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1.  Implementation and outcomes of a transfusion-related acute lung injury surveillance programme and study of HLA/HNA alloimmunisation in blood donors 
Blood Transfusion  2012;10(3):351-359.
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.
Materials and methods.
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.
PMCID: PMC3417735  PMID: 22395353
transfusion-related acute lung injury; HLA and HNA alloimmunisation; HNA frequencies
2.  Possible transfusion-related acute lung injury (TRALI) in cardiac surgery patients 
Croatian Medical Journal  2014;55(2):138-145.
To determine the incidence of possible transfusion-related acute lung injury (TRALI) and related risk factors in cardiac surgery patients.
A single-center prospective cohort study was conducted from January 2009 to March 2010 at the Zagreb University Hospital Center, Croatia. Patient-, transfusion-, and surgery-related data were collected. The study included 262 patients who were observed for respiratory worsening including measurements of arterial oxygen saturation (SaO2), fraction of inspired oxygen (FiO2), and partial pressure of arterial oxygen (PaO2). Possible TRALI was defined according to the Toronto Consensus Conference definition broadened for 24-hour post-transfusion. This cohort was divided in two groups. TRALI group included 32 participants with diagnosis of TRALI and the control group included 220 patients with or without respiratory worsening, but with no signs of ALI.
Possible TRALI was observed in 32 (12.2%) patients. Compared with the control group, possible TRALI patients had higher American Association of Anesthesiology scores, higher rate of respiratory comorbidity (43.8% vs 15.5%), and required more red blood cells (median 4, range [2.5-6] vs 2 [1-3]), plasma (5 [0-6] vs 0 [0-2]), and platelet units (0 [0-8] vs 0 [0-0]) (P < 0.001 all). Risk factors for possible TRALI were total number of transfused blood units (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.10-1.37) and duration of cardiopulmonary bypass (OR 1.08; 95% CI 1.05-1.11). Post-transfusion PaO2/FiO2 ratio was significantly decreased in possible TRALI patients and significantly increased in transfused controls without acute lung injury.
We observed a higher rate of possible TRALI cases than in other studies on cardiac surgery patients. Serial monitoring of PaO2/FiO2 ratio and detection of its post-transfusion worsening aids in identification of possible TRALI cases.
PMCID: PMC4009714  PMID: 24778100
3.  An association between decreased cardiopulmonary complications (TRALI and TACO) and implementation of universal leukoreduction of blood transfusions 
Transfusion  2010;50(12):2738-2744.
Cardiopulmonary adverse events after transfusion include acute lung injury (TRALI) and circulatory overload (TACO), which are potentially lethal and incompletely understood.
Study Design and Methods
To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective, before and after study of acute transfusion reactions for the seven years prior to and after introduction of universal leukoreduction in 2000, involving 778,559 blood components.
Substantial decreases occurred in the rates of TRALI (−83%; from 2.8 cases per 100,000 components pre- to 0.48 post-universal leukoreduction; p=0.01), TACO (−49%; 7.4 to 3.8 cases per 100,000; p=0.03) and febrile reactions (−35%; 11.4 to 7.4 cases per 10,000; p<0.0001). The incidence of allergic reactions remained unchanged (7.0 per 100,000 pre- and post-universal leukoreduction). These outcomes were primarily attributable to decreased TRALI/TACO associated with RBC and platelet transfusions (−64%) with notably smaller decreases associated with FFP or cryoprecipitate transfusions (−29%). The incidence of TRALI/TACO after 28,120 washed red cell and 69,325 platelet transfusions was zero.
These data suggest novel hypotheses for further testing in animal models, in prospective clinical trials, and via the new US Hemovigilance System : (1) Is TACO or TRALI mitigated by leukoreduction? (2) Is the mechanism of TACO more complex than excessive blood volume? (3) Does washing mitigate TRALI and TACO due to platelet and RBC transfusions?
PMCID: PMC2944002  PMID: 20561296
4.  Two septic transfusion reactions presenting as TRALI from a split plateletpheresis unit 
Critical care medicine  2012;40(8):2488-2491.
We report two simultaneous cases of Staphylococcus aureus sepsis initially consistent with and diagnosed as transfusion related acute lung injury (TRALI). The sepsis in both cases resulted from transfusion of two split products from a single contaminated plateletpheresis unit. In each case the platelets were given along with numerous other blood products during posterior spine surgery. The discussion includes presentation, clinical course, diagnosis and similarities between sepsis and TRALI. The cases and discussion highlight the importance of considering sepsis as part of the differential for any patient believed to have TRALI with clinical features of sepsis.
