title: Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C.
abstract: Hepatitis C virus (HCV) infection is a major problem worldwide. HCV is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis. A fatal complication of HCV-associated vascular disease is thrombosis. Polyriboinosinic:polyribocytidylic acid (poly (I:C)), a synthetic analog of viral RNA, induces a Toll-like receptor 3 (TLR3)-dependent arteriolar thrombosis without significant thrombus formation in venules in vivo. These procoagulant effects are caused by increased endothelial synthesis of tissue factor and PAI-1 without platelet activation. In addition to human umbilical endothelial cells (HUVEC), human mesangial cells (HMC) produce procoagulatory factors, cytokines and adhesion molecules after stimulation with poly (I:C) or HCV-containing cryoprecipitates from a patient with a HCV infection as well. Activated protein C (APC) is able to prevent the induction of procoagulatory factors in HUVEC and HMC in vitro and blocks the effects of poly (I:C) and HCV-RNA on the expression of cytokines and adhesion molecules in HMC but not in HUVEC. In vivo, protein C inhibits poly (I:C)-induced arteriolar thrombosis. Thus, endothelial cells are de facto able to actively participate in immune-mediated vascular thrombosis caused by viral infections. Finally, we provide evidence for the ability of protein C to inhibit TLR3-mediated arteriolar thrombosis caused by HCV infection.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.|Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Blüm
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.|Medizinische Klinik und Poliklinik I, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Merkle
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.|Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Czermak
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hennrich
authors.affiliation: Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Köppel
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.|Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Gaitzsch
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
mesh_terms: D000818:Animals; D001158:Arteries / Q000473:pathology*; D042783:Endothelial Cells / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D050527:Mesangial Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000008:administration & dosage; D011486:Protein C / Q000627:therapeutic use*; D013927:Thrombosis; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy*; D014699:Venules / Q000473:pathology*
chemical_list: D011486:Protein C; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C