Transfusion-related Lung Injury with Leukopenic Reaction Caused by Fresh Frozen Plasma Containing Anti-NB1

Leger, R.; Palm, Sebastian; Wulf, Hinnerk; Vosberg, Axel; Neppert, J.

doi:10.1097/00000542-199911000-00048

Cited by 61 publications

(56 citation statements)

References 16 publications

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“…34 Thrombocytopenia, on the other hand, has also been reported in human TRALI patients but appears to be more durable than the leukopenia. [34][35][36][37] Therefore, these laboratory parameters in human TRALI patients seem to be in accordance with our animal model of TRALI. The decreased platelet counts we observed may be explained by a recent study demonstrating that CRP together with antiplatelet antibodies can enhance platelet breakdown through Fc-receptor-mediated phagocytosis, 27 considering that 34-1-2s is also able to bind to platelets.…”

Section: Discussionsupporting

confidence: 87%

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C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Kapur

Kim

Shanmugabhavananthan

et al. 2015

Blood

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Key Points• CRP enhances antibodymediated lung damage when infused into TRALI-resistant mice.• CRP and TRALI-inducing antibodies generate a synergistic increase in MIP-2 production and pulmonary neutrophil accumulation in vivo.Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress triggered by blood transfusions and is the leading cause of transfusion-related mortality. TRALI has primarily been attributed to passive infusion of HLA and/or human neutrophil antigen antibodies present in transfused blood products, and predisposing factors such as inflammation are known to be important for TRALI initiation. Because the acute-phase protein C-reactive protein (CRP) is highly upregulated during infections and inflammation and can also enhance antibody-mediated responses such as in vitro phagocytosis, respiratory burst, and in vivo thrombocytopenia, we investigated whether CRP affects murine antibody-mediated TRALI induced by the anti-major histocompatibility complex antibody 34-1-2s. We found that BALB/c mice injected with 34-1-2s or CRP alone were resistant to TRALI, however mice injected with 34-1-2s together with CRP had significantly enhanced lung damage and pulmonary edema. Mechanistically, 34-1-2s injection with CRP resulted in a significant synergistic increase in plasma levels of the neutrophil chemoattractant macrophage inflammatory protein-2 (MIP-2) and pulmonary neutrophil accumulation. Importantly, murine MIP-2 is the functional homolog of human interleukin-8, a known risk factor for human TRALI. These results suggest that elevated in vivo CRP levels, like those observed during infections, may significantly predispose recipients to antibodymediated TRALI reactions and support the notion that modulating CRP levels is an effective therapeutic strategy to reduce TRALI severity. (Blood. 2015;126(25):2747-2751 Introduction Transfusion-related acute lung injury (TRALI) is characterized by respiratory distress following blood transfusions and is the leading cause of transfusion-related mortality.1,2 Approximately 80% of TRALI cases are associated with HLA-or human neutrophil antigen-specific antibodies present in donor blood.3,4 A 2-hit model was hypothesized to underlie antibody-mediated TRALI where the first hit comprises patient predisposing factors, such as inflammation, and the second hit is due to antibodies in the transfused blood.1 The pathogenesis of antibody-mediated TRALI, however, is still poorly understood, and controversy has arisen using animal models. For example, several cell types have been implicated in inducing lung damage by the TRALI-inducing anti-major histocompatibility complex (MHC) class I antibody 34-1-2s.5 Neutrophils were originally thought to be stimulated by 34-1-2s to produce reactive oxygen species that damaged the pulmonary endothelium in an Fc-dependent manner.1,5-13 Strait et al, 14 however, showed that neutrophil involvement was limited and that activated endothelial cells and complement interactions were the primary events in TRALI induction. Furth...

