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ATP‐binding cassette transporter 1 (ABCA1) deficiency decreases platelet reactivity and reduces thromboxane A2 production independently of hematopoietic ABCA1
Author(s) -
Lhermusier T.,
Severin S.,
Van Rothem J.,
Garcia C.,
BertrandMichel J.,
Le Faouder P.,
Hechler B.,
Broccardo C.,
Couvert P.,
Chimini G.,
Sié P.,
Payrastre B.
Publication year - 2016
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13247
Subject(s) - abca1 , tangier disease , platelet , atp binding cassette transporter 1 , medicine , thrombin , endocrinology , thromboxane , cholesterol , chemistry , platelet activation , biology , transporter , biochemistry , gene
Essentials The role of ATP‐binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1‐deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1.Summary Background The ATP ‐binding cassette transporter ABCA 1 is required for the conversion of apolipoprotein A‐1 to high‐density lipoprotein ( HDL ), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA 1 in platelet functions remains poorly characterized. Objective To determine the role of ABCA 1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. Methods and results We studied the impact of ABCA 1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA 1‐deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium‐induced phosphatidylserine exposure. Interestingly, ABCA 1‐deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 ( TXA 2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA 2, was primarily dependent on external environment and not on the hematopoietic ABCA 1. Decreased aggregation and production of TXA 2 and eicosanoids were also observed in platelets from Tangier patients. Conclusions Absence of ABCA 1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA 2 production through a hematopoietic ABCA 1‐independent mechanism.