Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245

Theme Issue
Coagulation proteases and cardiovascular disease

Issue: 2014: 112/5 (Nov) pp. 843–1075
Pages: 1014-1023
Ahead of Print: 2014-07-17

Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices

A. Rauch (1, 2, 3, 4), P. Legendre (1, 2), O. D. Christophe (1, 2), J. Goudemand (3, 4), E. van Belle (4, 5), A. Vincentelli (4, 5), C. V. Denis (1, 2), S. Susen (3, 4), P. J. Lenting (1, 2)

(1) INSERM Unit 770, Le Kremlin-Bicêtre, France; (2) UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France ; (3) Department of Hematology & Transfusion, Lille University Hospital, Lille, France; (4) Equipe d’Accueil 2693, Lille-II University, Lille, France ; (5) Department of Cardiology, Lille University Hospital, Lille, France


von Willebrand factor, ADAMTS13, Acquired von Willebrand syndrome, circulatory assist devices, antibody therapy


Haemorrhagic episodes in patients carrying circulatory assist devices represent a severe life-threatening clinical complication. These bleeding episodes may originate from a reduced functionality of von Willebrand factor (VWF), a multimeric protein pertinent to the formation of a haemostatic plug. It has been reported that the reduced functionality is due to increased proteolytic degradation by the enzyme ADAMTS13, a phenomenon that is facilitated by device-induced increases in shear stress to which VWF is exposed. Here, we have tested a series of VWF-derived protein fragments and monoclonal murine anti-VWF antibodies for their capacity to reduce shear stress-dependent degradation of VWF. Via direct binding experiments, we identified an anti-VWF antibody that partially blocked VWF-ADAMTS13 interactions (46 ± 14%). Epitope mapping experiments revealed that the antibody, designated mAb508, is directed against the distal portion of the VWF D4-domain (residues 2134–2301) and recognises a synthetic peptide encompassing residues 2158–2169. Consistent with its partial inhibition of VWF-ADAMTS13 interactions in binding assays, mAb508 reduced ADAMTS13-mediated VWF degradation in a vortex-based degradation assay by 48 ± 10%. In a HeartMateII-based whole blood-perfusion system, mAb508 was able to reduce degradation of high-molecular-weight (HMW)-VWF-multimers dose-dependently, with a maximal inhibition (83 ± 8%) being reached at concentrations of 10 μg/ml or higher. In conclusion, we report that partial inhibition of VWF-ADAMTS13 interactions using an anti-VWF antibody can prevent excessive degradation of HMW-VWF multimers. This strategy may be used for the development of therapeutic options to treat bleeding episodes due to shear stress-dependent VWF degradation, for instance in patients carrying circulatory assist devices.

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