Transfusion‐related immune modulation: functional consequence of extracellular vesicles?

Abstract

Extracellular vesicles (EVs) are small, subcellular vesicles that are released from a variety of cells and play important roles in cell-to-cell communication.• Transfused blood products, including red blood cell, platelet, and plasma products contain EVs that are capable of interacting with and altering immune cell function.• The extent to which EVs may contribute to clinically meaningful immunomodulatory effects of transfusion remains unclear and deserving of further study.T he term extracellular vesicle (EV) describes a broad class of small, subcellular vesicular particles that are released from a variety of cell types. Once considered inert debris, emerging data suggest that EVs play pivotal roles in cell-to-cell communication. 1 EVs contain a myriad of biologic response elements, including proteins, nucleic acids, lipid mediators, and other metabolites. While exact mechanisms of EV packaging and release remain unclear, EV content often does not match that of parent cells suggesting differential packaging and release for the purposes of intercellular transport. 2 EV contents also differ based on the mechanism of EV release. There are three main EV categories based on size and mechanism of release. Exosomes are nanoparticles smaller than 0.15 μm released by fusion of the plasma membrane with the endosomal compartment. Microvesicles (also termed ectosomes or microparticles) can be up to 1 to 2 μm and are released by membrane shedding. Finally, apoptotic bodies are the largest particles, ranging approximately 1 to 5 μm, produced from apoptotic cells. While size is often used to differentiate among classes, there is a fair degree of overlap in sizes and at present it is difficult to specifically distinguish EV subpopulations. Once released, EVs are taken up by target cells by a variety of mechanisms, including endocytosis, membrane fusion, micropinocytosis, or phagocytosis. 2 There, EVs are able to regulate a variety of cellular processes. EVs ACCUMULATE IN BLOOD PRODUCTSMuch attention has focused on red blood cell (RBC)-derived EVs as potential mediators of the RBC storage lesion. Membrane vesiculation and EV release are part of the RBC aging process, which is accelerated during hypothermic storage. 3 Multiple reports document accumulation of RBC-derived EVs during storage. 3 It is important to note, however, that RBC products also contain EVs from a variety of cell types, including platelets (PLTs), white blood cells (WBCs), and endothelial cells. Blood collection and component preparation methods significantly impact quantities and composition of EVs released from RBCs and from other cell types. 4,5 There is also a high degree of donor-related variability in EV populations, likely due to differences in donor circulating EV populations and/or in susceptibility of cells to form additional vesicles during component preparation and storage. Thus, each given bag of RBC product may contain vastly different EV populations with accompanying differences in biologic activity.While much of the work on transfusion-related ...

Exosomes From Packed Red Cells Induce Human Mast Cell Activation and the Production of Multiple Inflammatory Mediators

“…These results were in good agreement with a previous study showing that extracellular vesicles in RBCs could be separated using ultracentrifugation ( 4 ). RBCs contain EXs from various cell types, such as platelets and white blood cells ( 3 ). In this study, we did not identify the cell origin of EXs for two reasons as follows: (i) the valuable contents in EXs from different cells might be the same ( 8 ), and (ii) we focused on the pathogenic contents in the total EXs from RBCs rather than those in erythrocyte-derived EXs.…”

“…Recently, the potential immunologic effect of extracellular vesicles from RBCs has attracted growing interest ( 3 ). Extracellular vesicles are small double-membrane vesicles that can be secreted by RBCs and increase in number with storage time.…”

Extracellular vesicle–associated procoagulant activity is highest the first 3 hours after trauma and thereafter declines substantially: A prospective observational pilot study

“…Transfusion of blood products may affect measurements of EVs because they are EV rich. 48 A total of nine patients (27%) received transfusion of blood products as part of in-hospital standard care during the blood sampling period, and some patients also received packed red blood cells as part of prehospital standard care. Some patients received anticoagulants, but this is unlikely to have influenced the results because the patient’s plasma was washed away before EV-associated procoagulant activity measurements.…”

Transfusion‑related immunomodulation in patients with cancer: Focus on the impact of extracellular vesicles from stored red blood cells (Review)

“…However, in stored RBC supernatants, apart from leukocytes and the substances they release, EVs are also constantly secreted by RBCs in storage (77). EV numbers typically increase with longer storage durations and likely contribute to TRIM (77,78).…”

“…Previous studies have indicated that stored RBC-derived EVs are able to mediate TRIM and proinflammatory effects (78)(79)(80). RBC-derived EVs have been reported to inhibit the proliferation and activation of B cells and macrophages in a dose-dependent manner.…”