Platelet activation as a disease modifier in chronic chloestatic liver disease.

Cirrhosis is characterized by haemostatic disturbances (thrombocytopenia, prolonged prothrombin time), limiting invasive clinical procesures (e;g. liver biopsies) and some therapies (e.g. ingerferon treatment in viral hepatitis). (1). While disturbances in the pro- and anti-coagulatory pathways are well-known (for review see (2; 3)), the primary haemostatic system (platelet aggregation and initiation of clot formation) has received less attention. Nevertheless, platelet numbers are decreased in cirrhosis and the accompanying portal hypertension and additional functional defects have been demonstrated in various chronic liver diseases and cirrhosis (for review see (4)). In contrast, in cholestatic liver disease, some evidence suggests that, contrary to other types of cirrhosis, the platelets are hyperactive. Indeed, patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) have a better survival after variceal bleeding (5) and demonstrate less blood loss during liver transplantation (6; 7). An increased incidence of thrombosis of portal venules has also been detected in PBC explant livers, reaching 40% (8). Some platelet function studies in these patients are indicative of hyperaggregability as demonstrated by thromboelastography (9; 10), by sonoclot analysis (11) and PFA-100 analysis (10; 11). Stimulated platelets from bile-duct ligated (BDL) rats (a well-studied animal model of cholestatic liver disease), show an increased rise in cytosolic calcium, the final common pathway in platelet activation, compared to control animals. This could be consistent with increased platelet function (12). However, not all reports are equivocal on this hyperaggregability, as this could not be demonstrated by platelet aggregometry in either patients (13) or animal models with cholestatic liver disease (14; 15). Moreover, there is a prolonged bleeding time (14) and a loss of releasable ATP possibly due to loss of platelet granules during intravascular activation (13), as well as a reduced expression of CD62P after stimulation (10); which is all indicative of decreased platelet function. Recent evidence suggests that cholestatic liver disease not only affects platelet function but that platelets may also contribute to the liver disease itself. This was studied in bile-duct ligated mice (16) and in alpha-naphtylisothiocyanate- induced liver disease in rats (17). Platelet depletion or blockage of the P-selectin receptor of platelets led to decreased aggregate formation within the liver and decreased platelet-induced leucocyte accumulation, resulting in improved liver transaminase levels (16; 17). The primary aim of our study is to clarify the conflicting results on platelet function in cholestatic liver disease in two rat models of liver disease: liver fibrosis with cholestasis (by bile-duct ligation) and liver fibrosis without cholestasis (by thio-acetamide induced liver fibrosis). The secondary aim is to elucidate how platelets could contribute to the development of cholestatic liver disease.

Keywords:Liver disease

Disciplines:Gastro-enterology and hepatology, Systems biology, Hematology, Laboratory medicine, Physiology