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.

Current knowledge in pathophysiology and management of Budd-Chiari syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis.

Budd-Chiari syndrome and non-cirrhotic non-tumoral portal vein thrombosis are 2 rare disorders, with several similarities that are categorized under the term splanchnic vein thrombosis. Both disorders are frequently associated with an underlying prothrombotic disorder. They can cause severe portal hypertension and usually affect young patients, negatively influencing life expectancy when the diagnosis and treatment are not performed at an early stage. Yet, they have specific features that require individual consideration. The current review will focus on the available knowledge on pathophysiology, diagnosis and management of both entities.

Changes in arterial oxygenation after portal decompression in Budd-Chiari syndrome patients with hepatopulmonary syndrome.

OBJECTIVES: To evaluate the changes in arterial oxygenation after portal decompression in Budd-Chiari syndrome (BCS) patients with hepatopulmonary syndrome (HPS). METHODS: From June 2014 to June 2015, all patients with BCS who underwent balloon angioplasty or transjugular intrahepatic portosystemic shunt (TIPS) creation at our institution were eligible for inclusion in this study. Arterial blood gas analysis was performed with the patient in an upright position and breathing room air at 2-3 days and 1 and 3 months after the procedure. RESULTS: Eleven patients with HPS and 14 patients without HPS were included in this study. The procedure was technically successful in 24 patients. One patient with HPS had technically unsuccessful TIPS creation. Reobstruction or TIPS dysfunction was not detected in any patient within 3 months after the procedure. For patients with HPS, the alveolar-arterial oxygen gradient (A-aO2) remained comparable to baseline 2-3 days after the procedure (-3.2 ± 11.9 mmHg; p = .412), significantly improved 1 month after the procedure (-11.7 ± 6.4 mmHg; p < .001), and then returned to baseline 3 months after the procedure (-1.3 ± 12.5 mmHg; p = .757). For patients without HPS, the A-aO2 remained comparable to baseline at all three time points after the procedure (+1.4 ± 8.3 mmHg, +3.5 ± 8.1 mmHg, and +1.3 ± 8.2 mmHg; p = .543, p = .137, and p = .565). CONCLUSIONS: Arterial oxygenation transiently improves after portal decompression in BCS patients with HPS. KEY POINTS: • Intrapulmonary vascular dilation and hepatopulmonary syndrome are common in patients with Budd-Chiari syndrome. • Arterial oxygenation transiently improves after portal decompression in Budd-Chiari syndrome patients with hepatopulmonary syndrome.

A single-center retrospective study: Clinical features of different types of Budd-Chiari syndrome in Chinese patients in the Hubei area.

Background The characteristics and prevalence of Budd-Chiari syndrome in China remain unclear. This study aimed to analyze the clinical features of Budd-Chiari syndrome in Chinese patients in the Hubei area. Methods One-hundred and thirty patients with Budd-Chiari syndrome, admitted to Union Hospital from January 2002 to January 2011, were included in this retrospective study. Clinical features, laboratory data, imaging characteristics, and cumulative patency rates were analyzed. Results Of the 130 patients with Budd-Chiari syndrome, 77 were men (59.2%) and 53 women (40.8%). Budd-Chiari syndrome was more commonly associated with inferior vena cava block (56.9%, 74/130) than hepatic vein block (19.2%, 25/130) and combined inferior vena cava/hepatic vein block (23.9%, 31/130). The clinical features of Budd-Chiari syndrome varied based on the location of the obstruction. The incidence of bilirubin abnormality, elevated alkaline phosphatase, and γ-glutamyl peptide transferase levels was common in patients with Budd-Chiari syndrome. Liver injury was more severe in cases with combined inferior vena cava/hepatic vein block than in the other two types of Budd-Chiari syndrome. Color Doppler ultrasound imaging was better for the diagnosis of hepatic vein obstruction, while computed tomography and magnetic resonance imaging were superior in diagnosing inferior vena cava obstruction. The cumulative 1-, 5-, and 10-year patency rates were 97%, 69%, and 59%, respectively. Univariate analysis indicated that liver cirrhosis was an independent risk factor of recurrence. Conclusion The most prevalent type of Budd-Chiari syndrome is inferior vena cava obstruction in Chinese patients in the Hubei area. Different types of Budd-Chiari syndrome have diverse clinical and biochemical features, which may assist clinicians in diagnosing Budd-Chiari syndrome. Liver cirrhosis was found as an independent risk factor of recurrence.

