Bile acid-mediated tissue factor activation in hepatocytes

Blood coagulation (hemostasis) is a vital process that stops bleeding caused by injuries to blood vessels. Additionally, blood coagulation is closely linked to the development of inflammatory processes and the functions of the immune system. Recent studies have shown that blood coagulation also plays a role in a range of diseases that are not directly associated with clinical bleeding or thrombotic events. This has placed blood coagulation in the spotlight of interdisciplinary research projects in recent years. The research group led by Axel Schlagenhauf investigates the activation of blood coagulation within the liver in disorders of bile flow. Therefore, the group conducts research at the intersection of hemostasis and hepatology. The liver plays a crucial role in maintaining functional blood coagulation. Liver cells produce a variety of clotting factors that are released into the bloodstream. However, in a healthy liver, no clotting activity occurs. In patients with severe liver diseases, bile flow can be obstructed, leading to the accumulation of bile acids in the liver tissue. These patients may develop both bleeding and thrombosis in other parts of the body, as the balance of the blood coagulation system is disrupted due to impaired synthesis function. Of particular importance is the possibility of coagulation activation within the liver, which results in the formation of fibrin, the body`s natural "glue" for wound closure. It has already been observed that patients with chronic bile flow obstruction (cholestasis) have fibrin deposits in liver tissue. These deposits contribute to the development of fibrosis, which can ultimately lead to liver cirrhosis. However, it has been unclear which factors trigger blood coagulation in cases of bile flow obstruction. Researchers led by Axel Schlagenhauf have discovered that an accumulation of specific bile acids in liver tissue triggers a signaling cascade within liver cells that can activate blood coagulation, without direct contact between the bile acids and the clotting factors. This FWF project aims to investigate the precise mechanism of the interaction between bile acids and blood coagulation in the liver. Established molecular biology and enzymatic kinetic methods are being combined with specialized clotting assays developed at the Medical University of Graz. The goal is to explore the signal transduction processes that cause this coagulation activation. The project lays the foundation for future therapeutic approaches to prevent the formation of fibrin deposits in the liver in patients with chronic bile flow obstruction, thus slowing down the progression of the disease.