Abstract
BackgroundCirculating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. However, the source and mechanism of release of cfDNA in trauma is not well understood. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. The primary objective of our study was to determine if cfDNA has prognostic utility in trauma. The secondary objective of this study was to determine the source of cfDNA in trauma compared to sepsis.MethodsWe studied trauma patients from two prospective observational cohort studies: the DNA as a Prognostic Marker in ICU Patients (DYNAMICS) study and the Endotoxin in Polytrauma (ENPOLY) study. We also studied septic patients from the DYNAMICS study. Citrated plasma samples were collected longitudinally from the patients (days 1 to 7). The following molecules were measured in the plasma samples: cfDNA, protein C (PC), myeloperoxidase (MPO) (a marker of neutrophil activation), citrullinated Histone H3 (H3Cit, a marker of NETosis), cyclophilin A (a marker of necrosis), and caspase-cleaved K18 (a marker of apoptosis).ResultsA total of 77 trauma patients were included (n = 38 from DYNAMICS and n = 39 from ENPOLY). The median age was 49 years; 27.3% were female, and mortality was 16.9% at 28 days. Levels of cfDNA were elevated compared to healthy values but not significantly different between survivors and non-survivors. There was a positive correlation between MPO and cfDNA in septic patients (r = 0.424, p < 0.001). In contrast, there was no correlation between MPO and cfDNA in trauma patients (r = – 0.192, p = 0.115). Levels of H3Cit, a marker of NETosis, were significantly elevated in septic patients compared to trauma patients (p < 0.01) while apoptosis and necrosis markers did not differ between the two groups.ConclusionOur studies suggest that the source and mechanism of release of cfDNA differ between trauma and sepsis patients. In sepsis, cfDNA is likely primarily released by activated neutrophils via the process of NETosis. In contrast, cfDNA in trauma appears to originate mainly from injured or necrotic cells. Although cfDNA is elevated in trauma and sepsis patients compared to healthy controls, cfDNA does not appear to have prognostic utility in trauma patients.Trial registrationClinicalTrials.gov Identifier: NCT01355042. Registered May 17, 2011
Highlights
Circulating cell-free DNA may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma
CfDNA and protein C (PC) in trauma patients The median baseline level of cell-free DNA (cfDNA) in trauma patients, while lower than septic patients was significantly higher compared with healthy volunteers (Fig. 1a)
These results suggest that cfDNA is released via NETosis in septic patients but not in trauma patients
Summary
Circulating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. Clinical scoring systems have been developed such as the Injury Severity Score [4] and the Revised Trauma Score [5] for critically ill patients While these scores are useful for predicting mortality, they reflect external manifestations rather than underlying pathophysiologic mechanistic causes of organ dysfunction. Over the past several years, circulating cell-free DNA (cfDNA) has been suggested to contribute to the pathophysiology of post-injury inflammation and coagulation in trauma [6, 7]. Small molecular inhibitors of PAD4 can impair NET formation in mice [9]
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