title: Impaired platelet activation in familial high density lipoprotein deficiency (Tangier disease).
abstract: ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, alpha2beta1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, D-48129 Münster, Germany. nofer@uni-muenster.de
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.forename: Grazyna
authors.initials: G
authors.lastname: Herminghaus
authors.forename: Martin
authors.initials: M
authors.lastname: Brodde
authors.forename: Eberhard
authors.initials: E
authors.lastname: Morgenstern
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.forename: Thomas
authors.initials: T
authors.lastname: Engel
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
authors.forename: Gerd
authors.initials: G
authors.lastname: Assmann
authors.forename: Horst
authors.initials: H
authors.lastname: Bluethmann
authors.forename: Beate E
authors.initials: BE
authors.lastname: Kehrel
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood; D001792:Blood Platelets / Q000737:chemistry / Q000502:physiology / Q000648:ultrastructure; D015815:Cell Adhesion Molecules / Q000097:blood; D003094:Collagen / Q000097:blood / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000502:physiology / Q000648:ultrastructure; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000737:chemistry / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008875:Middle Aged; D010718:Phosphatidylserines / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins; D013631:Tangier Disease / Q000097:blood*; D060149:Tetraspanin 30; D013917:Thrombin / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015815:Cell Adhesion Molecules; D003094:Collagen; D005340:Fibrinogen; D051907:Lysosomal Membrane Proteins; D010718:Phosphatidylserines; D010980:Platelet Membrane Glycoproteins; D060149:Tetraspanin 30; D013917:Thrombin; C577836:ABCA1 protein, human; C554586:CD63 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C554587:Cd63 protein, mouse