Alterations in von Willebrand factor (VWF) have an important role in human health and disease. Deficiency of VWF is associated with symptoms of bleeding and excesses of VWF are associated with thrombotic outcomes. Understanding the mechanisms that drive VWF regulation can lead to a better understanding of modulation of VWF levels in humans. We identified clusterin (
CLU
) as a potential candidate regulator of VWF based on a single cell RNA sequencing (scRNA-seq) analysis in control endothelial cells (ECs) and von Willebrand disease (VWD) endothelial colony-forming-cells (ECFCs). We found that patients with deficiencies of VWF (von Willebrand disease, VWD) had decreased
CLU
expression and ECs with low
VWF
expression also had low
CLU
expression. Based on these findings, we sought to evaluate the role of
CLU
in the regulation of VWF, specifically as it relates to VWD. As
CLU
is primarily thought to be a golgi protein involved in protein chaperoning, we hypothesized that knockdown of
CLU
would lead to decreases in VWF and alterations in Weibel-Palade bodies (WPBs). We used both siRNA- and CRISPR-Cas9-based approaches to modulate
CLU
in human umbilical vein endothelial cells (HUVECs) and evaluated VWF protein levels,
VWF
mRNA copy number, and WPB quantity and size. We demonstrated that siRNA-based knockdown of
CLU
resulted in decreases in VWF content in cellular lysates and supernatants, but no significant change in WPB quantity or size. A CRISPR-Cas9-based knockdown of
CLU
demonstrated similar findings of decreases in intracellular VWF content but no significant change in WPB quantity or size. Our data suggests that
CLU
knockdown is associated with decreases in cellular VWF content but does not affect
VWF
mRNA levels or WPB quantity or size.