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Introduction: Red blood cell (RBC) transfusion may affect the recipient immune system. During RBC storage in an unphysiological environment, RBC quality and function are impaired, the cells bleb extracellular vesicles (EVs), and other bioactive substances accumulate in the storage medium. EVs can carry reactive biomolecules and mediate cell-cell interactions. Thus, EVs could explain RBC transfusion related immunomodulation, particularly after prolonged storage. Methods: We exposed peripheral blood mononuclear cells (PBMCs) to allogeneic RBC supernatant (SN) and EVs from fresh and longer-stored RBC units, diluted plasma, and storage solution SAGM, and studied activation and proliferation of T-cells by flow cytometry, and cytokine secretion of LPS-stimulated PBMCs by enzyme-linked immunosorbent assay (ELISA). Results: Both fresh and longer-stored RBC SN but not EVs induced immunomodulation in recipient cells. RBC SN and diluted plasma augmented the proliferation of particularly CD8+ T-cells in a 4-day proliferation assay. T-cell activation by SN was evident already after 5 h as shown by upregulation of CD69. SN suppressed monocyte TNF-α and increased IL-10 secretion while diluted plasma increased secretion of both cytokines. Conclusion: This in vitro study demonstrates that stored RBC SN will have mixed immunomodulatory effects depending on responder cells and conditions, independent of RBC storage age. Fresh RBCs containing relatively few EVs can induce immune responses. Residual plasma in the products may contribute to these effects. [ABSTRACT FROM AUTHOR]

Introduction: Eicosanoids are bioactive lipids present in packed red blood cells (PRBCs), and might play a role in transfusion-related immunomodulation (TRIM). We tested the feasibility of analyzing eicosanoid profiles in PRBC supernatant and in plasma samples of postoperative intensive care unit (ICU) patients transfused with one unit of PRBCs. Methods: We conducted a prospective, observational feasibility study enrolling postoperative ICU patients: 1) patients treated with acetylsalicylic acid following abdominal aortic surgery (Aorta); 2) patients on immunosuppressants after bilateral lung transplantation (LuTx); and 3) patients undergoing other types of major surgery (Comparison). Abundances of arachidonic acid (AA) and seven predefined eicosanoids were assessed by liquid chromatography and tandem mass spectrometry. PRBC supernatant was sampled directly from the unit immediately prior to transfusion. Spearman’s correlations between eicosanoid abundance in PRBCs and storage duration were assessed. Patient plasma was collected at 30-min intervals: Three times each before and after transfusion. To investigate temporal changes in eicosanoid abundances, we fitted linear mixed models. Results: Of 128 patients screened, 21 were included in the final analysis (Aorta n = 4, LuTx n = 8, Comparison n = 9). In total, 21 PRBC and 125 plasma samples were analyzed. Except for 20-hydroxyeicosatetraenoic acid (HETE), all analyzed eicosanoids were detectable in PRBCs, and their abundance positively correlated with storage duration of PRBCs. While 5-HETE, 12-HETE/8-HETE, 15-HETE, 20-HETE, and AA were detectable in virtually all plasma samples, 9-HETE and 11-HETE were detectable in only 57% and 23% of plasma samples, respectively. Conclusions: Recruitment of ICU patients into this transfusion study was challenging but feasible. Eicosanoid abundances increased in PRBC supernatants during storage. In plasma of ICU patients, eicosanoid abundances were ubiquitously detectable and showed limited fluctuations over time prior to transfusion. Taken together, larger clinical studies seem warranted and feasible to further investigate the role of PRBC-derived eicosanoids in TRIM. [ABSTRACT FROM AUTHOR]

Introduction: Eicosanoids are bioactive lipids present in packed red blood cells (PRBCs), and might play a role in transfusion-related immunomodulation (TRIM). We tested the feasibility of analyzing eicosanoid profiles in PRBC supernatant and in plasma samples of postoperative intensive care unit (ICU) patients transfused with one unit of PRBCs.Methods: We conducted a prospective, observational feasibility study enrolling postoperative ICU patients: 1) patients treated with acetylsalicylic acid following abdominal aortic surgery (Aorta); 2) patients on immunosuppressants after bilateral lung transplantation (LuTx); and 3) patients undergoing other types of major surgery (Comparison). Abundances of arachidonic acid (AA) and seven pre-defined eicosanoids were assessed by liquid chromatography and tandem mass spectrometry. PRBC supernatant was sampled directly from the unit immediately prior to transfusion. Spearman’s correlations between eicosanoid abundance in PRBCs and storage duration were assessed. Patient plasma was collected at 30-min intervals: Three times each before and after transfusion. To investigate temporal changes in eicosanoid abundances, we fitted linear mixed models.Results: Of 128 patients screened, 21 were included in the final analysis (Aorta n = 4, LuTx n = 8, Comparison n = 9). In total, 21 PRBC and 125 plasma samples were analyzed. Except for 20-hydroxyeicosatetraenoic acid (HETE), all analyzed eicosanoids were detectable in PRBCs, and their abundance positively correlated with storage duration of PRBCs. While 5-HETE, 12-HETE/8-HETE, 15-HETE, 20-HETE, and AA were detectable in virtually all plasma samples, 9-HETE and 11-HETE were detectable in only 57% and 23% of plasma samples, respectively.Conclusions: Recruitment of ICU patients into this transfusion study was challenging but feasible. Eicosanoid abundances increased in PRBC supernatants during storage. In plasma of ICU patients, eicosanoid abundances were ubiquitously detectable and showed limited fluctuations over time prior to transfusion. Taken together, larger clinical studies seem warranted and feasible to further investigate the role of PRBC-derived eicosanoids in TRIM.

