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Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C

Cellular & Molecular Immunology volume 14, pages 986–996 (2017)Cite this article

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.

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Acknowledgements

This work was supported by grants WO 1716/1-1 from the Deutsche Forschungsgemeinschaft (DFG), a grant from the Else Kröner-Fresenius-Stiftung and the Wilhelm-Vaillant-Stiftung to MW and a grant from the Friedrich Baur Stiftung to JP.

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Author notes

  1. Philipp Blüm and Joachim Pircher: These authors contributed equally to this work.

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, 80336 München, Germany

    Philipp Blüm, Monika Merkle, Thomas Czermak, Andrea Ribeiro, Simone Köppel, Erik Gaitzsch & Markus Wörnle

  2. Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, 80336 München, Germany

    Philipp Blüm, Joachim Pircher, Thomas Czermak, Hanna Mannell, Florian Krötz, Alexander Hennrich & Erik Gaitzsch

  3. Medizinische Klinik und Poliklinik I, Klinikum der Universität München, 80336 München, Germany

    Joachim Pircher

  4. Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinikum der Universität München, 80336 München, Germany

    Michael Spannagl

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Correspondence to Markus Wörnle.

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Blüm, P., Pircher, J., Merkle, M. et al. Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C. Cell Mol Immunol 14, 986–996 (2017). https://doi.org/10.1038/cmi.2016.10

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