Data Sources
Data were collected from the patients’ electronic medical records and the hospital laboratory medicine database.
Our cases highlight the importance of vigilant investigation in patients suspected of TRALI, as septic transfusions are easily missed and may mimic or coexist with TRALI. Sepsis should be strongly considered whenever clinical features such as hypotension, leucopenia and fever are noted in patients with suspected TRALI. In comparison to patients receiving red blood cells or plasma, platelet transfusion recipients are at a greater risk for sepsis from a contaminated unit. Patients developing sepsis from a contaminated blood product may meet the clinical definition of TRALI. In such cases, if the clinical syndrome is attributed solely to TRALI and bacterial sepsis is not suspected, the correct diagnosis may be missed or delayed. Consequently, appropriate treatment for sepsis would also be delayed or not provided and likely result in increased morbidity and mortality.
PMCID: PMC3733455  PMID: 22809916
TRALI; sepsis; transfusion; platelets; bacterial contamination
5.  Acute Lung Injury Complicating Blood Transfusion in Post-Partum Hemorrhage: Incidence and Risk Factors 
We retrospectively investigated the incidence and risk factors for transfusion-related acute lung injury (TRALI) among patients transfused for post-partum hemorrhage (PPH).
We identified a series of 71 consecutive patients with PPH requiring the urgent transfusion of three or more red blood cell (RBC) units, with or without transfusion of fresh frozen plasma (FFP) and/or platelets (PLT). Clinical records were then retrieved and examined for respiratory distress events. According to the 2004 consensus definition, cases of new-onset hypoxemia, within 6 hours after transfusion, with bilateral pulmonary changes, in the absence of cardiogenic pulmonary edema were identified as TRALI. If an alternative risk factor for acute lung injury was present, possible TRALI was diagnosed.
Thirteen cases of TRALI and 1 case of possible TRALI were identified (overall incidence 19.7%). At univariate analysis, patients with TRALI received higher number of RBC, PLT and FFP units and had a longer postpartum hospitalization. Among the diseases occurring in pregnancy- and various pre-existing comorbidities, only gestational hypertension and pre-eclampsia, significantly increased the risk to develop TRALI (p = 0.006). At multivariate analysis including both transfusion- and patient-related risk factors, pregnancy-related, hypertensive disorders were confirmed to be the only predictors for TRALI, with an odds ratio of 27.7 ( 95% CI 1.27–604.3, p=0.034).
Patients suffering from PPH represent a high-risk population for TRALI. The patients with gestational hypertension and pre-eclampsia, not receiving anti-hypertensive therapy, have the highest risk. Therefore, a careful monitoring of these patients after transfusions is recommended.
PMCID: PMC4235434  PMID: 25408855
6.  Role of Riboflavin- and UV Light-Treated Plasma in Prevention of Transfusion-Related Acute Lung Injury 
Risk reduction strategies for transfusion-related acute lung injury (TRALI) include the preferential use of male donors to provide fresh frozen plasma (FFP). Implementing this measure based on FFP quarantine program is a very complex process. To improve FFP inventory management and the availability of FFP from male donors, the Mirasol Pathogen Reduction Technology® (PRT) system for FFP using riboflavin and UV light was adopted in our region in 2012.
The percentage of male/female FFP units issued and TRALI cases in patients receiving FFP in the period before implementing riboflavin and UV light (2010–2011) was compared with the period post implementation of riboflavin and UV light (2012–2013).
In 2010 and 2011, there was one FFP transfusion-related TRALI case reported per year, when the proportion of male/female FFP distributed to the hospitals was 60/40. During 2012 and 2013, there have been no FFP transfusion-related TRALI cases, when the proportion of male/female FFP distributed to the hospitals was around 97/3. Mirasol PRT allows quick availability (24 h from collection) compared to quarantined FFP (≥3 months from collection).
Thanks to its readiness, simplicity and feasibility, riboflavin- and UV light-treated FFP implementation can facilitate the preferential use of FFP from male donors as a TRALI prevention strategy.
PMCID: PMC4086761  PMID: 25053929
Riboflavin; UV light; Plasma; TRALI
7.  The Effect of Previous Pregnancy and Transfusion on HLA Alloimmunization in Blood Donors: Implications for a Transfusion Related Acute Lung Injury (TRALI) Risk Reduction Strategy 
Transfusion  2009;49(9):1825-1835.