Transfusions of blood provide essential therapeutic measures in a number of pathological conditions. However, when carrying out blood component therapy, it is important to consider probability of post-transfusion complications. Most of them are immune-mediated side effects. The unfavorable consequences of blood transfusions can manifest at long-range time periods, and pathogenesis of these phenomena may be associated not only with the presence of alloantibodies. They may be caused by alloimmunization to HLA antigens, leukocyte factors, including cytokines, products of leukocyte degranulation, as well as storage-related erythrocyte damage («storage lesion»), immunomodulatory properties of extracellular vesicles or microparticles derived from blood components, and other factors. Despite significant number of publications on this issue, a lot of unresolved issues still remain, concerning transfusion-related effects of blood components on the immune system of recipients. The review article provides the results of current studies in this area. We present and discuss the results of current studies and the features of transfusion-mediated immunomodulation (TRIM) revealed over recent years, when transfusing different blood components. The role of plasma factors, microparticles, platelets and erythrocytes, HLA sensitization and microchimerism in the development of TRIM is highlighted, the data on occurrence and clinical features of TRIM in perioperative period are presented. A separate section of the review provides information about recent clinical studies, devoted to the issues of TRIM in different clinical cohorts, including newborns, patients with malignant neoplasms, immunocompromised patients after heart and vascular surgery. The data on TRIM incidence in the patients with exhausted immune system due to previous disease or treatment, severe comorbidity, extensive surgical thoracic/abdominal intervention and artificial circulation are also in scope. As based on the studies performed, the role of distinct measures, e.g., washing of erythrocyte concentrates, leukodepletion, and gamma irradiation are discussed in view of potential TRIM prevention. The results of published research do not allow us to draw definite conclusions about the effects of blood component transfusion on the immune system of recipients with respect to differences between the studied groups of patients, characteristics of the studied disorders and clinical situations, diversity of hemocomponents, as well as varying standards of transfusion therapy adopted in different countries. However, the systematic literature review may provide some guidance in transfusion-mediated immune modulation.

Background: Allogeneic red blood cell (RBC) transfusion can induce immunosuppression, which can then increase the susceptibility to postoperative infection. However, studies in different types of surgery show conflicting results regarding this effect.Methods: In this retrospective cohort study conducted in a tertiary referral centre, we included adult patients undergoing clean-contaminated surgery from 2014 to 2018. Patients who received allogeneic RBC transfusion from preoperative Day 30 to postoperative Day 30 were included into the transfusion group. The control group was matched for the type of surgery in a 1:1 ratio. The primary outcome was infection within 30 days after surgery, which was defined by healthcare-associated infection, and identified mainly based on antibiotic regimens, microbiology tests, and medical notes.Results: Among the 8098 included patients, 1525 (18.8%) developed 1904 episodes of postoperative infection. Perioperative RBC transfusion was associated with an increased risk of postoperative infection after controlling for 27 confounders by multivariable regression analysis (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.39-1.84; P<0.001) and propensity score weighing (OR: 1.64; 95% CI: 1.45-1.85; P<0.001) and matching (OR: 1.70; 95% CI: 1.43-2.01; P<0.001), and a dose-response relationship was observed. The transfusion group also showed higher risks of surgical site infection, pneumonia, bloodstream infection, multiple infections, intensive care admission, unplanned reoperation, prolonged postoperative length of hospital stay, and all-cause death.Conclusions: Perioperative allogeneic RBC transfusion is associated with an increased risk of infection after clean-contaminated surgery in a dose-response manner. Close monitoring of infections and enhanced prophylactic strategies should be considered after transfusion. [ABSTRACT FROM AUTHOR]

