Impairment of Annexin A2-Mediated Cell Surface Fibrinolysis in Nonalcoholic Steatohepatitis Cirrhosis with Portal Vein Thrombosis

Abstract The annexin A2 (A2) complex assembles tissue plasminogen activator and plasminogen on cell surfaces, resulting in efficient plasmin generation, and is markedly reduced in some patients with thrombophilia. Nonalcoholic steatosis (NASH) cirrhosis is the leading cause of cirrhosis in developed countries, and patients with NASH cirrhosis are at increased risk of portal vein thrombosis (PVT). However, the exact mechanism for PVT in NASH cirrhosis is poorly understood. Our objective was to determine the potential contribution of A2 to NASH thrombogenesis. Using semiquantitative immunoblot analysis, we examined A2 expression in peripheral blood mononuclear cell (PBMC) lysates from obese controls and NASH subjects with or without cirrhosis, and in human umbilical vein endothelial cells (HUVECs) treated with platelet-poor plasma (PPP) from patients with varying degrees of NASH cirrhosis. We also analyzed formalin-fixed liver tissue from patients with or without steatosis or NASH cirrhosis for A2 expression by immunofluorescence. Finally, we evaluated A2-dependent PBMC surface plasmin generation using a fluorogenic assay, and systemic fluid-phase fibrinolysis via plasmin-anti-antiplasmin (PAP) complex and D-dimer ELISAs. Total A2 expression in PBMC lysates did not differ among subjects with a range of severity of NASH cirrhosis versus obese controls. Src kinase-dependent tyrosine phosphorylation of A2, which is critical for its translocation to the cell surface, decreased in HUVECs after co-culture with NASH Child-Turcotte-Pugh C PPP despite no change in total A2. Immunofluorescence of liver tissue from patients with NASH cirrhosis who developed PVT revealed an 85% decrease in microvascular A2 expression compared to NASH cirrhosis patients without PVT. Similarly, PBMC surface plasmin generation decreased as NASH severity worsened, even though d-dimer and PAP complex level increased with worsening disease severity, indicating more activated systemic fibrinolysis in decompensated NASH cirrhosis. Despite preservation of total A2 and acceleration of systemic fibrinolysis in NASH, A2-mediated cell surface fibrinolysis decreased as NASH cirrhosis worsened. We show for the first time that impaired A2-related fibrinolysis may reflect inhibition of A2 phosphorylation by NASH plasma, and that reduction of A2 expression in the hepatic microvasculature may contribute to PVT in these subjects. Disclosures Desancho: Sanofi-Genzyme: Membership on an entity's Board of Directors or advisory committees.

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The Role of Portal Vein Thrombosis in the Clinical Course of Inflammatory Bowel Diseases: Report on Three Cases and Review of the Literature

Gastroenterology Research and Practice ◽

10.1155/2012/916428 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Emanuele Sinagra ◽

Emma Aragona ◽

Claudia Romano ◽

Simonetta Maisano ◽

Ambrogio Orlando ◽

...

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Inflammatory Bowel Diseases ◽

Vascular Complications ◽

Hepatic Abscess ◽

Vein Thrombosis ◽

Increased Risk ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Thromboembolism Events

Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic.

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Direct-Acting Oral Anticoagulants (DOACs) in Cirrhosis and Cirrhosis-Associated Portal Vein Thrombosis

Seminars in Liver Disease ◽

10.1055/s-0039-1679934 ◽

2019 ◽

Vol 39 (02) ◽

pp. 195-208 ◽

Cited By ~ 9

Author(s):

Ethan Weinberg ◽

Julia Palecki ◽

K. Reddy

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Treatment Guidelines ◽

Oral Anticoagulants ◽

Primary Prophylaxis ◽

Current Treatment ◽

Vein Thrombosis ◽

Increased Risk ◽

Direct Acting ◽

Direct Acting Oral Anticoagulants

AbstractDirect-acting oral anticoagulants (DOACs) have provided benefit in patients requiring anticoagulation for certain diseases by decreasing the burden of subcutaneous injections and the requirement for frequent monitoring through regular blood tests, to ensure adequacy of the therapeutic doses. Studies have demonstrated DOACs to be as safe, and in some instance safer, compared with traditional anticoagulants in the general population. However, the studies evaluating DOACs excluded patients with cirrhosis, a condition associated with an increased risk of developing portal vein thrombosis (PVT). Warfarin or low-molecular weight heparin are the standard-of-care treatment for acute PVT in cirrhosis, although there is enthusiasm in a paradigm shift switching to DOACs for the treatment of acute PVT in cirrhosis, particularly since the release of DOAC antidotes. This article reviews the current Food and Drug Administration-approved DOACs, hepatic metabolism of DOACs, pharmacokinetics of DOACs in patients with cirrhosis, safety of DOACs (including bleeding, hepatotoxicity, and pregnancy), current treatment guidelines for PVT in cirrhosis, and studies evaluating the use of DOACs in cirrhosis and for the treatment of PVT in cirrhosis. The potential use of DOACs for PVT primary prophylaxis in at-risk patients with cirrhosis and the possible antifibrotic effects of DOACs are also discussed.

