Blood Journal
Leading the way in experimental and clinical research in hematology

Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells

  1. Richard D. Starke1,
  2. Koralia E. Paschalaki2,
  3. Clare E.F. Dyer3,
  4. Kimberly J. Harrison-Lavoie3,
  5. Jacqueline A. Cutler4,
  6. Thomas A.J. Mckinnon5,
  7. Carolyn M. Millar5,
  8. Daniel F. Cutler3,
  9. Mike A. Laffan5, and
  10. Anna M. Randi1,*
  1. 1 Cardiovascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Hammersmith Campus, Imperial College London, London, United Kingdom;
  2. 2 Airway Disease Department, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom;
  3. 3 MRC Laboratory of Molecular Cell Biology, University College London, London, United Kingdom;
  4. 4 Molecular Haemostasis Laboratory, Department of Haemostasis and Thrombosis, GSTS Pathology, London, United Kingdom;
  5. 5 Department of Haematology, Hammersmith Campus, Imperial College London, London, United Kingdom
  1. * Corresponding author; email: a.randi{at}imperial.ac.uk

Key points

  • Blood outgrowth endothelial cells (BOEC) from VWD patients provide novel insight into the cellular mechanisms of the disease

Abstract

Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterised; however their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOEC) from peripheral blood of four type 1 VWD, four type 2 VWD patients and nine healthy controls. We confirmed the endothelial lineage of BOEC, then measured VWF mRNA and protein levels, both before and after stimulation, and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However BOEC from this group of patients also showed defects in processing, storage and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOEC from three type 2 VWD patients, supporting the dysfunctional VWF model. However, one type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into the cellular mechanisms of the disease.

  • Submitted June 6, 2012.
  • Accepted January 5, 2013.