In Focus
Transfusion Related Acute Lung Injury (TRALI)
On the quest of unrolling unexplained mechanisms for TRALI induction
Transfusion-related lung injury (TRALI) is an acute hypoxemia and non-cardiogenic pulmonary development during or within 6 hours after a transfusion.
Although rare, TRALI is considered a major cause of transfusion-related mortality. Antibodies against human neutrophil antigens (HNAs) or human leukocyte antibodies (HLA-I and II) are thought to be responsible for up to 85% of TRALI cases. In the remaining 20% of TRALI cases, where no antibodies to the recipient's antigen are detectable, the presence of bioreactive substances generated during transfusion storage has been introduced as a triggering factor for non-antibody-mediated TRALI. Despite numerous animal models confirming the effects of a storage lesion on the development of TRALI, recent analyses in human models have shown no evidence for the development of TRALI following transfusion of stored or fresh autologous red cells in lipopolysaccharide (LPS)-primed subjects1.
Figure 1. Classical and non-classical (reverse) antibody-mediated TRALI. The transfused antibodies in antigen-positive recipients activate antigen-positive cells and lead to classical antibody-mediated TRALI (left). In reverse antibody-mediated TRALI, the recipient's existing antibodies trigger the TRALI reaction after binding to the transfused antigen (right).
TRALI follows a “two-hit hypothesis” and a “threshold model” in which the recipient's health status as the first hit and the transfusion factor as the second hit combine to determine the outcome of TRALI. When the combined transfusion factor and the patient's clinical condition reach a certain threshold, TRALI can be expected to develop2. This fact explains why TRALI does not occur in all antigen-positive recipients of the same blood component with antibodies against the recipient's antigen.
Although the exclusion of antibody carriers from the donor pool has significantly reduced the number of cases, TRALI remains one of the most common causes of transfusion-related morbidity and mortality in industrialized countries. This indicates the presence of other, overlooked TRALI-causing factors.
Classical vs. Non-Classical (reverse) TRALI
Based on the origin of the TRALI-inducing antibody, antibody-mediated TRALI is divided into two groups: classical TRALI and non-classical TRALI. In classical TRALI, the transfused antibodies in antigen-positive recipients are known to activate antigen-positive cells. After antibody interaction with cell-bound antigens (expressed on granulocytes, monocytes or endothelial cells), activation of antigen-expressing cells induces endothelial damage and results in pulmonary edema and TRALI. In the second group of antibody-mediated TRALI, the presence of antibodies in recipients rather than donors is thought to be responsible for triggering TRALI (so-called reverse TRALI). The presence of anti-HLA antibodies in already immunized recipients after transfusion of leukocyte-rich blood products such as buffy coat granulocytes or stem cells is known to activate the antigen-positive transfused cells and thus triggers a TRALI reaction in the recipients (Figure 1).
To overcome this type of TRALI reaction, leuko-reduction strategies was adopted. This strategies by filtration of blood products eliminate leukocytes in the blood products to a very low number that does not elicit a response suppresses the possibility of binding of recipient alloantibodies (against HLA or HNA) to the antigen expressed on the membrane of the transfused leukocytes, thus inhibiting the activation of leukocytes by the recipient's antibodies.
Multiple analyses have doubted the efficiency of leuko-reduction strategies; analysis of Clippel and co-workers has reported reverse TRALI cases because of transfused nonirradiated RBCs in HLA pre-immunized recipients. In all reported cases the donor HLA type matched with anti-HLA antibodies circulating in the recipient's bloodstream. Since all transfused RBCs were leukoreduced, these observations questioned the efficiency of leuko-reduction to prevent reverse TRALI3. In addition, an unusual case of reverse TRALI in a pre-immunized HNA-2 negative recipient transfused with leukoreduced erythrocytes from a CD177-positive donor further puzzled the efficiency of leukoreduction.
After transfusion, the soluble CD177/PR3 either binds the activated partner protein PECAM-1 on endothelial cells or remains in the recipient's bloodstream. Binding of the recipient's anti-HNA-2 to CD177/PR3 bound to PECAM-1 on endothelial cells or to the unbound antigen leads to endothelial activation, barrier disintegration, permeability and TRALI.
Figure 2. Transfusion of target antigens to preimmunized recipients: a new mechanism in transfusion-related acute lung injury. Source: Bayat et al, Blood Adv, 2021. Copyright © 2025 American Society of Hematology
Despite the expectation that leukocyte reduction by filtration effectively prevents HLA and HNA immunization as well as negative transfusion effects in recipients, filtration is known to induce the release of neutrophil granules in the supernatant4,5. Accordingly, our analysis suggests that despite the effective elimination of leukocytes from the erythrocytes by filtration, the trapped leukocytes on the filter tend to be activated and therefore release soluble CD177/PR3. In addition, a significantly increased CD177/PR3 concentration was documented in the stored red cells after filtration compared to fresh red cell concentrate; this indicates an additional effect of storage on the release of CD177/PR3 from leukocytes and thus an increased concentration of this antigen in the filtered red cell concentrate6.
Conclusions
The persistence of TRALI cases despite significant TRALI reduction by all-male plasma and leuko-depletion strategies suggests the presence of overlooked mechanisms for TRALI induction that overcome avoidance strategies. Considering the unexplained mechanisms for TRALI induction that overcome current avoidance strategies, further analysis of TRALI mechanisms and more comprehensive preventive measures are needed to improve transfusion safety.
References
- Peters AL, van Hezel ME, Cortjens B, Tuip-de Boer AM, van Bruggen R, de Korte D, Jonkers RE, Bonta PI, Zeerleder SS, Lutter R, Juffermans NP, Vlaar AP. Transfusion of 35-Day Stored RBCs in the Presence of Endotoxemia Does Not Result in Lung Injury in Humans. Crit Care Med. 2016 Jun;44(6):e412-9.
- Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol. 2007 Mar;136(6):788-99. doi: 10.1111/j.1365-2141.2007.06492.x.
- De Clippel D, Emonds MP, Compernolle V. Are we underestimating reverse TRALI? Transfusion. 2019 Sep;59(9):2788-2793. doi: 10.1111/trf.15431.
- Andreu G, Dewailly J, Leberre C, Quarre MC, Bidet ML, Tardivel R, Devers L, Lam Y, Soreau E, Boccaccio C, et al. Prevention of HLA immunization with leukocyte-poor packed red cells and platelet concentrates obtained by filtration. Blood. 1988 Sep;72(3):964-9.
- Bianchi M, Vaglio S, Pupella S, Marano G, Facco G, Liumbruno GM, Grazzini G. Leucoreduction of blood components: an effective way to increase blood safety? Blood Transfus. 2016 May;14(2):214-27. doi: 10.2450/2015.0154-15
- Bayat B, Nielsen KR, Bein G, Traum A, Burg-Roderfeld M, Sachs UJ. Transfusion of target antigens to preimmunized recipients: a new mechanism in transfusionrelated acute lung injury. Blood Adv 2021;5: 3975–85.
