ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.
ADAMTS13
acquired von Willebrand syndrome
bleeding
mechanical circulatory support
von Willebrand factor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
revised:
31
08
2022
received:
23
06
2022
accepted:
18
09
2022
pubmed:
22
9
2022
medline:
16
11
2022
entrez:
21
9
2022
Statut:
ppublish
Résumé
Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti-ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined. We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella-induced aVWS calf model. Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.
Sections du résumé
BACKGROUND
Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13.
METHODS
Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti-ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined.
RESULTS
We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella-induced aVWS calf model.
CONCLUSION
Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.
Identifiants
pubmed: 36128768
doi: 10.1111/jth.15889
pmc: PMC9669188
mid: NIHMS1838572
pii: S1538-7836(22)18376-5
doi:
Substances chimiques
von Willebrand Factor
0
ADAMTS13 Protein
EC 3.4.24.87
Collagen
9007-34-5
ADAMTS13 protein, human
EC 3.4.24.87
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2797-2809Subventions
Organisme : NHLBI NIH HHS
ID : R25 HL145817
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM142926
Pays : United States
Informations de copyright
© 2022 International Society on Thrombosis and Haemostasis.
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