Pathogenesis of TRALI. (A) TRALI may be precipitated by a single clinical event, the infusion of donor antibodies directed against host leukocytes, which causes complement activation, pulmonary leukostasis, PMN activation, endothelial damage, capillary leak, and ALI. (B) TRALI may be the result of 2 clinical events: the first consists of the clinical condition of the host, which causes pulmonary endothelial activation and adherence of PMNs, resulting in pulmonary sequestration. The second event, consisting of the transfusion of biologic response modifiers (biologically active lipids, antibodies directed against specific HLA class I or II or granulocyte antigens) in the blood component then activates these adherent PMNs and precipitates TRALI in predisposed patients. ROS indicates reactive oxygen species. (C) In neutropenic patients, TRALI may be precipitated by agents that directly cause endothelial fenestration, including high levels of VEGF or high levels of HLA class II antibodies directed against antigens on the pulmonary endothelium.