Antibodies to human leukocyte antigens (HLA) in donated blood have been implicated as a cause of transfusion related acute lung injury (TRALI). A potential measure to reduce the risk of TRALI includes screening platelet apheresis donors for HLA antibodies. The prevalence of HLA antibodies and their relationship to previous transfusion or pregnancy in blood donors was determined.
Study design and methods
8171 volunteer blood donors were prospectively recruited by 6 U.S. blood centers from December 2006 to May 2007. Donors provided a detailed history of pregnancy and transfusion, and a sample for HLA class I and II antibody testing by multi-antigen bead flow analysis.
8171 donors were enrolled, 7920 (96.9%) had valid HLA antibody test results and 7841(99%) of those had complete pregnancy and transfusion information. The prevalence of any HLA antibody was similar in non-transfused (n=1138) and transfused (n=895) men, 1.0 vs. 1.7% (p=0.16). HLA antibodies were detected in 17.3% of all female donors (n=5834) and in 24.4 % of those with a history of previous pregnancy (n=3992). The prevalence of HLA antibodies increased in women with greater numbers of pregnancy: 1.7%(zero), 11.2%(one), 22.5%(two), 27.5%(three) and 32.2%(four or more pregnancies), p<0.0001.
HLA class I and class II antibodies are detectable at low prevalence in male donors regardless of transfusion and in female donors without known immunizing events. The prevalence of HLA antibodies increases significantly with more pregnancies. These data will allow blood centers to estimate the impact of HLA antibody testing as a potential TRALI risk-reduction measure.
PMCID: PMC2841001  PMID: 19453983
HLA antibody; pregnancy; transfusion; transfusion related acute lung injury
8.  Transfusion related acute lung injury after transfusion of maternal blood: a case control study 
Spine  2010;35(23):E1322-E1327.
Study Design
This is a single center retrospective case control study of 7 Transfusion Related Acute Lung Injury (TRALI) cases and 28 controls in the pediatric spinal surgery population.
To determine the association between maternal transfusion and risk of TRALI in pediatric spinal surgery patients.
Summary of Background Data
Previous studies support a “two-hit” model for the pathogenesis of TRALI – activation and sequestration of neutrophils in the pulmonary vasculature followed by transfusion of a biologic response modifier such as anti-leukocyte antibodies. Maternal donation of blood products is a potential risk factor for TRALI due to the development of anti-leukocyte antibodies during pregnancy. Until now there have been no studies specifically addressing the risk of TRALI following maternal transfusions.
This is a retrospective case control study of 7 TRALI cases with 4 controls per case, matched by strata for volume of plasma transfused. All cases identified by the Transfusion Biology and Medicine Specialized Center of Clinically Oriented Research (SCCOR) with a TRALI diagnosis were eligible for inclusion. Electronic medical records and operative notes were reviewed to obtain demographic data, diagnosis, surgical approach and number of spine levels for each operation.
An increased prevalence of maternal blood transfusion was found among the TRALI cases compared to the control cases: 43% (3 of 7) versus 7% (2 of 28), p = 0.044. There were otherwise no statistical differences between the groups, including age, gender, surgical approach, number of spinal levels, or type of blood product transfused.
Pediatric patients undergoing spinal surgery may be at increased risk for the development of TRALI following the transfusion of maternal blood products. Accordingly, we recommend that directed donation of maternal blood products should be avoided in this population. This study also found that TRALI may be under-recognized and under-reported to the transfusion service.
PMCID: PMC2964398  PMID: 20938390
9.  Establishing Assay Cutoffs for HLA Antibody Screening of Apheresis Donors 
Transfusion  2011;51(10):2092-2101.
TRALI is the leading cause of transfusion-related deaths. Donor HLA antibodies have been implicated in TRALI cases. Blood centers are implementing TRALI risk reduction strategies based on HLA antibody screening of some subpopulations of ever-pregnant apheresis platelet donors. However, if screening assay cutoffs are too sensitive, donation loss may adversely impact blood availability.
Pregnancy history and HLA antibody screening and single antigen bead (SAB) data from blood donors in the REDS-II Leukocyte Antibody Prevalence Study (LAPS) were evaluated for correlations between assay screening values, HLA antibody titer, and number of HLA antigen specificities. The probabilities of matching a cognate antigen in a recipient were calculated and examined in association with total number of specificities observed and screening values. The relative impact of imposing various screening assay cutoffs or pregnancy stratification was examined in relation to detection of HLA antibody reactive donations and loss of donors and donations.
