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Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation

Clark, Stephen Robert ORCID:, Thomas, Christopher P. ORCID:, Hammond, Victoria Jayne, Aldrovandi, Maceler, Wilkinson, Gavin William Grahame ORCID:, Hart, Keith William, Murphy, Robert C., Collins, Peter William ORCID: and O'Donnell, Valerie Bridget ORCID: 2013. Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation. Proceedings of the National Academy of Sciences of the United States of America 110 (15) , pp. 5875-5880. 10.1073/pnas.1222419110

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Aminophospholipid (APL) trafficking across the plasma membrane is a key event in cell activation, apoptosis, and aging and is required for clearance of dying cells and coagulation. Currently the phospholipid molecular species externalized are unknown. Using a lipidomic method, we show that thrombin, collagen, or ionophore-activated human platelets externalize two phosphatidylserines (PSs) and five phosphatidylethanolamines (PEs). Four percent of the total cellular PE/PS pool (∼300 ng/2 × 108 cells, thrombin), is externalized via calcium mobilization and protease-activated receptors-1 and -4, and 48% is contained in microparticles. Apoptosis and energy depletion (aging) externalized the same APLs in a calcium-dependent manner, and all stimuli externalized oxidized phospholipids, termed hydroxyeicosatetraenoic acid-PEs. Transmembrane protein-16F (TMEM-16F), the protein mutated in Scott syndrome, was required for PE/PS externalization during thrombin activation and energy depletion, but not apoptosis. Platelet-specific APLs optimally supported tissue factor-dependent coagulation in human plasma, vs. APL with longer or shorter fatty acyl chains. This finding demonstrates fatty acids as molecular determinants of APL that regulate hemostasis. Thus, the molecular species of externalized APL during platelet activation, apoptosis, and energy depletion were characterized, and their ability to support coagulation revealed. The findings have therapeutic implications for bleeding disorders and transfusion therapy. The assay could be applied to other cell events characterized by APL externalization, including cell division and vesiculation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
Publisher: National Academy of Sciences
ISSN: 0027-8424
Last Modified: 24 Oct 2022 10:41

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