Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population

Plompen, Elisabeth P.C.; Murad, Sarwa Darwish; Hansen, Bettina E.; Loth, Daan W.; Schouten, Jeoffrey N.L.; Taimr, Pavel; Hofman, Albert; Uitterlinden, André G.; Stricker, Bruno H. Ch.; Janssen, Harry L A; Leebeek, Frank W.G.

doi:10.1016/j.jhep.2015.07.026

Cited by 30 publications

(45 citation statements)

References 58 publications

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“…Increased plasma VWF levels are closely associated with poor outcome in patients with cirrhosis, and VWF levels are associated with fibrosis in the general population (La Mura et al , 2011; Ferlitsch et al , 2012; Maieron et al , 2014; Plompen et al , 2015; Kalambokis et al , 2016). Building on this clinical association, we provide the first experimental evidence that VWF directly contributes to liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies report that plasma levels of VWF (Reuken et al , 2015) are increased in patients with acute liver failure, as well as cirrhosis, with high levels predictive of poor outcome in this patient population (La Mura et al , 2011; Ferlitsch et al , 2012; Hugenholtz et al , 2013; Maieron et al , 2014; Kalambokis et al , 2016). Suggesting a functional connection, VWF levels are associated with the severity of liver fibrosis in the general population (Plompen et al , 2015). Thus, there is strong evidence in patients linking elevated VWF levels with both acute liver injury and with consequences of chronic liver disease such as cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

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Von Willebrand factor deficiency reduces liver fibrosis in mice

Joshi

Kopec

Ray

et al. 2017

Toxicology and Applied Pharmacology

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Liver diseases are associated with complex changes in the hemostatic system and elevated levels of the platelet-adhesive protein Von Willebrand factor (VWF) are reported in patients with acute and chronic liver damage. Although elevated levels of VWF are associated with fibrosis in the general population, the role of VWF in acute and chronic liver injury has not been examined in depth in experimental settings. We tested the hypothesis that VWF deficiency inhibits experimental liver injury and fibrosis. Wild-type (WT) and VWF-deficient mice were challenged with carbon tetrachloride (CCl4) and the impact of VWF deficiency on acute liver injury and chronic liver fibrosis was determined. VWF deficiency did not significantly affect acute CCl4-induced hepatocellular necrosis in mice. Chronic CCl4 challenge, twice weekly for 6 weeks, significantly increased hepatic stellate cell activation and collagen deposition in livers of WT mice. Interestingly, hepatic induction of several profibrogenic and stellate cell activation genes was attenuated in VWF-deficient mice. Moreover, birefringent sirius red staining (indicating type I and III collagens) and type I collagen immunofluorescence indicated a reduction in hepatic collagen deposition in CCl4-exposed VWF-deficient mice compared to CCl4-exposed WT mice. The results indicate that VWF deficiency attenuates chronic CCl4-induced liver fibrosis without affecting acute hepatocellular necrosis. The results are the first to demonstrate that VWF deficiency reduces the progression of liver fibrosis, suggesting a mechanistic role of elevated plasma VWF levels in cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Von Willebrand factor deficiency reduces liver fibrosis in mice

Joshi

Kopec

Ray

et al. 2017

Toxicology and Applied Pharmacology

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“…27 The G20210A mutation of the factor II gene is more common in patients with NCPVT (Table 1) than in the general Caucasian population ($2%). 50 By contrast, the role of factor V Leiden in patients with NCPVT and factor II gene mutation in patients with BCS appears to be negligible. The mechanism underlying this site specificity is unknown.…”

Section: Other Haematological Conditionsmentioning

confidence: 99%

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

Hernández‐Gea

Gottardi

Leebeek

et al. 2019

Journal of Hepatology

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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.

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“…Prothrombotic genetic risk factors such as FV Leiden or prothrombin G20210A mutations have been associated with an increased risk of clinically relevant liver fibrosis (assessed by transient elastography) in the general population [64].…”

Section: Potential Role Of Coagulation System On the Development Of Tmentioning

confidence: 99%

Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review

Ballestri¹,

Capitelli²,

Fontana³

et al. 2020

Adv Ther

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Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent and relevant healthcare issues. Direct oral anticoagulants (DOACs) are now the first-choice for anticoagulant treatment of these conditions displaying a better efficacy/safety profile than vitamin-K antagonists, mainly due to significantly reduced risk of major bleeding, especially of intracranial haemorrhage. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries showing a continuously growing prevalence. Nonalcoholic steatohepatitis (NASH), its evolutive form, will be the leading cause for liver transplantation by 2020. NAFLD is independently associated with an increased risk of abnormalities of cardiac structure and function, including cardiac rhythm disorders (mainly AF). Moreover, data suggest an increased risk of unprovoked VTE associated with NAFLD/NASH. Therefore, a growing number of patients with chronic liver disease (CLD) will be candidate for anticoagulant therapy in the near future. Cirrhosis of any etiology is characterized by an unstable thrombosis/bleeding haemostatic balance, making anticoagulant therapy particularly challenging in this condition. Given that patients with significant active liver disease and cirrhosis were excluded from all pivotal randomized controlled trials on DOACs, this comprehensive review aims at critically discussing real-world evidence, including the latest population studies, regarding the use of DOACs in patients with CLD/cirrhosis.

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Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population

Cited by 30 publications

References 58 publications

Von Willebrand factor deficiency reduces liver fibrosis in mice

Von Willebrand factor deficiency reduces liver fibrosis in mice

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

Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review

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