Experimental Models of Transfusion-Related Acute Lung Injury

Abstract

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 transfusionrelated 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.Cases of non-cardiogenic pulmonary edema due to blood transfusion were described in the literature as early as the 1950s (1-3), but the term transfusion-related acute lung injury (TRALI) was not used until 1983 when Popovsky and Moore described five patients who developed acute lung injury (ALI) following transfusion of blood containing donor-derived leukoagglutinating antibodies (4). In this seminal article, the authors reported a TRALI incidence of 1:3130 per patient transfused and suggested that donors who are anti-leukocyte antibody positive increase the risk of TRALI.The release of additional reports and the implementation of hemovigilance programs have significantly raised the awareness of TRALI, and TRALI was reported by the FDA as the most common cause of transfusion-related death in the United States during 2005-2009 (5). TRALI has now been formally defined by the Canadian Consensus Conference (6) and a NHBLI expert panel (7) as acute lung injury that develops during or within six hours of the transfusion of any blood product.Despite relative consensus on the definition of TRALI, the diagnostic ambiguity, rapid progression, and the relatively rare nature of TRALI have made it difficult to study from a clinical and epidemiologic perspective. As the most accessible means of studying TRALI, animal models have significantly advanced our understanding of TRALI pathogenesis and defined those characteristics that separate TRALI from other types of acute lung injury.Corresponding Author: Mark R. Looney, M.D., 513 Parnassus Avenue, HSE 1355A, San Francisco, CA 94143-0130, Phone: (415) 502-5125, Fax: (415) 502-2126, mark.looney@ucsf.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author M...

Analysis of leucocyte antibodies, cytokines, lysophospholipids and cell microparticles in blood components implicated in post‐transfusion reactions with dyspnoea

“…Cytokines in L‐RBCs, PLTs and FFP transfused to TRALI patients were not tested, but the levels of IL‐1β, IL‐8 and sCD40L in these three types of blood components transfused to patients who developed TACO and TAD were not higher than in control. Moreover, concentrations of all tested cytokines in FFP transfused to patients who developed TACO and TAD fell within the range for healthy donors previously tested for cytokine levels .…”

“…The ‘two‐event’ model is postulated as a pathophysiologic mechanism of TRALI, which is supported by experimental and clinical studies . The ‘first event’ is the patient's clinical condition which causes proinflammatory activation leading to neutrophil adherence (priming) and sequestration in the lung vasculature.…”

The Impact of Perioperative Packed Red Blood Cell Transfusion on Survival in Epithelial Ovarian Cancer

“…In addition, although there is limited data on the perioperative impact of PRBCT among women undergoing EOC cytoreduction, PRBCT administration has been identified as an independent risk factor of perioperative morbidity in cancer and benign surgery. 10,19–21 Whether it is receipt of a transfusion, intraoperative blood loss, or clinical factors associated with PRBCT driving worse outcomes, such factors may be modifiable. Because minimizing blood loss and judicious use of PRBCT may impact DFS and OS among women with EOC, we examined the factors associated with PRBCT and the impact of PRBCT administration on survival and recurrence among women undergoing primary EOC cytoreduction.…”

In reply

“…Animal models developed for the study of pathogenesis of transfusion‐related acute lung injury (TRALI) differ by induction of the priming event, the second event, and the variables measured to demonstrate ALI. The antibody‐based model 7 referred to in the commentary has been criticized on several aspects: 1) It is based on a unique mouse monoclonal antibody to MHC Class I antigen (other mouse antibodies of the same isotype and allospecificity do not produce this effect), 2) the dose (4.5 mg/kg) is much higher than in a transfusion product, suggesting that the model may be less sensitive than the clinical situation, and 3) the antibody is administered at a much faster rate compared to administration of a transfusion product 8,9 . In spite of the limitations, this model is the basis of the current proposed pathogenesis of antibody‐based TRALI.…”