Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/4262075

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Laan, S.N.J. (2025)

The endothelial compartment as a disease modifier in bleeding disorders

Doctoral Thesis

In people with bleeding disorders such as Von Willebrand Disease (VWD), blood clotting does not function properly. An important clotting protein, Von Willebrand Factor (VWF), is normally produced and stored in endothelial cells, which line the inside of blood vessels. When a vessel is damaged, VWF is released to help stop the bleeding. Some patients produce too little or abnormal VWF, or do not respond well to medications that stimulate its release. For some patients, the cause of this is still unknown. 

In this study, we investigated the role of endothelial cells in bleeding disorders. We grew endothelial cells from patients’ white blood cells, allowing us to closely examine how these cells function in individuals. We found that in some patients, VWF remains trapped inside the cells and is not properly released. We also observed that medication response strongly depends on the specific subtype of the disorder. 

In addition, we found considerable variation...

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In people with bleeding disorders such as Von Willebrand Disease (VWD), blood clotting does not function properly. An important clotting protein, Von Willebrand Factor (VWF), is normally produced and stored in endothelial cells, which line the inside of blood vessels. When a vessel is damaged, VWF is released to help stop the bleeding. Some patients produce too little or abnormal VWF, or do not respond well to medications that stimulate its release. For some patients, the cause of this is still unknown. 

In this study, we investigated the role of endothelial cells in bleeding disorders. We grew endothelial cells from patients’ white blood cells, allowing us to closely examine how these cells function in individuals. We found that in some patients, VWF remains trapped inside the cells and is not properly released. We also observed that medication response strongly depends on the specific subtype of the disorder. 

In addition, we found considerable variation between endothelial cells from different individuals. To address this, we developed a method to characterize this variation and created an automated quantification pipeline to analyze microscopic images. These insights may contribute to improved diagnosis and more personalized treatment strategies for bleeding disorders.

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Endothelial Cells
Von Willebrand Factor
Von Willebrand disease
Coagulation
Bleeding
Weibel-Palade body
Endothelial colony-forming cell
Induced pluripotent stem cell
All authors
Laan, S.N.J.
Supervisor
Eikenboom, H.C.J.; Leebeek, F.W.G.; Bierings, R.
Committee
Versteeg, H.H.; Vlijmen, B.J.M. van; Cnossen, M.H.; Voorberg, J.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2025-09-24
ISBN (print)
9789465222653

Funding

Sponsorship
The research described in this thesis was funded by a grant from the Netherlands Organization for Scientific Research (NWO) in the framework of the NWA-ORC Call grant agreement NWA.1160.18.038 (SYMPHONY: personalized treatment for patients with a bleeding disorder)