Transfusion-related immunomodulation (TRIM) has been described in adults; however, its existence in neonates is not confirmed. The generation of TRIM is attributed to increased concentrations of IL-8, sICAM-1 and other pro-inflammatory cytokines. This study aimed to monitor changes in IL-8, sICAM-1 as markers for TRIM in premature infants at different postnatal ages. Preterm infants with a gestational age between 28 and 32 weeks who were receiving PRBC transfusion during the first 28 days of life were included in the study. Infants were stratified into two groups according to their postnatal age: Group 1 with postnatal ages of (0–14) days and Group 2 of (15–28) days. The concentrations of IL-8 and sICAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) before transfusion, 6 h after the end of transfusion and in the donor's PRBCs bag immediately before infusion into the baby. IL-8 concentration in the PRBCs bags correlated with post-transfusion level in Group 2 (r = 0.59, p = 0.002) but not in Group 1 (r = 0.39, p = 0.06). sICAM-1 concentration in the bag correlated with infants'concentrations in neither group. In Group 1, pre-transfusion concentrations of both cytokines (IL-8 and sICAM-1) did not correlate whereas post-transfusion concentrations did correlate (r = –0.09, p = 0.68 and r = 0.4, p = 0.05 respectively). In Group 2, the concentrations of both cytokines did not correlate with each other during pre-transfusion (r = 0.11, p = 0.58) as well as post-transfusion (r = 0.12, p = 0.56). There was no significant increase in either cytokines after transfusion in each group. This study showed positive correlation between IL-8 concentration in the transfusion bag and post transfusion in Group 2 infants which could be attributed to passive transmission from the bags. This study does not support an immune modulatory effect for packed RBC in preterm infants. [ABSTRACT FROM AUTHOR]

Anaemia of prematurity will affect 90% of all very preterm infants, resulting in at least one red blood cell (RBC) transfusion. A significant proportion of preterm infants require multiple transfusions over the course of hospital admission. Growing evidence supports an association between transfusion exposure and adverse neonatal outcomes. In adults, transfusion-associated sepsis, transfusion-related acute lung injury and haemolytic reactions are the leading causes of transfusion-related morbidity and mortality; however, these are seldom recognised in newborns. The association between transfusion and adverse outcomes remains inconclusive. However, the evidence from preclinical studies demonstrates that RBC products can directly modulate immune cell function, a pathway termed transfusion-related immunomodulation (TRIM), which may provide a mechanism linking transfusion exposure with neonatal morbidities. Finally, we discuss the impact of TRIM on transfusion medicine, how we may address these issues and the emerging areas of research aimed at improving the safety of transfusions in this vulnerable population. [ABSTRACT FROM AUTHOR]

In the United States, roughly 4.5 million patients per year receive transfusions of various blood products. Despite the lifesaving benefits of transfusion therapy, it is an independent risk factor for infection, morbidity, and death in critically ill patients. It's important for nurses to understand the potential complications patients face when blood products are administered and to recognize that patients who have received blood products in the past remain at risk for delayed reactions, including immune compromise and infection. Here, the authors review the blood products that are commonly transfused; discuss potential complications of transfusion, as well as their associated signs and symptoms; and outline current recommendations for transfusion therapy that are widely supported in the medical and nursing literature. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Worldwide, cardiac surgery is a common procedure requiring a large quantity of allogeneic blood products, which are associated with postoperative complications. Leukocytes present in blood products may play a role in these complications, which are referred to as transfusion-related immunomodulation (TRIM). Several randomized controlled trials (RCTs) in different settings investigated the effects of allogeneic leukocytes in red blood cells (RBCs). Cardiac surgery studies reported a reduction in postoperative infections and mortality in patients that received leukocyte-reduced RBCs compared with leukocyte-containing RBCs; this was mainly due to more deaths due to infections and multiple organ dysfunction syndrome (MODS) in the group that received leukocyte-containing RBCs. Patients with postoperative complications had higher concentrations of inflammatory mediators. These findings suggest that leukocyte-containing transfusion during cardiac surgery induces a second insult to the systemic inflammatory response. In the present review we discuss the possible role of blood transfusions in cardiac surgery. Especially, we focus on the possible role of allogeneic leukocytes associated with postoperative complications after cardiac surgery.

Worldwide, cardiac surgery is a common procedure requiring a large quantity of allogeneic blood products, which are associated with postoperative complications. Leukocytes present in blood products may play a role in these complications, which are referred to as transfusion-related immunomodulation (TRIM). Several randomized controlled trials (RCTs) in different settings investigated the effects of allogeneic leukocytes in red blood cells (RBCs). Cardiac surgery studies reported a reduction in postoperative infections and mortality in patients that received leukocyte-reduced RBCs compared with leukocyte-containing RBCs; this was mainly due to more deaths due to infections and multiple organ dysfunction syndrome (MODS) in the group that received leukocyte-containing RBCs. Patients with postoperative complications had higher concentrations of inflammatory mediators. These findings suggest that leukocyte-containing transfusion during cardiac surgery induces a second insult to the systemic inflammatory response. In the present review we discuss the possible role of blood transfusions in cardiac surgery. Especially, we focus on the possible role of allogeneic leukocytes associated with postoperative complications after cardiac surgery.

