development of a more precise risk classification and tailored therapy.

Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. METHODS: This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. RESULTS: Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). CONCLUSIONS: Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Milestones in the discovery of Budd-Chiari syndrome.

In 1845, George Budd published a brief report regarding three patients who developed an obstruction of the hepatic veins. The condition has never been reported before, and was related to sepsis and alcoholism. Fifty-three years later, Hans Chiari postulated that syphilis was causing the obstruction of the hepatic veins, and enriched the debate with clinical and pathological correlations. Following the hypothesis on the 'phlebitis obliterans', several authors proposed other pathophysiological explanations including congenital causes, chronic trauma and exogenous toxins. RG Parker, in 1959, first recognized the relationship between obstruction of hepatic veins and thrombophilic conditions such as polycythaemia vera, pregnancy and hormonal therapy. Based on that, anticoagulant treatment was attempted, but with unsatisfactory outcome. We need to wait until the mid 1980s to see a widespread adoption of anticoagulants, with a consequent improvement of patients' survival. The fear of haemorrhagic events in patients with liver disease discouraged this therapeutic approach, and other surgical interventions (mainly port-systemic shunts) were conceived, but with high morbidity and mortality. The first liver transplantation in 1976 and the first trans-jugular intra-hepatic porto-systemic shunt in 1993 represented two major cornerstones in the management of Budd-Chiari syndrome (BCS). Such progresses allowed modifying the treatment of BCS until the modern concept of stepwise therapy. The present review thoroughly reviews the major landmarks in the discovery, treatment and clinical management of patients with BCS.

Infliximab in the treatment of Budd-Chiari syndrome in Behçet's disease.

Behçet's disease is a chronic autoinflammatory disorder that usually presents with recurrent oral and genital ulcers, uveitis, skin lesions and arthritis. Any organ, however, can be involved and in a subgroup of patients the large vascular lesions are the predominant feature (vasculo-Behçet disease). We report a case of a 27-yearold man with Behçet's disease who developed Budd-Chiari syndrome while on immunosuppressive therapy. Infliximab resulted in a rapid and total clinical remission. Literature data have shown that antitumor necrosis factor alpha (anti-TNF-α) agents including infliximab can suppress disease activity but there is no long-term experience on tapering and/or discontinuation of treatment under clinical remission. Our case supports the use of infliximab in vasculo-Behçet patients.

Gender differences in liver disease and the drug-dose gender gap.

Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases.

Approach to thrombosis at unusual sites: Splanchnic and cerebral vein thrombosis.

Splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT) are two manifestations of unusual site venous thromboembolism (VTE). SVT includes thrombosis in the portal, mesenteric or splenic veins, and the Budd-Chiari syndrome. CVT encompasses thrombosis of the dural venous sinuses and thrombosis of the cerebral veins. Unusual site VTE often represents a diagnostic and therapeutic challenge because of the heterogeneity in clinical presentation, the limited evidence available in the literature on the acute and long-term prognosis of these diseases, and the lack of large randomized controlled trials evaluating different treatment options. This narrative review describes the approach to patients with SVT or CVT by examining the diagnostic process, the assessment of potential risk factors and the appropriate anticoagulant treatment.

Early radiological intervention and haematology screening is associated with excellent outcomes in Budd-Chiari syndrome.

BACKGROUND: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder, resulting from thrombosis of the hepatic veins. Various treatments, including pharmacological, radiological and surgical interventions, have been used. AIM: To describe retrospectively our institution's experience with management of patients with BCS. METHODS: A retrospective study of all cases of primary Budd-Chiari syndrome presenting to our institution between January 2000 and August 2012 was performed. Patients with secondary Budd-Chiari syndrome due to malignancy or local mass compression were excluded. RESULTS: Between 2000 and 2012, 27 patients with primary BCS presented with a median Rotterdam score of 1.16 (range: 0.07-2.11). A total of 24 patients (89%) had at least one risk factor, with the commonest being myeloproliferative neoplasm (MPN), detected in 17 of 24 (71%) of the tested patients, including four patients with normal blood counts at diagnosis. All patients were anticoagulated with warfarin or low-molecular-weight heparin (LMWH). A total of 25 (92.6%) patients also had primary radiological interventions, consisting of transjugular intrahepatic portosystemic shunt (TIPS) in 18 (67%) patients and/or angioplasty/stenting in 11 (40%). A total of 14 patients developed TIPS stenoses, requiring a median of 1.5 (range: 1-14) revisions. No patient developed TIPS failure requiring alternative therapy. Two patients were lost to follow-up. At a median follow up of 59 months (range: 2-248 months), the overall survival was 96% at 1 year and 81% at 5 years, much greater than predicted by the Rotterdam score. No patients required liver transplantation. CONCLUSION: There is a high incidence of MPN in patients with primary BCS, including patients with normal peripheral blood counts at the time of diagnosis. Our approach of anticoagulation, aggressive and early radiological intervention aimed at rapid decompression of the congested liver resulted in excellent medium-term outcomes.

Spontaneous retroperitoneal hematoma in a patient under anticoagulant agents presenting as upper gastrointestinal bleeding.

We present the case of a 44-year-old woman with past history of repeated miscarriage and Budd-Chiari syndrome secondary to primary myelofibrosis. Because of this she was under treatment with oral anticoagulant agents. The patient was admitted in hospital as she presented with gastrointestinal bleeding (melena), asthenia and progressive anemia. In an initial upper endoscopy an extrinsic duodenal compression associated with an ulcer on the posterior face of the first portion of duodenum and upper duodenal knee was observed. In the following days a huge spontaneous retroperitoneal hematoma due to anticoagulation was diagnosed by computed tomography. This was treated with a percutaneous drainage and withdrawal of the antithrombotic drugs. The evolution of the patient was initially satisfactory but she suffered subclavian and jugular vein thrombosis, and reintroduction of anticoagulant agents at the lowest therapeutic doses was required.

[Vascular liver diseases]. / MALADIES VASCULAIRES DU FOIE.

Vascular liver diseases include a group of rare, even exceptional, diseases: portal vein thrombosis, obliterative portal venopathy and Budd-Chiari syndrome. Here we will discuss in detail the least rare, portal vein thrombosis, of which the main complication (when recanalization was not reached during the acute-phase) is esophageal variceal bleeding. However, a prothrombotic condition (including myeloproliferative syndrome) is often the cause of portal vein thrombosis. Thereby, in certain cases, a long-term anticoagulation is necessary despite the bleeding risk. Aside from these rare diseases, vascular and thrombotic involvement participate in the pathophysiology of cirrhosis, and anticoagulant treatment might be beneficial in some patients.

Splanchnic Vein Thrombosis: The State-of-the-Art on Anticoagulant Treatment.

Splanchnic vein thrombosis (SVT) is a rare type of venous thromboembolism occurring within the splanchnic venous system. Portal vein thrombosis is the most common presentation, while Budd-Chiari syndrome is the least common. Liver cirrhosis and abdominal solid cancer are the main local risk factors for SVT, whereas myeloproliferative neoplasms are the predominant systemic risk factors. Signs and symptoms of SVT are nonspecific and include abdominal pain, gastrointestinal bleeding, and ascites. Asymptomatic SVT is not uncommon, and the majority would be detected incidentally on routine abdominal imaging performed for the follow-up of liver diseases and tumors. The management of SVT aims to prevent thrombus progression, promote vessel recanalization, and prevent recurrent venous thromboembolism. Anticoagulation should be started early in order to increase the chances of vessel recanalization and reduce the risk of portal hypertension-related complications. Direct oral anticoagulants have been included in recent guidelines, as alternatives to vitamin K antagonists, after clinical stability has been reached; however, caution is required in patients with liver or kidney dysfunction. Treatment duration is based on the presence (or absence) and type (transient vs. permanent) of risk factors. This narrative review aims to summarize the latest evidence on SVT, with a particular focus on the anticoagulant treatment in special categories of patients (e.g., liver cirrhosis, solid cancer, myeloproliferative neoplasms, pancreatitis, incidentally detected SVT, Budd-Chiari syndrome, and chronic SVT).

A case of Budd-Chiari syndrome associated with alveolar echinococcosis.

Although alveolar echinococcosis (AE) can cause a serious disease with high mortality and morbidity similar to malign neoplasms. A 62-year-old woman admitted to a hospital located in Sivas, Turkey, with the complaints of fatigue and right upper abdominal pain. On contrast abdominal CT, a 54×70×45 mm sized cystic lesion was detected in the left lobe of the liver that was seen to extend to the posterior mediastinum and invade the diaphragm, esophagus, and pericardium. The cystic lesion was seen to be occluding the inferior vena cava and left hepatic vein at the level where the hepatic veins poured into the inferior vena cava. Bilateral pleural effusion was also detected. We discussed this secondary Budd-Chiari Syndrome (BCS) case, resulting from the AE occlusion of the left hepatic vein and inferior vena cava, in light of the information in literature.

CD55 Deficiency With Budd-Chiari Syndrome Treated by Liver Transplantation and Eculizumab.

We report the case of a male patient who had a history of early-onset protein-losing enteropathy, chronic diarrhea, and repeated thrombotic events since early childhood. He developed Budd-Chiari syndrome with consequent acute liver failure that required liver transplantation when he was 12 years old. The initial graft failed to function and he required retransplantation. Steroid-resistant rejection complicated the clinical course after the second transplant. Treatment with antithymocyte globulin stabilized graft function but abdominal symptoms and enteral protein loss persisted. The patient remained dependent on intravenous albumin and immunoglobulin. Extended work-up for thrombophilia was unremarkable. Flow cytometry analysis of the peripheral blood cells revealed an unexplained CD55 deficiency. By sequencing of CD55 and, later, exclusion of alternative rare diseases by whole-exome sequencing, we discovered a novel, likely pathogenic homozygous splice-site variant in CD55 c.578 + 5G>A, NM_000574.4, OMIM 125240. The staining of liver and colon biopsies revealed a lack of CD55 protein expression. After initiation of treatment with eculizumab, the patient achieved and has maintained a complete clinical remission throughout 56 months of follow-up. We recommend testing for CD55 deficiency in patients with protein-losing enteropathy. In addition, CD55 deficiency should be considered in the differential diagnosis of patients with Budd-Chiari syndrome in whom an underlying cause is uncertain.