A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from type 1 VWD patients.

Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs following hemostatic challenge, may contribute to bleeding in Type 1 VWD, but the pathogenic mechanisms are poorly defined. In the present study, a layered multiomic approach including mRNA and miRNA sequencing was used to evaluate transcriptome-wide differences between Type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from eight Type 1 VWD patients and four controls were included in this study. VWF protein analysis revealed heterogenous responses to stimulation amongst Type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between Type 1 VWD and control ECFCs and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and five mRNAs were differentially regulated between Type 1 VWD and control ECFCs and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signalling were also differentially regulated in Type 1 VWD ECFCs during stimulated release. We have shown for the first time that transcriptome-wide differences exist between Type 1 VWD and control ECFCs. These differences may contribute to bleeding in Type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.