Background and Objectives: Multi-transfused thalassemic patients are prone to transfusions related complications. Study of these reactions and correlating them with the leukodepletion of the transfused packed red blood cells (PRBCs) reduces transfusion complications due to the transfused leukocytes. Materials and Methods: This is a retrospective study carried out on 1152 transfusions in 161 thalassemic patients at our institute between January 2011 and December 2011. The total transfusions were classified into three categories depending on the leukodepletion status of the PRBC. The clinical records and the reaction workup done to rule out the hemolytic reactions were recorded. Results: Reactions were noted in three (0.2%) out of 161 thalassemic patients were recorded. Two reactions were recorded on transfusions of leukoreduced (buffy-coat method) and one reaction in nonleukoreduced PRBC, respectively. No reactions were recorded on transfusions leucodepleted done by bedside filter. Conclusion: Leukodepletion by using bedside filter is a better method for avoiding transfusion reactions. Though in resource limited settings, leukoreduction using the buffy-coat method is also effective in reducing the transfusion reactions. Leukoreduction of transfused blood cellular components in thalassemic patients is helpful in preventing transfusion reactions.

Although allogeneic blood transfusion (ABT) is a valuable medical practice, it has some critical complications. One of these complications is transfusion-related immunomodulation (TRIM). Transfusionrelated immunomodulation describes the changes and its results in recipient's immune system after ABT. After ABT, some outcomes may be observed in the recipient including increased graft survival, decreased Crohn's disease recurrences and recurrent spontaneous abortuses, increased postoperative bacterial infections, cancer recurrences and mortality, and reactivation of latent infections such as cytomegalovirus and human immunodeficiency virus. It has been postulated that TRIM may originate from leukocytes within the product, biologic response modifiers-immunologic mediators (BRM-IM) that accumulate within the plasma or soluble human leukocyte antigen-class I molecules within the allogeneic plasma. A lso, s ome p roperties o f e rythrocytes, s torage t ime o f blood c omponents, a nd t he n umber o f transfused products are accused of TRIM development. However, main factors held responsible for TRIM development are allogeneic leukocytes and related BRM-IMs. It is thought that mechanisms such as clonal deletion, immunosuppression, anergy, microchimerism, the polarization of the immune response from T helper 1 (Th1) to Th2 and, apoptosis in the recipient immune system may cause TRIM. For this reason, leukoreduction is suggested for prevention. However, this application may not be efficient since reasons other than leukocytes may limit leukoreduction. [ABSTRACT FROM AUTHOR]

Background Leukocyte filtration has been hypothesized to reduce the risk of postoperative infections by alleviating the immunosuppressive effect of whole blood. However, the literature regarding the clinical efficacy of leukocyte filtration remains conflicted. This meta-analysis investigates the impact of allogeneic and autologous leukocyte-filtered blood transfusions on the incidence of postoperative infections in adult surgical patients. Methods A comprehensive literature search of PubMed, Google Scholar, and Cochrane Central Registry of Controlled trials (1966-2016) was completed for all published randomized controlled trials. Postoperative infections under “as-per-protocol” (APP) and “intention-to-treat” (ITT), length of stay, and mortality were analyzed. Results Sixteen randomized controlled trials involving 6586 randomized (ITT) patients (4615 APP patients) in various clinical settings were evaluated. The leukocyte-filtered blood group demonstrated an overall 26% risk reduction in postoperative infections when analyzed by APP (relative risk [RR] = 0.74; 95% confidence interval [CI, 0.60-0.92]; P = 0.007) and a 22% risk reduction when analyzed by ITT (RR = 0.78; 95% CI [0.65-0.94]; P = 0.009). Leukocyte-filtered blood was also associated with a significant reduction in length of stay (standardized difference of mean [SDM] = −0.74; 95% CI [−1.32 to −0.15]; P = 0.014) and all-cause mortality (RR = 0.74; 95% CI [0.57-0.95]; P = 0.018). Conclusions Leukocyte-filtered blood transfusions are associated with significantly lower postoperative infection rates in both the APP and ITT populations. Leukocyte filtration also shortens length of stay and decreases all-cause mortality in surgical patients and should be considered in all surgical patients. [ABSTRACT FROM AUTHOR]

Blood transfusions reportedly modulate the recipient's immune system. Transfusion-related immunomodulation has been suggested as a mechanism of some adverse clinical outcomes. Extracellular nucleic acids circulate in plasma and activate relevant immune responses, but little is known about their mechanism of action in transfusion-related immunomodulation (TRIM). The aim of this study was to investigate the effects of cell-free nucleic acids (CFNAs) produced by red blood cells (RBCs) on innate immunity, especially peripheral blood mononuclear cells (PBMCs) and macrophages, and to investigate the mechanism of action. Differentially expressed genes (DEGs) between PBMCs exposed to RBC-produced CFNA and normal PBMCs were analyzed by gene expression data combined with bioinformatics. KEGG and GO enrichment analyses were performed for the DEGs, and in vitro experiments were performed for the effects of key genes on the release of inflammatory factors from macrophages. Analysis of microarray data showed that exposure of monocytes to RBC-produced CFNAs increased the expression of genes involved in the innate immune response, including chemokines, chemokine receptors, and innate response receptors, and that calcium channel activity was highly regulated, with a key gene being CaMKIV. CaMKIV played a critical role in LPS-induced inflammatory factor release from macrophages, which was exacerbated by overexpression of the CaMKIV gene. RBCs regulate the release of inflammatory factors during blood transfusion by releasing CFNAs and affecting expression of the CaMKIV gene in PBMCs or macrophages, which is a potential regulatory mechanism of blood transfusion–related immune regulation and related adverse reactions. • CNFAs in RBCs render CaMKIV activation of PBMCs / macrophages, which is a key regulatory gene in TRIM. • CaMKIV promotes macrophage M1 polarization and inflammatory release. • CaMKIV is a developmental therapeutic target for transfusion related adverse reactions. [ABSTRACT FROM AUTHOR]

