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The contribution of recipient platelets in TRALI: has the jury reached a verdict?

D espite the successful mitigation strategy of excluding donors with anti-HLA antibodies, transfusionrelated acute lung injury (TRALI) remains among the leading causes of transfusion-related deaths. Inflammation is a general risk factor for the development of TRALI, and the pathogenesis appears to be complex and warrants further investigations. Risk factors in the transfusion recipient (reflecting the underlying clinical condition) in combination with components in the transfusion product trigger the TRALI reaction within 6 hours of transfusion. White blood cell antibodies or biologic response modifiers in the transfused product are assumed to initiate TRALI. Murine models of TRALI, especially based on the anti-major histocompatibility complex (MHC) Class I monoclonal antibody 34-1-2S, have provided useful insights. Controversies, however, have also arisen and this includes the contribution of recipient platelets (PLTs) to the pathogenesis of TRALI. Platelets are classically known for their hemostatic functions. However, over the past decade it has become increasingly clear that PLTs also serve nonhemostatic immune functions, particularly during inflammatory conditions. These immune functions include targeting pathogens via surface immune receptors such as Toll-like receptors or triggering formation of neutrophil extracellular traps (NETs) and communicating with a variety of immune cells via for instance secretion of cytokines or shedding of PLTmicroparticles. Considering that inflammation is a risk factor for the development of TRALI, and that PLTs are immune-sensing cells, it has been hypothesized that PLTs may have a significant role to play in the onset of TRALI. Mild thrombocytopenia frequently occurs in TRALI patients. Mild thrombocytopenia has also been demonstrated in the 34-1-2S–based TRALI mouse model. This at least suggests that PLTs are involved to some degree during TRALI development. To establish the involvement of PLTs in the onset of TRALI, Looney and colleagues initially depleted PLTs in a 34-1-2S mouse model of TRALI, and this was found to result in protection from TRALI. PLT depletion in this study was accomplished using a rabbit antimouse PLT serum was administered 4 hours before 34-1-2S injection. Aspirin treatment also protected against murine TRALI in the same study. A subsequent study by Strait and coworkers was able to reproduce the data with a 4-hour difference between antibody-mediated PLT depletion and TRALI induction. These authors, however, did not find an effect when PLT depletion was conducted 24 or 48 hours before 34-1-2S– mediated TRALI induction. They argued that the antibodies used to eliminate PLTs might interfere with TRALI perhaps via depletion of complement or desensitizing effector cells through stimulatory or inhibitory receptors and, thus, PLTs are not involved in the onset of murine TRALI. In that same study, PLTs were also depleted by a nonimmune mechanism using neuraminidase treatment and it was also found that TRALI still developed. Furthermore, in an elegant study by Hechler and coworkers, PLT depletion was carried out via diphtheria toxin (DT) administration to PLT factor 4-Cre/inducible DT receptor mice or by infusion of anti-glycoprotein (GP)Ibα antibody. A 34-1-2S–based TRALI mouse model was used and the authors found PLTs to be dispensable for the onset and development of TRALI using both methods of PLT depletion. The authors, however, did find that PLTs were required to prevent lung hemorrhage but not pulmonary edema and respiratory distress. TRALI was also found to occur when mice were treated with clopidogrel or aspirin, the latter being in apparent contrast to the study of Looney and coworkers. In the April issue of TRANSFUSION, Cognasse and colleagues also investigate the effect of PLT depletion using a 34-1-2S–mediated TRALI mouse model. At 30 minutes before TRALI induction with 34-1-2S, they treated mice with an antiGPIbα to deplete PLTs. Additionally, they also treated mice with the protease receptor 4 pathway inhibitor ML354 to inhibit PLT activation. In line with the data from Hechler and colleagues, PLT depletion did not prevent the development of murine TRALI but did reduce its severity. In addition, prophylactic inhibition of PLT activation with ML354 did not affect the occurrence of murine TRALI. Neutrophils (PMNs) are crucial pathogenic cells in TRALI and have been found to be critically required for TRALI induction in mice, as PMN depletion prevented the onset of TRALI in 34-1-2S–mediated TRALI mouse models. NETs have also been described to be present in 34-1-2S–mediated TRALI as well as in TRALI patient samples. One of these studies found PLTs to be triggers of NET formation in TRALI mice, while the other study reported that PLT depletion did not prevent the occurrence of NET biomarkers in the lungs of TRALI mice. Notably, in both of these studies, priming with low-dose lipopolysaccharide (LPS) followed by 34-1-2S infusion resulted in TRALI and NET formation. However, both studies did not This article was published online on 18 May 2020. An error was subsequently identified in the authors' affiliations section. This notice is included in the online version to indicate that online version have been corrected on 03 June 2020. doi:10.1111/trf.15814 © 2020 AABB TRANSFUSION 2020;60;886–888