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Value of Protein C and D-Dimer in Predicting Non Hepatocellular Carcinoma Portal Vein Thrombosis in Patients with Liver Cirrhosis

Afro-Egyptian Journal of Infectious and Endemic Diseases ◽

10.21608/aeji.2016.9669 ◽

2016 ◽

Vol 6 (9) ◽

pp. 68-74

Author(s):

Sahar El-Nemr ◽

Sherief Galal ◽

Hoda El-Hady ◽

Naglaa Khalifa

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Portal Vein ◽

Portal Vein Thrombosis ◽

Protein C ◽

Vein Thrombosis ◽

D Dimer

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A rare hepatic mass in an Italian resident

BMC Gastroenterology ◽

10.1186/s12876-020-01440-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Matteo Borro ◽

Giuseppe Murdaca ◽

Monica Greco ◽

Simone Negrini ◽

Maurizio Setti

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Liver Abscess ◽

Developed Countries ◽

Abscess Cavity ◽

Amoebic Liver Abscess ◽

X Rays ◽

Left Liver Lobe ◽

Vein Thrombosis ◽

Left Portal Vein

Abstract Background Amebiasis is a rare condition in developed countries but epidemiologically growing. Clinical manifestation may range from asymptomatic to invasive disease, amoebic liver abscess being the most common manifestation. We report a peculiar case of left hepatic amoebic liver abscess in a patient without a well-known source of infection and presenting with left portal vein thrombosis. Case presentation Patient, working as longshoreman, presented with complaints of remittent-intermittent fever lasting from 2 weeks. Physical examination was normal. Blood tests showed mild anemia, neutrophilic leukocytosis and elevated inflammation markers. Chest x-rays was normal. Abdominal ultrasound showed multiple hypoechoic liver masses. CT-scan of abdomen showed enlarged left liver lobe due to the presence of large abscess cavity along with thrombosis of left portal vein. The indirect hemagglutination test for the detection of antibodies to Entamoeba histolytica (Eh) was positive. Ultrasound-guided percutaneous drainage revealed “anchovy sauce” pus. Metronidazole and a follow up imaging at 3 months showed resolution of abscess cavity. Conclusion This case shows that amoebic liver abscess is possible even in first world country patients without travel history. Left sided abscess and portal vein thrombosis are rare and hence reported.

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Splenic and portal vein thrombosis following laparoscopic splenectomy in a pediatric patient with chronic myeloid leukemia

Sao Paulo Medical Journal ◽

10.1590/s1516-31802006000500008 ◽

2006 ◽

Vol 124 (5) ◽

pp. 275-277 ◽

Cited By ~ 2

Author(s):

Henrique Manoel Lederman ◽

Evan Fieldston

Keyword(s):

Magnetic Resonance ◽

Chronic Myeloid Leukemia ◽

Portal Vein ◽

Portal Vein Thrombosis ◽

Laparoscopic Splenectomy ◽

Myeloid Leukemia ◽

Rare Complication ◽

Marrow Transplant ◽

Vein Thrombosis ◽

Increased Risk

CONTEXT: Splenic or portal vein thrombosis is a rare complication following splenectomy. CASE REPORT: We report a case of splenic and portal venous thrombosis in a 10-year-old girl with chronic myeloid leukemia who underwent laparoscopic splenectomy prior to bone marrow transplant. Clinical suspicion of such thrombosis should be high for patients who have had splenectomy. The diagnosis is confirmed by Doppler ultrasound or contrast-enhanced computed tomography; magnetic resonance imaging magnetic resonance angiography or arteriography can also be used. Proposals for postoperative screening protocols are discussed. Patients with primary myeloproliferative disorders are at increased risk of portal vein thrombosis, independent of surgical intervention, perhaps due to platelet dysfunction resulting from abnormalities of pluripotent stem cells. Marked splenomegaly (with larger draining veins) is thought to increase the risk of thrombosis.

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Pregnancy in a Woman with Latent Myeloproliferative Neoplasm Induced Chronic Portal Vein Thrombosis, Portal Cavernoma, and Gastric Varices

Case Reports in Obstetrics and Gynecology ◽

10.1155/2019/5702983 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Andréanne Durivage ◽

Geneviève Le Templier ◽

Annabelle Cumyn ◽

Nadine Sauvé

Keyword(s):

Portal Hypertension ◽

Portal Vein ◽

Portal Vein Thrombosis ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Vascular Complications ◽

Breech Presentation ◽

Gastric Varices ◽

Vein Thrombosis ◽

Increased Risk

Extra-hepatic portal vein thrombosis (EHPVO) represents the obstruction of the portal vein outside the liver and is not related to chronic liver disease or neoplasia. In chronic EHPVO, collateral veins and portal hypertension develop, resulting in splenomegaly and variceal formation. Myeloproliferative neoplasms (MPN) are the most frequent acquired etiology of EHPVO. These conditions put pregnant women at increased risk of vascular complications, including venous thrombosis, occlusion of the placental circulation, and variceal bleeding. In this report, we present a 36-year-old pregnant woman with chronic, anticoagulated EHPVO secondary to latent MPN who developed severe intrauterine growth restriction and had cesarean section at 32+1 weeks for increased umbilical doppler resistance and breech presentation. The article will emphasize outcome and management of pregnancies complicated by chronic EHPVO, portal hypertension, and MPN.

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A Systematic Review and Meta-Analysis of Safety and Efficacy for Pre-Procedural Use of Thrombopoietin Receptor Agonists in Hepatic Cirrhosis Patients

Blood ◽

10.1182/blood-2019-132063 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1094-1094

Author(s):

Kunhwa Kim ◽

Faustine Ong ◽

Gabor Varadi ◽

Sorab Gupta ◽

Vinicius Machado Jorge

Keyword(s):

Liver Cirrhosis ◽

Portal Vein ◽

Portal Vein Thrombosis ◽

Risk Ratio ◽

Meta Analysis ◽

Statistical Significance ◽

P Value ◽

Receptor Agonists ◽

Vein Thrombosis ◽

Increased Risk

Introduction Thrombocytopenia is common in liver cirrhosis patients, which often complicates with patients' frequent issue with gastrointestinal bleeding and procedural needs. Based on biologic understanding of decreased thrombopoietin(TPO) level in liver cirrhosis patients, use of TPO agonists in liver cirrhosis have been actively studied. Over the period of time, new studies have come out about 2 FDA-approved TPO agonists, Avatrombopag and Lusutrombopag, for prophylaxis before procedure in liver cirrhosis patients with thrombocytopenia. In the past, there have raised concerns of increased risk of portal vein thrombosis and other thrombotic risks in other agents. In our study, we aimed to study the effectiveness and safety of TPO receptor agonists for pre-procedural use in patients with liver cirrhosis. Study design Study was conducted from August 2018 to July 2019. Previous studies were identified through database searching MEDLINE, CENTRAL, Clinicaltrial.gov and google search. Randomized clinical trials with active treatment arm with TPO receptor agonists in the use of liver cirrhosis patients, with intention of pre-procedural prophylaxis, and having placebo for direct comparisons were included. One of the major exclusions was TPO receptor agonists to increase platelet counts for anti-viral treatment in cirrhosis patients. 14 studies were identified. Studies were reviewed and eligibility was determined by two independent clinically trained researchers. 5 duplicated studies were removed, and in total of 7 studies were included for quantitative and qualitative analysis. Details of studies were collected by 2 independent researchers and compared. When there is a discrepancy, repeat review of the study was conducted. Studies were conducted or published from 2012 to 2018. 1 trial from Eltrombopag, 3 trials from Avatrombopag, and 3 trials from Lusutrombopag were included. Result Characteristics of included studies are summarized in table 1. Our studies found that 5.5(95% CI : 4.35-7.15) times higher risk ratio(RR) of reaching platelet target before procedure compared to placebo. Target platelet number goal was 50,000 to 80,000 depending on the study. Studies showed homogenous result with I-squared was 30.8% and q-statistics of p-value 0.193.(Figure 1) Subgroup analysis by FDA-approved medication of Avatrombopag and Lusutrombopag showed statistically significant higher risk ratio of 4.74(3.36-6.68) and of 5.52(3.65-8.34) each compared to placebo. Risk ratio for preventing platelet transfusion was not able to be calculated with heterogeneity of study with I-square higher than 90%. Lusutrombopag study showed significant benefits (RR 6.33, 95% CI 2.95-13.58) with heterogeneity inside the same medications, which might be explained with different doses in studies. No statistical significance in risk ratio in a study with Avatrombopag. Subgroup analysis limited to phase 3 studies showed risk ratio of preventing transfusion of 2.87(95% CI 2.15-3.82) but heterogeneity with q-statistics of p-value at 0.029. Relative risk for adverse event related to portal vein thrombosis was not statistically significant with RR of 0.99(95% CI : 0.35-2.85) in total of 1,229 patients.(Figure 2) Study result was homogenous result by I-square 0%, q-statistics of p-value 0.794. Other severe adverse events, major bleeding risk, overall thrombosis risk were not statistically significant. Only increased risk without statistical significance was reported in trail with Eltrombopag which was early terminated. Conclusion Our meta-analysis of pre-procedural use of TPO agonist in liver cirrhosis patients showed statistically significant benefit of reaching platelet count goal by 5.58 times with risk ratio, but no benefit of preventing transfusion. Compared to prior studies including use of TPO agonists for Interferon-Ribavirin treatment, meta-analysis limited to pre-procedural use did not show statistically significant increase in portal vein thrombosis. Serious adverse events including thrombosis events and bleeding risk were not statistically significant. Most studies described that portal-vein thrombosis events were often related to high platelet counts about 200,000 and longer use of TPO agonist. In current era with lesser use of Interferon and Ribavirin as an anti-viral therapy, TPO agonists use in setting of pre-procedure mostly with lower platelet targets can be safely used. Disclosures No relevant conflicts of interest to declare.

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Tu1565 - Nonselective Beta-Blockers are Associated with an Increased Risk of Portal Vein Thrombosis in Adults with Cirrhosis: A Case Control Study

Gastroenterology ◽

10.1016/s0016-5085(18)34115-5 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1253 ◽

Cited By ~ 1

Author(s):

Teresa Menadier ◽

Sa Ra Park ◽

Javelle A. Wynter ◽

Jonathan G. Stine ◽

Patrick G. Northup

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Case Control Study ◽

Beta Blockers ◽

Case Control ◽

Vein Thrombosis ◽

Increased Risk ◽

Control Study

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Exploring the Outcomes of Portal Vein Thrombosis in the Clinical Setting of Cirrhosis, Malignancy, and Intra-abdominal Infections with and without Anticoagulation: A Retrospective 5-Year Study

International Journal of Angiology ◽

10.1055/s-0037-1607049 ◽

2017 ◽

Vol 27 (04) ◽

pp. 208-212

Author(s):

Joanne Joseph ◽

Samuel Chew ◽

Julie George ◽

Tay Chin ◽

Ashish Sule

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Complete Resolution ◽

Vein Thrombosis ◽

Risk Of Bleeding ◽

Partial Resolution ◽

Outcomes Measures ◽

Increased Risk ◽

Abdominal Infections

AbstractThe aim of this study was to understand the differences in clinical outcomes in portal vein thrombosis (PVT) patients with cirrhosis, malignancy, and abdominal infections, with or without anticoagulation. This study was approved by ethics committee. Data were collected from 2011 to 2016. Patients were classified into three groups: PVT with cirrhosis, malignancy, and infections. Primary outcomes measures collected were clot resolution, bleeding, recurrence, and death. Frequency, means, and percentages were calculated. In total, 30 patients were analyzed in this study. Mean age was 60.8 years (range of 30–91 years). There were 19 (63.3%) males and 11 (36.7%) females with ethnicity: 21 (70.0%) Chinese, 2 (6.7%) Malay, 2 (6.7%) Indian, and 5 (16.7%) other race. Fifteen patients received anticoagulation and 15 did not receive anticoagulation. Of the 15 patients who received anticoagulation, there was complete resolution of thrombus in 5 (33.3%), partial resolution in 1 (6.7%), and no resolution in 9 (60.0%). Of these 15 patients, there was bleeding in 3 (20.0%), there was no recurrence in 9 (60.0%), and 3 (20.0%) died during the period of follow-up. Of the 15 patients who did not receive anticoagulation, there was complete resolution of thrombus in 2 (13.3%), partial resolution in 0 (0.0%), and no resolution in 13 (86.7%). Of these 15 patients, there was bleeding in 0 (0%), there was recurrence in 2 (13.3%), and 6 (40.0%) died during the period of follow-up. Anticoagulation is effective in PVT. It reduces mortality with lower rate of recurrence. However, it is associated with increased risk of bleeding.

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