To be at risk of TRALI via this mechanism, the blood recipient must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies.

The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema.

[10] A proposed mechanism for non-antibody-mediated TRALI involves the accumulation of bioactive lipids in stored blood components (red cells, platelets, or plasma) that are capable of priming neutrophils.

[13] In TRALI, first-hit risk factors include long-term excessive alcohol use, shock, liver surgery, current smoking, higher peak airway pressure while undergoing mechanical ventilation, positive intravascular fluid balance, low levels of interleukin-10, and systemic inflammation.

In approximately 80% of cases, anti-HLA class I or II or anti-HNA antibodies are implicated as involved in triggering TRALI, although that figure may be even higher depending on the detection methods used.

In the remaining 20% of TRALI cases, non–antibody factors or biological response modifiers are suggested to contribute the second hit, and these may possibly include lipid mediators, extracellular vesicles, and aged blood cells.

[12] Incidents have also been reported with other blood products including "cryoprecipitate, granulocytes, intravenous immune globulin, allogeneic and autologous stem cells".

[17] It is a diagnosis upon examination of clinical manifestations that appear within 6 hours of transfusion, such as acute respiratory distress, tachypnea, hypotension, cyanosis, and dyspnea.

In most cases leukoagglutination results in mild dyspnea and pulmonary infiltrates within about 6 hours of transfusion, and spontaneously resolves.

Oxygen supplementation is employed in all reported cases of TRALI, and 72% of patients require aggressive respiratory support.