Patient blood management (PBM) is a systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood and minimizing allogenic transfusion need and risk. According to the PBM approach, the goals of perioperative anemia management include early diagnosis, targeted treatment, blood conservation, restrictive transfusion except in cases of acute and massive hemorrhage, and ongoing quality assurance and research efforts to advance overall blood health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Red blood cell (RBC) transfusion may affect the recipient immune system. During RBC storage in an unphysiological environment, RBC quality and function are impaired, the cells bleb extracellular vesicles (EVs), and other bioactive substances accumulate in the storage medium. EVs can carry reactive biomolecules and mediate cell-cell interactions. Thus, EVs could explain RBC transfusion related immunomodulation, particularly after prolonged storage., Methods: We exposed peripheral blood mononuclear cells (PBMCs) to allogeneic RBC supernatant (SN) and EVs from fresh and longer-stored RBC units, diluted plasma, and storage solution SAGM, and studied activation and proliferation of T-cells by flow cytometry, and cytokine secretion of LPS-stimulated PBMCs by enzyme-linked immunosorbent assay (ELISA)., Results: Both fresh and longer-stored RBC SN but not EVs induced immunomodulation in recipient cells. RBC SN and diluted plasma augmented the proliferation of particularly CD8 + T-cells in a 4-day proliferation assay. T-cell activation by SN was evident already after 5 h as shown by upregulation of CD69. SN suppressed monocyte TNF-α and increased IL-10 secretion while diluted plasma increased secretion of both cytokines., Conclusion: This in vitro study demonstrates that stored RBC SN will have mixed immunomodulatory effects depending on responder cells and conditions, independent of RBC storage age. Fresh RBCs containing relatively few EVs can induce immune responses. Residual plasma in the products may contribute to these effects., Competing Interests: The authors declare no conflict of interests., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Abstract: Background: Transfusion of packed red blood cells (RBCs) produces a myriad of immunologic derangements, from suppressive to stimulatory. Proliferation of human T cells is suppressed in vitro after exposure to processed red blood cells (PRBCs). We hypothesized that this effect would be mitigated by using fresh RBCs. We also hypothesized that this suppressive effect was a generalized effect on lymphocyte proliferation and would be observed in both CD4+ and CD8+ T-cell subpopulations as well as B cells. Materials and methods: We isolated human T cells from donor peripheral blood mononuclear cells and exposed them to either blood bank PRBCs or fresh RBCs from volunteer donors and stimulated them with anti-CD3/anti-CD28. Human B cells were stimulated with lipopolysaccharide and exposed to PRBCs or fresh RBCs. We measured proliferation of B cells by thymidine incorporation assays. We also treated RBCs with citrate-phosphate-dextrose (CPD) at different time points before culture them with stimulated T cells to determine the role of this common RBC storage solution in lymphocyte proliferation. Results: In vitro proliferation of CD4+ and CD8+ T cells was suppressed by blood bank RBCs. This suppression is eliminated when fresh RBCs were used. The B cells showed inhibition of proliferation when exposed to similar conditions, which appeared to be consistent over serial dilutions. Fresh RBCs exposed to CPD did not appear suppressive in the first 6 h after exposure. Conclusions: T-cell and B-cell proliferation inhibition by blood banked RBCs suggests a generalized effect of RBCs on cellular proliferation. The lack of suppression by fresh RBCs further suggests that something involved in blood banking alters RBC properties such that they attain a suppressive phenotype. One such blood banking component, CPD, does not appear to affect this suppressive phenotype within the first 6 h. [Copyright &y& Elsevier]

Abstract: Many biological molecules in the stored blood were involved in transfusion-related immunomodulation. One important effect was the differentiation bias of immune cells to Th2 type. In this study, we observed the immune regulation of extracellular ubiquitin accummulated in the plasma of whole blood on the differentiation of T help cells in vitro using ELISA and quantitative fluorescence real-time PCR with the help of LPS stimulated human peripheral blood mononuclear cells. We found extracellular ubiquitin promoted Th2 cytokine IL-4 production and Th2-inducing transcription factor STAT6 expression, but inhibited Th1 cytokine IFN-γ and Th1-inducing transcription factor T-bet, at the same time, proinflammation cytokine TNF-α was also inhibited. These findings probably contribute to the potent evidence that extracellular ubiquitin plays an indispensable role in the differentiation of T help cells which is crucial to the effects of transfusion-related immunomodulation. [Copyright &y& Elsevier]

