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Recipients' immune systems are triggered by blood and blood component therapy. Transfusion-related immunomodulation (TRIM) is a complicated immunological response to transfusion that results in immunosuppression. The mechanisms of TRIM include the presence of residual white blood cells and apoptotic cells, the infusion of immunosuppressive cytokines that are present in donor components or that occur during blood processing, the transfer of metabolically active growth factor-loaded particles and extracellular vesicles, and the presence of hemoglobin or extracellular vesicles binds to hemoglobin. TRIM variables include donor-specific factors and processing variables. TRIM can explain, at least partially, the controversial negative clinical results observed in patients with covid19. Many potential treatment methods have been used in clinical practice, including supportive interventions, immunomodulators, antiviral therapy, and infusion of convalescent plasma. Here, we summarize current potential treatments for COVID-19 infection-related diseases and discuss the clinical value of blood transfusion-related technologies for COVID-19 treatment in blood transfusion-related immune regulation.

Red blood cell (RBC) transfusions may have a negative impact on the prognosis of patients with cancer, where transfusion‑related immunomodulation (TRIM) may be a significant contributing factor. A number of components have been indicated to be associated with TRIM. Among these, the impact of extracellular vesicles (EVs) has been garnering increasing attention from researchers. EVs are defined as nano‑scale, cell‑derived vesicles that carry a variety of bioactive molecules, including proteins, nucleic acids and lipids, to mediate cell‑to‑cell communication and exert immunoregulatory functions. RBCs in storage constitutively secrete EVs, which serve an important role in TRIM in patients with cancer receiving a blood transfusion. Therefore, the present review aimed to first summarize the available information on the biogenesis and characterization of EVs. Subsequently, the possible mechanisms of TRIM in patients with cancer and the impact of EVs on TRIM were discussed, aiming to provide an outlook for future studies, specifically for formulating recommendations for managing patients with cancer receiving RBC transfusions.

Transfusion-related immunomodulation is a side effect of allogeneic transfusion. During the development of orthotopic renal transplantation, red cell transfusions were administered as an effective immunosuppressant. In the 1980s–90s, the focus and lay hysteria was on viral transmission (hepatitis and AIDS) as risks for blood transfusion. These viral risks are now reduced to very low levels and evidence has emerged that transfusion-related immunomodulation contributes to a number of adverse outcomes associated with allogeneic transfusion. Controversy remains due to the largely retrospective data published. This review will outline historical perspectives as well as look into mechanisms and outcomes. It is important to understand the controversy so that research going forward may be well focused and evidence based.

OBJECTIVES In this study, we aimed to determine the consequences of different amounts of leukocyte transfusion on the outcome of patients undergoing cardiac surgery. DESIGN This was a prospective, single-blinded cohort study conducted for 1 year from July 2018 to June 2019. SETTING The study setting was the Department of Transfusion Medicine, along with Cardiac Anaesthesia, Cardiac Surgery and Cardiac biochemistry departments in a tertiary care cardiac centre. PARTICIPANTS A total of 150 patients undergoing cardiac surgery during the study period were divided into three groups (50 in each): Leukofiltered (LR), Buffy coat depleted (BCD) and Non-leukoreduced (NLR). INTERVENTION The intervention was intra- and postoperative transfusion of packed red blood cells (PRBCs) having different amounts of leukocytes. MEASUREMENTS AND MAIN RESULTS Patient details about length of intensive care unit (ICU) and hospital stay, blood usage, inotropic drug duration, mechanical ventilation, urine output and infection were recorded from the patient data sheet, whereas patients were followed up for 30 days post-operation, and any mortality was noted. Haematological parameters and biochemical parameters for renal function test were analysed on pre- and post-surgical days 1, 3, 5 and 7, whereas on postoperative days 1 and 7, cytokine-like FAS ligands, Interleukin-10 (IL-10) and Interferon-γ (INF-γ) were tested. Patients in all three groups received an average of four, two and two units of packed red blood cells, platelets and fresh frozen plasma, respectively. There was a statistically significant (P

