FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly. Blood 2011 Aug 25;118(8):2285-95
Date
06/10/2011Pubmed ID
21652675Pubmed Central ID
PMC3162356DOI
10.1182/blood-2011-04-348482Scopus ID
2-s2.0-80052144121 (requires institutional sign-in at Scopus site) 93 CitationsAbstract
Filamin A (FlnA) is a large cytoplasmic protein that crosslinks actin filaments and anchors membrane receptors and signaling intermediates. FlnA(loxP) PF4-Cre mice that lack FlnA in the megakaryocyte (MK) lineage have a severe macrothrombocytopenia because of accelerated platelet clearance. Macrophage ablation by injection of clodronate-encapsulated liposomes increases blood platelet counts in FlnA(loxP) PF4-Cre mice and reveals the desintegration of FlnA-null platelets into microvesicles, a process that occurs spontaneously during storage. FlnA(loxP) PF4-Cre bone marrows and spleens have a 2.5- to 5-fold increase in MK numbers, indicating increased thrombopoiesis in vivo. Analysis of platelet production in vitro reveals that FlnA-null MKs prematurely convert their cytoplasm into large CD61(+) platelet-sized particles, reminiscent of the large platelets observed in vivo. FlnA stabilizes the platelet von Willebrand factor receptor, as surface expression of von Willebrand factor receptor components is normal on FlnA-null MKs but decreased on FlnA-null platelets. Further, FlnA-null platelets contain multiple GPIbα degradation products and have increased expression of the ADAM17 and MMP9 metalloproteinases. Together, the findings indicate that FlnA-null MKs prematurely release large and fragile platelets that are removed rapidly from the circulation by macrophages.
Author List
Jurak Begonja A, Hoffmeister KM, Hartwig JH, Falet HAuthors
Herve Falet PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinKarin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ADAM ProteinsADAM17 Protein
Animals
Blood Platelets
Cell Differentiation
Cell Size
Female
Filamins
Integrin beta3
Male
Matrix Metalloproteinase 9
Megakaryocytes
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Microtubules
Nerve Tissue Proteins
Platelet Count
Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
Pregnancy
Protein Stability
Thrombocytopenia
Thrombopoiesis
