Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

Research output: Contribution to journalArticlepeer-review


  • Mohsen Malehmir
  • Dominik Pfister
  • Suchira Gallage
  • Marta Szydlowska
  • Donato Inverso
  • Elena Kotsiliti
  • Valentina Leone
  • Moritz Peiseler
  • Bas G J Surewaard
  • Dominik Rath
  • Adnan Ali
  • Monika Julia Wolf
  • Hannah Drescher
  • Marc E Healy
  • Daniel Dauch
  • Daniela Kroy
  • Oliver Krenkel
  • Marlene Kohlhepp
  • Thomas Engleitner
  • Alexander Olkus
  • Tjeerd Sijmonsma
  • Julia Volz
  • Carsten Deppermann
  • David Stegner
  • Patrick Helbling
  • César Nombela-Arrieta
  • Anahita Rafiei
  • Martina Hinterleitner
  • Marcel Rall
  • Florian Baku
  • Oliver Borst
  • Caroline L Wilson
  • Jack Leslie
  • Tracy O'Connor
  • Ana Teijeiro
  • Marco Prinz
  • Ruzhica Bogeska
  • Natasha Anstee
  • Malte N Bongers
  • Mike Notohamiprodjo
  • Tobias Geisler
  • Dominic J Withers
  • Jerry Ware
  • Derek A Mann
  • Hellmut G Augustin
  • Alexandros Vegiopoulos
  • Michael D Milsom
  • Adam J. Rose
  • Josep M Llovet
  • Roser Pinyol
  • Frank Tacke
  • Roland Rad
  • Matthias Matter
  • Nabil Djouder
  • Paul Kubes
  • Percy A Knolle
  • Kristian Unger
  • Lars Zender
  • Bernhard Nieswandt
  • Meinrad Gawaz
  • Achim Weber
  • Mathias Heikenwalder

External organisations

  • University Hospital Zürich
  • Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Heidelberg University
  • Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
  • Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • Department of Medical Microbiology, University Medical Center, Utrmeecht, the Netherlands.
  • Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
  • Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany.
  • Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen, Germany.
  • Heidelberg University Hospital
  • Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.
  • Division of Oncology and Hematology, University Children's Hospital Zurich, Children's Research Center, Zurich, Switzerland.
  • Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
  • Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
  • Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, UK.
  • Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
  • Center for NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • DKFZ-ZMBH Alliance, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
  • Department of Diagnostic and Interventional Radiology, University Hospital of Tübingen, Tübingen, Germany.
  • Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany.
  • Imperial College London
  • Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
  • Liver Cancer Translational Research Laboratory, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain.
  • Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
  • DKFZ (German Cancer Research Centre)
  • Monash University


Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.


Original languageEnglish
Pages (from-to)641-655
Number of pages15
JournalNature Medicine
Issue number4
Publication statusPublished - 1 Apr 2019


  • Animals, Blood Platelets/drug effects, Body Weight/drug effects, Cytokines/metabolism, Cytoplasmic Granules/drug effects, Endothelium/drug effects, Hepatocytes/drug effects, Humans, Hyaluronan Receptors/metabolism, Hyaluronic Acid/metabolism, Kupffer Cells/drug effects, Liver/drug effects, Liver Neoplasms/blood, Mice, Transgenic, Non-alcoholic Fatty Liver Disease/blood, Platelet Aggregation/drug effects, Platelet Aggregation Inhibitors/pharmacology, Platelet Count, Platelet Glycoprotein GPIb-IX Complex/metabolism