Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model

Vlaar, Alexander P.J.; Hofstra, Jorrit J.; Kulik, Wim; Lenthe, Henk van; Nieuwland, Rienk; Schultz, Marcus J.; Levi, Marcel; Roelofs, Joris J. T. H.; Tool, Anton T.J.; Korte, Dirk de; Juffermans, Nicole P.

doi:10.1182/blood-2009-10-248732

Cited by 90 publications

(116 citation statements)

References 46 publications

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“…Therefore, the amount of lysoPCs seems merely to reflect RBC volume. In line with this, we recently showed that aged blood products cause TRALI in rats both in the presence and absence of accumulation of bioactive lipids, 45,46 suggesting that the link between lysoPCs and lung injury is not strong. Taken together, the present results do not indicate that a transfusion policy of fresh blood only is beneficial in reducing TRALI.…”

Section: Discussionsupporting

confidence: 54%

“…A threshold model has been proposed, 19 in which the presence of a strong "first event" may require only a weak second event before TRALI occurs. [44][45][46] In accordance, in a mouse model of TRALI, the presence of an inflammatory reaction resulted in onset of TRALI after a lower dose of antibodies compared with healthy controls. 47,48 Our data suggest that patients with an expected prolonged time on the cardiopulmonary bypass may benefit from HLA/HNA antibody-free blood products.…”

Section: Discussionmentioning

confidence: 74%

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The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study

Vlaar

Hofstra²,

Determann³

et al. 2011

Blood

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 74%

The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study

Vlaar

Hofstra²,

Determann³

et al. 2011

Blood

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188

176

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“…37,42 Other groups have also reported effects of components present and accumulating in the supernatant of stored platelets on neutrophil activation both in vitro and in animal models. 2,22,[43][44][45] A recent study showed that longer platelet storage was associated with an increased risk of TRALI in patients. 46 One such biologically active lipid that could be formed during platelet storage, plateletactivating factor, is a good inducer of NET formation in vitro, 29 and other biologically active lipids could be as well.…”

Section: Discussionmentioning

confidence: 99%

Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice

Thomas

Carbó

Curtis

et al. 2012

Blood

281

229

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Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biologic processes contributing to TRALI are poorly understood. All blood products can cause TRALI, and no specific treatment is available. A "2-event model" has been proposed as the trigger. The first event may include surgery, trauma, or infection; the second involves the transfusion of antileukocyte antibodies or bioactive lipids within the blood product. Together, these events induce neutrophil activation in the lungs, causing endothelial damage and capillary leakage. Neutrophils, in response to pathogens or under stress, can release their chromatin coated with granule contents, thus forming neutrophil extracellular traps (NETs). Although protective against infection, these NETs are injurious to tissue. Here we show that NET biomarkers are present in TRALI patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset. We suggest that NETs form in the lungs during TRALI, contribute to the disease process, and thus could be targeted to prevent or treat TRALI. IntroductionTransfusion-related acute lung injury (TRALI) is a rare but serious complication of blood transfusion that occurs within 6 hours of transfusion and is characterized by hypoxemia, respiratory distress, and pulmonary infiltrates. 1 Over the years, prevention measures have resulted in a significant reduction in cases. However, TRALI is still the leading cause of transfusion-related mortality, and its prevalence is likely underestimated; one study suggested that more than 2% of cardiac surgery patients are affected. 2 Only supportive treatment is available to the patient, including mechanical ventilation and oxygen supplementation. Many of the severe cases have been linked to the presence of antineutrophil antibodies in the transfused product. 3,4 These antibodies bind to the recipients' neutrophils, activate them, and induce sequestration in the pulmonary capillaries, resulting in tissue injury. 5 Activated neutrophils can release neutrophil extracellular traps (NETs) 6 that are composed of DNA fibers decorated with histones and antimicrobial proteins 7 originally contained in the neutrophil granules. The structure and the composition of NETs allow them to trap and prevent the spread of pathogens and also to kill Gram-negative and Gram-positive bacteria, as well as yeast. 6 NET formation follows a specific pattern characterized by histone hypercitrullination, 8 chromatin decondensation, dissolution of the granular and nuclear membranes, and cytolysis. 9 Despite NETs' beneficial antimicrobial function, 6,10 their formation at the wrong time, in the wrong place, or in the wrong amount can have a negative effect on the host. NETs and their c...

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“…Washing of RBC units removes proinflammatory activity, including both antibodies and lipids, and ALI may be mitigated in high-risk populations by washing of cellular components. [38][39][40] TRALI secondary to RBC infusion results in a number of reported fatalities, and that number has likely increased with antibody-negative plasma transfusion strategies. [1][2][3][4]41,42 Moreover, removal of the lipophilic compounds may also diminish the clinical effects of stored RBCs especially in the critically ill and in the injured.…”

Section: Discussionmentioning

confidence: 99%

Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo

Silliman

Kelher

Khan³

et al. 2014

Blood

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Key Points• TRALI may be induced by antibodies to HLA or HNA antigens or lipids, which accumulate during storage.• Prestorage experimental filtration of RBCs removes HLA and HNA antibodies, decreases lipid priming activity, and mitigates TRALI in an animal model.Transfusion-related acute lung injury (TRALI) remains a significant cause of transfusionrelated mortality with red cell transfusion. We hypothesize that prestorage filtration may reduce proinflammatory activity in the red blood cell (RBC) supernatant and prevent TRALI. Filters were manufactured for both small volumes and RBC units. Plasma containing antibodies to human lymphocyte antigen (HLA)-A2 or human neutrophil antigen (HNA)-3a was filtered, and immunoglobulins and specific HNA-3a and HLA-2a neutrophil (PMN) priming activity were measured. Antibodies to OX27 were added to plasma, and filtration was evaluated in a 2-event animal model of TRALI. RBC units from 31 donors known to have antibodies against HLA antigens and from 16 antibody-negative controls were filtered. Furthermore, 4 RBC units were drawn and underwent standard leukoreduction. Immunoglobulins, HLA antibodies, PMN priming activity, and the ability to induce TRALI in an animal model were measured. Small-volume filtration of plasma removed >96% of IgG, antibodies to HLA-A2 and HNA-3a, and their respective priming activity, as well as mitigating antibodymediated in vivo TRALI. In RBC units, experimental filtration removed antibodies to HLA antigens and inhibited the accumulation of lipid priming activity and lipid-mediated TRALI. We conclude that filtration removes proinflammatory activity and the ability to induce TRALI from RBCs and may represent a TRALI mitigation step. (Blood. 2014;123(22):3488-3495)

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Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model

Cited by 90 publications

References 46 publications

The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study

The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study

Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice

Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo

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