We provide evidence that higher HLA Ab screening assay values are associated with maintaining higher screening signals upon dilution and an increased breadth of specificities compared with lower screening values; the latter correlated with an increased risk of a cognate antigen match in potential recipients. Depending upon the TRALI risk reduction strategy used, the potential loss of donations ranged between 0.9 and 6.0%.
This analysis should enable blood centers to decide upon a TRALI risk reduction strategy for apheresis platelets that is consistent with how much donation loss the blood center can tolerate.
PMCID: PMC3108003  PMID: 21332726
TRALI; Transfusion-Related Acute Lung Injury; HLA antibodies; platelet transfusions
10.  Blood donations from previously transfused or pregnant donors: a multicenter study to determine the frequency of alloexposure 
Transfusion  2010;51(6):1197-1206.
Transfusion-related acute lung injury (TRALI) mitigation strategies include the deferral of female donors from apheresis platelet (PLT) donations and the distribution of plasma for transfusion from male donors only. We studied the implications of these policies in terms of component loss at six blood centers in the United States.
We collected data from allogeneic blood donors making whole blood and blood component donations during calendar years 2006 through 2008. We analyzed the distribution of donations in terms of the sex, transfusion and pregnancy histories, and blood type.
A TRALI mitigation policy that would not allow plasma from female whole blood donors to be prepared into transfusable plasma components would result in nearly a 50% reduction in the units of whole blood available for plasma manufacturing and would decrease the number of type AB plasma units that could be made from whole blood donations by the same amount. Deferral of all female apheresis PLT donors, all female apheresis PLT donors with histories of prior pregnancies, or all female apheresis PLT donors with histories of prior pregnancies and positive screening test results for antibodies to human leukocyte antigens (HLAs) will result in a loss of 37.1, 22.5, and 5.4% of all apheresis PLT donations, respectively.
A TRALI mitigation policy that only defers female apheresis PLT donors with previous pregnancies and HLAs would result in an approximately 5% decrease in the inventory of apheresis PLTs, but would eliminate a large proportion of components that are associated with TRALI.
PMCID: PMC3606016  PMID: 21182532
11.  Transfusion-related acute lung injury in ICU patients admitted with gastrointestinal bleeding 
Intensive care medicine  2010;36(10):1710-1717.
Transfusion of blood components is common in patients admitted to the intensive care unit (ICU) for gastrointestinal (GI) bleeding, yet the incidence and risk factors for development of transfusion-related acute lung injury (TRALI) in these patients are unknown.
Patients admitted to a medical ICU for GI bleeding (n = 225) were analyzed for patient-and transfusion-specific risk factors for development of TRALI.
In transfused patients (n = 150), the incidence of TRALI was 15% [95% confidence interval (CI), 10–21%] and accounted for 76% (22/29) of all acute lung injury (ALI) cases. Transfused patients with end-stage liver disease (ESLD) (n = 72) developed TRALI more frequently than those without ESLD (29% versus 1%, p < 0.01). Fresh frozen plasma (FFP) was temporally associated with TRALI in 86% of cases. Transfusion-specific risk factors for development of TRALI included number of transfused units of FFP and nonleukoreduced red blood cells. Patient-specific risk factors included Model for End-Stage Liver Disease (MELD) score, admission serum albumin level, and presence of ALI risk factors.
TRALI is common in critically ill ESLD patients with gastrointestinal bleeding. Nonleukoreduced red blood cells and FFP are significant transfusion-specific risk factors and their use should be re-evaluated in bleeding patients with ESLD.
PMCID: PMC3727900  PMID: 20658125
Transfusion-related acute lung injury; Transfusion complications; Acute respiratory distress syndrome; Variceal bleeding; Chronic liver disease; Plasma transfusion
12.  Age of blood and recipient factors determine the severity of transfusion-related acute lung injury (TRALI) 
Critical Care  2012;16(1):R19.
Critical care patients frequently receive blood transfusions. Some reports show an association between aged or stored blood and increased morbidity and mortality, including the development of transfusion-related acute lung injury (TRALI). However, the existence of conflicting data endorses the need for research to either reject this association, or to confirm it and elucidate the underlying mechanisms.
