Cause Of Transfusion-associated Mortality Research Articles

Platelet Component False Positive Detection Rate in Aerobic and Anaerobic Primary Culture: A Systematic Review and Meta-Analysis.

Septic reactions from platelet transfusions are one of the leading causes of transfusion-associated mortality. The FDA guidance for platelet bacterial risk control includes bacterial culture using both aerobic and anaerobic bottles. Several studies have reported false positive rates (FPR) of culture, but these data have not been summarized or influencing factors analyzed. A systematic review and meta-analysis was performed according to published guidelines to assess the false positive rate and influencing factors. Eighteen studies were included for analysis. The combined aerobic/anaerobic FPR was 2.4 events per thousand (EPT) with a prediction interval of 0.5 to 5.7, while the aerobic FPR rate was 1.0 EPT (prediction interval: 0.2-2.2) and the anaerobic rate was 1.8 EPT. Estimates were based on a total of almost 5 million units tested. The rate of false positives due to instrument error was between 0.5-1.7 EPT, while it was between 0.3-1.0 EPT for sampling contamination based on whether only aerobic, anaerobic, or aerobic/anaerobic cultures were performed. The FPR is approximately 2 to 5 times higher than the literature reported true positive rate of 0.5 EPT.

The Nlrp3 Inflammasome Does Not Regulate Alloimmunization to Transfused Red Blood Cells in Mice

Red blood cell (RBC) transfusions are essential for patients with hematological disorders and bone marrow failure syndromes. Despite ABO matching, RBC transfusions can lead to production of alloantibodies against “minor” blood group antigens. Non-ABO alloimmunization is a leading cause of transfusion-associated mortality in the U.S. Despite its clinical importance, little is known about the immunological factors that promote alloimmunization. Prior studies indicate that inflammatory conditions place patients at higher risk for alloimmunization. Additionally, co-exposure to pro-inflammatory pathogen associated molecular patterns (PAMPs) promotes alloimmunization in animal models, suggesting that RBC alloimmunization depends on innate immune cell activation. However, the specific innate immune stimuli and sensors that induce a T cell-dependent alloantibody response to transfused RBCs have not been identified. The NLRP3 inflammasome senses chemically diverse PAMPs and damage associated molecular patterns (DAMPs), including extracellular ATP and iron-containing heme. We hypothesized that activation of the NLRP3 inflammasome by endogenous DAMPs from RBCs promotes the alloimmune response to a sterile RBC transfusion. Using genetically modified mice lacking either NLRP3 or multiple downstream inflammasome response elements, we ruled out a role for the NLRP3 inflammasome or any Caspase-1 or -11 dependent inflammasome in regulating RBC alloantibody production to a model antigen.

Transfusion-related acute lung injury in an era of TRALI risk mitigation

Abstract Transfusion-related acute lung injury (TRALI) is a rare complication of transfusion, for which the true incidence remains obscure, since there are a number of factors that may lead to misdiagnosis. Despite this, it continues to be the leading cause of transfusion-associated mortality. Here we present a historical case of TRALI in an elderly female who received group AB plasma and discuss how current mitigation strategies would likely have prevented its occurrence. It is important to remember that both immune and non-immune factors play a role in TRALI pathogenesis, and although current preventative strategies may decrease TRALI’s incidence, they likely will not eliminate it. Immunohematology 2015;31:155–158.

Anti-Granulocyte Antibodies in Transfusion Medicine

Granulocyte antibodies, in contrast to antibodies recognizing red blood cells and platelets, have been widely neglected in transfusion medicine for several decades, although their clinical relevance is well-described. Autoimmune neutropenia of infancy and neonatal alloimmune neutropenia are probably the most well-known granulocyte antibody-induced disorders. The facts that antibody-induced neutropenias are rare disorders with a favorable prognosis and that sophisticated, labor-intensive in-house techniques are required for granulocyte antibody detection may both have contributed to this negligence. When transfusion-related acute lung injury (TRALI) was delineated as the leading cause of transfusion-associated mortality and, subsequently, granulocytes were identified as key players in TRALI, granulocyte antibodies received progressively higher attention. It took only a short period of time to unravel that transfusion of granulocyte antibodies can lead to activation of the transfusion recipient’s own granulocytes with subsequent breakdown of the pulmonary endothelial barrier and lung edema. Clinical and regulatory pressure has prompted the identification of new target antigens on granulocytes, the development of better diagnostic approaches for antibody identification, and drastic changes in blood component production in order to reduce the risk of TRALI. There were two major fields of controversy in this rather straight-forward process. First, there are two groups of antibodies associated with TRALI: 1) granulocyte antibodies in sensu strictu, i.e., those which recognize human neutrophil antigens (HNA); and 2) human leukocyte antigen (HLA) antibodies which can bind to granulocytes, but also to other cells. These observations led to a debate on whether granulocytes are primary target cells or, at least in some cases, “auxiliary” cells in TRALI. Evidence from animal studies supports the idea that HLA class I antibodies may bind to endothelial cells and recruit granulocytes to the vessel wall, where they get activated; and that HLA class II antibodies, since their target antigen is not expressed on quiescent granulocytes, may bind to monocytes which then activate granulocytes. Recent data on HNA antibodies which cause TRALI by direct binding to pulmonary endothelium in the absence of granulocytes have added to the complexity, as has the observation from prospective clinical trials that HLA class I antibodies are of less relevance than previously anticipated. Today, there is consensus that different antibodies can cause TRALI by different pathways which do partially overlap. Second, the presence of granulocyte antibodies in blood components as the only causative factor for TRALI appeared partially doubtful: a minority of components produced from the same donor and transfused to different recipients led to TRALI. These doubts were further substantiated by the fact that in some TRALI cases, no antibodies whatsoever could be identified. Other substances often referred to as biological response modifiers (BMR) were demonstrated causative for TRALI, but only in animals pre-exposed to priming agents. This observation was crucial in understanding that not only factors present in a blood component (antibody or BMR) need to be considered, but also factors present in the recipient; this led to the “two-hit model” or “threshold model” of TRALI. Nowadays, there is consensus that antibody-mediated TRALI and non-antibody-mediated TRALI exist, with the latter one posing new challenges for transfusion medicine. This overview will start from pre-TRALI knowledge of granulocyte antibodies, consider antibody-mediated TRALI in detail, and will finally return to non-TRALI disorders in the light of relevant new findings in the field. DisclosuresNo relevant conflicts of interest to declare.

Implementation and outcomes of a transfusion-related acute lung injury surveillance programme and study of HLA/HNA alloimmunisation in blood donors.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality. Antibodies against human leucocyte antigens (HLA) and human neutrophil antigens (HNA) are often detected in the implicated donors. We investigated the incidence and aetiology of TRALI in Lombardy. Moreover, we determined the rate of HLA and HNA alloimmunisation and the HNA genotype in a cohort of local blood donors. During a 2-year observational study in eight blood transfusion services, suspected TRALI cases were collected and characterised by means of HLA and HNA antibody screening of implicated donors, donor/recipient cross-matching and HLA/HNA molecular typing. In addition, 406 Italian donors were evaluated for alloimmunisation and in 102 of them HNA gene frequencies were determined. Eleven cases were referred to the central laboratory, of whom three were diagnosed as having TRALI, seven as having possible TRALI and one as having transfusion-associated circulatory overload. Seven TRALI cases were immune-mediated whereas in three we did not find either alloantibodies in implicated donors or a positive reaction in the cross-match. The most frequently implicated blood component was red blood cells (in 5 males and in 1 female), whereas four cases of TRALI were associated with transfusion of fresh-frozen plasma (in 3 females and in 1 male). The frequency of reported TRALI/possible TRALI cases was 1:82,000 for red blood cells and 1:22,500 for fresh-frozen plasma. No cases were observed for platelets. Overall, the frequency of HLA or HNA alloimmunisation in blood donors was 29% for females and 7% for males. The latter could be related, at least in part, to natural antibodies. HNA gene frequencies showed that HNA-1b is more frequent than HNA-1a in our sample of donors. The recently adopted national policy to prevent TRALI, i.e. using only plasma donated by males, would have had a positive impact in our setting.

Intravenous immunoglobulin prevents murine antibody-mediated acute lung injury at the level of neutrophil reactive oxygen species (ROS) production.

Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg) may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature) and respiratory distress (dyspnea) were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios) and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage.

Mechanism of transfusion-related acute lung injury induced by HLA class II antibodies

AbstractTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality in the United States and other countries. In most TRALI cases, human leukocyte antigen (HLA) class II antibodies are detected in implicated donors. However, the corresponding antigens are not present on the cellular key players in TRALI: neutrophils and endothelium. In this study, we identify monocytes as a primary target in HLA class II–induced TRALI. Monocytes become activated when incubated with matched HLA class II antibodies and are capable of activating neutrophils, which, in turn, can induce disturbance of an endothelial barrier. In an ex vivo rodent model, HLA class II antibody–dependent monocyte activation leads to severe pulmonary edema in a relevant period of time, whenever neutrophils are present and the endothelium is preactivated. Our data suggest that in most TRALI cases, monocytes are cellular key players, because HLA class II antibodies induce TRALI by a reaction cascade initiated by monocyte activation. Furthermore, our data support the previous assumption that TRALI pathogenesis follows a threshold model. Having identified the biologic mechanism of HLA class II antibody–induced TRALI, strategies to avoid plasma from immunized donors, such as women with a history of pregnancy, appear to be justified preventive measures.

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality in the US. Previously, we established an immune-mediated TRALI mouse model, wherein mice with cognate antigen were challenged with MHC class I mAb. In this study, when mice housed in a rodent, specific pathogen-free barrier room were challenged with MHC I mAb, there was significant protection from TRALI compared with nonbarrier mice. Priming mice with LPS restored lung injury with mAb challenge. Using TLR4-deficient bone marrow chimeras, the priming phenotype was restricted to animals with WT hematopoietic cells, and depletion of either neutrophils or platelets was protective. Both neutrophils and platelets were sequestered in the lungs of mice with TRALI, and retention of platelets was neutrophil dependent. Interestingly, treatment with aspirin prevented lung injury and mortality, but blocking the P selectin or CD11b/CD18 pathways did not. These data suggest a 2-step mechanism of TRALI: priming of hematopoietic cells, followed by vascular deposition of activated neutrophils and platelets that then mediate the severe lung injury. Furthermore, our data offer an explanation for the increased incidence of TRALI in patients with immune priming conditions, and we suggest what we believe to be a novel therapeutic approach.

Protecting the blood supply from emerging pathogens: The role of pathogen inactivation

As a consequence of the many blood-safety interventions introduced since the mid-1980s, the major causes of transfusion-associated mortality have shifted from being mainly due to transfusion-transmitted infections (TTIs) to being mainly due to non-infectious serious events such as TRALI, hemolytic reactions, transfusion overload, and graft versus host disease. Thus, TTIs now account for only 10 to 15% of all transfusion associated mortalities! Relevantly, manufacturers of purified plasma protein fractions have, over the same time period, shown that pathogen inactivation technologies can be successfully implemented resulting in little or no transmission of HIV, HCV or HBV since the late 1980s. These technologies, however, cannot be applied to cellular blood components. Thus, new technologies have evolved over the past decade to treat cellular blood components as well as plasma. These technologies, particularly those involving plasma and platelets, have begun to be used in Europe and this proactive paradigm has evolved to become a potential pre-emptive approach for ridding the blood supply of most TTIs (virus, bacteria, and protozoa). However, in order for pathogen inactivation technologies to become widely accepted, they must be shown to be both cost effective and not associated with new risks to recipients!

Patient‐specific transfusion‐related acute lung injury

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-associated mortality. The inadvertent transfusion of neutrophil antibodies can cause pulmonary transfusion reactions and TRALI. However, not all patients transfused with neutrophil antibodies experience transfusion reactions. A 22-year-old man with severe aplastic anaemia (SAA) experienced TRALI after a platelet transfusion. The donor was found to be alloimmunized to human neutrophil antigen (HNA)-3a, an antigen expressed by neutrophils from approximately 90% of Caucasians. Eleven other platelet components from this donor were transfused prior to this event and two caused reactions: one chills and one TRALI. Both episodes of TRALI occurred in the same male patient with SAA. The fact that one patient experienced TRALI following both exposures to anti-HNA-3a from the same donor whereas nine other recipients did not adds evidence to the observation that patient factors make a significant contribution to neutrophil antibody-mediated transfusion reactions.