Allogeneic blood components are commonly transfused in trauma, surgery, and intensive care units and are related with adverse effects, such as postoperative infections, multi-organ failure, and mortality. The adverse effects of blood transfusions on the immune system are called as transfusion-related immunomodulation (TRIM). Many clinical trials are conducted to show the clinical effects of TRIM. They found in different clinical settings controversial results. There are many possible mechanisms of TRIM. Although until now, the exact mechanisms are not elucidated resulting in a challenge to unravel this complex interaction between immunomodulation and clinical events leading to morbidity and mortality. It has been postulated that allogeneic leukocytes are associated with the clinical adverse effects of TRIM that predominantly is observed in high-risk patients as cardiovascular surgery. Allogeneic leukocytes could activate inflammation cascade leading to adverse events in high-risk patients. Also other blood components as red cells, plasma, and platelets can play a role in the development of inflammatory complications after blood transfusions. In this review, we will discuss the clinical effects and the possible mechanisms of TRIM in relation with allogeneic leukocytes and mediators derived from allogeneic blood transfusions.

Blood transfusions are common practice across medical disciplines. With the advent of increased testing, blood components continue being made safer, and they are currently the safest they have ever been. This is not always the case. One entity that has been the reason for concern in the literature for the better part of the last 4 decades is what has been termed as “transfusion-related immunomodulation.” This entity encompasses processes by which the transfused blood leads to changes to the immune responses of the recipient causing a number of possible sequelae. The goal of this chapter is to shed some light at this entity and present the current data indicating the potential elements within blood responsible for either the activation of inflammatory responses or immunosuppression and, in some cases, changes to a recipient's gene expression.

Background Adverse events following blood transfusion include allosensitization and generalized immunosuppression, collectively referred to as transfusion-related immune modulation. We evaluated the immunological effects of red blood cell (RBC) and platelet transfusions on alloantibody responses and on immunoregulatory cells in nonimmunosuppressed patients undergoing cardiovascular surgery. Study design and methods Patients were randomized to receive standard unmodified (STD), leukoreduced (LR), or leukoreduced and γ-irradiated (LRγ) RBCs. Patients received only apheresis platelets that were in-process LR and were γ-irradiated for the third arm. Nontransfused patients served as controls for the effects of surgery itself on immunologic changes. Antibodies to HLA were assessed with use of solid-phase assays. The effects of transfusion on adaptive and innate immunity were evaluated by assessing T regulatory cells (Tregs) and invariant natural killer T (iNKT) cells. Results LR of blood products reduced the development of human leukocyte antigen (HLA) alloantibodies, but only in patients without preexisting HLA antibodies. However, if LR blood products were γ-irradiated, HLA antibody production was not reduced. Compared to nontransfused patients, recipients of STD or LR transfusions showed a significant increase in CD4+CD25hi T cells expressing FoxP3 or CTLA4 and also of iNKT cells producing interleukin-4. In contrast, recipients of LRγ blood products showed markedly lower increases in all three cellular assays. Conclusion LR decreased HLA alloantibody production in naive recipients, but did not reduce the immunosuppressive effects of transfusion. LRγ reduced immunosuppression and was not associated with decreased HLA alloantibody production.

This review summarizes current and prior observations regarding transfusion-related immunomodulation (TRIM) and puts these ideas into a modern immunological context, incorporating concepts from innate, adaptive, and nutritional immunity. We propose that TRIM research focus on determining whether there are specific, well-defined immunosuppressive effects from transfusing 'pure' red blood cells (RBCs) themselves, along with the by-products produced by the stored RBCs as a result of the 'storage lesion.' Macrophages are a key cell type involved in physiological and pathological RBC clearance and iron recycling. The plasticity and diversity of macrophages makes these cells potential mediators of immune suppression that could constitute TRIM.Recent reports identified the capacity of macrophages and monocytes to exhibit 'memory.' Exposure to various stimuli, such as engulfment of apoptotic cells and interactions with ß-glucan and lipopolysaccharide, were found to induce epigenetic, metabolic, and functional changes in certain myeloid cells, particularly macrophages and monocytes.Macrophages may mediate the immunosuppressive aspects of TRIM that arise as a result of transfused RBCs and their storage lesion induced by-products.