Twenty-eight sheep were randomised into two groups, receiving saline or lipopolysaccharide (LPS). Sheep were further randomised to also receive transfusion of pooled and heat-inactivated supernatant from fresh (Day 1) or stored (Day 42) non-leucoreduced human packed red blood cells (PRBC) or an infusion of saline. TRALI was defined by hypoxaemia during or within two hours of transfusion and histological evidence of pulmonary oedema. Regression modelling compared physiology between groups, and to a previous study, using stored platelet concentrates (PLT). Samples of the transfused blood products also underwent cytokine array and biochemical analyses, and their neutrophil priming ability was measured in vitro.
TRALI did not develop in sheep that first received saline-infusion. In contrast, 80% of sheep that first received LPS-infusion developed TRALI following transfusion with "stored PRBC." The decreased mean arterial pressure and cardiac output as well as increased central venous pressure and body temperature were more severe for TRALI induced by "stored PRBC" than by "stored PLT." Storage-related accumulation of several factors was demonstrated in both "stored PRBC" and "stored PLT", and was associated with increased in vitro neutrophil priming. Concentrations of several factors were higher in the "stored PRBC" than in the "stored PLT," however, there was no difference to neutrophil priming in vitro.
In this in vivo ovine model, both recipient and blood product factors contributed to the development of TRALI. Sick (LPS infused) sheep rather than healthy (saline infused) sheep predominantly developed TRALI when transfused with supernatant from stored but not fresh PRBC. "Stored PRBC" induced a more severe injury than "stored PLT" and had a different storage lesion profile, suggesting that these outcomes may be associated with storage lesion factors unique to each blood product type. Therefore, the transfusion of fresh rather than stored PRBC may minimise the risk of TRALI.
PMCID: PMC3396258  PMID: 22297161
13.  Transfusion-Related Acute Lung Injury: Incidence, Pathogenesis and the Role of Multicomponent Apheresis in Its Prevention 
Although transfusion-related acute lung injury (TRALI) is now appreciated as the most common cause of death from transfusion, its incidence remains unknown. The most frequently cited figure is 1:5,000 plasma-containing components. Certain patient groups may be at significantly higher risk. TRALI is both underdiagnosed and un-derreported. It is misdiagnosed as transfusion-associated circulatory overload. Several mechanisms have been proposed for its pathogenesis-leukocyte antibodies and the 2-hit model. These may overlap, and both involve transfusion of leukocyte antibodies. Passive transfusion of leukocyte antibodies is strongly associated with TRALI; these are identified in 60–85% of cases. Multiparous blood donors are the most frequent source of these antibody-containing components. The antibodies are HLA class I and II and/or granulocyte-specific. In 50% of cases the antibody corresponds to an epitope in the patient. HLA class I antibodies have been shown to prime and activate neutrophils. Clinical reports and animal models link HNA-3a antibodies with severe lung injury. A number of TRALI prevention and risk mitigation strategies have been proposed. In the UK and the USA, these strategies have centered upon excluding ‘high risk’ (HLA/HNA antibody containing) plasma from fresh frozen plasma and platelet products. Multicomponent apheresis collection of platelets, plasma and red blood cells is a means of accomplishing this objective.
PMCID: PMC3076338  PMID: 21512631
Transfusion-related acute lung injury; Multicomponent collection; Apheresis
14.  The Impact of Policies to Restrict the Use of Plasma Containing Products and Apheresis Platelets from Female Donors to Mitigate Transfusion Related Acute Lung Injury (TRALI) in Brazil 
Background and Objectives
Although the incidence of TRALI is unknown in Brazil, some blood centers have adopted strategies to prevent TRALI. We evaluated the impact of three policies to mitigate TRALI on the supply of blood products: to divert the production of whole blood-derived plasma from female donors; to defer all female donors from apheresis platelet collections, and to defer only multiparous female donors from apheresis platelet collections.
Materials and Methods
Data from allogeneic whole blood and apheresis platelet donations from April 2008 to December 2009 were collected in three Brazilian blood centers and the impact of the aforementioned strategies was evaluated.
Of 544,814 allogeneic blood donations, 30.8% of whole blood plasma and 24.1% of apheresis platelet donations would be reduced if only male donor plasma was issued for transfusion and all female donors were deferred from apheresis donation, respectively. If only multiparous donors were deferred from apheresis donation, there would be a 5% decrease of all apheresis platelet collections.
Restricting the use of whole blood derived plasma to male-only donors and deferring all female apheresis platelet donors would impact two out of three Brazilian blood centers. A deferral policy on multiparous apheresis platelet donors may be acceptable as a temporary measure, but may cause more stress on a system that is already working at its limit.
