Contribution of ADAMTS13-independent VWF regulation in sickle cell disease

Von Willebrand factor (VWF) is elevated in sickle cell disease (SCD) and contributes to vaso-occlusion through its thrombogenic properties. VWF is regulated by ADAMTS13, a plasma protease that cleaves VWF into less bioactive multimers. Independent investigations have shown VWF to be elevated in SCD, whereas measurements of ADAMTS13 have been variable. Objectives: We assessed ADAMTS13 activity using multiple activity assays and measured levels of alternative VWF-cleaving proteases in SCD.

This is the first demonstration of accessory plasma enzymes contributing to the regulation of VWF in a specific disease state and may have implications for assessing the VWF/ADAMTS13 axis in other settings.

ADAMTS13 activity was found to be moderately deficient across the SCD cohort as assessed by activity assays using a VWF A2 domain peptide substrate. However, SCD plasma showed preserved ability to digest full-length VWF, suggesting assay-discrepant results. Neutrophil and endothelial-derived proteases were found to be elevated in SCD plasma. Matrix metalloproteinase 9 specifically showed preferential cleavage of full-length VWF. Upregulation of alternative VWF-cleaving proteases occurred in endothelial cells exposed to SCD stimuli such as heme and hypoxia. Conclusions: This is the first demonstration of accessory plasma enzymes contributing to the regulation of VWF in a specific disease state and may have implications for assessing the VWF/ADAMTS13 axis in other settings.