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von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3
Caterina Casari, … , Cécile V. Denis, Marijke Bryckaert
Caterina Casari, … , Cécile V. Denis, Marijke Bryckaert
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5071-5081. https://doi.org/10.1172/JCI69458.
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Research Article

von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3

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Abstract

von Willebrand disease type 2B (vWD-type 2B) is characterized by gain-of-function mutations in von Willebrand factor (vWF) that enhance its binding to the glycoprotein Ib-IX-V complex on platelets. Patients with vWD-type 2B have a bleeding tendency that is linked to loss of vWF multimers and/or thrombocytopenia. In this study, we uncovered evidence that platelet dysfunction is a third possible mechanism for bleeding tendency. We found that platelet aggregation, secretion, and spreading were diminished due to inhibition of integrin αIIbβ3 in platelets from mice expressing a vWD-type 2B–associated vWF (vWF/p.V1316M), platelets from a patient with the same mutation, and control platelets pretreated with recombinant vWF/p.V1316M. Impaired platelet function coincided with reduced thrombus growth. Further, αIIbβ3 activation and activation of the small GTPase Rap1 were impaired by vWF/p.V1316M following exposure to platelet agonists (thrombin, ADP, or convulxin). Conversely, thrombin- or ADP-induced Ca2+ store release, which is required for αIIbβ3 activation, was normal, indicating that vWF/p.V1316M acts downstream of Ca2+ release and upstream of Rap1. We found normal Syk phosphorylation and PLCγ2 activation following collagen receptor signaling, further implying that vWF/p.V1316M acts directly on or downstream of Ca2+ release. These data indicate that the vWD-type 2B mutation p.V1316M is associated with severe thrombocytopathy, which likely contributes to the bleeding tendency in vWD-type 2B.

Authors

Caterina Casari, Eliane Berrou, Marilyne Lebret, Frédéric Adam, Alexandre Kauskot, Régis Bobe, Céline Desconclois, Edith Fressinaud, Olivier D. Christophe, Peter J. Lenting, Jean-Philippe Rosa, Cécile V. Denis, Marijke Bryckaert

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Figure 2

Analysis of adhesive receptors and granule contents of platelets from a patient with vWD-type 2B exhibiting the vWF/p.V1316M mutation.

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Analysis of adhesive receptors and granule contents of platelets from a ...
(A and B) The expression of adhesive receptors was analyzed by flow cytometry or immunoblotting. (A) Control and patient platelet suspensions were incubated with antibodies directed against αIIbβ3 (HIP8) and α2β1 (MAR4) integrins or against GPIbα (HIP1). Antibody binding was assessed by flow cytometry. (B) GPVI expression was quantified by immunoblotting. (C) α Granule content was assessed by immunoblotting with an anti-vWF and an anti-PF4. Results are representative of 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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