Worldwide, cardiac surgery is a common procedure requiring a large quantity of allogeneic blood products, which are associated with postoperative complications. Leukocytes present in blood products may play a role in these complications, which are referred to as transfusion-related immunomodulation (TRIM). Several randomized controlled trials (RCTs) in different settings investigated the effects of allogeneic leukocytes in red blood cells (RBCs). Cardiac surgery studies reported a reduction in postoperative infections and mortality in patients that received leukocyte-reduced RBCs compared with leukocyte-containing RBCs; this was mainly due to more deaths due to infections and multiple organ dysfunction syndrome (MODS) in the group that received leukocyte-containing RBCs. Patients with postoperative complications had higher concentrations of inflammatory mediators. These findings suggest that leukocyte-containing transfusion during cardiac surgery induces a second insult to the systemic inflammatory response. In the present review we discuss the possible role of blood transfusions in cardiac surgery. Especially, we focus on the possible role of allogeneic leukocytes associated with postoperative complications after cardiac surgery. [ABSTRACT FROM AUTHOR]

Objective– To review the evolution of and controversies associated with allogenic blood transfusion in critically ill patients. Data sources– Veterinary and human literature review. Human Data Synthesis– RBC transfusion practices for ICU patients have come under scrutiny in the last 2 decades. Human trials have demonstrated relative tolerance to severe, euvolemic anemia and a significant outcome advantage following implementation of more restricted transfusion therapy. Investigators question the ability of RBCs stored longer than 2 weeks to improve tissue oxygenation, and theorize that both age and proinflammatory or immunomodulating effects of transfused cells may limit efficacy and contribute to increased patient morbidity and mortality. Also controversial is the ability of pre- and post-storage leukoreduction of RBCs to mitigate adverse transfusion-related events. Veterinary Data Synthesis– While there are several studies evaluating the transfusion trigger, the RBC storage lesion and transfusion-related immunomodulation in experimental animal models, there is little research pertaining to clinical veterinary patients. Conclusions– RBC transfusion is unequivocally indicated for treatment of anemic hypoxia. However, critical hemoglobin or Hct below which all critically ill patients require transfusion has not been established and there are inherent risks associated with allogenic blood transfusion. Clinical trials designed to evaluate the effects of RBC age and leukoreduction on veterinary patient outcome are warranted. Implementation of evidence-based transfusion guidelines and consideration of alternatives to allogenic blood transfusion are advisable. [ABSTRACT FROM AUTHOR]

Context: Transfusion of packed red blood cells is an independent risk factor for postoperative bacterial infections and multiple organ failure. Materials and Methods: Whole blood was obtained from healthy volunteers to investigate the role of mitogen associated protein kinase (MAPK) pathways in PRBC-induced neutrophil respiratory burst, hypothesizing that the attenuating effects of pentoxifylline on this process are due to modulations in MAPK-associated signaling. Results: Pre-incubation of neutrophils with supernatant prior to fMLP stimulation increased p38 MAPK and ERK phosphorylation over fMLP alone pentoxifylline significantly reduced p38MAPK and ERK phosphorylation in similarly stimulated neutrophils. Conclusion: The addition of pentoxifylline stored red blood cells attenuates neutrophil activation. [ABSTRACT FROM AUTHOR]

Abstract: In recent years there has been increasing interest in the idea that allogeneic blood transfusions (ABTs) may be associated with immunosuppression. This syndrome has been termed transfusion-related immunomodulation (TRIM). TRIM was first demonstrated in the renal transplant setting, when significantly improved renal allograft survival after transplant was seen in patients who had received ABTs before transplant. There remains much controversy regarding the possible mechanisms of TRIM and its clinical significance. Mechanisms may be specifically human leucocyte antigen dependent or related to non-specific bioactive soluble factors. It is likely that transfused allogeneic white blood cells (WBCs) are responsible for the majority of TRIM effects. After ABT there is impaired natural killer cell function, decreased macrophage phagocytic function, suppression of lymphocyte production and effective antigen presentation. Possible adverse clinical effects of TRIM include increased risk of cancer recurrence, postoperative infection and short-term mortality. Many of the studies investigating these issues have been observational, with significant methodological problems that make the interpretation of the clinical significance of any findings difficult. Randomized controlled trials (RCTs) in the cardiac surgery setting have demonstrated an increase in short-term mortality, of unspecified cause, in patients receiving non-WBC-reduced ABTs. Results of RCTs looking at the risk of bacterial infection and ABTs have been conflicting, although most recent trials tended to report negative findings. A meta-analysis of RCTs investigating an association between ABTs and cancer recurrence showed no increased risk of cancer recurrence in the ABT cohort. Universal WBC reduction is increasingly common, although its role in mitigating TRIM remains controversial. [Copyright &y& Elsevier]

The article discusses risks that patients face when they receive blood transfusions and steps that can be taken to lessen these risks. Complications that can arise when patients receive blood transfusions are mentioned, such as contracting the diseases syphilis, hepatitis B and HIV. Testing that is done on blood donated within the U.S. to screen for illness is discussed. The transfusion of blood substitute products instead of blood is discussed.

