In the critical care setting, TRALI represents the most severe end of transfusion-related lung injury, where pre-existing neutrophil priming from critical illness amplifies the immune response to donor antibodies. The two-hit model is particularly relevant: the first hit (sepsis, major surgery, massive trauma) primes pulmonary neutrophils through endotoxin, cytokines, or complement activation. The second hit (donor anti-HLA or anti-HNA antibodies, or bioactive lipids from stored blood products) triggers full neutrophil activation with release of elastase, myeloperoxidase, and reactive oxygen species. The resulting alveolar-capillary damage produces severe non-cardiogenic pulmonary edema that can progress to full ARDS criteria.