Trauma and Transfusion Phenotypes

It has been shown that patients with trauma-associated ARDS have markedly different clinical characteristics than patients with other clinical etiologies of ARDS [7]. These differences were associated with lower plasma levels of several biomarkers previously found to be associated with poor clinical outcomes in ARDS, including ICAM-1, SP-D, sTNFr-1, and vWF. Although one previous study [3] focused solely on the prevalence of ARDS based on the Berlin definition among military burn victims, the authors provide important information about the ARDS phenotype. Regardless of trauma, patients were discriminated into mild, moderate, and severe ARDS groups, with mortality rates of 11.1%, 36.1%, and 43.8%, respectively. The following variables were independently associated with moderate or severe ARDS in this population: inhalation injury, injury severity score, pneumonia, and use of fresh frozen plasma. In fact, previous studies have shown a strong link between administration of fresh frozen plasma and development of ARDS in severely injured patients [24, 64]. Transfusion-related acute lung injury (TRALI) could be implicated. Classically, TRALI has been associated with immune-mediated and non- immune-mediated events. The former is caused by human leukocyte antigen (HLA) class I and II and/or less frequent antibodies directed against specific granulocyte antigens, human neutrophil antigen (HNA), which can be present in the serum of the recipient or donor and thus react with donor or recipient leukocytes, respectively [43]. The non-immune-mediated events can be attributed to transfusion of biologically active compounds which accumulate in stored blood components, such as bioactive lipids, proinflammatory cytokines, or platelet microparticles with high procoagulant activity [59]. One further mechanism could be the release of proinflammatory mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial deoxyribonucleic acid (mtDNA) fragments and mtDNA- associated proteins [30]. Clinically, hemodynamic monitoring helps distinguish TRALI from cardiogenic pulmonary edema. Normal or low pulmonary capillary wedge pressure and central venous pressure values are characteristic of TRALI [56]. Hemodynamic monitoring is needed to exclude other causes of TRALI, because its symptoms are similar to those of other conditions, including anaphylactic reaction, cardiogenic pulmonary edema, ARDS, and bacterial infection. Occasionally, leukopenia, neutropenia, hypoalbuminemia, and hypocomplemente- mia can be detected. The most prevalent symptom is a transient leukopenia, which arises in 5-35% of patients [14].

The lungs tend to be more frequently affected than any other organ in patients who die of clinical shock or after trauma, a phenomenon associated with neutrophil infiltration, pulmonary edema, hemorrhage, and microvascular thrombosis [32]. The fundamental pathogenic events related to trauma remain incompletely characterized. Studies have shown that nuclear proteins, such as high mobility group box-1 (HMGB-1) [46], and histones [1] are elevated after trauma events related to ARDS scenarios. Histones in particular have demonstrated ability to mediate remote organ damage, particularly in the lungs, and contribute to multiple organ failure. One possible mechanism could be that extracellular histones bind phospholipids, disrupt cell membranes, and cause calcium influx. This indiscriminate activity on all cells tested resulted in sustained elevation of [Ca⁺²]i, causing cell damage and release of cellular stores and content. Furthermore, the increase in histone levels could be associated with NET formation and may become a novel marker reflecting disease activity. In fact, the predominant source of histones in ARDS may be neutrophils that have been activated by C5a to form NETs, which seems to be an ongoing process toward inflammation perpetuation [20]. Extracellular histones are highly proinflammatory and have been shown to cause severe damage to respiratory function. Intratracheal instillation of histones resulted in proinflammatory mediator production, epithelial cell damage, disturbances in alveolar-capillary gas exchange, lung consolidation, and activation of the coagulation cascade [20]. Targeting histones with neutralizing antibody or heparin shows potent protective effects, suggesting a therapeutic strategy [70].

Within trauma populations, different patterns of ARDS onset with distinct ARDS risk factors have been empirically described and may involve different pathogenesis pathways [11]. By using latent class analysis (LCA), a statistical method used to identify unobserved (latent) patterns underlying the observed heterogeneity in a population, one study identified three subgroups of ARDS based on timing of onset and certainty of diagnosis in a cohort of critically ill trauma patients [47]. The model identified a cutoff point of approximately 48 h after presentation separating the early- and late-onset subgroups of ARDS. Early-onset ARDS was associated with increased severity of thoracic trauma, more severe early hypertension, and increased red blood cell transfusion during the initial resuscitation when compared with the later-onset subgroup. In addition, the biomarkers sRAGE and Angpt-2 were significantly higher in the serum of patients with early-onset ARDS, while all other biomarkers, including markers of systemic inflammation, were similar between the two classes of ARDS, suggesting distinct molecular profiles in the early post-trauma period.