Preservation of recipient plasma sphingosine-1-phosphate levels reduces transfusion-related acute lung injury.

Cold-stored (CS) platelets are once again being reintroduced for clinical use. Transfused CS platelets offer benefits over room temperature-stored (RTS) platelets such as increased hemostatic effects and prolongation of shelf-life. Despite these advantages little is known about their association with transfusion-related acute lung injury (TRALI). TRALI is associated with prolonged storage of RTS platelets and has a mortality of >15%. Determining the safety of CS platelets is important considering their proposed use in TRALI-vulnerable populations with inflammation such as surgical patients or patients with trauma. Donor platelet-derived ceramide causes TRALI, whereas donor platelet sphingosine-1-phosphate (S1P) is barrier protective. Females have higher plasma levels of S1P than males. Cold temperatures increase S1P levels in cells. Therefore, we hypothesized that female (donors or recipients) and/or CS platelets would decrease TRALI. To test this, we compared how male and female donor and recipient allogeneic platelet transfusions of CS (4°C) versus RTS (23°C) platelets stored for 5 days influence murine TRALI. Transfusion of CS platelets significantly reduced recipient lung tissue wet-to-dry ratios, bronchoalveolar lavage total protein, lung tissue myeloperoxidase enzyme activity, histological lung injury scores, and increased plasma sphingosine-1-phosphate (S1P) levels compared with RTS platelet transfusions. Female as opposed to male recipients had less TRALI and higher plasma S1P levels. Female donor mouse platelets had higher S1P levels than males. Mouse and human CS platelets had increased S1P levels compared with RTS platelets. Higher recipient plasma S1P levels appear protective considering females, and males receiving platelets from females or male CS platelets had less TRALI.NEW & NOTEWORTHY Transfusion-related acute lung injury (TRALI) though relatively rare represents a severe lung injury. The sphingolipid sphingosine-1-phosphate (S1P) regulates the severity of platelet-mediated TRALI. Female platelet transfusion recipient plasmas or stored platelets from female donors have higher S1P levels than males, which reduces TRALI. Cold storage of murine platelets preserves platelet-S1P, which reduces TRALI in platelet-transfused recipients.

Transfusion-Associated Circulatory Overload and Transfusion-Related Acute Lung Injury.

OBJECTIVES: To review the new current diagnostic criteria of transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) from the literature while highlighting distinguishing features. We provide comprehensive understanding of the importance of hemovigilance and its role in appropriately identifying and reporting these potentially fatal transfusion reactions. METHODS: A review of the English language literature was performed to analyze TACO and TRALI while providing further understanding of the rationale behind the historical underrecognition and underreporting. RESULTS: Our review demonstrates the new 2018 and 2019 case definitions for TACO and TRALI, respectively. With more comprehensive diagnostic strategies, adverse transfusion events can be better recognized from mimicking events and underlying disease. In addition, there are mitigation strategies in place to help prevent complications of blood product transfusion, with emphasis on the prevention of TACO and TRALI. CONCLUSIONS: TACO and TRALI are potentially fatal adverse complications of blood transfusion. Both have been historically underrecognized and underreported due to poor defining criteria and overlapping symptomatology. Developing a thorough clinical understanding between these two entities can improve hemovigilance reporting and can contribute to risk factor identification and preventative measures.

Acute lung injury after exchange transfusion in two newborns with Glucose-6-phosphate dehydrogenase deficiency.

Transfusion-related lung injury (TRALI) is a condition that develops suddenly within the first six hours after a blood transfusion and it is one of the most important causes of blood transfusion-related mortality. There are few data in the literature about TRALI in the neonatal period. We present two newborn patients who developed TRALI after exchange transfusion due to high bilirubin levels. Our first case was a late preterm LGA baby and was on CPAP. The baby was intubated due to sudden deterioration after the exchange transfusion. Our second case was born at term and, an exchange transfusion was performed on the 5th day of life. He developed respiratory distress unexpectedly soon after the exchange transfusion and was intubated. Glucose-6- phosphate dehydrogenase (G6PD) deficiency was detected in both of our cases. We wanted to emphasize that TRALI should be considered in the differential diagnosis of respiratory distress that develops soon after a transfusion in the newborn period and to draw attention to that TRALI may develop more frequently in patients with G6PD deficiency.

NT-proBNP levels in the identification and classification of pulmonary transfusion reactions.