Blood and blood-component therapy triggers immunological reactions in recipients. Transfusion-related immunomodulation [TRIM] is an important complex biological immune reaction to transfusion culminating in immunosuppression. The mechanisms underlying TRIM include the presence of residual leukocytes and apoptotic cells, the transfusion of immunosuppressive cytokines either present in donor components or generated during blood processing, the transfer of metabolically active growth factor-loaded microparticles and extracellular vesicles and the presence of free hemoglobin or extracellular vesicle-bound hemoglobin. TRIM variables include donor-specific factors as well as processing variables. TRIM may explain, at least in part, the controversial negative clinical outcomes observed in cancer patients receiving transfusion in the context of curative-intent surgeries. The use of novel technologies including metabolomics and proteomics on stored blood may pave the way for a deeper understanding of TRIM in general and its impact on cancer progression.

Background Blood transfusion is suggested to be immunosuppressive in surgical patients. However, the immunomodulatory effect of blood transfusion in obstetric patients with massive haemorrhage remains unknown. Methods Three hundred and fifty-five patients at active labour in the obstetric department were enrolled, and clinical characteristics were extracted from electrical medical records, inpatient notes, anaesthesia notes and discharge summaries. The transfused blood products included RBC, FFP and PLTs. RT-PCR was used to quantify gene expression in the blood samples, and the Spearman rank correlation coefficient was used to test correlation. Results Among the 355 patients, 138 received a diagnosis of obstetric haemorrhage and were treated with blood transfusion. The risk factors for blood transfusion included maternal age, gestational age, preterm labour and instrumental delivery. The infants delivered by the transfusion group had significantly lower birthweight and 1- and 5-min Apgar scores. Most importantly, blood transfusion is associated with a broad suppression of Th cells and an increased IL-10 response. Conclusions Our results show that blood transfusion is associated with immunomodulation in obstetric haemorrhage patients, suggesting more stringent criteria for blood transfusion should be taken into account in the obstetric haemorrhage patients.

Purpose. To elucidate the microRNAs existent in exosomes derived from stored red blood cell (RBC) unit and their potential function. Materials and Methods. Exosomes were isolated from the supernatant derived from stored RBC units by sequential centrifugation. Isolated exosomes were characterized by TEM (transmission electron microscopy), western blotting, and DLS (dynamic light scattering). MicroRNA (miRNA) microarray was performed to detect the expression of miRNAs in 3 exosome samples. Results revealed miRNAs that were simultaneously expressed in the 3 exosome samples and were previously reported to exist in mature RBCs. Functions and potential pathways of some detected miRNAs were illustrated by bioinformatic analysis. Validation of the top 3 abundant miRNAs was carried out by qRT-PCR (quantitative reverse transcription‐polymerase chain reaction). Results. TEM and DLS revealed the mean size of the exosomes (RBC-derived) as 64.08 nm. These exosomes exhibited higher abundance of short RNA than the long RNA. 78 miRNAs were simultaneously detected in 3 exosome samples and mature RBCs. Several biological processes might be impacted by these miRNAs, through their target gene(s) enriched in a particular signalling pathway. The top 3 (abundant) miRNAs detected were as follows: miR-125b-5p, miR-4454, and miR-451a. qRT-PCR revealed higher abundance of miR-451a than others. Only miR-4454 and miR-451a abundance tended to increase with increasing storage time. Conclusion. Exosomes derived from stored RBC units possessed multiple miRNAs and, hence, could serve various functions. The function of exosomes (RBC-derived) might be implemented partly by the predominantly enriched miR-451a.

