Pathophysiology Of Transfusion-related Acute Lung Injury Research Articles

A pulmonary endothelial amplification loop aggravates ex-vivo transfusion-related acute lung injury via increased toll-like receptor 4 and intra-cellular adhesion molecule-1 expression.

Transfusion-Related Acute Lung Injury (TRALI) is a life-threatening complication of blood transfusions characterized by pulmonary endothelial cell damage and edema, with a high incidence in critically ill patients. The pathophysiology of TRALI is unresolved, but can generally be hypothesized to follow a 2-hit model in which the first hit is elicited by the underlying clinical condition of the patient (e.g., inflammation, which can be reflected by LPS in experimental models), and the second hit is delivered by the blood transfusion product (e.g., HLA class I antibodies). Here, we report a synergistic role for LPS and HLA class I antibody binding to pulmonary endothelium resulting in enhanced inflammatory responses. Pulmonary endothelial cells were treated with PBS or low-dose LPS, exclusively or in combination with anti-HLA class I. Endothelial surface expression of HLA class I, TLR4, and inflammatory marker ICAM-1 were measured, and trans-endothelial migration (TEM) of neutrophils was investigated. LPS treatment of pulmonary endothelium enhanced HLA class I antibody binding, and combined LPS and HLA class I antibody binding enhanced TLR4 (LPS receptor) and ICAM-1 expression on the endothelial cell surface. Low-dose LPS and HLA antibody together also increased neutrophil TEM under physiological flow by on average 5-fold. We conclude that LPS and anti-HLA class I antibody have the ability to activate the pulmonary endothelium into a spiral of increasing inflammation, opening the opportunity to potentially block TLR4 to prevent or reduce the severity of TRALI in vivo.

Evidence of CD40L/CD40 pathway involvement in experimental transfusion-related acute lung injury

Platelet transfusions can cause adverse reactions in their recipients, including transfusion-related acute lung injury (TRALI). The pathophysiology of TRALI depends on a number of signaling pathways and the inflammatory role played by blood platelets remains controversial. Platelets are important in inflammation, particularly via the immunomodulator complex CD40/CD40L. We studied the specific function of the CD40/CD40L interaction in regulating an experimental TRALI Two-hit model. A mouse model of immune TRALI was triggered by injection of LPS and an anti-MHC I antibody, and the effect of injection of a neutralizing anti-CD40L antibody before induction of TRALI investigated. The characteristics of TRALI were decreased body temperature, pulmonary lesions, and immune cell infiltration into the alveolar space. Pulmonary infiltration was evaluated by blood counts of specific immune cells and their detection in lung sections. Inhibition of the CD40/CD40L immunomodulator interaction significantly reduced communication between immune and/or endothelial cells and the development of pulmonary edema. Hence, our results indicate that targeting of the CD40/CD40L interaction could be an important method to prevent TRALI. While considering that our work concerned a mouse model, we postulate that improvement of the conditions under which platelet concentrates are prepared/stored would assist in alleviating the risk of TRALI.

Slit2/Robo4 signaling pathway modulates endothelial hyper-permeability in a two-event in vitro model of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) remains the leading cause of transfusion-related mortality. Endothelium semipermeable barrier function plays a critical role in the pathophysiology of transfusion-related acute lung injury (TRALI). Recently, Roundabout protein 4 (Robo4), interaction with its ligand Slit 2, was appreciated as a modulator of endothelial permeability and integrity. However, not much is known about the role of Slit2/Robo4 signaling pathway in the pathophysiology of TRALI. In this study, the TRALI model was performed by the “two-event” model of polymorphonuclear neutrophils (PMN)-mediated pulmonary microvascular endothelial cells (PMVECs) damage. We investigated the expression of Slit2/Robo4 and VE-cadherin and examined the pulmonary endothelial hyper-permeability in TRALI model. We found that the expression of Slit2/Robo4 and VE-cadherin were significantly decreased in a time-dependent manner, whereas the PMVECs permeability was gradually increased over time in TRALI model. Moreover, the treatment with Slit2-N, an active fragment of Slit2, increased the expression of Slit2/Robo4 and VE-cadherin to protect PMVECs from PMN-mediated pulmonary endothelial hyper-permeability. These results indicate that targeting Slit2/Robo4 signaling pathway may modulate the permeability as well as protect the integrity of endothelial barrier. In addition, Slit2-N appears to be a promising candidate for developing novel therapies against TRALI.