Blood donor and component management strategies to prevent transfusion-related acute lung injury (TRALI)

Discuss the pros and cons of using donor and blood product-management strategies to prevent transfusion-related acute lung injury (TRALI). A review of the literature was performed. Despite therapeutic advances in pulmonary and critical care medicine, TRALI is now considered to be one of the leading causes of transfusion-associated mortality, and thus determining how to prevent TRALI is extremely important. Donor and product-management strategies to prevent this life-threatening condition have been suggested, but because of gaps in our understanding of TRALI, blood-bankers do not know how beneficial these interventions will be, nor the amount of potential harm-such as decreasing the availability of blood-that could arise if they were implemented. This article discusses the advantages and disadvantages of the various preventive measures that have been described in the literature. Preventing TRALI poses a difficult challenge for blood-banking experts, because it is unknown which measures will be effective in decreasing the incidence of TRALI and which could have significant drawbacks. Only additional research into TRALI prevention will provide the answers on how to best protect patients from this potentially fatal reaction.

Transfusion related acute lung injury: A pediatric perspective

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality. TRALI occurs in children and adults, but the syndrome has not been reviewed from a pediatric perspective. We reviewed the literature on TRALI from a pediatric perspective. TRALI has been documented in pediatric patients, especially in the setting of hematologic malignancy. Additional TRALI cases have been reported in pediatric patients with a variety of diagnoses. TRALI is likely to be much more common than previously appreciated in the pediatric patient population. TRALI should be considered in the differential diagnosis of all pediatric patients who develop new acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) during or within six hours of a blood product transfusion. When a case of TRALI is suspected, a transfusion reaction report to the blood bank is important to initiate the investigation and identify the implicated donor.

Transfusion-related acute lung injury: Definition and review

Transfusion-related acute lung injury (TRALI) is now the leading cause of transfusion-associated mortality, even though it is probably still underdiagnosed and underreported. The National Heart, Lung, and Blood Institute convened a working group to identify areas of research needed in TRALI. The working group identified the immediate need for a common definition and thus developed the clinical definition in this report. The major concept is that TRALI is defined as new acute lung injury occurring during or within 6 hrs after a transfusion, with a clear temporal relationship to the transfusion. Also, another important concept is that acute lung injury temporally associated with multiple transfusions can be TRALI, because each unit of blood or blood component can carry one or more of the possible causative agents: antileukocyte antibody, biologically active substances, and other yet unidentified agents. Using the definition in this report, clinicians can diagnose and report TRALI cases to the blood bank; importantly, researchers can use this definition to determine incidence, pathophysiology, and strategies to prevent this leading cause of transfusion-associated mortality.

Transfusion‐Associated Septic Reactions

SUMMARYTransfusion reactions associated with bacteria and/or their products, during or following a blood transfusion, were one of the earliest recognized complications of allogeneic blood transfusions. Bacterial contamination of blood products has, therefore, been a problem for many decades and, at the present time, is likely the most common microbiological cause of transfusion‐associated mortality and morbidity. Septic reactions associated with platelet concentrates appear to be much more common than those associated with contaminated red blood cells. The overall prevalence of contaminated cellular blood products has been estimated to be approximately 1 in 3000; however, the transfusion of contaminated platelet or red blood cell units may not necessarily be associated with clinically apparent morbidity in recipients because the majority of contaminated blood product units contain relatively few organisms. Unfortunately, though, in a minority of instances, contaminated blood product units contain clinically significant numbers of bacteria as well as endotoxins that may be associated with significant mortality and/or morbidity. The incidence of clinically evident severe septic episodes has not yet been clearly established, but is probably in the order of 1 per 50,000 platelet units transfused and 1 per 500,000 red blood cell units transfused. In recent years, a variety of interventions have been proposed, and in some instances implemented, in an effort to reduce this significant and potentially preventable transfusion risk.