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

Antoine Rauch; Paulette Legendre; Olivier D. Christophe; Jenny Goudemand; Eric van Belle; André Vincentelli; Cécile V. Denis; Sophie Susen; Peter J. Lenting

doi:10.1160/th14-02-0148

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(05): 1014-1023
DOI: 10.1160/th14-02-0148

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

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

Antoine Rauch

¹INSERM Unit 770, Le Kremlin-Bicêtre, France

²UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France

³Department of Hematology & Transfusion, Lille University Hospital, Lille, France

⁴Equipe d’Accueil 2693, Lille-II University, Lille, France

,

Paulette Legendre

¹INSERM Unit 770, Le Kremlin-Bicêtre, France

²UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France

,

Olivier D. Christophe

¹INSERM Unit 770, Le Kremlin-Bicêtre, France

²UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France

,

Jenny Goudemand

³Department of Hematology & Transfusion, Lille University Hospital, Lille, France

⁴Equipe d’Accueil 2693, Lille-II University, Lille, France

,

Eric van Belle

⁴Equipe d’Accueil 2693, Lille-II University, Lille, France

⁵Department of Cardiology, Lille University Hospital, Lille, France

,

André Vincentelli

⁴Equipe d’Accueil 2693, Lille-II University, Lille, France

⁵Department of Cardiology, Lille University Hospital, Lille, France

,

Cécile V. Denis

¹INSERM Unit 770, Le Kremlin-Bicêtre, France

²UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France

,

Sophie Susen

³Department of Hematology & Transfusion, Lille University Hospital, Lille, France

⁴Equipe d’Accueil 2693, Lille-II University, Lille, France

,

Peter J. Lenting

¹INSERM Unit 770, Le Kremlin-Bicêtre, France

²UMR_S 770, Univ Paris-Sud, Le Kremlin-Bicêtre, France

› Author Affiliations

Abstract

Summary

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 bloodperfusion system, mAb508 was able to reduce degradation of highmolecular- 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.

Keywords

von Willebrand factor - ADAMTS13 - circulatory assist devices - acquired von Willebrand syndrome - antibody therapy

Full Text

References

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