Journal Article

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Gowert, Nina Sarah, Reusswig, Friedrich, Elvers, Margitta, Klier, Meike, Keitel, Verena, Häussinger, Dieter, Reich, Maria, Donner, Lili

2017

Overview

Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin α IIb β 3 on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

• Publisher: S. Karger AG,Cell Physiol Biochem Press GmbH & Co KG
• Subject: Acids / Animals / Atherosclerosis / Bile / Blood platelets / Blood Platelets - cytology / Blood Platelets - metabolism / Cell Adhesion Molecules / Cholestasis - metabolism / Cholestasis - pathology / Cholestatic liver disease / Collagen / Defects / Disease Models, Animal / Enzyme-Linked Immunosorbent Assay / Epoprostenol - analysis / Gallbladder diseases / Glycoproteins / Hemorrhage - etiology / Hemostasis / Liver - pathology / Liver cirrhosis / Liver diseases / Mice / Mice, Inbred C57BL / Microfilament Proteins / Nitric Oxide - metabolism / Original Paper / Peptides / Phosphoproteins / Phosphorylation / Platelet Activation / Platelet Count / Platelet Glycoprotein GPIIb-IIIa Complex - metabolism / Platelet Membrane Glycoproteins - metabolism / Platelets / Proteins / Rodents / Signal transduction / Spleen - pathology / Thrombosis - metabolism / Thrombosis - pathology / Tissue Plasminogen Activator - blood / Vasodilator-stimulated phosphoprotein