Background: Transfusion-related immunomodulation (TRIM) can be caused by exosomes and microRNA (miRNA) is one of the critical functional components in exosomes. This study intends to investigate the differences in the expression of exosomal miRNAs in red blood cell (RBC) suspensions at different storage times, also the potential functions related to TRIM of the abundant miRNAs. Methods: Twenty-five bags of RBC suspensions were selected randomly, and exosomes were separated by ultracentrifugation at different storage times. Isolated exosomes were identified by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), and Western Blot (WB). Exosomal miRNA profiles were analyzed using genechip in 5 RBC suspension samples, and the miRNA expressions between different storage times were compared. For the statistically upregulated microRNAs, the bioinformation of their predicted target genes was analyzed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to identify the miRNAs upregulated more than 10 folds at 5weeks storage time in 20 RBC suspension samples.Results: The detection of the gene chip showed most exosomal miRNAs were up-regulated as storage time increases. Compared to RBC suspensions stored for 1 week, that kept for 5 weeks had 539 differential miRNA expressions, among which 159 were significantly different (PConclusions: As storage time increased, various exosomal miRNAs in RBC suspensions accumulated and involved multiple immuno-signaling pathways. The predominantly accumulated miRNA-1246 and miRNA-150-3p were confirmed to participate in pro-inflammation responses and immune-regulation, which might exert essential roles in TRIM.

There is an emerging interest in the risks posed by the ability of blood transfusion to modulate the immune system of recipients. Observational trials suggest that RBC transfusions may be associated with increased morbidity and mortality, however studies demonstrating the deleterious consequences of transfusion-related immunomodulation have had conflicting results. Efforts to understand the biological mechanisms responsible for TRIM are under way, and are focusing on the role that the extracellular vesicles (EVs) that accumulate in a red cell concentrate (RCC) during storage may play. EVs are heterogeneous submicron-sized vesicles that vary in size, composition and surface biomarkers. The biophysical and biochemical parameters of EVs reflect their mechanism of formation and cell sources. RCCs have been shown to contain a mixed population of EVs and not all EVs in RCC are solely from the constituent RBCs. The concentration of the different EVs (the RBC EVs and the non-RBC EVs), their composition, as well as their effects on the quality of the blood product vary depending on the manufacturing methods used to produce the RCC units. This article will review current evidence of the role of extracellular vesicles in transfusion-related immunomodulation and will discuss the impact that different methods used to collect, manufacture and store blood have on the composition and characteristics of EVs in RCCs.

Purported deleterious effects of allogeneic transfusion-related immunomodulation (TRIM) have included increased recurrence of resected malignancies and of postoperative bacterial infections, increased short-term (up to 3-months post-transfusion) mortality from all causes, and activation of endogenous Cytomegalovirus or human immunodeficiency virus infection in transfused compared with untransfused patients. The only established clinical TRIM effect is beneficial: it is the enhanced survival of renal allografts after pretransplant transfusions. However, clinical use of this effect (i.e., administration of deliberate allogeneic, white-cell-reduced pretransplant transfusions to enhance renal allograft survival) is seldom made today. Of the deleterious clinical TRIM effects, which have been investigated in some 200 observational studies and in 20 randomized trials, only increased short-term mortality in cardiac surgery, secondary to non-white-cell-reduced (compared with white-cell-reduced) allogeneic blood transfusion has been consistently documented. Across all available randomized trials in cardiac surgery, there is a 72 % increase in short-term mortality from all causes (p < 0.05), although the mechanism of the effect remains unknown and there is no association with a specific cause of death. Until the effect is disproven or its mechanism is elucidated, all cellular blood components transfused in cardiac surgery should be white-cell-reduced. It is not appropriate to introduce universal white-cell reduction of all transfused cellular blood components for the prevention of TRIM.

Transfusion-related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions.