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

SJ Deconinck, C Nix, S Barth, E Bennek-Schöpping, A Rauch, AS Schelpe, E Roose, Hendrik Feys (UGent) , I Pareyn, A Vandenbulcke, et al.
(2022) JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 20(12). p.2797-2809
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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 mu g/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.
Keywords
von Willebrand factor, mechanical circulatory support, bleeding, ADAMTS13, acquired von Willebrand syndrome

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MLA
Deconinck, SJ, et al. “ADAMTS13 Inhibition to Treat Acquired von Willebrand Syndrome during Mechanical Circulatory Support Device Implantation.” JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 20, no. 12, 2022, pp. 2797–809, doi:10.1111/jth.15889.
APA
Deconinck, S., Nix, C., Barth, S., Bennek-Schöpping, E., Rauch, A., Schelpe, A., … Vanhoorelbeke, K. (2022). ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 20(12), 2797–2809. https://doi.org/10.1111/jth.15889
Chicago author-date
Deconinck, SJ, C Nix, S Barth, E Bennek-Schöpping, A Rauch, AS Schelpe, E Roose, et al. 2022. “ADAMTS13 Inhibition to Treat Acquired von Willebrand Syndrome during Mechanical Circulatory Support Device Implantation.” JOURNAL OF THROMBOSIS AND HAEMOSTASIS 20 (12): 2797–2809. https://doi.org/10.1111/jth.15889.
Chicago author-date (all authors)
Deconinck, SJ, C Nix, S Barth, E Bennek-Schöpping, A Rauch, AS Schelpe, E Roose, Hendrik Feys, I Pareyn, A Vandenbulcke, J Muia, C Vandenbriele, S Susen, B Meyns, C Tersteeg, S Jacobs, SF De Meyer, and K Vanhoorelbeke. 2022. “ADAMTS13 Inhibition to Treat Acquired von Willebrand Syndrome during Mechanical Circulatory Support Device Implantation.” JOURNAL OF THROMBOSIS AND HAEMOSTASIS 20 (12): 2797–2809. doi:10.1111/jth.15889.
Vancouver
1.
Deconinck S, Nix C, Barth S, Bennek-Schöpping E, Rauch A, Schelpe A, et al. ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation. JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 2022;20(12):2797–809.
IEEE
[1]
S. Deconinck et al., “ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation,” JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 20, no. 12, pp. 2797–2809, 2022.
@article{01GP18ZC77FC3HDK7JNNM1H6HY,
  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 mu g/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.}},
  author       = {{Deconinck, SJ and Nix, C and Barth, S and Bennek-Schöpping, E and Rauch, A and Schelpe, AS and Roose, E and Feys, Hendrik and Pareyn, I and Vandenbulcke, A and Muia, J and Vandenbriele, C and Susen, S and Meyns, B and Tersteeg, C and Jacobs, S and De Meyer, SF and Vanhoorelbeke, K}},
  issn         = {{1538-7933}},
  journal      = {{JOURNAL OF THROMBOSIS AND HAEMOSTASIS}},
  keywords     = {{von Willebrand factor,mechanical circulatory support,bleeding,ADAMTS13,acquired von Willebrand syndrome}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2797--2809}},
  title        = {{ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation}},
  url          = {{http://doi.org/10.1111/jth.15889}},
  volume       = {{20}},
  year         = {{2022}},
}
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