Faculty Collaboration Database

ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation. J Thromb Haemost 2022 Dec;20(12):2797-2809

Date

09/22/2022

Pubmed ID

36128768

Pubmed Central ID

PMC9669188

DOI

10.1111/jth.15889

Scopus ID

2-s2.0-85139957186 (requires institutional sign-in at Scopus site)   13 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.

Author List

Deconinck SJ, Nix C, Barth S, Bennek-Schöpping E, Rauch A, Schelpe AS, Roose E, Feys HB, Pareyn I, Vandenbulcke A, Muia J, Vandenbriele C, Susen S, Meyns B, Tersteeg C, Jacobs S, De Meyer SF, Vanhoorelbeke K

Author

Joshua Muia PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADAMTS13 Protein
Animals
Cattle
Collagen
Heart-Assist Devices
Hemostasis
Humans
von Willebrand Diseases
von Willebrand Factor