Characteristics of hepatocellular carcinoma in Egyptian patients with primary Budd-Chiari syndrome.

BACKGROUND & AIM: Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction. This work aimed at analyzing characteristics and factors associated with development of hepatocellular carcinoma (HCC) in patients with primary BCS. METHODS: A total of 348 Egyptian BCS patients were included. They were presented to the Budd-Chiari Study Group of Ain Shams University Hospital. BCS was confirmed using abdominal Doppler US. Abdominal magnetic resonance imaging (MRI), MR venography and/or multislice computed tomography (CT) were performed to confirm all diagnoses and to assess vascular anatomy. Hepatic focal lesions detected during the study period (2005-2011) were evaluated using serum alpha foetoprotein (AFP) level, imaging features and histopathological examination. RESULTS: Diagnosis of HCC was confirmed in 15/348 patients (4.3%). Imaging studies showed that 60% had multiple hepatic focal lesions ranging from 2 to 6.3 cm in size. The median level of serum AFP in BCS with HCC was 300 ng/mL vs 11 ng/mL in those without HCC (P<.001). A cut-off level >24.5 ng/mL for serum AFP showed sensitivity 80%, specificity 97.9%, positive predictive value 93.18% and negative predictive value 99.1% for detection of HCC in BCS patients. Male gender, older age, cigarette smoking, serum AFP (>24.5 ng/mL) and shrunken liver by ultrasonography were independent factors associated with HCC development. CONCLUSION: Male gender, older age and cigarette smoking are independent risk factors for development of HCC in BCS. Serum AFP is a good screening test in BCS.

[Experience in treating portal thromboses in patients with chronic myeloproliferative diseases].

Patients with myeloproliferative diseases (MPD) are noted to be at high risk for portal thromboses. This problem gives rise to disability if it is untimely treated or resistant to therapy. The paper gives the experience of the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, in using antithrombin III in MPD patients (3 patients with primary myelofibrosis, 3 with essential thrombocythemia) and acute and subacute portal vein thromboses resistant to therapy with direct anticoagulants. In all 5 cases, the use of antithrombin III in combination with low-molecular-weight heparin showed a positive clinical effect as rapid relief of pain syndrome and comparatively early (3-week to 1.5-2-month) recanalization of thrombosed vessels. Three clinical cases are described in detail.

Acute Budd-Chiari syndrome associated with non-viral cryptogenic hepatocellular carcinoma: revisiting the 'chicken or the egg' theory.

Budd-Chiari syndrome is an eponym for "hepatic venous outflow tract obstruction". BCS left untreated has a high mortality rate. Diagnosis can be difficult because of the wide spectrum of presentation of the disease and the varying severity of liver damage. The onset of disease may be insidious, with a chronic, asymptomatic course, or also present on other occasions as an acute, life-threatening condition. In rare instances, BCS is associated with hepatocellular carcinoma (HCC), which may be both a cause and a consequence of BCS. Presented here is a case of acute, rapidly fatal severe BCS associated with HCC. The association between BCS and HCC in 'the chicken or the egg' analogy is revisited.

Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome.

In Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasma-based clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL, P < .001). Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 microg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329). A subgroup of cases displayed clearly elevated CLTs. A CLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT. Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS.

Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences.

