The coagulation factor Xa/protease activated receptor-2 axis in the progression of liver fibrosis: a multifaceted paradigm

Introduction Activation of the coagulation cascade during liver fibrosis: a puzzling paradox Protease-activated receptors: the link between coagulation cascade activation and liver fibrosis Expression and distribution of human PAR-2 in normal and pathological liver tissue FXa signalling on PAR-2 expressing cells, and the relevance for liver fibrosis FXa triggers fibroproliferative and pro-inflammatory responses in mesenchymal cells via PAR-2 activation FXa triggers pro-inflammatory responses and modulates the survival of epithelial cells via PAR-2 activation FXa and PAR-2 signalling in inflammatory cells FX-induced PAR-2 activation modulates endothelial barrier permeability Targeting FXa in animal models of liver fibrosis Summary and conclusions Hepatic fibrosis is a common response to virtually all forms of chronic liver injury independent of the etiologic agent. Despite the relatively large population of patients suffering from hepatic fibrosis and cirrhosis, no efficient and well-tolerated drugs are available for the treatment of this disorder. The lack of efficient treatment options is at least partly because the underlying cellular mechanisms leading to hepatic fibrosis are only partly understood. It is thus of pivotal importance to better understand the cellular processes contributing to the progression of hepatic fibrosis. Interestingly in this perspective, a common feature of fibrotic disease of various organs is the activation of the coagulation cascade and hepatic fibrosis is also accompanied by a local hypercoagulable state. Activated blood coagulation factors directly target liver cells by activating protease-activated receptors (PAR) thereby inducing a plethora of cellular responses like (among others) proliferation, migration and extracellular matrix production. Coagulation factor driven PAR activation thus establishes a potential link between activation of the coagulation cascade and the progression of fibrosis. The current review focuses on blood coagulation factor Xa and summarizes the variety of cellular functions induced by factor Xa-driven PAR-2 activation and the subsequent consequences for tissue repair and hepatic fibrosis.