Pathophysiology of transfusion-related acute lung injury

Looney, Mark R.; Gilliss, Brian M.; Matthay, Michael A.

doi:10.1097/moh.0b013e32833c07d3

Cited by 50 publications

(42 citation statements)

References 38 publications

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“…Recently competent review articles have been published that are devoted to current insights into mechanisms of pathogenesis of TRALI [5,17,34,35,36,37,38,39,40,41]. Quoting briefly from these articles, TRALI primarily consists of acute bilateral pulmonary edema occurring within 6 h of a transfusion in the absence of cardiac failure or intravascular volume overload.…”

Section: Pathogenesis Of Tralimentioning

confidence: 99%

Transfusion-Related Acute Lung Injury: The Work of DAMPs*

Land¹

2013

Transfus Med Hemother

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Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non-pathogen-induced tissue injury with ‘sterile’ tissue inflammation. In this review, evidence has been collected in support of the notion that the transfusion-related acute lung injury induces a ‘sterile’ inflammation in the lung of transfused patients in terms of an acute innate inflammatory disease. The inflammatory response is mediated by the patient’s innate immune cells including lung-passing neutrophils and pulmonary endothelial cells, which are equipped with pattern recognition receptors. These receptors are able to sense injury-induced, damage-associated molecular patterns (DAMPs) generated during collection, processing, and storage of blood/blood components. The recognition process leads to activation of these innate cells. A critical role for a protein complex known as the NLRP3 inflammasome has been suggested to be at the center of such a scenario. This complex undergoes an initial ‘priming’ step mediated by 1 class of DAMPs and then an ‘activating’ step mediated by another class of DAMPs to activate interleukin-1beta and interleukin-18. These 2 cytokines then promote, via transactivation, the formation of lung inflammation.

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Section: Pathogenesis Of Tralimentioning

confidence: 99%

Transfusion-Related Acute Lung Injury: The Work of DAMPs*

Land¹

2013

Transfus Med Hemother

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“…Presently, there is no standard for TRALI diagnosis. Current definitions of TRALI are heavily dependent on clinical symptoms, rather than on objective laboratory findings [29], making a precise diagnosis difficult.…”

Section: Transfusion-related Acute Lung Injurymentioning

confidence: 99%

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

2013

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Context: Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet drugs (aspirin, ticlopidoine, clopidogrel, and prasugrel) or intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) do not increase the incidence of dyspnea in randomized trials. Dyspnea after oral reversible antiplatelet agents remains unexplained. A transfusion-related acute lung injury (TRALI) hypothesis has been proposed. The dyspnea risks after cangrelor, an intravenous reversible antiplatelet agent, are not well defined but may offer a universal mechanism linking TRALI, dyspnea, and reversible platelet inhibition. Objective: We analyzed safety data from recent head-to-head randomized trials with reversible antiplatelet agents (ticagrelor, elinogrel, and cangrelor) compared to irreversible (clopidogrel/placebo) comparators. Results: All three reversible antiplatelet agents cause excess dyspnea. In contrast to the high double-digit rates after oral ticagrelor or elinogrel, the dyspnea risks after intravenous cangrelor were smaller (<2%) but still consistently and significantly higher than in the corresponding control arms. Conclusions: The clinical utility of reversible antiplatelet strategies has been challenged. Despite a potential advantage of fewer bleeding events during heart surgery, reversible antiplatelet agents carry the risk of potential autoimmune reactions manifesting as dyspnea. Repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets are among the potential mechanism(s) responsible for dyspnea after reversible antiplatelet agents.

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“…This syndrome, which has been termed transfusion-related ALI (TRALI), is the leading cause of death from transfusion therapy in the US (2) and a major cause of transfusion morbidity, but its pathogenesis is poorly understood (3). TRALI is an especially troubling condition for health care providers, since it is an unintended and unpredictable consequence of physician-directed care.…”

Section: Introductionmentioning

confidence: 99%

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

Caudrillier¹,

Kessenbrock²,

Gilliss³

et al. 2012

J. Clin. Invest.

890

908

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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.

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Pathophysiology of transfusion-related acute lung injury

Abstract: 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.

Cited by 50 publications

References 38 publications

Transfusion-Related Acute Lung Injury: The Work of DAMPs*

Transfusion-Related Acute Lung Injury: The Work of DAMPs*

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

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