Abnormal megakaryocyte development and platelet function in Nbeal2-/- mice

Walter H.A. Kahr, Richard W. Lo, Ling Li, Fred G. Pluthero, Hilary Christensen, Ran Ni, Nima Vaezzadeh, Cynthia E. Hawkins, Andrew S. Weyrich, Jorge Di Paola, Carolina Landolt-Marticorena, Peter L. Gross

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79 Scopus citations

Abstract

Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and α-granule-deficient platelets. GPS has been linked to loss of function mutations in NEABL2 (neurobeachin-like 2), and we describe here a murine GPS model, the Nbeal2-/- mouse. As in GPS, Nbeal2-/- mice exhibit splenomegaly, macrothrombocytopenia, and a deficiency of platelet α-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1, and platelet factor 4. The platelet α-granule membrane protein P-selectin is expressed at 48%of wild-type levels and externalized upon platelet activation. The presence of P-selectin and normal levels of VPS33B and VPS16B in Nbeal2-/- platelets suggests that NBEAL2 acts independently of VPS33B/VPS16B at a later stage of α-granule biogenesis. Impaired Nbeal2-/- platelet function was shown by flow cytometry, platelet aggregometry, bleeding assays, and intravital imaging of laser-induced arterial thrombus formation. Microscopic analysis detected marked abnormalities in Nbeal2-/- bone marrow megakaryocytes, which when cultured showed delayed maturation, decreased survival, decreased ploidy, and developmental abnormalities, including abnormal extracellular distribution of VWF. Our results confirmthat α-granule secretion plays a significant role in platelet function, and they also indicate that abnormal α-granule formation in Nbeal2-/- mice has deleterious effects on megakaryocyte survival, development, and platelet production.

Original languageEnglish
Pages (from-to)3349-3358
Number of pages10
JournalBlood
Volume122
Issue number19
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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    Kahr, W. H. A., Lo, R. W., Li, L., Pluthero, F. G., Christensen, H., Ni, R., Vaezzadeh, N., Hawkins, C. E., Weyrich, A. S., Di Paola, J., Landolt-Marticorena, C., & Gross, P. L. (2013). Abnormal megakaryocyte development and platelet function in Nbeal2-/- mice. Blood, 122(19), 3349-3358. https://doi.org/10.1182/blood-2013-04-499491