Patients with aortic stenosis have von Willebrand factor abnormalities and increased proliferation of endothelial colony forming cells

Abstract

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.

Gastrointestinal bleeding during the transcatheter aortic valve replacement perioperative period: A Review

“…[13] Consequently, this leads to the loss of VWF high-molecular-weight multimers and platelet-mediated hemorrhage. [14,15] This type of acquired von Willebrand disease (aVWD) ascribed to high shear rate is known to occur in patients with AVS, hypertrophic cardiomyopathy, and mitral and aortic insufficiency. [16]…”

Non-Coding RNAs as Blood-Based Biomarkers in Cardiovascular Disease

“…Previously, members of the miR-17-92 cluster, to which miR-19 belongs, were reported to regulate myocardial fibrosis and angiogenesis [34]. However, the role of angiogenesis is still unclear, with some studies reporting that the degree of myocardial angiogenesis is accompanied by increased hypertrophy, worsening of systolic function, and severe AS [35,36]. On the other hand, a study demonstrated that increased angiogenesis and cardiomyocytes proliferation prevent maladaptive remodeling in a model of LV pressure-overload [37].…”

Illustrated State‐of‐the‐Art Capsules of the ISTH 2020 Congress

“…Previous studies have shown that endothelial von Willebrand factor (VWF) is a negative regulator of angiogenesis 18 . Patient derived endothelial colony‐forming cells from both patients with type 3 VWD and patients with aortic stenosis (AVWS) display abnormal angiogenesis in vitro 19,20 . In vivo studies in VWF knockout mice show increased vessel growth in the ears and increased tubule formation in Matrigel plugs at 7 days when compared with wild type.…”