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Platelet Biology & its Disorders
Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence
Annabelle Dupont,1,2 Christelle Soukaseum,3 Mathilde Cheptou,3 Frédéric Adam,3 Thomas Nipoti,3 Marc-Damien Lourenco-Rodrigues,3 Paulette Legendre,3 Valérie Proulle,3,4 Antoine Rauch,1,2 Charlotte Kawecki,3 Marijke Bryckaert,3 Jean-Philippe Rosa,3 Camille Paris,2 Catherine Ternisien,5 Pierre Boisseau,6 Jenny Goudemand,1,2 Delphine Borgel,3,7 Dominique Lasne,3,7 Pascal Maurice,8 Peter J. Lenting,3 Cécile V. Denis,3 Sophie Susen1,2,*
Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2493-2500
and Alexandre Kauskot3,*
1Université de Lille, UMR Inserm 1011, Institut Pasteur de Lille, EGID, F-59000 Lille; 2Department of Hematology, CHU de Lille, F-59000 Lille; 3HITh, UMR_S 1176, INSERM Université Paris-Sud, Université Paris-Saclay, F-94270 Le Kremlin-Bicêtre; 4AP-HP, Department of Biological Hematology, CHU Bicêtre, Hôpitaux Universitaires Paris Sud, F- 94270 Paris; 5Laboratory of Hematology, CHU de Nantes, F-44000 Nantes; 6Medical Genetic Department, CHU de Nantes, F-44000 Nantes; 7AP-HP, Department of Biological Hematology, Hôpital Necker, F-75015 Paris and 8UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix aging and Vascular remodelling", Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, F-51000 Reims, France
ABSTRACT
Patients with type 2B von Willebrand disease (vWD) (caused by gain- of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocy- topenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypoth- esis has not been tested in vivo. The relationship between platelet desialyla- tion and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified aIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia.
Introduction
Type 2B von Willebrand disease (vWD) is characterized by gain-of-function mutations in the gene coding for von Willebrand factor (vWF), which enhance the factor’s ability to bind platelet glycoprotein Iba (GPIba). Patients with type 2B vWD display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia described in type 2B vWD, including the incorporation of platelets bound to plasma vWF into circulating aggregates,1-3 and defective platelet production.4,5 In many cases, multiple mecha- nisms may contribute to the development of thrombocytopenia and may lead to
*SS and AK contributed equally as co-senior authors
Correspondence:
ALEXANDRE KAUSKOT
alexandre.kauskot@inserm.fr
Received: September 13, 2018. Accepted: February 26, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.206250
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