Mechanisms of red blood cell transfusion‐related immunomodulation

Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient‐specific risk factors. Unpacking these complexities requires an in‐depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion‐related immunomodulation and provide suggestions for future research directions.     

Infectious and immunologic consequences of blood transfusion

Blood transfusions remain common practice in the critical care and surgical settings. Transfusions carry significant risks, including risks for transmission of infectious agents and immune suppression. Transmission of bacterial infections, although rare, is the most common adverse event with transfusion. The risk for transmission of viral infections has decreased over time, clearly because tests are becoming more sensitive in detecting certain viral infections such as hepatitis B, hepatitis C, and HIV. Several immunomodulatory effects are thought to be related to transfusions, and these can result in cancer recurrence, mortality, and postoperative infections. Numerous studies have been performed to examine the role of leukoreduction in decreasing these transfusion-related complications but results remain contradictory. We review the infectious risks associated with blood transfusion and the most recent data on its immunologic effects, specifically on cancer recurrence, mortality, and postoperative infections in surgical patients. We also review the use of leukoreduction in blood transfusion and its role in preventing transfusion-transmitted infections and immunomodulatory complications.     

Best practice in critical care: anaemia in acute and critical illness

Anaemia is common in critical illness, and standard treatment is red blood cell (RBC) transfusion, typically using a restrictive transfusion threshold of 70 g L^?1. However, there are subgroups of patients in whom it is biologically plausible that a higher transfusion threshold may be beneficial, namely, acute sepsis, traumatic brain injury and coexisting cardiovascular disease. In this review article, we will discuss the pathophysiology of anaemia, as well as its prevalence and time course. We will explore the limitations of using haemoglobin concentration as a surrogate for oxygen delivery and the concept of the critical haemoglobin concentration. We will then discuss transfusion thresholds for the general intensive care unit (ICU) population and specific subgroups.     

Reports of 355 transfusion-associated deaths: 1976 through 1985

From 1976 through 1985, the United States Food and Drug Administration received reports of 355 fatalities associated with transfusion, 99 of which were excluded from further review because they were unrelated to transfusion or involved hepatitis or acquired immune deficiency syndrome. Of the remaining 256 reported deaths, 51 percent resulted from acute hemolysis following the transfusion of ABO-incompatible products. These deaths were due primarily to managerial, not clerical, errors. Other causes of death (in order of frequency of report) included acute pulmonary injury (15%), bacterial contamination of product (10%), delayed hemolysis (10%), damaged product (3%), and graft-versus-host disease (0.4%). Management systems for transfusion facilities should be created or revised to include the specific identification of personnel eligible to administer transfusions to provide written guidance and appropriate training (including recognition and management of errors), and to implement measures that target safe transfusion practices. Continued research into acute pulmonary injury, the immunologic hazards of transfusion, and the prevention of bacterial contamination of blood components is necessary.     

CFNAs of RBCs affect the release of inflammatory factors through the expression of CaMKIV in macrophages

BackgroundBlood 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.MethodsDifferentially 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.ResultsAnalysis 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.ConclusionRBCs 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.     

Is there a place for epoetin alfa in managing anemia during critical illness?

BACKGROUND: Anemia is a common problem in critically ill patients. As a result, blood transfusions are often used in the intensive care unit (ICU) setting. However, mounting evidence shows that blood transfusions may contribute to negative outcomes, such as transfusion-related infections, organ dysfunction, and immunosuppression. Supplementation with epoetin alfa is currently used in some medical centers to manage anemia in critically ill patients. OBJECTIVE: This review discusses the risks with blood transfusions and the clinical evidence supporting the use of epoetin alfa in managing edema during critical illness. METHODS: A search was conducted in MEDLINE and Current Contents (1966-2003) using the terms epoetin alfa, recombinant human erythropoietin, and anemia. Articles addressing anemia and the use of epoetin alfa in critically ill patients were selected and assessed. From this selection, the cited references addressing the etiology of anemia in the ICU and the risks associated with blood transfusions were manually extracted and reviewed. RESULTS: Several reports have shown that critically ill patients display evidence of anemia due to a blunted erythropoietin response. One large, randomized, placebo-controlled study assessed the effect of SC epoetin alfa on blood transfusions in the ICU. In this study, 40, 000 IU administered weekly for up to 4 weeks resulted in an overall transfusion reduction (9.9% absolute risk reduction; P<0.001 ). Other, smaller studies using different dosing regimens in critically ill patients have also demonstrated that epoetin alfa can decrease the need for transfusion. CONCLUSION: The use of epoetin alfa in critically ill patients can decrease the number of blood transfusions required during hospitalization, and potentially result in transfusion avoidance. Because of the scarce amount of evidence and the diversity of dosing regimens used used, no strict recommendations can be drawn from this review.     