Platelet and TRALI: From blood component to organism

Even though used systematically with leukocyte reduction, platelet transfusions still cause adverse reactions in recipients. They include Transfusion-Related Acute Lung Injury (TRALI), respiratory distress that occurs within six hours of the transfusion. The pathophysiology of this transfusion complication brings complex cellular communication into play. The role, particularly inflammatory, played by blood platelets in TRALI pathophysiology has been demonstrated, but is still under debate. Blood platelets play a role in inflammation, particularly via the CD40/CD40L (sCD40L) immunomodulator complex. In this study, we examine in particular the specific involvement of the CD40/CD40L (sCD40L) complex in the inflammatory pathogenesis of TRALI. This molecular complex could be a major target in a TRALI prevention strategy. Improving the conditions in which the platelet concentrates (PC) are prepared and stored would contribute to controlling partly the risks of non-immune TRALI.

Redefining transfusion-related acute lung injury: don't throw the baby out with the bathwater.

Recently two articles have been published in TRANSFUSION in which the authors propose to change the current definition on transfusion-related acute lung injury (TRALI). It was proposed to view TRALI from the perspective of detectability versus nondetectability of leukoreactive alloantibodies (Transfusion 2015;55:1128-34). The authors argue that only cases in which leukoreactive alloantibodies can be detected should be defined as "true" TRALI in analogy with the understanding of the pathophysiology of heparin-induced thrombocytopenia. In the other article (Transfusion 2015;55:947-52), the authors propose to redefine possible TRALI to transfused acute respiratory distress syndrome (ARDS) as their study in intensive care unit patients did not show a relation between the number of transfusions and possible TRALI.We discuss these two propositions in light of the current evidence on pathophysiology of TRALI and possible TRALI. We argue that it is too early to redefine TRALI, as 1) factors, such as storage time of platelets, which induce TRALI in preclinical studies, have not yet been properly investigated in humans. Further research is needed on these agents before it is concluded that antibody-mediated TRALI is the only "true" TRALI. 2) In light of the current knowledge, it makes perfect sense that multiple transfusion is not related to possible TRALI: ARDS risk factors in these patients result in a very sensitive equilibrium in which even only one transfusion induces TRALI. Excluding possible TRALI from the TRALI definition would result in further underrecognition of TRALI induced by alloantibodies and interferes with exclusion of donors related to TRALI cases and thus TRALI prevention.

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Introduction: Transfusion Related Acute Lung Injury (TRALI) is a form of acute lung injury (ALI) seen after exposure to blood products. We present a case of respiratory failure secondary to TRALI in an 18 year old status post scoliosis surgery. We review the medical literature and present diagnostic criteria, pathophysiology and differential diagnosis of TRALI. An 18 year old male with severe spastic quadraparesis and scoliosis with scoliotic curve 80 degrees and restrictive lung disease without prior respiratory requirement was admitted to our pediatric critical care unit (PCCU) status post posterior spinal fusion of T2-S1. Operative course was significant for coagulopathy causing approximate blood loss of 2 liters requiring transfusion of 6 units of packed red blood cells, 4 units of fresh frozen plasma and 2 units of platelets. While in the recovery room his oxygen was easily weaned to a Fi02 of 40%. In the PCCU, he remained intubated and sedated. Three hours after arrival, he developed significant hypoxia with a PaO2/FiO2 ratio of less than 300 suggestive of ALI. His x-ray 4 hours post transfusion revealed diffuse bilateral infiltrates consistent with pulmonary edema and no cardiomegaly. His ventilator requirements significantly increased to a PEEP of 15 and FiO2 of 80% to maintain oxygen saturation above 90%. He remained afebrile and hemodynamics remained stable off vasoactive medications. There were no findings of infection. On post-operative day 2, he tolerated weaning of oxygen. His imaging revealed improvement of pulmonary edema. He was extubated successfully on post-operative day 3 and was transferred to the pediatric floor on postoperative day 4. Our patient met all the criteria for TRALI (acute onset ALI within 6 hours of exposure to blood products, bilateral pulmonary infiltrates and no evidence of fluid overload or cardiogenic pulmonary edema. Given his surgery he fits the two hit theory hypothesized as pathophysiology of TRALI. Non-immune mediated cases are thought to be due to bioreactive lipids and cytokines that accumulate during the storage of blood products. These are referred to as biologic response modifiers (BRM). The non-immune reaction is not caused solely by BRMs. The proposed hypothesis involves a preceding event presensitzing a patient's lungs and leukocytes to this transfusion reaction. This theory is often referred to as the two hit theory. The first hit includes a predisposing event such as infection, a malignancy or a surgery as in our patient above. This first hit activates neutrophils in the pulmonary endothelium. The second hit involves the transfused BRMs causing further neutrophil activation and endothelial damage. The mortality rate from TRALI ranges from 5% to 25%. Most patients recover within 72 hours; as did our patient. However, there have been cases of severe TRALI lasting about 7 days cited in the literature. Morbidity and mortality may be underappreciated because of lack of recognition and underreporting of this diagnosis. Since TRALI is a transient form of ALI, management is usually supportive with mechanical ventilatory support. The pulmonary infiltrates and hypoxemia usually resolve completely without sequelae.

Transfusion-related acute lung injury: advances in understanding the role of proinflammatory mediators in its genesis

Transfusion-related acute lung injury (TRALI) is the most common cause of serious morbidity and mortality due to hemotherapy. The pathogenesis is the result of two events: the first related to the recipient’s clinical condition, predisposing to acute lung injury (ALI) through neutrophil or polymorphonuclear leukocyte sequestration, and the second being the infusion of antibodies or mediators that activate these adherent polymorphonuclear neutrophils, resulting in endothelial damage, capillary leak and ALI. TRALI is most prevalent in the critically ill, although many of these cases are termed ALI. Although mitigation strategies, such as the use of male-only plasma, have decreased the number of TRALI cases and deaths, TRALI still occurs. This review will detail the pathophysiology of TRALI, provide insight into newer areas of research and critically assess current practices to mitigate TRALI and improve transfusion safety.

Platelet-neutrophil Interactions as a Target for Prevention and Treatment of Transfusion- related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is a major cause of morbidity and mortality in transfused hosts and like other causes of acute lung injury, there is no effective pharmacologic treatment. The pathophysiology of TRALI is still being defined, but neutrophils have a major role in the pathogenesis of both human and experimental studies. Recently, MHC antibody-based experimental TRALI models have revealed that platelets sequester in the lung microvasculature and that platelet activation contributes to lung injury. Platelets, in general, have been increasingly implicated as major contributors to acute inflammation and injury in a variety of diseases. The role of platelets in TRALI may be through critical interactions with neutrophils and therapeutically this could present a target for pharmacologic intervention. Experimentally, aspirin pre-treatment of mice before TRALI is protective from acute lung injury and mortality. Other therapeutic interventions could include agents that uncouple neutrophils and platelets or prevent aggregation and activation, however targeting platelet activation in TRALI is complicated by the presence of bleeding as the indication for many transfusions. In conclusion, experimental studies are elucidating the role of platelets in acute lung injury and with this new understanding, clinical trials of anti-platelet agents should be considered.

Transfusion-related acute lung injury: a preventable syndrome?

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Recent insights into the pathophysiology of TRALI have led to various preventive strategies. Strategies in donor management range from antibody testing of sensitized donors to the deferral of female plasma donors altogether. However, knowledge on the efficacy of measures to reduce TRALI is limited. In addition, the various measures may lead to a substantial loss of donors, hampering steady blood supply. Thereby, consensus among countries and blood-collecting facilities regarding the optimal strategy to prevent TRALI is lacking. In this review, the advantages and disadvantages of various preventive measures to prevent TRALI are discussed, related to both patient factors as well as blood component-processing strategies, including transfusion policy, donor management and practices of preparation and storage conditions of blood components.

Red blood cells, transfusion‐related acute lung injury, and lipids: a role for liporeduction?

Red blood cells, transfusion‐related acute lung injury, and lipids: a role for liporeduction?

Recent insights into the mechanism of transfusion-related acute lung injury

This review summarizes the recent clinical and experimental literature on the pathogenesis of transfusion-related acute lung injury (TRALI), with a focus on mechanistic aspects. Mechanisms by which leukocyte antibodies induce TRALI have been unraveled, including a multistep cascade for HLA class II-induced TRALI. Significant advances have also been made in the field of recipient-related factors that contribute to the development of TRALI, both in clinical and animal studies. In contrast, TRALI associated with the transfusion of blood components that do not contain antibodies is an emerging problem, especially because the relevance of mechanisms proposed earlier is questioned by the recent findings. New mechanisms need yet to be defined. The diversity of newly described factors contributing to TRALI demonstrates that a two-hit model falls too short to explain this complex syndrome and rather supports the previously proposed threshold model of TRALI. Activated neutrophils are central in the pathophysiology of TRALI as their interaction with the lung endothelium causes capillary leak and pulmonary edema. Typically, numerous factors must act together in order to overcome a critical activation threshold of the neutrophil. At least one of these factors originates from a transfused blood component.

Evidence behind the pathophysiology of TRALI

Transfusion‐related acute lung injury (TRALI) is a serious transfusion complication that may lead to significant morbidity and mortality. This has driven a significant research effort focused on understanding why and how TRALI develops. The ultimate goal must be prevention or at least mitigation of the clinical consequences of TRALI.The underlying pathophysiology of TRALI is presently best described by two hypotheses which are not mutually exclusive. These are the antibody mediated TRALI mechanism and the two‐event or priming TRALI mechanism. One of the key initial findings in TRALI research was the frequent presence of leucocyte antibodies in associated blood products, providing strong evidence for an antibody driven pathogenesis. In contrast, the two‐event mechanism proposed that these transfused antibodies activated neutrophils that had first been primed by the patient’s clinical condition.Together, data from haemovigilance programs, clinical reports and experimental findings have led several countries to introduce TRALI risk‐reduction strategies. These include either limiting the transfusion of plasma from female donors or, screening female donors for the presence of leucocyte antibodies. Both approaches are justified by adoption of the immune mechanism as the prime driver of the pathogenesis of TRALI. TRALI incidence has gratifyingly been reduced by these measures. Nevertheless, TRALI cases persist and they remain a major concern because of continuing significant morbidity and mortality.While the majority of earlier TRALI research has focused on the role of antibodies in TRALI, evidence for the role of non‐antibody factors in TRALI is now growing, based on an increasing number of in vitro, ex vivo and in vivo models. This review aims to present data from such models, which are the foundation for our current understanding of the pathophysiology behind antibody mediated and non‐antibody mediated TRALI.

Experimental Models of Transfusion-Related Acute Lung Injury

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 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.

Mechanism of Transfusion-Related Acute Lung Injury Induced by HLA Class II Antibodies.

Abstract 19 Introduction:Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated fatalities in developed countries. It has been demonstrated that antibodies to human neutrophil antigens (HNA) present in a blood product can precipitate a TRALI reaction in the blood recipient. In the majority of TRALI cases, however, HLA class II antibodies rather than HNA antibodies are detected in the implicated donor. HLA class II antigens are not present on neutrophils or endothelial cells, the cellular key players in TRALI pathophysiology. Whether or not HLA class II antibodies are capable of inducing TRALI is thus under discussion. Here, we investigated a possible mechanism of HLA class II antibody-induced TRALI via monocytes. Methods and Results: Plasma from blood donors containing HLA class II antibodies (H2+plasma) is capable of activating monocytes expressing cognate antigen(s) as demonstrated by the release of IL-8, GRO-alpha, and TNF-alpha in culture supernatants. H2+plasma does not activate monocytes that do not express the cognate HLA class II antigen(s). Culture supernatants from matched pairs, but not H2+plasma itself, induce a respiratory burst reaction in neutrophils. In Boyden chamber experiments, FITC-albumin transendothelial flux is significantly increased in the presence of H2+plasma, matched monocytes, and neutrophils, but unchanged in the presence of non-matched monocytes. Diphenyleneiodonium chloride inhibits this barrier breakdown. In the ex vivo rat lung model, supernatants from matched pairs, but not from non-matched pairs, are capable of inducing TRALI in the presence, but not in the absence, of neutrophils. H2+plasma precipitates a TRALI in this model if neutrophils and matched, but not non-matched, monocytes are present. IgG-depletion of H2+plasma abolishes this effect. Conclusions: HLA class II antibodies present in donor plasma can induce TRALI in a transfusion recipient via monocyte activation. Once activated, monocytes stimulate neutrophils to produce reactive oxygen species, which lead to an increase in endothelial permeability and subsequent lung edema. This cascade depends on a match between the donor's antibodies and the recipient's HLA class II antigens and can be reproduced in a rat lung model. Our findings have important impact on current strategies that aim to prevent TRALI by donor testing and/or exclusion. Disclosures:No relevant conflicts of interest to declare.

The Role of Neutrophils in the Pathogenesis of Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is the major cause of transfusion related morbidity and mortality, world wide. Efforts to reduce or eliminate this serious complication of blood transfusion are hampered by an incomplete understanding of its pathogenesis. Currently, TRALI is thought to be mediated by donor alloantibodies directed against host leukocytes or the result of 2 distinct clinical events. For both proposed mechanisms, the neutrophil is the key effector cell. This article reviews TRALI pathophysiology, explores the role of the neutrophil, details practical information for appropriate diagnosis and promotes further studies into the pathogenesis of TRALI.