BACKGROUND: Consensus definitions for transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) have recently been revised; however, pulmonary transfusion reactions remain difficult to diagnose. We hypothesized that N-terminal pro-brain natriuretic peptide (NT-proBNP) levels could have utility in the identification and classification of pulmonary transfusion reactions. STUDY DESIGN AND METHODS: We performed a secondary analysis of a case-control study of pulmonary transfusion reactions at four academic hospitals. We evaluated clinical data and measured NT-proBNP levels prior to and following transfusion in patients with TACO (n = 160), transfused acute respiratory distress syndrome (ARDS) [n = 51], TRALI [n = 12], TACO/TRALI [n = 7], and controls [n = 335]. We used Wilcoxon Rank-Sum tests to compare NT-proBNP levels, and classification and regression tree (CART) algorithms to produce a ranking of covariates in order of relative importance for differentiating TACO from transfused controls. RESULTS: Pre-transfusion NT-proBNP levels were elevated in cases of transfused ARDS and TACO (both P < .001) but not TRALI (P = .31) or TACO/TRALI (P = .23) compared to transfused controls. Pre-transfusion NT-proBNP levels were higher in cases of transfused ARDS or TRALI with a diagnosis of sepsis compared to those without (P < .05 for both). CART analyses resulted in similar differentiation of patients with TACO from transfused controls for models utilizing either NT-proBNP levels (AUC 0.83) or echocardiogram results (AUC 0.80). CONCLUSIONS: NT-proBNP levels may have utility in the classification of pulmonary transfusion reactions. Prospective studies are needed to test the predictive utility of pre-transfusion NT-proBNP in conjunction with other clinical factors in identifying patients at risk of pulmonary transfusion reactions.

Pulmonary complications of transfusion: Changes, challenges, and future directions.

The pulmonary complications of transfusion (TACO, TRALI and TAD) are the leading cause of transfusion-related mortality and major morbidity. Advance in this area is essential in improving transfusion safety. This review describes the drivers for change in haemovigilance practice, the influence of recent key publications and future directions.

An animal model of transfusion-related acute lung injury and the role of soluble CD40 ligand.

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is a life-threatening complication of transfusion and is one of leading causes of transfusion-associated fatalities. However, the pathogenesis of TRALI is still unclear. Soluble CD40 ligand (sCD40L) is a proinflammatory cytokine that accumulates during blood component storage and is involved in transfusion reactions. The objective of this study was to establish a clinically relevant TRALI animal model and to evaluate the role of sCD40L in TRALI. MATERIALS AND METHODS: Rats' red-blood-cell (RBC) suspensions were prepared, and the quality of RBC was evaluated. A trauma-haemorrhage-transfusion strategy was applied to build the animal model. Lung oedema was evaluated by histopathology examination, total bronchoalveolar lavage fluid (BALF) protein concentration, Evans blue dye (EBD) leakage and inflammatory cytokines. The sCD40L concentrations were measured. RESULTS: Storage lesions of RBCs gradually increased over time. Obvious histological evidence of lung injury of rats transfused with a 35-day RBC was observed. The total BALF protein concentration, EBD leakage, inflammatory cytokines concentration were increased significantly in the Day 35 group. The sCD40L concentration increased significantly in the storage RBC suspension over time but was slightly elevated in rat plasma. CONCLUSIONS: These findings indicated successful establishment of a TRALI animal model with trauma-haemorrhage-transfusion, in which sCD40L may play a minor role in the development of TRALI.

Fibrinogen Supplementation and Its Indications.

Adequate plasma levels of fibrinogen are essential for clot formation, and in severe bleeding, fibrinogen reaches a critically low plasma concentration earlier than other coagulation factors. Although the critical minimum concentration of fibrinogen to maintain hemostasis is a matter of debate, many patients with coagulopathic bleeding require fibrinogen supplementation. Among the treatment options for fibrinogen supplementation, fibrinogen concentrate may be viewed by some as preferable to fresh frozen plasma or cryoprecipitate. The authors review major studies that have assessed fibrinogen treatment in trauma, cardiac surgery, end-stage liver disease, postpartum hemorrhage, and pediatric patients. Some but not all randomized controlled trials have shown that fibrinogen concentrate can be beneficial in these settings. The use of fibrinogen as part of coagulation factor concentrate based therapy guided by point-of-care viscoelastic coagulation monitoring (ROTEM [rotational thromboelastometry] or TEG [thromboelastography]) appears promising. In addition to reducing patients' exposure to allogeneic blood products, this strategy may reduce the risk of complications such as transfusion-associated circulatory overload, transfusion-related acute lung injury, and thromboembolic adverse events. Randomized controlled trials are challenging to perform in patients with critical bleeding, and more evidence is needed in this setting. However, current scientific rationale and clinical data support fibrinogen repletion in patients with ongoing bleeding and confirmed fibrinogen deficiency.

Ten years of TRALI mitigation: measuring our progress.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality for which multiple mitigation strategies have been implemented over the past decade. However, product-specific TRALI rates have not been reported longitudinally and may help refine additional mitigation strategies. STUDY DESIGN AND METHODS: This retrospective multicenter study included analysis of TRALI rates from 2007 through 2017. Numerators included definite or probable TRALI reports from five blood centers serving nine states in the United States. Denominators were components distributed from participating centers. Rates were calculated as per 100,000 components distributed (p < 0.05 significant). RESULTS: One hundred four TRALI cases were reported from 10,012,707 components distributed (TRALI rate of 1.04 per 100,000 components). The TRALI rate was 2.25 for female versus 1.08 for male donated components (p < .001). The TRALI rate declined from 2.88 in 2007 to 0.60 in 2017. From 2007 to 2013, there was a significantly higher TRALI rate associated with female versus male plasma (33.85 vs. 1.59; p < 0.001) and RBCs (1.97 vs. 1.15; p = 0.03). From 2014 through 2017, after implementation of mitigation strategies, a significantly higher TRALI rate only from female-donated plateletpheresis continued to be observed (2.98 vs. 0.75; p = 0.04). CONCLUSION: Although the TRALI rates have substantially decreased secondary to multiple strategies over the past decade, a residual risk remains, particularly with female-donated plateletpheresis products. Additional tools that may further mitigate TRALI incidence include the use of buffy coat pooled platelets suspended in male donor plasma or platelet additive solution due to the lower amounts of residual plasma.