Blood conservation for critically ill patients

Anemia may be the most common illness of critically ill patients. The majority of critically ill patients are anemic at admission to the intensive care unit (ICU), and hemoglobin concentrations typically decline during the first 3 days of ICU stay. Hemoglobin continues to decline for patients with sepsis and higher severity of illness. This patient population may be at particular risk of adverse consequences of anemia given the cardiovascular, respiratory, and metabolic compromise frequently encountered during critical illness. The etiology of anemia of critical illness is multifactorial, resulting from phlebotomy, gastrointestinal bleeding, coagulation disorders, blood loss from vascular procedures, renal failure, nutritional deficiencies,bone marrow suppression, and impaired erythropoietin response.     

Scope of the problem: epidemiology of anemia and use of blood transfusions in critical care

Anemia is a common problem in critically ill patients. It is caused, in part, by blood loss related to phlebotomy for diagnostic testing, occult gastrointestinal bleeding, renal replacement therapies, surgical intervention, and traumatic injuries. Reduced red cell life span and nutritional deficiencies (iron, folate, vitamin B12) may be other contributing factors. In addition, critically ill patients have impaired erythropoiesis because of blunted endogenous erythropoietin production and the direct inhibitory effects of inflammatory cytokines on red blood cell production by the bone marrow. Blood transfusions are commonly utilized for treatment of anemia in critical care, resulting in high use of blood transfusions in the intensive care unit (ICU). The percentage of patients transfused in the ICU is inversely related to admission hemoglobin and directly related to age and severity of illness. Patients with an increased length of stay in the ICU are also at increased risk for receiving blood transfusions. Studies are needed to improve our understanding of the pathophysiology of ICU-acquired anemia, to determine the efficacy of blood transfusions in critical care, and to investigate alternatives to blood transfusion for the treatment of anemia in the ICU.     

Transfusion-related immunomodulation and cancer

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.     

The role of erythropoietin therapy in the critically ill

Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units (ICUs) receive at least one allogeneic red blood cell (RBC) unit and average close to 5 U of RBCs during their ICU admission. RBC transfusion is not risk-free, and there is little evidence that "routine" transfusion of stored allogeneic RBCs is beneficial to critically ill patients. It is clear that most critically ill patients can tolerate hemoglobin levels as low as 7 g/dL, and therefore, a more conservative approach to RBC transfusion is warranted. Anemia of critical illness is a distinct clinical entity characterized by blunted erythropoietin (EPO) production and abnormalities in iron metabolism identical to what is commonly referred to as anemia of chronic disease. As such, the bone marrow in many of these patients responds to the administration of exogenous EPO, in spite of their underlying critical illness. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients, rHuEPO therapy will also stimulate erythropoiesis. In randomized placebo-controlled trials, therapy with rHuEPO resulted in a significant reduction in allogeneic RBC transfusions. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the ICU and decrease the transfusion threshold in the management of all critically ill patients.     

