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J. Biol. Chem., Vol. 279, Issue 32, 34032-34037, August 6, 2004

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Impaired Platelet Activation in Familial High Density Lipoprotein Deficiency (Tangier Disease)^*

Jerzy-Roch Nofer¶, Grazyna Herminghaus, Martin Brodde||, Eberhard Morgenstern**, Stephan Rust, Thomas Engel, Udo Seedorf, Gerd Assmann, Horst Bluethmann, and Beate E. Kehrel||

From the Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, D-48129 Münster, Germany, the Institut für Arterioskleroseforschung an der Universität Münster, D-48149 Münster, Germany, ^||Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Experimentelle und Klinische Hämostaseologie, Universitätsklinik, D-48129 Münster, Germany, ^**Medizinische Biologie, Campus Homburg, Universität des Saarlandes, D-66421 Homburg-Saar, Germany, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland

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, ₂₁ 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 p72^syk 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.

Received for publication, May 10, 2004 , and in revised form, May 25, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität Münster, Albert Schweizer Str. 33, D-48129 Münster, Germany. Tel./Fax: 49-251-8356276; E-mail: nofer{at}uni-muenster.de.

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