Contribution of ADAMTS13-independent VWF regulation in sickle cell disease.
J Thromb Haemost
; 20(9): 2098-2108, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35753044
ABSTRACT
BACKGROUND:
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. METHODS/ PATIENTS Plasma samples were collected from adult patients with SCD (n = 20) at a single institution when presenting for routine red cell exchange transfusion therapy. ADAMTS13 activity was measured by FRETS-VWF73, Technozym ADAMTS-13 Activity ELISA kit and a full-length VWF digestion reaction. Alternative VWF-cleaving proteases were identified by ELISA. A cell culture model was used to study the impact of SCD stimuli on endothelial ADAMTS13 and alternative VWF-cleaving proteases.RESULTS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor de von Willebrand
/
Anemia de Células Falciformes
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Humans
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos