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

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          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.

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          The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF-beta and cellular fibronectin (ED-A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours. Copyright 2003 John Wiley & Sons, Ltd.
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            Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.

            Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.
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                Author and article information

                J Cell Mol Med
                J. Cell. Mol. Med
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                Jan-Feb 2010
                28 November 2009
                : 14
                : 1-2
                : 143-153
                [a ]Center for Experimental and Molecular Medicine, Academic Medical Center Meibergdreef, Amsterdam, The Netherlands
                [b ]Department of Pathology, Academic Medical Center Meibergdreef, Amsterdam, The Netherlands
                [c ]Department of Cell Biology, University of Groningen, Antonius Deusinglaan Groningen, the Netherlands
                Author notes
                *Correspondence to: Keren BORENSZTAJN, Center for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, NL-1105 AZ, Amsterdam, The Netherlands. Tel.: +31 20 56 67 906 Fax: +31 20 69 77 192 E-mail: K.S.Borensztajn@
                © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

                Molecular medicine

                coagulation factor xa, fibrosis, protease-activated receptor-2


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