TACO and TRALI: biology, risk factors, and prevention strategies.

Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the leading causes of transfusion-related morbidity and mortality. These adverse events are characterized by acute pulmonary edema within 6 hours of a blood transfusion and have historically been difficult to study due to underrecognition and nonspecific diagnostic criteria. However, in the past decade, in vivo models and clinical studies utilizing active surveillance have advanced our understanding of their epidemiology and pathogenesis. With the adoption of mitigation strategies and patient blood management, the incidence of TRALI and TACO has decreased. Continued research to prevent and treat these severe cardiopulmonary events is focused on both the blood component and the transfusion recipient.

How do I implement a whole blood program for massively bleeding patients?

Building on the successful military experience, interest has been rekindled in transfusing whole blood (WB) early in the resuscitation of traumatically injured civilians, often before their ABO group is known. WB efficiently provides treatment for shock and coagulopathy, as well as platelet hemostatic function, to patients losing large volumes of blood. Unlike group O uncrossmatched red blood cells (RBCs), group O WB contains a substantial amount of plasma, which is incompatible with the RBCs of all non-group O recipients. Thus, when implementing a WB program, it is important to decide how to mitigate the risk of immune-mediated hemolysis. Other questions that a hospital needs to answer before implementing a WB program include determining which patients will be eligible for this product, how many units eligible patients can receive, for how long it should be stored and under what conditions, and how to monitor for adverse events. The donor center needs to consider if the WB should be leukoreduced, how to comply with the AABB's transfusion-related acute lung injury risk mitigation standard, and into which storage solution it should be collected. This report describes the multidisciplinary approach taken to implementing a civilian WB program at a multihospital health care system in the United States.

Elevation of C-reactive protein levels in patients with transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within six hours following blood transfusion. In most cases, donor antibodies are suggested to be involved, however, the pathogenesis is poorly understood. A two-hit model is generally assumed to underlie TRALI pathogenesis where the first hit consists of a patient predisposing factor such as inflammation and the second hit is due to donor antibodies present in the transfused blood. We recently demonstrated that the acute phase protein C-reactive protein (CRP) could enhance murine anti-major histocompatibility complex (MHC) class I-mediated TRALI. Whether CRP is increased in human TRALI patients which would support its role as a risk factor for human TRALI, is currently unknown. For that purpose, we measured CRP levels in the plasma of human TRALI patients and found CRP levels to be significantly elevated compared to transfused control patients. These data support the notion that CRP may be a novel first hit risk factor in human TRALI and that modulation of CRP levels could be an effective therapeutic strategy for this serious adverse event of transfusion.

Platelets are dispensable for antibody-mediated transfusion-related acute lung injury in the mouse.

UNLABELLED: Essentials Role of platelets in immunological transfusion-related acute lung injury (TRALI) is debated. Immunological TRALI was tested in mice exhibiting severe thrombocytopenia or platelet dysfunction. Platelets are required to prevent lung hemorrhage but not edema formation and respiratory distress. Platelets are dispensable for the initiation and development of TRALI. SUMMARY: Background Transfusion-related acute lung injury (TRALI) is a serious transfusion-related complication. Previous conflicting studies have indicated that platelets are either crucial or dispensable for TRALI. Objectives To evaluate the role of platelets in major histocompatibility complex (MHC) I-induced-TRALI. Methods Antibody-mediated TRALI was experimentally induced in mice by lipopolysaccharide priming followed by the administration of an anti-MHC I mAb. Results TRALI was tested in the context of severe thrombocytopenia provoked by the administration of diphtheria toxin (DT) in transgenic iDTR mice selectively expressing DT receptor in megakaryocytes. The pathologic responses occurring within the first 10 min following the injection of the anti-MHC I mAb, i.e. the severity of lung edema and the drop in aortic blood oxygenation, were similar in severely thrombocytopenic DT-iDTR and control mice. At later times, mortality was nevertheless increased in DT-iDTR mice, owing to lung hemorrhages. When less severe thrombocytopenia was induced with an antiplatelet mAb, TRALI started and developed similarly as in control mice, but hemorrhages were absent. Furthermore, when platelet functions were defective because of administration of aspirin or clopidogrel, or because of glycoprotein (GP)IIbIIIa deficiency, TRALI still developed but no lung hemorrhages were observed. In contrast, when GPVI was immunodepleted, TRALI still occurred, but was occasionally accompanied by hemorrhages. Conclusions Platelets are dispensable for the initiation and development of MHC I-induced TRALI. Although they do not protect against the disruption of the vascular endothelial cell barrier and the subsequent plasma leakage and edema formation, platelets are essential to prevent more serious damage resulting in hemorrhages in alveoli.