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 after hemostatic challenge, may contribute to bleeding in type 1 VWD, but the pathogenic mechanisms are poorly defined. In this study, a layered multiomic approach including messenger RNA (mRNA) and microRNA (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 8 patients with type 1 VWD and 4 other patients were included in this study as controls. VWF protein analysis revealed heterogenous responses to stimulation among 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 5 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 signaling were also differentially regulated in type 1 VWD ECFCs during stimulated release. To our knowledge, 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.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, resulting from a deficiency and/or dysfunction of von Willebrand factor (VWF). Since its first description 100 years ago, the diagnosis of VWD has evolved due to advancements in laboratory diagnostic tests and clinical guidelines and recommendations. There are 3 established diagnostic criteria for VWD: a personal history of excessive mucocutaneous bleeding, a family history of bleeding, and reduced VWF levels. Over the years, the diagnosis of VWD has been challenging, due to a lack of consensus and barriers to achieving an accurate and timely diagnosis. In 2021 evidence-based clinical practice guidelines were developed. These guidelines have provided clarity and consensus but there continues to be opposing views and challenges. Additionally, there remain barriers to achieving a diagnosis of VWD that need to be addressed.

IntroductionSevere aortic stenosis (AS) can lead to degradation of high molecular weight (HMW) von Willebrand factor (VWF) which can result in haemostatic abnormalities. While studies have explored changes in VWF profiles before and after surgical aortic valve replacement (SAVR), the longer-term changes in VWF profiles pre- and post-transcatheter aortic valve implantation (TAVI) are less understood. AimOur primary objective was to identify differences in VWF multimer profiles and VWF function pre-TAVI and 1-month post-TAVI. Our secondary objective was to correlate VWF markers with measures of AS severity. MethodsAdult patients with severe AS referred for TAVI at our institution were prospectively enrolled in this cohort study. Blood samples were collected for plasma analysis at three time points for all patients: 1 day pre-TAVI, 3 days post-TAVI, and 1-month post-TAVI. VWF antigen, activity, propeptide, collagen binding, multimers, and factor VIII coagulant activity were determined at each time point. Correlations between VWF parameters and severity of AS were assessed. ResultsTwenty participants (15 males, five females) with severe AS were recruited for the study. There was a significant increase in HMW VWF between pre-procedure and 1-month post-TAVI (p < .05). There was a transient increase in VWF antigen levels and activity at 3-days post TAVI that decreased to pre-TAVI levels at 1-month. There were no statistically significant correlations between VWF markers and AS severity. ConclusionsThis is the first study to elucidate longer-term (>1 week) improvements in HMW VWF after a TAVI procedure in severe AS patients.