Transfusion-related acute lung injury (TRALI): Current concepts and misconceptions

Transfusion-related acute lung injury (TRALI) is the most common cause of serious morbidity and mortality due to hemotherapy. Although the pathogenesis has been related to the infusion of donor antibodies into the recipient, antibody negative TRALI has been reported. Changes in transfusion practices, especially the use of male-only plasma, have decreased the number of antibody-mediated cases and deaths; however, TRALI still occurs. The neutrophil appears to be the effector cell in TRALI and the pathophysiology is centered on neutrophil-mediated endothelial cell cytotoxicity resulting in capillary leak and ALI. This review will detail the pathophysiology of TRALI including recent pre-clinical data, provide insight into newer areas of research, and critically assess current practices to decrease it prevalence and to make transfusion safer.

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is recognized as the number-one cause of transfusion-associated death in the United States. Although TRALI was not designated as the number-one cause until 2004, respiratory-related symptoms associated with blood transfusion have been reported for decades. More recently, our understanding of the pathophysiology and clinical significance of TRALI has advanced significantly, and great efforts are being implemented for patient safety. This article reviews the background, history, definitions, clinical features, and pathophysiology of TRALI. It also discusses some of the difficulties in diagnosing TRALI, compares some of the important components in the differential diagnosis, and describes some of the efforts being implemented for patient safety.

Transfusion related acute lung injury (TRALI)

Transfusion-related acute lung injury (TRALI) is a complication following transfusion of blood products and is potentially a life-threatening adverse event of transfusion. The first case of fatal pulmonary edema following transfusion was reported in the 1950s. In recent time, TRALI has developed from an almost unknown transfusion reaction to the most common cause of transfusion related major morbidities and fatalities. A clinical definition of TRALI was established in 2004, based on acute respiratory distress which has temporal association with transfusion of blood components. In 2008 a distinction between classic and delayed syndrome was proposed. However, pathophysiology of TRALI still remains controversial. A number of different models were proposed to explain the pathogenesis. The two, presently most accepted models, are not mutually exclusive. The first is the antibody mediated model and the second is the two-event model.In this review article the definition of TRALI, patient predisposition, treatment, prevention and reporting guidelines are exa-mined. The current knowledge on the topic TRALI is summarized.

Pathophysiology of TRALI: current concepts

Transfusion-related acute lung injury (TRALI) is a life-threatening adverse event in blood transfusion and is considered the most common cause of transfusion-related fatalities in the United States and the United Kingdom. TRALI and acute respiratory distress syndrome (ARDS) share a common clinical definition except that TRALI is temporally and mechanistically related to blood transfusion. Two different mechanisms have been proposed. The first is leuko-agglutination due to infusion of leukocyte Antibodies with the blood product transfused. The second proposes a two-event model where the first event is the clinical condition of the patient, and the second the infusion of lipids that accumulate in blood products during storage. An emerging common pathway of granulocyte activation is discussed, as is the relevance of immune and non-immune TRALI from a practical point of view. Some unresolved questions in TRALI pathophysiology, including the relevance of Antibodies to HLA class-II antigens and the participation of the endothelium, are examined, as are the suggested preventive measures for both immune and non-immune TRALI. It is concluded that further clinical and experimental data are necessary before any recommendations can be made regarding non-immune TRALI. In contrast, in immune TRALI, preventive measures to avoid transfusion of blood products that contain leukocyte Antibodies should be taken now.

Interference with TRALI‐causing anti‐HLA DR alloantibody induction of human pulmonary microvascular endothelial cell injury by purified soluble HLA DR

Antibodies to human leucocyte antigens (HLA) and human polymorphonuclear neutrophil (PMN) antigens are considered etiologic agents of transfusion-related acute lung injury (TRALI). The aim of this study was to clarify the role of anti-HLA DR antibodies in the pathophysiology of TRALI and the ability of purified soluble HLA DR (psHLA DR) to inhibit the release of cytokines in an in vitro model. A coculture of human pulmonary microvascular endothelial cells (HMVEC) and monocytes in the presence of serum containing anti-HLA DR alloantibodies previously associated with cases of TRALI was used as an in vitro TRALI model. The release of leukotriene B(4) (LTB(4)) and tumour necrosis factor-alpha (TNF-alpha), the apoptosis of HMVECs were measured. The release of LTB(4) and TNF-alpha and apoptosis of HMVECs were observed in the model. The addition of psHLA DR markedly reduced the release of LTB(4) and TNF-alpha and inhibited apoptosis of HMVECs. These results support the critical role of anti-HLA DR alloantibodies in the pathogenesis of TRALI and suggest that the soluble HLA DR could inhibit TRALI development caused by anti-HLA DR alloantibodies.