Problem The allogeneic leukocytes in transfused blood can modulate the recipient’s immune system so as to induce TGF-β-producing suppressor cells, and the cell-surface CD200 tolerance-signaling molecule on mononuclear dendritic cells is required for this effect. A subset of couples with unexplained recurrent pregnancy loss appears to benefit from transfusion of allogeneic paternal blood leukocytes (LIT), and considerable effort has been devoted to characterizing those who may benefit. Some data has been accumulated for LIT as sole therapy in patients with classical spontaneous abortions with respect to dose–response, duration of protection, need for boosting, excluding patients with autoimmunity, and inefficacy of paternal mononuclear cells stored at 4°C overnight before use which causes loss of cell-surface CD200. Recent data emphasize an important role of expression of the CD200 tolerance-signaling molecule on cells used to prevent abortions both in mice and humans. Method of study An observational study of outcome as a function of the number of CD200+ paternal mononuclear cells was performed. Fourteen patients constituted the pilot group. Patients with autoimmunity who had failed inspite of treatment with IVIG + Heparin + Aspirin ± Prednisone were allowed to have paternal mononuclear cells added to their therapy. CD200 on purified paternal blood mononuclear cells was measured by flow cytometry. Results The number of CD200+ cells administered was significantly greater in women achieving pregnancy (39.2 × 106 versus 20.8 × 106, P < 0.025) and in those who achieved a live birth (50.2 × 106 versus 20.8 × 106, P < 0.005) compared to those who did not achieve pregnancy, and % of paternal cells that were CD200+ was greater (11–12.5% versus 5.6%, P < 0.01). Amongst those achieving pregnancy which failed, the CD200+ cell dose was not significantly different from the non-pregnant group (30.5 × 106 versus 20.8 × 106). Conclusion The number of CD200+ paternal mononuclear leukocytes may be an important determinant of subsequent reproductive outcome in a subset of patients. A lower % CD200+ cell number may also reflect hitherto unappreciated paternal factors bearing on reproductive success. It is feasible to recruit women to enter observational studies and to obtain useful data as a foundation for further studies. More complete patient characterization in a larger study is needed. [ABSTRACT FROM AUTHOR]

Allogeneic blood transfusions are dose-dependently associated with postoperative complications. Leucocytes present in blood components may play a role in these effects, referred to as transfusion-related immunomodulation. Of 19 randomized controlled trials of the effect of allogeneic leucocytes in transfusions, 13 looked into the effect of leucocyte-containing red blood cells (RBCs) in the surgical setting on the occurrence of postoperative infections and/or mortality. In contrast to conflicting outcomes of the trials in other settings, in cardiac surgery there is evidence that leucocyte-containing RBCs increase postoperative complications associated with mortality. The studies performed in cardiac surgery show less heterogeneity than studies in other surgical interventions and had been conducted either in one or a few participating centres. In this review, we discuss possible explanations for these results in cardiac surgery (as opposed to other settings), which may relate to clinical as well as transfusional factors. We suggest that leucocyte-containing transfusions during and after cardiac surgery add a second insult to the cardiopulmonary bypass procedure-induced systemic inflammatory response. [ABSTRACT FROM AUTHOR]

Intention-to-treat analyses of randomized controlled trials (RCTs) of the association between non-white-blood-cell (WBC)-reduced allogeneic blood transfusion (ABT) and postoperative infection were reported as the reason why meta-analyses of RCTs of this association have produced discordant results. We examined three possible reasons for disagreements between meta-analyses: (i) sources of medical heterogeneity and integration of RCTs despite extreme heterogeneity; (ii) reliance on as-treated (vs. intention-to-treat) comparisons; and (iii) inclusion (or not) of the three most recent RCTs. When nine RCTs reported up to 2002 were combined despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found an association between non-WBC-reduced ABT and postoperative infection [summary odds ratio (OR) = 1·38, 95% confidence interval (CI) 1·03–1·85, P < 0·05; and summary OR = 1·56, 95% CI 1·06–2·31, P < 0·05, respectively]. When 12 RCTs reported up to 2005 were integrated despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found no association of non-WBC-reduced ABT with postoperative infection (summary OR = 1·24, 95% CI 0·98–1·56, P > 0·05; and summary OR = 1·31, 95% CI 0·98–1·75, P > 0·05, respectively). In both analyses, the separate integration of four RCTs transfusing red blood cells (RBCs) or whole blood filtered after storage showed an association between non-WBC-reduced ABT and postoperative infection, whereas the separate integration of six (or nine) RCTs, reported through 2002 or 2005, and transfusing prestorage-filtered RBCs showed no association, whether intention-to-treat or as-treated comparisons were used. Thus, the published meta-analyses have produced discordant results because they did (or did not) investigate medical sources of heterogeneity and did (or did not) include the most recent RCTs. Intention-to-treat and as-treated comparisons produced concordant results. [ABSTRACT FROM AUTHOR]

