PTH-101 The role of tissue factor pathway inhibitor (tfpi) in liver injury

Abstract

Introduction Studies have demonstrated that pro-coagulant states are associated with rapidly advancing liver fibrosis and that anticoagulation limits this. In acute liver injury studies have suggested that decreased coagulation cascade activation results in reduced acute liver injury. TFPI is a serine protease inhibitor that acts as a homeostatic brake in the coagulation cascade. TFPI is a potential target for the inhibition of the coagulation cascade to modify liver disease. To further investigate this, transgenic mice expressing human TFPI were used in models of liver injury. The transgenic mice carry a genetic modification that allows cells expressing alpha smooth muscle actin (αSMA) to simultaneously express TFPI. This results in cells, such as activated hepatic stellate cells, expressing TFPI in a manner not seen in wild type mice. Method Transgenic and wild type mice were used in a chronic liver injury model (carbon tetrachloride, CCl4) or an acute liver injury model (paracetamol) and culled at set time points after dosing. Results Chronic liver injury: At 24 h after the last dose of CCl4there was a significant decrease in αSMA expression in the transgenic mice compared to wild type (Mann-Whitney test, p = 0.003). At 24 h there was also a decrease in tissue inhibitor of metalloproteinase (TIMP) -1 gene expression but normal matrix metalloproteinase (MMP) -2 and -9 gene expression. This suggested a microenvironment that would promote fibrosis resolution through decreased hepatic stellate activation and loss of inhibition of MMPs. However after 24 h this difference was lost. At 24 h after the last dose of CCl4and at all subsequent time points there was no significant difference between fibrosis in transgenic and wild type mice as demonstrated by Sirius red staining, hydroxyproline assay and collagen 1α1 gene expression. Acute liver injury: In early paracetamol induced liver injury (2–12 h post-dose) there was no significant difference in parenchymal necrosis in transgenic compared to wild type mice. However, at 24 h and 48 h after dosing there was a significant decrease in parenchymal necrosis in transgenic compared to wild type mice (24 h: mean percentage necrosis 6% vs. 30% respectively, Mann-Whitney test p = 0.008. 48 h: percentage necrosis 2% vs. 20% respectively, Mann-Whitney test p = 0.036). Conclusion These results suggest that TFPI is not a potential therapeutic target in chronic liver injury. However in acute paracetamol induced liver injury TFPI appears to reduce liver injury in a sustained manner from 24 h after the initial insult. This suggests a role for TFPI in managing acute liver injury and warrants further investigation. Disclosure of interest None Declared.