Use of epoetin alfa in critically ill patients

OBJECTIVE: To discuss the controversies regarding the use of epoetin alfa (EPO) for reducing red blood cell (RBC) transfusions in critically ill patients with anemia. DATA SOURCES: A MEDLINE search (1966-July 2003) was conducted using the search terms anemia; critical illness; erythropoietin; epoetin alfa; and erythropoietin, recombinant. References of selected articles were reviewed for studies that may have been missed by the computerized search. STUDY SELECTION AND DATA EXTRACTION: Studies pertaining to the use of EPO for anemia of critical illness with an emphasis on data obtained from controlled trials. DATA SYNTHESIS: Anemia is a common complication in patients admitted to the intensive care unit (ICU). Two prospective, randomized studies have demonstrated decreased transfusion requirements associated with EPO administration in medical/surgical patients who were in the ICU for at least 3 days and had hematocrit concentrations <38%. No differences were found in length of stay or mortality. A multicenter trial found that a restrictive strategy of RBC transfusion (hemoglobin goal 7-9 g/dL) was associated with in-hospital mortality lower than that with a more liberal approach, which calls into question the 38% hematocrit goal in the EPO trials. Furthermore, preliminary results from an economic analysis of EPO use in the ICU setting have demonstrated that EPO is not cost-effective. CONCLUSIONS: Given the controversies surrounding EPO administration in critically ill patients, institutions are encouraged to develop EPO guidelines to help ensure the most appropriate use of this expensive product. Additional studies regarding patients most likely to benefit from EPO therapy, the most effective dosing regimen, and use of adjunctive therapies are needed.     

Retrospective analysis of effect of low-dose aprotinin priming on allogeneic blood transfusion in repeated cardiac operations.

The objective of this retrospective study was to investigate efficacy of low-dose aprotinin priming therapy on the requirement of allogeneic transfusion and to identify risk factors for allogeneic transfusion in patients undergoing repeated cardiac operations. The present study includes a critical review of 124 consecutive charts of patients undergoing elective repeat cardiac surgery. We examined the effect of low-dose aprotinin priming therapy on blood loss, amounts of mediastinal drainage following intensive care unit (ICU) administration and the number of units of blood products given during the perioperative period. The rate of nonallogeneic transfusion was not affected by low-dose aprotinin priming therapy, although aprotinin reduced the amount of allogeneic transfusion and the amount of mediastinal drainage 12 h following ICU admission. In conclusion, low-dose aprotinin priming therapy is effective in reducing blood loss and the amount of allogeneic transfusion. However, it failed to improve the rate of cardiac reoperations without allogeneic blood transfusion.     

RBC transfusion and postoperative length of stay in the hospital or the intensive care unit among patients undergoing coronary artery bypass graft surgery: the effects of confounding factors

BACKGROUND: Data on the independent association between perioperative allogeneic blood transfusion (ABT) and postoperative length of stay at the hospital or in the intensive care unit (ICU) are sparse. STUDY DESIGN AND METHODS: The records of 421 consecutive patients undergoing coronary artery bypass graft (CABG) operations at the Massachusetts General Hospital were reviewed. The effect of perioperative ABT in explaining the variation in the postoperative length of stay (LOS) at the hospital or in the ICU was calculated after adjustment for the effects of 20 confounding factors that pertained to severity of illness, difficulty of operation, and risk of postoperative wound infection or pneumonia. RESULTS: Postoperative LOS averaged (mean +/- SE) 8.0 +/- 0.3 days in the hospital and 50.0 +/- 4.1 hours in the ICU. After adjustment for the effects of confounding factors, the postoperative length of hospitalization increased by 0.837 percent (95% CI, 0.249-1.425%) per RBC unit transfused (p<0.001), and the postoperative length of stay in the ICU increased by 0.873 percent (95% CI, -0.068-1.814%) per RBC unit transfused (p<0.10). CONCLUSION: Allogeneic blood transfusion was independently associated with longer postoperative stays in the hospital or the ICU, but the observed independent association is perhaps too small to be clinically relevant. This independent association may be due to a relationship between ABT and a higher incidence of septic complications of surgery, or it may reflect the function of blood transfusion as a surrogate marker for severity of illness.     

