Platelet defects upon surgical liver disease models in mice

Question:

Acute and chronic liver diseases are characterized by alterations in primary hemostasis including thrombocytopenia and platelet function defects. Moreover, different studies show that hypercoagulability play a prominent role in liver diseases. Due to the undefined consequences of liver failure on platelet function we analyzed platelet activity, thrombus formation and hemostasis in liver injury models.

Methods:

In vitro and in vivo experiments using Bile Duct Ligation (BDL) and Partial Hepatectomy (PHx) in mice.

Results:

24h and 3 days after BDL a moderate decrease of platelet counts occurred, whereas the platelet counts increased to normal levels after 7 and 21 days. Platelet counts after PHx were slightly reduced after 3 days and fully recovered at later time points. However, intrinsic platelet activation was strongly reduced upon CRP activation at early time points in both BDL and PHx operated mice compared to sham controls. 7 days after BDL platelets displayed a complete activation defect with all agonists tested, whereas in the PHx model acute platelet activation defects were measured in the first 3 days. This activation defects resulted in strongly reduced thrombus formation under flow in both models as well as reduced platelet adhesion to fibrinogen. In line with the activation defects we could firstly prove the expression of the bile acid receptor TGR5 in human and murine platelets. In vivo platelet defects resulted into bleeding complications, predominantly in BDL mice as measured by tail bleeding experiments. The analysis of platelet activation defects revealed a contribution of altered glycoprotein expression to defective signal transduction. Moreover, high plasma levels of NO, PG-E and bile acids increased endogenous levels of VASP phosphorylation resulting in almost non-functional platelets after liver injury.

Conclusion:

These results indicate that liver diseases affect intrinsic platelet activation and impair thrombus formation that might contribute to bleeding complications in patients with acute or chronic hepatic failure and resection.