Two-hit model of TRALI. The first hit represents patient predisposing factors including CRP, which is now identified as a novel first hit by the current study. The second hit represents antibodies and factors directly related to the transfused blood product. Inflammation causes an increase in IL-6, which stimulates a rapid elevation of CRP. CRP together with anti-HLA class I antibodies trigger a synergistic increase in both IL-8 and pulmonary polymorphnuclear neutrophil (PMN) accumulation, resulting in TRALI induction. CRP or anti-HLA class I antibodies alone are not sufficient to induce TRALI. Professional illustration by Somersault18:24.