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. 2025 Aug;23(8):2634-2650.
doi: 10.1016/j.jtha.2025.04.024. Epub 2025 May 6.

von Willebrand disease-specific defects and proteomic signatures in endothelial colony-forming cells

Sebastiaan N J Laan  1 , Stijn Groten  2 , Richard J Dirven  3 , Petra E Bürgisser  4 , Frank W G Leebeek  4 , Iris van Moort  4 , Maartje van den Biggelaar  2 , Ruben Bierings  4 , Jeroen Eikenboom  5 ; SYMPHONY consortium
Collaborators, Affiliations
Free article

von Willebrand disease-specific defects and proteomic signatures in endothelial colony-forming cells

Sebastiaan N J Laan et al. J Thromb Haemost. 2025 Aug.
Free article

Abstract

Background: Endothelial cells are crucial for hemostasis as they produce von Willebrand factor (VWF). von Willebrand disease (VWD) results from a deficiency of, or defects in, VWF.

Objectives: We analyzed the endothelial compartment of VWD patients with an unexplained decrease in VWF level or nonresponse to 1-8-deamino-D-arginine vasopressin (DDAVP) using endothelial colony-forming cells (ECFCs).

Methods: Thirteen healthy controls and 10 VWD type 1 and 2 patients were included, and a total of 29 ECFC clones were obtained. Plasma was analyzed, and ECFCs were morphologically and functionally characterized by quantitative polymerase chain reaction, ELISA, imaging, migration assay, and mass spectrometry.

Results: VWF plasma levels were reduced in all patients. ECFCs were categorized into 2 previously defined transcriptional clusters and matched between patients and controls. Four ECFC clones, all from DDAVP nonresponders, retained VWF in the endoplasmic reticulum. Cluster 1 ECFCs from DDAVP nonresponders closed more slowly in the migration assay and had lower basal release of VWF antigen than control ECFCs. Proteomic data of ECFC lysates showed overlap in clustering with RNA profiles, including ALDHA1, TGFB1, and other endothelial-to-mesenchymal/inflammatory markers. However, no patient group-specific phenotype was observed. Finally, regulated secretion of VWF and Weibel-Palade body count in ECFCs correlated with various secretory machinery components.

Conclusion: Lower plasma VWF was linked to reduced production and secretion by ECFCs obtained from patients. Furthermore, nonresponse to DDAVP in some patients was explained by VWF retention in the endoplasmic reticulum. The correlation between functional aspects of ECFCs and their quantitative polymerase chain reaction and proteome profiles yielded potential targets for further research.

Keywords: endothelial cells; hemostasis; mass spectrometry; von Willebrand diseases; von Willebrand factor.

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Conflict of interest statement

Declaration of competing interests The Willebrand in the Netherlands study was supported by the Dutch Haemophilia Foundation, the Erasmus University Medical Center, CSL Behring, and Takeda (funding obtained by F.W.G.L.). F.W.G.L. is a consultant for CSL Behring, BioMarin, and Takeda, with the fees going to the university. J.E. received research funding from CSL Behring, with funds going to the university. All other authors declare no conflicts of interest.

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