Immunomodulation and blood transfusion

Over the past three decades, evidence from a variety of sources has suggested that allogeneic blood transfusions can induce clinically significant immunosuppression in recipients. This clinical syndrome is referred to in the transfusion medicine literature as transfusion-associated immunomodulation (TRIM) and has been linked to an improved clinical outcome in the setting of renal transplantation. Possible deleterious TRIM-associated effects include increased prevalence of cancer recurrence and postoperative bacterial infections. The recognition that TRIM can increase morbidity and mortality in allogeneically transfused individuals has become a major concern for those involved in transfusion medicine. Whether TRIM predisposes recipients to increased risk for cancer recurrence and/or bacterial infections is still not proven, however. In contrast to the available clinical data, studies in experimental animal models suggest that TRIM is an immunologically mediated biologic effect associated with the infusion of allogeneic leukocytes, which can be ameliorated by prestorage leukoreduction. Although considerable data have been accumulated in an attempt to unravel the clinically adverse effects of TRIM, the precise mechanism of TRIM has yet to be elucidated. Further studies, both basic and applied, to establish the clinically relevant manifestations of TRIM as well as the mechanism(s) are urgently required.     

The Effects of red Blood Cell Transfusion on Tissue Oxygenation and the Microcirculation in the Intensive Care Unit: A Systematic Review

The transfusion of red blood cells (RBCs) is a common intervention in intensive care unit (ICU) patients, yet the benefits are far from clear in patients with moderate anemia (eg, hemoglobin (Hb) levels of 7–10 g/dL). Determining which of these patients benefit, and how to even define benefit, from transfusion is challenging. As the intended physiological benefit underpinning RBC transfusion is to improve tissue oxygenation, several studies utilizing a wide range of assessment techniques have attempted to study the effects of transfusion on tissue oxygenation and microcirculatory function. The objective of this systematic review was to determine whether RBC transfusion improves tissue oxygenation/microcirculatory indices in the ICU population, and to provide an introduction to the techniques used in these studies. Eligible studies published between January 1996 and February 2017 were identified from searches of PubMed, Embase, Cinahl, ScienceDirect, Web of Science, and The Cochrane Library. Seventeen studies met inclusion criteria, though there was significant heterogeneity in study design, patient population, assessment techniques and outcomes reported. Overall, the majority of studies (11 of 17) concluded that transfusion did not generally improve tissue oxygenation or microcirculation. Inter-individual effects were highly variable, however, and closer review of sub-groups available in 9 studies revealed that patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion had improvement in these indices with transfusion, irrespective of assessment method. This finding suggests a new strategy for future trials in the ICU: utilizing tissue oxygenation/microcirculatory parameters to determine the need for transfusion rather than largely arbitrary hemoglobin concentrations.     

急性危重病患者血乳酸(LACT)与血气检测的临床应用

目的 探讨急性危重病患者血清乳酸(LACT)和血气的临床应用.方法 对65例急性危重病患者和25例正常对照组同步测定乳酸(LACT)与血气指标.结果 急性危重病患者组血气指标与正常对照组差异无显著性(P＞0.05);但危重病患者组乳酸浓度和血糖浓度较正常对照组明显升高(P＜0.01).结论 急性危重病患者由于缺氧、高代谢、低灌注等原因,在未出现明显酸中毒之前即可有高乳酸血症存在,因此对危重病患者进行乳酸和血气检测有非常重要的临床意义.     

