Coagulation and fibrosis in chronic liver disease

Abstract

In the hepatic tissue repair mechanism, hepatic stellate cells (HSCs) are recruited at the site of injury and their changes reflect paracrine stimulation by all neighbouring cell types, including sinusoidal endothelial cells, Kupffer cells, hepatocytes, platelets and leucocytes. Thrombin converts circulating fibrinogen to fibrin, promotes platelet aggregation, is a potent activator of endothelial cells, acts as a chemoattractant for inflammatory cells and is a mitogen and chemoattractant for fibroblasts and vascular smooth muscle cells. Most of the cellular effects elicited by thrombin are mediated via a family of widely expressed G-protein-coupled receptors termed protease activated receptors (PARs). All known members of the PAR family stimulate cell proliferation/activation in a rat HSC line. Thrombin receptors are constitutively expressed in the liver, and their expression increases in parallel with the severity and/or the duration of liver disease. In human studies, thrombotic risk factors were found to be independently associated with the extent of fibrosis; severity of hepatitis C virus (HCV)-associated liver disease appears to be less in patients with haemophilia when compared with those with HCV alone. Several studies, based mostly on rat models, demonstrate that anticoagulants or antiplatelet agents prevent hepatic necrosis and fibrosis by acting on HSCs. These drugs could be therapeutic agents in patients with chronic liver disease and specific studies should be initiated.

Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?

“…An important aspect is whether platelet hyper-function has some relationship with the thrombotic outcomes that may complicate the clinical course of cirrhosis. Also, experimental data demonstrate that platelet hyperactivity might be implicated in the progression of liver disease [139,140], and fibrosis [141].…”

Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells

“…There is therefore compelling evidence that MASP-1 has a regulatory role in the complement lectin activation pathway. We also note that MASP-1 is related structurally and functionally to thrombin [12,13], and several lines of evidence suggest that thrombin has an important role in the generation of fibrosis in chronic liver disease [14,15]. Against this background, we set out to test the hypothesis that MASP-1 directly activates HSC, and may therefore promote liver fibrosis in HCV infection.…”

MR Imaging of activated hepatic stellate cells in liver injured by CCl4 of rats with integrin-targeted ultrasmall superparamagnetic iron oxide

“…HSCs have been taken for many years for a prognostic indicator of progression of liver fibrosis as well as a potential target for cell-specific therapeutic intervention to prevent the development of cirrhosis [6][7][8][9]. The integrin-linked adhesions (the cell-cell and cell-matrix interactions) could promote the migration, proliferation, and inhibition of apoptosis of the HSCs in the pathological process of liver fibrosis [10,11].…”