PMCID: PMC3547161  PMID: 22985535
TRALI; multiparous donors; apheresis platelets; leukocyte antibodies; Brazil; transfusion reactions
15.  Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury 
The Journal of Clinical Investigation  2009;119(11):3450-3461.
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.
PMCID: PMC2769181  PMID: 19809160
16.  The Leukocyte Antibody Prevalence Study-II (LAPS-II): a retrospective cohort study of transfusion-related acute lung injury in recipients of high-plasma-volume human leukocyte antigen antibody–positive or –negative components 
Transfusion  2011;51(10):2078-2091.
We used a multicenter retrospective cohort study design to evaluate whether human leukocyte antigen (HLA) antibody donor screening would reduce the risk of transfusion-related acute lung injury (TRALI) or possible TRALI.
In the Leukocyte Antibody Prevalence Study-II (LAPS-II), we evaluated pulmonary outcomes in recipients of 2596 plasma-rich blood components (transfusable plasma and plateletpheresis) sent to participating hospitals; half of the components were collected from anti-HLA–positive donors (study arm) and half from anti-HLA–negative donors (control arm) matched by sex, parity, and blood center. A staged medical record review process was used. Final recipient diagnosis was based on case review by a blinded expert panel of pulmonary or critical care physicians.
TRALI incidence was 0.59% (seven cases) in study arm recipients versus 0.16% (two cases) in control arm recipients for an odds ratio (OR) of 3.6 (95% confidence interval [CI], 0.7–17.4; p = 0.10). For possible TRALI cases (nine study arm, eight control arm), the OR was 1.2 (95% CI, 0.4–3.0; p = 0.81), and for TRALI and possible TRALI aggregated together, it was 1.7 (95% CI, 0.7–3.7; p = 0.24). Transfusion-associated circulatory overload incidence was identical in the two arms (1.17 and 1.22%, respectively; OR, 1.0; p = 1.0).
TRALI incidence in recipients of anti-HLA–positive components was relatively low for a look-back study (1 in 170) and was higher than in the control arm, but did not reach significance. Based on this trend, the data are consistent with the likelihood that TRALI risk is decreased by selecting high-volume plasma components for transfusion from donors at low risk of having HLA antibodies.
PMCID: PMC3606005  PMID: 21446938
17.  Experimental Models of Transfusion-Related Acute Lung Injury (TRALI) 
Transfusion medicine reviews  2011;25(1):1-11.
Transfusion-related acute lung injury (TRALI) is defined clinically as acute lung injury occurring within six hours of the transfusion of any blood product. It is the leading cause of transfusion-related death in the United States, but under-recognition and diagnostic uncertainty have limited clinical research to smaller case control studies. In this review we will discuss the contribution of experimental models to the understanding of TRALI pathophysiology and potential therapeutic approaches. Experimental models suggest that TRALI occurs when a host, with a primed immune system, is exposed to an activating agent such as anti-leukocyte antibody or a biologic response modifier such as lysophosphatidylcholines. Recent work has suggested a critical role for platelets in antibody-based experimental models and identified potential therapeutic strategies for TRALI.
PMCID: PMC3011933  PMID: 21134622
18.  Acute lung injury after platelet transfusion in a patient with dengue fever 
Transfusion-related acute lung injury (TRALI) is a serious clinical syndrome associated with the transfusion of plasmacontaining blood components. Recently, TRALI has come to be recognized as the leading cause of transfusion-related mortality. This complication typically presents as shortness of breath, hypoxemia, hypotension, fever, and non cardiogenic pulmonary edema, occurring within 6 h after transfusion. Although the mechanism of TRALI has not been exactly known, it has been associated with human leukocyte antigen antibodies and with biologically active mediators in stored cellular blood components. We, hereby, present a case of a patient with dengue fever who developed acute lung injury (ALI), presumably TRALI, after transfusion of platelet concentrates. He was treated with supportive measures and mechanical ventilation. Greater knowledge and increased awareness especially amongst the clinicians regarding TRALI is needed for prevention and treatment of this potentially severe complication of blood/component transfusion.
PMCID: PMC4140058  PMID: 25161356
Acute lung injury; blood transfusion; non cardiogenic pulmonary edema; transfusion-related acute lung injury
19.  MHC class I–specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice 
The Journal of Experimental Medicine  2011;208(12):2525-2544.
In a manner partially independent of activating Fcγ receptors, antibody-mediated production of complement component C5a and recruitment of macrophages elicit transfusion-related acute lung injury in mice.