An association of white blood cell (WBC) reduction with decreased mortality was reported by one observational, before-and-after study. A meta-analysis was undertaken to examine whether this finding is supported by all the evidence currently available from before-and-after studies, and whether these studies support an association of WBC reduction with a decreased risk of postoperative infection. Observational, before-and-after studies were retrieved that reported on postoperative infection and/or mortality between January 1997 and June 2003. Six studies met the criteria for meta-analysis. Unadjusted summary odds ratios (ORs) of postoperative infection or mortality in patients transfused after (compared with before) WBC reduction were calculated across the studies if the hypothesis of homogeneity was not rejected. Adjusted summary ORs were calculated across three studies that had reported multivariate analyses. There was an unadjusted association of WBC reduction with a decreased risk of postoperative infection [summary OR = 0·93; 95% confidence interval (95% CI), 0·88–0·99; P < 0·01] that did not persist following adjustment for confounding factors (summary OR = 0·94; 95% CI, 0·85–1·04; P > 0·05). There was neither an unadjusted nor an adjusted association of WBC reduction with decreased mortality (summary OR = 0·94; 95% CI, 0·71–1·23; P > 0·05; and OR = 0·92; 95% CI, 0·80–1·05; P > 0·05, respectively). An association of WBC reduction with decreased mortality was not detected across the results available from all before-and-after studies. An unadjusted association of WBC reduction with a decreased risk of postoperative infection exists, but this was not detected across the three studies that reported multivariate analyses. [ABSTRACT FROM AUTHOR]

Background and Objectives A previous meta-analysis of randomized controlled trials (RCTs), comparing the risk of postoperative infection between recipients of allogeneic blood or autologous blood obtained by preoperative autologous blood donation (PABD), did not detect an immunomodulatory (TRIM) effect of allogeneic blood transfusion (ABT). If such a TRIM effect was mediated by white blood cell (WBC)-derived soluble mediators accumulating during storage, however, stored autologous blood obtained by PABD would not prevent the TRIM effect, whereas unstored autologous blood obtained by acute normovolemic haemodilution (ANH), intraoperative blood recovery (IBR), or postoperative blood recovery (PBR), would abrogate the TRIM effect. Materials and Methods RCTs reported through January 2002 were retrieved, and five studies met the criteria for meta-analysis. Summary odds ratios (ORs) of postoperative infection in recipients of allogeneic vs. autologous blood were calculated across studies. Results No difference in the risk of infection between the comparison arms was detected across all five RCTs [summary OR = 1·22, 95% confidence interval (95% CI): 0·75–1·98], or when the results of studies using PABD or ANH/IBR/PBR were integrated separately (summary OR = 1·35; 95% CI: 0·45–4·08; and summary OR = 1·49; 95% CI: 0·69–3·22, respectively). Conclusions The finding of no TRIM effect of ABT across RCTs using ANH/IBR/PBR to obtain autologous blood does not support the hypothesis that a TRIM effect of ABT is mediated by WBC-derived soluble mediators accumulating during storage. The null finding of the overall meta-analysis also does not support a TRIM effect of ABT mediated by other blood constituents. [ABSTRACT FROM AUTHOR]

Background and Objectives In patients undergoing open-heart surgery, allogeneic blood transfusion (ABT) may be related to an enhanced inflammatory response and impaired pulmonary function, resulting in a need for prolonged mechanical ventilation. Transfused red blood cell (RBC) supernatant, platelet supernatant or plasma components, may exercise varying effects on pulmonary function, because these fluids differ in their content of soluble biological-response modifiers. Materials and Methods The records of 416 patients undergoing coronary artery bypass graft operations at the Massachusetts General Hospital were reviewed. Possible predictors and the number of days of postoperative ventilation, as well as the number of all transfused blood components, were recorded. The association between mechanical ventilation past the day of operation and the volume of transfused RBC supernatant, platelet supernatant, or plasma components, was calculated by logistic regression analyses. Results The volume of each transfused fluid differed (P < 0·0001) among patients ventilated for 0, 1, 2, 3, or ≥ 4 days after the day of the operation. After adjusting for the effects of confounding factors, the volume of administered RBC supernatant was associated (P = 0·0312) with the likelihood of postoperative ventilation past the day of operation, but the volume of platelet supernatant, plasma components, or total transfused fluid was not (P = 0·1528, P = 0·1847, and P = 0·0504, respectively). Conclusions These results are congruent with the hypotheses that ABT may impair postoperative pulmonary function and that any such adverse effect of ABT is probably mediated by the supernatant fluid of stored RBCs. Both hypotheses should be examined further, in future studies of the outcomes of ABT. [ABSTRACT FROM AUTHOR]