In this review, we provide an overview of the risk factors for venous thromboembolism, focusing on hypercoagulability and hypofibrinolysis. In the first part of this review, we discuss the risk factors for commonly occurring venous thrombosis, in particular deep vein thrombosis and pulmonary embolism. In the second part, we provide an overview of the risk factors for the Budd-Chiari syndrome and portal vein thrombosis. These are rare, life-threatening forms of venous thromboembolism located in the splanchnic veins. There are many similarities in the risk profiles of patients with common venous thrombosis and splanchnic vein thrombosis. Inherited thrombophilia and hypofibrinolysis increase the risk of both common venous thrombosis and splanchnic vein thrombosis. However, there are also apparent differences. Myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria have a remarkably high frequency in patients with thrombosis at these unusual sites but are rarely seen in patients with common venous thrombosis. There are also clear differences in the underlying risk factors for Budd-Chiari syndrome and for portal vein thrombosis, suggesting site specificity of thrombosis even within the splanchnic venous system. These clear differences in underlying risk factors provide leads for further research on the site specificity of venous thrombosis and the development of thrombosis at these distinct sites.

Proteomic analysis reveals that apolipoprotein A1 levels are decreased in patients with Budd-Chiari syndrome.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare vascular liver disorder caused by thrombosis of the hepatic veins. In some patients, no known thrombophilic factor can be identified. This study aimed to identify novel factors that might play a role in thrombosis in BCS-patients by using a proteomic approach. METHODS: The abundance of plasma clot-bound proteins was compared between nine BCS-patients and nine controls by using two-dimensional difference gel electrophoresis. The protein with the most significant decrease in patients was identified by mass spectrometry. Plasma levels of this protein were measured and the results were validated in a large cohort of BCS-patients. RESULTS: A total of 26 protein spots significantly differed (p<0.001). The spot that decreased with the highest statistical significance in patients was identified by mass spectrometry as apolipoprotein A1 (apo A1). The mean level of apo A1 in the plasma of these BCS-patients (0.74 g/L) was also significantly lower than in controls (1.45 g/L, p=0.002). This finding was validated in a large cohort of 101 BCS-patients and 101 controls (0.97 g/L vs. 1.32 g/L, p<0.0001). There was no major correlation between plasma levels of apo A1 and various liver function tests. CONCLUSIONS: BCS-patients show decreased clot-bound protein abundance and plasma levels of apo A1. Decreased levels of apo A1 may play a role in the etiology of thrombosis in BCS-patients and possibly in other patients with venous thrombosis.

Superior mesenteric vein-caval-right atrium Y shunt for treatment of Budd-Chiari syndrome with obstruction to the inferior vena cava and the hepatic veins--a study of 62 patients.

OBJECTIVE: To explore the use of superior mesenteric vein-caval-right atrium Y shunt (SMV-CV-RA Y shunt) as a treatment for Budd-Chiari syndrome (B-CS) with a long stenotic segment of IVC ≥ 2 cm and complete obstruction of all major hepatic veins with no compensating hypertrophy of the small hepatic veins that drain from the liver into the inferior vena cava (IVC) (type IIIB mixed pattern of B-CS). METHODS: The clinical data of 101 consecutive patients with this mixed pattern of B-CS treated by surgery using artificial vascular grafts were retrospectively studied: 62 patients were treated with SMV-CV-RA Y shunt compared with historical groups of 26 patients treated with splenic vein-caval shunt and 13 patients with superior mesenteric vein-caval shunt. RESULTS: On follow-up, the clinical results assessed to be good/improved for the groups of patients who received SMV-CV-RA Y shunt, splenic vein-caval shunt, and superior mesenteric vein-caval shunt were 57/62 (91.9%), 11/26 (42.3%), and 5/13 (38.5%), respectively (P < 0.05). The patency rates of the artificial vascular grafts were 95.2% (59/62), 69.2% (18/26), and 38.4% (5/13), respectively (P > 0.05). Compared with patients who received splenic vein-caval shunt and superior mesenteric vein-caval shunt, the platelet count of the 62 patients who received SMV-CV-RA Y shunt increased significantly 1 mo after surgery (P < 0.05). The portal venous pressure of the patients with SMV-CV-RA Y shunt decreased significantly than before shunting (P < 0.05), although this pressure decrease in patients who received splenic vein-caval shunt and superior mesenteric vein-caval shunt were insignificant (P > 0.05). CONCLUSION: Compared with the historical splenic vein-caval shunt and superior mesenteric vein-caval shunt, SMV-CV-RA Y shunt more satisfactorily improved clinical results of patients with a special mixed pattern of B-CS, and in reducing the portal and inferior vena venous pressures. The shunt could reverse hypersplenism. The splenic vein-caval shunt and superior mesenteric vein-caval shunt were not useful for this type of patients.

Anticoagulation with warfarin for Budd-Chiari syndrome with chronic inferior vena cava thrombosis: an initial clinical experience.

BACKGROUND: To evaluate the initial clinical safety and feasibility of anticoagulation using warfarin for Budd-Chiari syndrome (BCS) with chronic inferior vena cava (IVC) thrombosis. METHODS: Between October 2005 and June 2009, a total of 16 consecutive BCS patients with chronic IVC thrombosis were treated with warfarin. Warfarin was administered orally at 2.5 mg/d for approximately 3-12 months. Transluminal balloon dilatation of the IVC with a 30-mm balloon catheter was applied for the patients with complete resolution of the thrombus. Data relating to the technical success, angiographic results, complications, and final clinical outcome were collected retrospectively and follow-ups were performed at 1, 3, 6, and 12 months after the stent placement, and annually thereafter. RESULTS: Warfarin was successfully used for anticoagulation in all patients without any complications. Patients were followed up as outpatients for 6.43 ± 2.19 months, and in 14 cases, complete disappearance of the thrombosis was achieved with successful treatment by balloon dilation. In two patients with partial resolution of the thrombosis, Z-stent placement was initiated to compress the thrombus to prevent migration of the thrombosis, followed by dilation of the IVC. During the follow-up for 20.94 ± 10.31 months after the procedure, all the IVC remained patent without complications or pulmonary embolus, and all patients were alive with resolution of symptoms at the time of this study. CONCLUSIONS: The use of warfarin for anticoagulation proved to be simple, safe, and feasible for BCS with chronic IVC thrombosis.

[Budd-Chiari syndrome--case presentation]. / Sindrom Budd-Chiari--prezentare de caz.

The Budd-Chiari syndrome represents the obstruction of hepatic veins usually due to a hepatocarcinoma. We present the case of a 68 year old patient, in medical evidence for ten years with a Child A ethanolic liver cirrhosis, who was admitted in emergency for hematemesis and melena. Clinical examination and the laboratory findings at the admittance revealed signs of decompensated cirrhosis and severe anemia. Ultrasound examination showed a cirrhotic liver with portal hypertension signs and a multinodular mass in the right lobe of the liver with portal, biliary and right hepatic vein invasions extended to inferior caval vein. In upper digestive endoscopy stage IV esophageal varices were evidenced with signs of recent bleeding (sclerotherapy was performed) along with gastric varices and portal gastropathy. The particularity of the case consists in the invasive complications of the hepatocarcinoma regarding hepatic and inferior caval veins wich defines the Budd-Chiari syndrome (posthepatic portal hypertension added to the intrahepatic and prehepatic ones), the invasions of the biliary tract and portal vein being more frequent.

Retrospective comparative study of efficacy, safety and outcome of percutaneous intervention for Budd-Chiari syndrome patients with bilirubin less than 3 and 3-6 mg/dl.

OBJECTIVE: Comparing the efficacy, safety and outcome of percutaneous intrervention for Budd-Chiari Syndrome (BCS) patients with bilirubin less than 3 and 3-6 mg dl-1. METHODS AND MATERIALS: 188 BCS patients having serum bilirubin ≤6 mg dl-1 and underwent percutaneous interventions were divided into two groups based on bilirubin level: 151 patients having bilirubin <3 mg dl-1 were included in Group 1; and 37 patients having bilirubin 3-6 mg dl-1 were included in Group 2. Both group were compare for technical success (successful recanalization of hepatic venous stenosis or creation of portocaval shunt with post-procedure gradient ≤5 mm of Hg), Safety (procedure-related mortality/morbidity or patient required transplantation) and outcome (resolution of clinical symptoms and survival). RESULTS: Technical success was 94.7% in Group 1-89.1% in Group 2 with overall success rate was 93.6%. No significant differences observed between the two groups in regards to procedure related complication. Overall transplant-free survival at 1 and 5 years after intervention in both groups was 96.3 and 91.2% respectively. 1-year and 5-year survivals in Group 1 was 96.7%, and 93.1%, whereas Group 2 was 94.6 and 90.1% with no statically significantly difference between the two groups (p = 0.59). Percutaneous intervention results are good in patients having bilirubin up to 6 mg dl-1, i.e. mild to moderate liver dysfunctions. CONCLUSION: Technical success, survival and outcome of percutaneous intervention in BCS patients having serum bilirubin 3-6 mg dl-1 was comparable to patients having bilirubin level <3 mg dl-1. ADVANCES IN KNOWLEDGE: Percutaneous intervention treatment is suitable for treatment for symptomatic BCS patients having bilirubin up to 6 mg dl-1.

