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TRALI appears to have multiple mechanisms, the most common being HLA and/or human neutrophil antibodies (HNA) in the plasma of the donor that react with recipient antigens.

Anti-HLA antibodies can be formed in response to exposure to foreign antigens from transfusion or pregnancy. Because HLA antibodies are frequently stimulated by pregnancy, multiparous women are the most frequently implicated donors. Transfused antibodies react with the recipient which results in leukocyte emboli aggregating in the lung capillary bed. Capillary damage triggers interstitial edema and fluid in the alveolar spaces, causing decreased air exchange and hypoxia.