Dissimilar Respiratory and Hemodynamic Responses In TRALI Induced by Stored Red Cells and Whole Blood Platelets.

Abstract

Abstract Abstract 1112 Background & Aims: Transfusion-related acute lung injury (TRALI) is a predominant cause of transfusion-related morbidity and mortality, however the mechanism underlying its development remains undefined. We have previously demonstrated that heat-treated supernatant from stored (day 5) human whole blood platelet components (d5-PLT-S/N) cause TRALI in lipopolysaccharide (LPS) treated sheep (Tung et al. Vox Sang 2010). This two-event in-vivo model was used to further investigate TRALI due to heat-treated supernatant from stored (day 42) human red cells (d42-PRBC-S/N), and a comparison of the two models is reported here. Methods: Sheep were infused with LPS (15μg/kg; to model a first event of clinical infection), and then transfused with either d5-WB-PLT-S/N or d42-PRBC-S/N (10% of estimated blood volume; second event), with saline and supernatant from fresh blood components as controls. Microarray techniques were used to analyze cytokine and chemokine expression levels in both the supernatants. A range of hemodynamic and respiratory parameters were recorded with continuous in-line monitoring. This data was then analyzed using non-linear mixed effects modelling. TRALI was defined by both hypoxemia during or within 2 hours of transfusion and histological evidence of pulmonary edema. Results & Discussion: TRALI developed in 80% of LPS-treated sheep following transfusion with either d5-WB-PLT-S/N (n=5) or d42-PRBC-S/N (n=5), with significantly lower (P<0.05) incidence of TRALI in control sheep (9%; n=23). These results demonstrated: (i) that LPS-infusion made sheep susceptible to development of TRALI; (ii) that heat-treated supernatant from either stored human whole blood platelets or red cell components were able to cause TRALI in LPS-treated sheep; and (iii) that TRALI pathogenesis followed a two-event mechanism. Importantly, several differences in respiratory and hemodynamic responses were observed between the two models. To further characterize these differences, data from only sheep that developed TRALI were re-analyzed using non-linear mixed effects modelling. Changes in pulmonary artery pressure, cardiac output and central venous pressure proved to be more severe in the d42-PRBC-S/N model (P<0.05). These re-analyses also demonstrated that rather than being the result of independent responses to LPS and transfusion, the measured changes were due to interactions between these first and second events. To investigate the cause of these pathophysiological differences we analyzed the cytokine and chemokine expression in the d5-PLT-S/N and d42-PRBC-S/N. Both stored supernatants displayed high levels of EGF, ENA-78, and GRO relative to supernatant from equivalent fresh blood components, however d42-PRBC-S/N also displayed high levels of IGFBP-1, IGF-1, IL-8, IL-16, MCP-1 and MIF. These results therefore indicated that while the clinical incidence of TRALI was identical in the two models, the mechanisms of TRALI pathogenesis in each model may have been different. Conclusions: Together, these in-vivo ovine TRALI models provide further evidence that factors in stored cellular blood components as well as the patients' underlying clinical condition are important determinants in the pathogenesis of TRALI. The differing pathophysiological responses in the two models in conjunction with the divergent cytokine and chemokine profiles of the two supernatants, provide novel evidence that each type of stored blood component may cause TRALI by different mechanisms. TRALI pathogenesis is therefore more likely to be multifacted than a single mechanism. Disclosures: No relevant conflicts of interest to declare.