Transfusion-related acute lung injury (TRALI), a form of noncardiogenic pulmonary edema that develops during or within 6 h after a blood transfusion, is the most frequent cause of transfusion-associated death in the United States. Because development of TRALI is associated with donor antibodies (Abs) reactive with recipient major histocompatibility complex (MHC), a mouse model has been studied in which TRALI-like disease is caused by injecting mice with anti–MHC class I monoclonal Ab (mAb). Previous publications with this model have concluded that disease is caused by FcR-dependent activation of neutrophils and platelets, with production of reactive oxygen species that damage pulmonary vascular endothelium. In this study, we confirm the role of reactive oxygen species in the pathogenesis of this mouse model of TRALI and show ultrastructural evidence of pulmonary vascular injury within 5 min of anti–MHC class I mAb injection. However, we demonstrate that disease induction in this model involves macrophages rather than neutrophils or platelets, activation of complement and production of C5a rather than activation of FcγRI, FcγRIII, or FcγRIV, and binding of anti–MHC class I mAb to non-BM–derived cells such as pulmonary vascular endothelium. These observations have important implications for the prevention and treatment of TRALI.
PMCID: PMC3256958  PMID: 22025304
20.  Female donors and transfusion-related acute lung injury: A case-referent study from the International TRALI Unisex Research Group 
Transfusion  2010;50(11):2447-2454.
Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion-related acute lung injury (TRALI) are caused by female blood donors. We aimed to examine the relation between female donors and the occurrence of TRALI.
We performed an international, multicenter case-referent study. TRALI patients who were diagnosed clinically, independent of serology or donor sex, and had received transfusions either only from male donors or only from female donors (unisex cases) were selected. The observed sex distribution among the donors of these TRALI patients was compared to the expected sex distribution, based on the relevant donor populations.
Eighty-three clinical TRALI cases were included; 67 cases received only red blood cells (RBCs), 13 only plasma-rich products, and three both. Among RBC recipients the relative risk (RR) of TRALI after a transfusion from a female donor was 1.2 (95% confidence interval [CI], 0.69–2.1) and among plasma-rich product recipients the RR was 19 (95% CI, 1.9–191). The p value for the difference between RBCs and plasma was 0.023.
Our data support the notion that plasma from female donors is associated with an increased risk of TRALI, while RBCs from female donors are not.
PMCID: PMC3740332  PMID: 20529001
21.  TRALI - Definition, mechanisms, incidence and clinical relevance 
Transfusion-related acute lung injury (TRALI) is defined as new acute lung injury (ALI) that occurs during or within six hours of transfusion, not explained by another ALI risk factor. Transfusion of part of one unit of any blood product can cause TRALI. The mechanism may include factors in unit(s) of blood, such as antibody and biologic response modifiers. In addition, yet to be described factors in a patient’s illness may predispose to the condition. The current incidence is estimated to be 1 in 5,000 units. Patients present with acute dyspnea, or froth in the endotracheal tube in intubated patients. Hypertension, hypotension, acute leukopenia have been described. Management is similar to that for ALI and is predominantly supportive. When TRALI is suspected, Blood banks should be notified to quarantine other components from the same donation. No special blood product is required for subsequent transfusion of a patient who has developed TRALI.
PMCID: PMC2767181  PMID: 17650771
Blood transfusion/ adverse effects; Pulmonary edema; Acute lung injury
22.  Transfusion Reactions: Newer Concepts on the Pathophysiology, Incidence, Treatment and Prevention of Transfusion Related Acute Lung Injury (TRALI) 
Critical Care Clinics  2012;28(3):363-372.
Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. Clinically, TRALI presents as acute lung injury (ALI) (characterized by dyspnea and hypoxemia, with bilateral pulmonary infiltrates) within 6 hours after transfusion of one or more blood products. The pathophysiology of TRALI is incompletely understood, but in part is due to transfusion of certain anti-leukocyte antibodies, or possibly other bioactive substances, into susceptible recipients. Transfusion recipient risk factors are higher interleukin-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking and higher positive fluid balance. Transfusion risk factors are female plasma, quantity of strong antibody that matches recipient class II human leukocyte antigens, and volume of plasma containing antibody to human neutrophil antigens. Diagnosing TRALI requires a high index of suspicion, and the exclusion of circulatory overload, heart failure or other major ALI risk factors as the cause of pulmonary edema. Treatment should include cessation of the offending transfusion, but is otherwise supportive. Reduced transfusion of female plasma has been associated with a lower TRALI incidence. Further prevention strategies may include reduced transfusion of platelets that contain leukocyte antibodies, and reduction of recipient susceptibility by improving treatment of shock and limiting peak airway pressure while being mechanically ventilated.
