ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation

Shannen J. Deconinck, Christoph Nix, Svenja Barth, Eveline Bennek-Schöpping, Antoine Rauch, An Sofie Schelpe, Elien Roose, Hendrik B. Feys, Inge Pareyn, Aline Vandenbulcke, Joshua Muia, Christophe Vandenbriele, Sophie Susen, Bart Meyns, Claudia Tersteeg, Steven Jacobs, Simon F. De Meyer, Karen Vanhoorelbeke

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2797-2809
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number12
DOIs
StatePublished - Dec 2022

Keywords

  • acquired von Willebrand syndrome
  • ADAMTS13
  • bleeding
  • mechanical circulatory support
  • von Willebrand factor

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