Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have traditionally been considered separate entities. Defects in the regulation of the complement alternative pathway occur in atypical hemolytic uremic syndrome, and defects in the cleavage of von Willebrand factor (VWF)-multimers arise in thrombotic thrombocytopenic purpura. However, recent studies suggest that both entities are related as defects in the disease-causing pathways overlap or show functional interactions. Here we investigate the possible functional link of VWF-multimers and the complement system on endothelial cells. Blood outgrowth endothelial cells (BOECs) were obtained from 3 healthy individuals and 2 patients with Type 3 von Willebrand disease lacking VWF. Cells were exposed to a standardized complement challenge via the combination of classical and alternative pathway activation and 50% normal human serum resulting in complement fixation to the endothelial surface. Under these conditions we found the expected release of VWF-multimers causing platelet adhesion onto BOECs from healthy individuals. Importantly, in BOECs derived from patients with von Willebrand disease complement C3c deposition and cytotoxicity were more pronounced than on BOECs derived from normal individuals. This is of particular importance as primary glomerular endothelial cells display a heterogeneous expression pattern of VWF with overall reduced VWF abundance. Thus, our results support a mechanistic link between VWF-multimers and the complement system. However, our findings also identify VWF as a new complement regulator on vascular endothelial cells and suggest that VWF has a protective effect on endothelial cells and complement-mediated injury.
Kidney international. 2016 May 25 [Epub ahead of print]
Damien G Noone, Magdalena Riedl, Fred G Pluthero, Mackenzie L Bowman, M Kathryn Liszewski, Lily Lu, Yi Quan, Steve Balgobin, Reinhard Schneppenheim, Sonja Schneppenheim, Ulrich Budde, Paula James, John P Atkinson, Nades Palaniyar, Walter H A Kahr, Christoph Licht
Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada., Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria., Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada., Clinical and Molecular Hemostasis Research Group, Queen's University, Kingston, Ontario, Canada., Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri, USA., Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada., Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada., Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada., Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Medilys Laborgemeinschaft mbH, Coagulation Laboratory, Hamburg, Germany., Medilys Laborgemeinschaft mbH, Coagulation Laboratory, Hamburg, Germany., Clinical and Molecular Hemostasis Research Group, Queen's University, Kingston, Ontario, Canada., Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri, USA., Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Haematology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada., Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: .