PMCID: PMC3380279  PMID: 22713611
transfusion related acute lung injury; acute lung injury; transfusion reaction; multiple transfusions; pulmonary edema
23.  The approach taken to reducing the risk of transfusion related acute lung injury in Canada 
Transfusion related acute lung injury (TRALI) has become a major reported cause of severe transfusion reactions and mortality. Over the past four years significant changes have been taken in Canada in order both to improve the recognition of the risk and to decrease its incidence. An international meeting was held in April of 2004 entitled “Towards an Understanding of TRALI". As a result of the analysis and recommendations from this meeting, the Canadian Blood Services established an ongoing review committee and established a laboratory diagnostic facility to identify at risk donors and recipients. A system has been developed to identify implicated donors and exclude them from the blood donor pool. Other steps have been taken to exclude potentially high risk donors, such as previously pregnant females, from the plasma and platelet donor pool. A considerable amount of education also has been offered to clinical services in the country. This paper summarizes the definitions, categorizations of implicated donors, and the ongoing precautionary activities related to plasma products. Noted within the article are the methods used for locating and selecting data. These were primarily based on the international TRALI conference in 2004, and from ongoing discussions and information provided by the Canadian Blood Services TRALI Review Committee. No ethics referral or approval was requested, and a summary is included in the article.
PMCID: PMC2798766  PMID: 20041083
Transfusion related acute lung injury risk reduction
24.  Epidemiology of Transfusion Related Acute Lung Injury in France: Preliminary Results 
The French Hemovigilance Network has been established in 1994 and records all adverse events associated with the transfusion of a labile blood products (LBP) regardless of their severity. From 1994 to 2006 35,423,172 LBP were issued, 85,812 adverse transfusion reactions notified, and 139 cases of transfusion related acute lung injury (TRALI) observed. The LBP most at risk is fresh frozen plasma (FFP), followed by platelets concentrates (PC) and packed red cells (PRC). However, because the use of FFP is not frequent in France, it only accounts for about 10% of TRALI, whereas PRC and PC are involved in the remaining cases. In no case, pooled FFP treated with solvent-detergent were involved. Patients’ profiles are peculiar with a high disease burden. Therefore, targeting a prevention policy only on FFP would result in a marginal reduction of TRALI in France.
PMCID: PMC3076340  PMID: 21512633
TRALI; Hemovigilance; Blood transfusion; Sickle cell disease; Public health
25.  Comparison of acute non-haemolytic transfusion reactions in female and male patients receiving female or male blood components 
To study the relationship between antibodies detected in patients’ and/or donors’ sera and the clinical features of acute non-haemolytic transfusion reactions (ANHTRs), and to determine any gender-related difference. ANHTRs range from urticaria to transfusion-related acute lung injury (TRALI). Antibodies to human leukocyte antigen (HLA), granulocytes, platelets, and/or plasma proteins are implicated in some of the ANHTRs. A higher antibody positivity is expected for females than for males. A comparative study of ANHTRs for antibody positivity and their clinical features between females and males for both patients and donors is helpful for characterizing ANHTRs including TRALI more clearly, but such studies are few and outdated. Two hundred and twenty-three ANHTR cases reported by 45 hospitals between October 2000 and July 2005 were analysed. The patients and 196 donors of suspect blood products were screened for antibodies to HLA Class I, HLA Class II, granulocytes, and platelets. The patients were also screened for anti-plasma protein antibodies. The types and severity of ANHTR did not differ significantly between female and male patients. The frequency of the anti-HLA antibodies, but not that of the non-HLA antibodies, was significantly higher in females. Non-HLA antibodies were significantly associated with severe reactions in females. All the TRALI cases had predisposing risk factors for acute lung injury, and 60% of the cases showed anti-leucocyte antibodies. Although the anti-HLA antibodies were detected more frequently in females than males, no significant association of ANHTRs including TRALI with gender, not only for patients, but also for donors, could be shown in this study.
PMCID: PMC2440557  PMID: 18067650
acute non-haemolytic transfusion reaction; anti-granulocyte antibody; anti-HLA antibody; anti-plasma protein antibody; anti-platelet antibody; TRALI

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