| First Author | Kahr WH | Year | 2013 |
| Journal | Blood | Volume | 122 |
| Issue | 19 | Pages | 3349-58 |
| PubMed ID | 23861251 | Mgi Jnum | J:203707 |
| Mgi Id | MGI:5528579 | Doi | 10.1182/blood-2013-04-499491 |
| Citation | Kahr WH, et al. (2013) Abnormal megakaryocyte development and platelet function in Nbeal2(-/-) mice. Blood 122(19):3349-58 |
| abstractText | Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and alpha-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 alpha-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1, and platelet factor 4. The platelet alpha-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 alpha-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 confirm that alpha-granule secretion plays a significant role in platelet function, and they also indicate that abnormal alpha-granule formation in Nbeal2(-/-) mice has deleterious effects on megakaryocyte survival, development, and platelet production. |
