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, ␣ 2 ␤ 1 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 Ca 2؉ 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.

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

“…We show that pantethine effects on platelets are mediated primarily by the maintenance of the redox status, whereas impaired platelet activation associated with ABCA1 defects is mediated by ineffective maturation of dense granules (41). The central role played by platelets in the processes leading to endothelial cell injury may then result in convergent protective effects.…”

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

“…A higher rate of platelet production was also observed for both the S Ϫ L + and S Ϫ L Ϫ mice despite their lower platelet counts, suggesting that these mice must have a higher rate of platelet turnover. Cholesterol enrichment of platelets is known to lead to increased platelet aggregation ( 20,22,75,76 ), which could account for the lower platelet counts in the S Ϫ L + and S Ϫ L Ϫ mice.…”

Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice

“…20,21 Several dyslipidemic states, such as spur cell anemia, 22 sitosterolaemia, 23,24 acanthocytosis, 21 and Tangier disease 25,26 are associated with concurrent defects in platelets and RBCs. Hyperlipidemia and dyslipidemia have been linked with reduced platelet survival time and thrombocytopenia (eg, inverse correlation of plasma total cholesterol and platelet survival time), 23,27,28 although the mechanism by which circulating lipids induce thrombocytopenia remains uncertain.…”