There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.

Summary As screening for transfusion-associated infections has improved, non-infectious complications of transfusion now cause the majority of morbidity and mortality associated with transfusion in the United States. For example, transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion-reactions are the first, second, and third leading causes of death from transfusion respectively. These complications and others are reviewed here and several controversial methods for prevention of non-infectious complications of transfusion are discussed; universal leukoreduction of red cell units, use of male-only plasma, and restriction of red cell storage age.

TRALI requires an immune priming step followed by transfusion of a blood product with either leukocyte allo-antibodies or biological response modifiers. TRALI invokes an acute immune response dominated by neutrophils interacting with platelets and the lung endothelium.

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...

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