fibrin and Hypertension--Portal

Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis.. Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls.. In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension.. By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

Topics: Animals; Antithrombins; Cell Line; Chemical and Drug Induced Liver Injury; Collagen; Cytoprotection; Dabigatran; Extracellular Signal-Regulated MAP Kinases; Fibrin; Hepatic Stellate Cells; Hypertension, Portal; Liver; Liver Cirrhosis, Experimental; Male; Neovascularization, Pathologic; Phosphorylation; Portal Pressure; Rats, Sprague-Dawley; Thioacetamide

Topics: Abdomen, Acute; Blood Platelets; Endoscopy, Gastrointestinal; Esophageal and Gastric Varices; Fibrin; Hematemesis; Humans; Hypertension, Portal; Ligation; Liver Cirrhosis; Male; Middle Aged; Pressure; Rupture, Spontaneous; Treatment Outcome; Varicose Veins

To assess the contribution of naturally occurring portal-systemic shunts to the coagulopathy of patients with liver disease, we studied laboratory parameters of hemostasis in 20 adult patients with extrahepatic portal hypertension, secondary to portal vein thrombosis, that had resulted in variceal bleeding. All extrahepatic portal hypertension patients had normal liver function and histological appearance. None had any evidence of preexisting coagulation disorders, and none had bled or undergone sclerotherapy in the 6 mo before study. Age- and gender-matched groups of 20 healthy individuals and 20 stable patients with cirrhosis and portal hypertension who had a history of variceal bleeding served as controls. Both patient groups had thrombocytopenia consistent with hypersplenism and portal hypertension. Prothrombin international normalized ratio (extrahepatic portal hypertension, 1.3 +/- 0.12; cirrhosis, 1.7 +/- 0.2; control, 1.02 +/- 0.06; p < 0.05) and partial thromboplastin time ratios (extrahepatic portal hypertension, 1.12 +/- 0.1; cirrhosis, 1.26 +/- 0.2; controls, 1.01 +/- 0.03; p < 0.05) were significantly prolonged in both patient groups. Extrahepatic portal hypertension and cirrhotic patient groups had significantly increased levels of serum total fibrin(ogen)-related antigen (extrahepatic portal hypertension, 818 +/- 150 ng/ml; cirrhosis, 454 +/- 52 ng/ml; controls, 124 +/- 7.3 ng/ml; p < 0.05), fibrin monomer (extrahepatic portal hypertension, 168.8 +/- 16.9 ng/ml; cirrhosis, 115.6 +/- 11.1 ng/ml; controls, 19.7 +/- 0.4 ng/ml; p < 0.05) and D-dimer (extrahepatic portal hypertension, 118 +/- 9.6 ng/ml; cirrhosis, 129 +/- 10 ng/ml; controls, 53.2 +/- 1.6 ng/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Coagulation; Blood Coagulation Factors; Female; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Portal Vein; Thrombosis

The effects of intravenously administered endotoxin on the hepatic and systemic circulation as well as on the coagulation system were evaluated in normal rats (n = 26), in rats with experimental portal hypertension (n = 15), and in rats with portacaval anastomosis (n = 22). Endotoxin (1-5 mg/kg) in the normal rat leads to a prompt increase of transaminase activity and to a hyperdynamic circulation with a consequent increase in the total hepatic blood flow. In a later phase (6 h postoperatively) the hepatic artery dilated with a consequent hepatic arterial hyperperfusion. The coagulation system was affected with signs of consumption coagulopathy. In the rats with portal hypertension and portacaval collaterals as well as in those with portacaval anastomosis, the endotoxin injection resulted in acute liver necrosis within 12 to 15 hours. The hepatic artery became overdilated with a cardiac output fraction of 25% (normal 5-5%). Blood extravasates and thrombi, rich in fibrin, were detected in the liver. It is suggested that this exaggeration of the endotoxin effect was due to an impaired clearance function of the reticuloendothelial system, probably as consequence of portacaval collateral circulation. It is concluded that endotoxins (1) damage the liver even in a normal organism; (2) are potent to induce acute liver necrosis, if the reticuloendothelial system is altered; (3) have to be taken into consideration as contribution to the pathogenesis of acute as well as chronic liver diseases.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Blood Coagulation Factors; Blood Glucose; Blood Volume; Cardiac Output; Collateral Circulation; Endotoxins; Erythrocyte Aggregation; Fibrin; Fibrinogen; Hypertension, Portal; Liver; Liver Circulation; Liver Diseases; Necrosis; Phagocytosis; Portacaval Shunt, Surgical; Rats; Regional Blood Flow; Time Factors

Topics: Acute Kidney Injury; Aged; Bronchopneumonia; Diagnosis, Differential; Fibrin; Humans; Hypertension, Portal; Kidney Cortex Necrosis; Kidney Glomerulus; Liver Cirrhosis; Male; Mesenteric Veins; Portal Vein; Sclerosis; Shwartzman Phenomenon; Splenic Vein; Thrombosis

Topics: Afibrinogenemia; Bone and Bones; Bone Diseases; Fibrin; Gastrointestinal Diseases; Humans; Hypertension; Hypertension, Portal; Lung Diseases; Male; Siblings