Liver damage increases the risk of bleeding due to reduced production of coagulation factors in hepatocytes. However, the mechanisms of an often-overlooked aspect of hypercoagulation and increased incidence of thrombotic complications in patients with liver diseases remain poorly understood. Fibrinolysis is a physiological mechanism to breakdown blood clot, and it is primarily regulated by the balance between plasminogen activators and their inhibitors. Here, we show a transcription repressor, DACH1, inhibits the expression of tissue-type plasminogen activator (tPA) in liver hepatocytes, a cell type not previously appreciated as an important source for tPA secretion. Knocking out hepatocyte DACH1 in mice significantly increases liver tPA mRNA (Plat), circulating tPA antigen and enzymatic activities. Hepatocyte-DACH1 knockout mice also had longer tail bleeding time and the time to occlude carotid artery in FeCl3 and Rose Bengal-photochemical injury-induced thrombosis models with recanalization pattern, consistent with hyperfibrinolysis. Moreover, specifically silencing hepatic Plat gene in hepatocyte-DACH-knockout mice reversed these effects. We also found a striking inversed correlation of higher DACH1 with lower tPA protein levels in liver biopsies from patients with hepatic arterial thrombosis (HAT), while lower DACH1 and higher tPA protein levels were observed in livers from portal vein thrombosis (PVT) patients. We discovered a hepatic DACH1-tPA pathway as a key determinant of fibrinolysis and its effects on bleeding and thrombosis, which provides considerable therapeutic potentials.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.