Background Patients with aortic stenosis (AS) can experience bleeding complications including gastrointestinal bleeding from angiodysplastic lesions due to acquired von Willebrand syndrome. Studies have pointed to a role for von Willebrand factor (VWF) in angiogenesis. Objective The objective of this study was to assess VWF defects in AS patients over time and the impact on angiogenesis using patient‐derived endothelial colony‐forming cells (ECFCs). Patients/Methods Plasma sample collection and ECFC isolations were performed before valve replacement surgery, 3 to 5 days after, and 6 months after surgery. Plasma VWF antigen, activity, propeptide, collagen binding, multimers, factor VIII coagulant activity, and ADAMTS13 activity (a disintegrin‐like and metalloprotease with thrombospondin type 1 motifs 13) were determined. ECFCs were assessed for VWF and angiopoietin‐2 (Ang‐2) storage and secretion, cell proliferation, and tubule formation in Matrigel. Results and Conclusions Aortic stenosis patients exhibited quantitative and qualitative abnormalities of VWF including significantly increased VWF antigen, activity, and propeptide levels following surgery (P < .01). Increased high molecular weight VWF multimers were observed at all time points and in particular 3 to 5 days after surgery (mean = 14% ± 6%) relative to before (mean = 10% ± 4%), suggesting increased proteolysis by ADAMTS13 pre‐operatively in a shear‐dependent manner. ECFCs from patients with aortic stenosis were more proliferative than controls (P < .05) and had increased retention of Ang‐2 (P < .05) suggesting epigenetic modification of the cells. Overall, there are hemostatic changes in AS patients that are present before valve replacement surgery and these persist long after surgery has occurred. These findings have implications for the current clinical management of AS 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.

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