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

Abstract

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.

Fig 1

Vitamin K-dependent protein carboxylation. The gammacarboxylation of coagulation factors requires the conversion of reduced vitamin K1 hydroquinone into vitamin K1 epoxyde. The K1 epoxyde is then converted to vitamin K1 quinone by vitamin K1 epoxyde reductase and then recycled to vitamin K1 hydroquinone by the enzyme vitamin K reductase. R: phytyl group.

Fig 2

Immunostaining for PAR-2 in normal and cirrhotic human liver. (A–C) In normal liver, a very intense PAR-2 staining is present in hepatocytes (A, 100×), and more weakly in the endothelium of larger vessels (B, **, 400×), and in bile duct epithelial cells (B, *). Staining was strong in KCs (C, arrows, 400×). (D–F). In fibrotic liver, PAR-2 staining remained strong in hepatocytes in regenerative nodules (D, 40×). Staining was strongly increased in the epithelium of newly formed biliary structures (E, arrows, 100×) and in the endothelium and smooth muscle cells of small vascular structures (F, arrows, 400×), compared with weaker staining in pre-existing bile ducts (E+F,*).

Fig 3

Model for the contribution of FXa-PAR-2 signalling in liver fibrosis. Depicted are the different PAR-2 expressing liver cells and their potential contribution to the progression of fibrosis as a functional consequence of FXa-signalling. FXa induces cytokine release in hepatocytes (1), cholangiocytes (2) and KCs (3), it decreases barrier porosity in SECs (4), and it leads to proliferation, migration, ECM production and differentiation into myofibroblasts of portal fibroblasts (5) and HSCs (6). Moreover, FXa-induced paracrine activation of portal fibroblast (7) and HSCs (8) also leads to proliferation, migration, ECM production and differentiation into myofibroblasts.