Von Willebrand factor deficiency reduces liver fibrosis in mice

Abstract

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.

von Willebrand Disease, A Rare Cause of Massive Upper GI Bleeding: A Case Report

“…12 It is most common in elderly patients with type 2 or 3 VWD. 12,13 The presenting patient had history of gastrointestinal bleeding in the form of haematemesis and melena. During admission, the child was well thriving, moderately pale, multiple bruises over extremities, and she had no active bleeding from any site.…”

Chronic liver injury drives non‐traditional intrahepatic fibrin(ogen) crosslinking via tissue transglutaminase

“…Hepatic fibrosis was quantified with multiple complementary approaches as described previously . Staining of formalin‐fixed paraffin‐embedded liver sections to assess hepatic fibrosis was performed by the MSU Investigative Histopathology Laboratory, a division of Human Pathology.…”

“…Expression of α‐smooth muscle actin (αSMA) was detected by immunohistochemical labeling of paraffin‐embedded liver tissues as described previously . For quantification of the total area of PSR and αSMA staining, slides were first scanned by use of a Virtual Slide System VS110 (Olympus, Waltham, MA, USA) with a 20× objective, and sample images were then digitally captured from the entire left lateral lobe (Visiopharm, Broomfield, CO, USA) as described previously . The total area of positive staining was calculated in an unbiased fashion from 200 images per slide (captured with a 10× virtual objective) by use of a batch macro and color deconvolution tool in imagej fiji .…”

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

“…43 Depletion of VWF in in vivo mice models of acute liver injury resulted in decreased liver fibrosis. 44 In contrast, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), a VWF cleaving enzyme, is often decreased in cirrhosis. A study evaluating the effects of ADAMTS13 in a mouse model of nonalcoholic fatty liver disease demonstrated that ADAMTS-13 deficiency led to increased fibrosis and microthromboses in the liver.…”