LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B - Institut Pasteur Access content directly
Journal Articles JCI Insight Year : 2016

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

Alexandre Kauskot
Sonia Poirault-Chassac
  • Function : Author
Frédéric Adam
  • Function : Author
Vincent Muczynski
Caterina Casari
Jean-Claude Bordet
  • Function : Author
Christelle Soukaseum
  • Function : Author
Chantal Rothschild
  • Function : Author
Valérie Proulle
  • Function : Author
Audrey Pietrzyk-Nivau
  • Function : Author
Eliane Berrou
  • Function : Author
Olivier Christophe
Jean-Philippe Rosa
  • Function : Author
Peter Lenting
  • Function : Author
Marijke Bryckaert
  • Function : Author
Cécile Denis
Dominique Baruch
  • Function : Author

Abstract

von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein's multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p.V1316M mutation in the murine Vwf gene and in a patient bearing this mutation. We provide evidence of a profound defect in megakaryocyte (MK) function since: (a) the extent of proplatelet formation was drastically decreased in 2B MKs, with thick proplatelet extensions and large swellings; and (b) 2B MKs presented actin disorganization that was controlled by upregulation of the RhoA/LIM kinase (LIMK)/cofilin pathway. In vitro and in vivo inhibition of the LIMK/cofilin signaling pathway rescued actin turnover and restored normal proplatelet formation, platelet count, and platelet size. These data indicate, to our knowledge for the first time, that the severe macrothrombocytopenia in VWD-type 2B p.V1316M is due to an MK dysfunction that originates from a constitutive activation of the RhoA/LIMK/cofilin pathway and actin disorganization. This suggests a potentially new function of vWF during platelet formation that involves regulation of actin dynamics.

Dates and versions

pasteur-03209475 , version 1 (27-04-2021)

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Alexandre Kauskot, Sonia Poirault-Chassac, Frédéric Adam, Vincent Muczynski, Gabriel Ayme, et al.. LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B. JCI Insight, 2016, 1 (16), pp.e88643. ⟨10.1172/jci.insight.88643⟩. ⟨pasteur-03209475⟩

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