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Section: Discussionsupporting

confidence: 87%

“…Although transient leukopenia has been observed in human TRALI patients, [34][35][36][37] it has often been an infrequent finding, most likely due to the dynamic nature of the leukopenia. 34 Thrombocytopenia, on the other hand, has also been reported in human TRALI patients but appears to be more durable than the leukopenia.…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Kapur

Kim

Shanmugabhavananthan

et al. 2015

Blood

View full text Add to dashboard Cite

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“…Importantly, when Two-event TRALI produces mild thrombocytopenia and sequestration of platelets in the lungs. Thrombocytopenia has been occasionally reported in clinical TRALI (22)(23)(24), and we observed mild thrombocytopenia in mice primed with i.p. LPS ( Figure 7A), which worsened after MHC I mAb administration.…”

Section: Severity Of Experimental Trali Is Significantly Influenced Bsupporting

confidence: 60%

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury

Looney¹,

Nguyen²,

Hu³

et al. 2009

J. Clin. Invest.

300

497

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Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality in the US. Previously, we established an immune-mediated TRALI mouse model, wherein mice with cognate antigen were challenged with MHC class I mAb. In this study, when mice housed in a rodent, specific pathogen-free barrier room were challenged with MHC I mAb, there was significant protection from TRALI compared with nonbarrier mice. Priming mice with LPS restored lung injury with mAb challenge. Using TLR4-deficient bone marrow chimeras, the priming phenotype was restricted to animals with WT hematopoietic cells, and depletion of either neutrophils or platelets was protective. Both neutrophils and platelets were sequestered in the lungs of mice with TRALI, and retention of platelets was neutrophil dependent. Interestingly, treatment with aspirin prevented lung injury and mortality, but blocking the P selectin or CD11b/CD18 pathways did not. These data suggest a 2-step mechanism of TRALI: priming of hematopoietic cells, followed by vascular deposition of activated neutrophils and platelets that then mediate the severe lung injury. Furthermore, our data offer an explanation for the increased incidence of TRALI in patients with immune priming conditions, and we suggest what we believe to be a novel therapeutic approach.

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“…Similar to the human cases, we also observed acute neutropenia in the MHC I mAb-treated animals ( Figure 5C). Thrombocytopenia has also been reported in some cases in the human TRALI literature (19)(20)(21), but none was detected in this experimental model (data not shown).…”

Section: Mhc I Mab-treated Mice Have Increased Alveolar Epithelial Pementioning

confidence: 48%

Neutrophils and their Fc receptors are essential in a mouse model of transfusion-related acute lung injury

Looney

Su²,

Ziffle³

et al. 2006

Journal of Clinical Investigation

279

346

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Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality.To explore the pathogenesis of TRALI, we developed an in vivo mouse model based on the passive transfusion of an MHC class I (MHC I) mAb (H2K d ) to mice with the cognate antigen. Transfusion of the MHC I mAb to BALB/c mice produced acute lung injury with increased excess lung water, increased lung vascular and lung epithelial permeability to protein, and decreased alveolar fluid clearance. There was 50% mortality at a 2-hour time point after Ab administration. Pulmonary histology and immunohistochemistry revealed prominent neutrophil sequestration in the lung microvasculature that occurred concomitantly with acute peripheral blood neutropenia, all within 2 hours of administration of the mAb. Depletion of neutrophils by injection of anti-granulocyte mAb Gr-1 protected mice from lung injury following MHC I mAb challenge. FcRγ -/-mice were resistant to MHC I mAb-induced lung injury, while adoptive transfer of wild-type neutrophils into the FcRγ -/-animals restored lung injury following MHC I mAb challenge. In conclusion, in a clinically relevant in vivo mouse model of TRALI using an MHC I mAb, the mechanism of lung injury was dependent on neutrophils and their Fcγ receptors.

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Transfusion-related Lung Injury with Leukopenic Reaction Caused by Fresh Frozen Plasma Containing Anti-NB1

Cited by 61 publications

References 16 publications

C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury

Neutrophils and their Fc receptors are essential in a mouse model of transfusion-related acute lung injury

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