High‐density lipoprotein 3 and apolipoprotein A‐I alleviate platelet storage lesion and release of platelet extracellular vesicles

Background Stored platelet (PLT) concentrates ( PLC s) for transfusion develop a PLT storage lesion ( PSL ), decreasing PLT viability and function with profound lipidomic changes and PLT extracellular vesicle ( PL‐EV ) release. High‐density lipoprotein 3 ( HD L 3 ) improves PLT homeostasis through silencing effects on PLT activation in vivo. This prompted us to investigate HDL 3 and apolipoprotein A ‐ I (apo A ‐ I ) as PSL ‐antagonizing agents. Study Design and Methods Healthy donor PLC s were split into low‐volume standard PLC storage bags and incubated with native (n) HDL 3 or apo A ‐ I from plasma ethanol fractionation (precipitate IV ) for 5 days under standard blood banking conditions. Flow cytometry, B orn aggregometry, and lipid mass spectrometry were carried out to analyze PL‐EV release, PLT aggregation, agonist‐induced PLT surface marker expression, and PLT and plasma lipid compositions. Results Compared to control, added n HDL 3 and apo A ‐ I significantly reduced PL‐EV release by up to −62% during 5 days, correlating with the added apo A ‐ I concentration. At the lipid level, n HDL 3 and apo A ‐ I antagonized PLT lipid loss (+12%) and decreased cholesteryl ester ( CE )/free cholesterol ( FC ) ratios (−69%), whereas in plasma polyunsaturated/saturated CE ratios increased (+3%) and CE 16:0/20:4 ratios decreased (−5%). Administration of n HDL 3 increased PLT bis(monoacylglycero)phosphate/phosphatidylglycerol (+102%) and phosphatidic acid/lysophosphatidic acid (+255%) ratios and improved thrombin receptor–activating peptide 6–induced PLT aggregation (+5%). Conclusion n HDL 3 and apo A ‐ I improve PLT membrane homeostasis and intracellular lipid processing and increase CE efflux, antagonizing PSL ‐related reduction in PLT viability and function and PL‐EV release. We suggest uptake and catabolism of n HDL 3 into the PLT open canalicular system. As supplement in PLCs , n HDL 3 or apo A ‐ I from F raction IV of plasma ethanol fractionation have the potential to improve PLC quality to prolong storage.