Leukodepletion of autologous whole blood has no impact on perioperative infection rate and length of hospital stay

BACKGROUND: Several mechanisms have been proposed as possible causes of transfusion‐related immunomodulation (TRIM) after allogeneic transfusion. If one of these mechanisms, the release of mediators of immunity and inflammation (“biologic response modifiers”[BRMs]) from disintegrating blood cells during storage of blood products, really causes TRIM, it should in principle also occur after autologous transfusion. As a consequence, prestorage leukoreduction of autologous blood should be able to prevent the clinical consequences of TRIM after autologous transfusion. STUDY DESIGN AND METHODS: This hypothesis was investigated in a multicenter, double‐blind, randomized controlled trial. A total of 1089 patients scheduled for total hip arthroplasty and eligible for preoperative autologous blood donation were randomly assigned to receive autologous whole blood (AWB) either unmodified or leukoreduced when transfusion was indicated. RESULTS: Neither the primary study outcome, that is, the overall postoperative infection rate (17.3% vs. 17.6%, p = 0.59), nor several secondary outcomes like median length of hospital stay (14 days vs. 14 days, p = 0.17) were significantly different between groups, whether analyzed according to the intention‐to‐treat principle or “as treated.” CONCLUSION: This trial provides strong evidence, from clinically relevant outcome data, that leukoreduction of AWB does not improve postoperative patient outcome and that the release of BRMs from disintegrating blood cells during storage cannot explain the immunomodulatory effect of blood transfusion.     

Possible mechanisms of allogeneic blood transfusion-associated postoperative infection

Four possible mechanisms have been reported to underlie the apparent association of allogeneic blood transfusion (ABT) with postoperative bacterial infection. These are (1) a transfusion-related immunomodulatory (TRIM) effect of ABT mediated by immunologically active allogeneic white blood cells (WBCs) that downregulate the recipient's immune function, thereby predisposing to infection; (2) a TRIM effect of ABT mediated by soluble biologic response modifiers released in a time-dependent manner from WBC granules or membranes into the supernatant fluid of red blood cells (RBCs) during storage; (3) a TRIM effect of ABT mediated by soluble HLA peptides that circulate in allogeneic plasma; and (4) a related non-TRIM effect of ABT, whereby ABT causes postoperative organ dysfunction that predisposes to infection. The available clinical studies examining the association of ABT with postoperative infection were not designed to specifically test 1 or more of these 4 hypotheses. Thus, it is difficult to make inferences from the published data about the specific mechanism(s) that may underlie the purported association of ABT with infection. To permit such inferences, future studies of the association of ABT with postoperative infection should consider 2 outcomes (ie, postoperative organ dysfunction in addition to postoperative infection), as well as 3 possible exposures (ie, allogeneic WBCs, soluble biologic response modifiers originating in WBC granules or membranes, and/or soluble HLA molecules circulating in allogeneic plasma).     

Transfusion-Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens

Traditionally, alloimmunization to transfused blood products has focused exclusively on recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunologic sequelae of alloimmunization have been antibody mediated effects (ie, hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection—under reduced intensity conditioning with HLA-matched or HLA-identical marrow. Bone marrow transplant of this nature is the only existing cure for a series of nonmalignant hematologic diseases (eg, sickle cell disease, thalassemias, etc); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion-induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or natural killer cells. In this case, rejection occurs in the absence of alloantibodies and would not be detected by existing immune-hematologic methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion, which current blood bank methodologies are unable to detect.     

The microbiome and transfusion in cancer patients

Our microbiota is determined by many variables including ABO blood groups. The microbiota is not only confined to the gut and skin but is also recoverable from blood of healthy donors.The microbiota shape our immune system through cross reactivity with antigens, the expression of direct molecular patterns, the release of cytokines, the effects on nutrients and micronutrients and even through an interplay with epigenetics. It is likely, therefore, that a donor's microbiota could alter the antigenicity of blood and its components and potentially contribute to transfusion-related immune modulation [TRIM]. It could also potentially transmit infections. The recipient's microbiome contributes, on the other hand, to the tolerance to transfused blood, or to the development of transfusion reactions. Cancer patients are a particularly vulnerable population, often immunosuppressed with a significantly altered microbiota. They are more at risk for transmission of “dormant” bacteria via blood transfusion. Furthermore, chemotherapy and radiation induce mucositis that likely results in significant translocation of gut microbiota and abnormal immune reactions to transfused blood. It is therefore relevant to revisit transfusion thresholds and consider transfusion-saving strategies in cancer patients.