Association of Budd-Chiari syndrome and celiac disease.

BACKGROUND AND AIMS: An association between Budd-Chiari syndrome (BCS) and celiac disease (CD) is uncommon. The aims of our study were to investigate the etiology of BCS and to search for a particular HLA Ag pattern among patients. PATIENTS AND METHODS: BCS diagnosis was based on Doppler ultrasound and CD diagnosis on duodenal biopsy, transglutaminase (TGAb) and gliadin antibodies (GAb). Patients were screened for prothrombotic disorders and seven had a PCR-SSO test for HLA genotypes. Patients were treated with anticoagulants and gluten-free diet. RESULTS: Nine patients were included; mean age 27 years (20-42); sex ratio (F/M) 2; mean follow-up duration 31 months (6-54). All patients had endoscopic and histological features of CD. GAb/TGAb were found in 78 % (n=7). Ag HLA found were HLA DQß1(*)02 (n=6) and DQß1(*)03 (n=3). Prothrombotic conditions identified were latent myeloproliferative disorder (n=1), protein C deficiency (n=1), probable factor V Leiden (n=1) and oral contraceptive use (n=1). No prothrombotic state could be identified in the five other patients. CONCLUSION: The BCS-CD association is relatively frequent in our country. Underlying prothrombotic conditions were absent in more than 50 % of cases, suggesting CD plays a role in the occurrence of thrombosis. HLA alleles found are strongly associated with CD, without any particular pattern for the BCS-CD association.

A Preclinical Porcine Model of Portal Vein Thrombosis in Liver Cirrhosis.

BACKGROUND: This study aimed at presenting a novel method of developing a porcine model of portal vein thrombosis (PVT) in cirrhosis by intravenous administration of thrombin and insertion of a fibered coil. We further investigated changes of biochemical parameters, coagulation, and proinflammatory cytokine expression in the cirrhosis-PVT group. METHODS: Twelve male pigs were randomized into the control group (n = 3) and cirrhosis group (n = 9). In cirrhotic pigs, three were randomly selected to establish PVT by ultrasound-guided percutaneous puncture of the main portal vein (MPV) followed by intravenous thrombin administration and fibered coil insertion. Thrombosis in the MPV was detected by abdominal enhanced computer tomography (CT). The changes of hepatic function, coagulation system, and inflammation cytokines were compared among normal, cirrhosis, and cirrhosis with PVT groups. RESULTS: As manifested by the presence of a filling defect in MPV on portal venous-phase CT angiography, fibrin thrombi were formed in the MPV in cirrhotic pigs within one week and persisted for four weeks. Five weeks after surgery, abnormal liver functions occurred in association with PVT formation in cirrhosis. Both coagulation and thromboelastography parameters showed that cirrhosis-PVT pigs exhibited a procoagulant state through hyperfunction of platelets and clotting factors. Interleukin 6 (IL-6) as a potential inflammatory marker stimulated PVT-mediated inflammation activation in cirrhosis. CONCLUSIONS: Our study provides in vivo evidence that intravenous injection of a coil and thrombin into MPV under interventional guided devices enables a feasible method in thrombus creation. Further exploration and validation of large-sample cases are required to characterize utilities of this model.