Abstract
BackgroundCell free deoxyribonucleic acid (cfDNA) has been proposed as a biomarker of secondary complications following trauma. Raised thrombomodulin and syndecan-1 levels have been used to indicate endotheliopathy, and are associated with inflammation, coagulopathy, and mortality. The current study aimed to analyse the association between cfDNA and biomarkers of endotheliopathy in a cohort of trauma patients, and whether raised levels of cfDNA were associated with poorer clinical outcomes.MethodsSerum thrombomodulin and syndecan-1 were used as biomarkers of endotheliopathy and compared to plasma cfDNA in trauma patients from two prospective longitudinal observational studies. Cohort A (n = 105) had a predicted injury severity score (ISS) >8, and had blood sampled within 1h of injury and at 4–12h. Cohort B (n = 17) had evidence of haemorrhagic shock, and had blood sampled at a median time of 3.5h after injury. Relationships between biomarkers were tested using multivariable linear regression models that included the covariates of gender, age, ISS, Glasgow Coma Scale, lactate, systolic blood pressure, and heart rate. A model was fitted to investigate whether changes in cfDNA were associated with similar changes in endothelial biomarkers.ResultsThe mean age was 41 (SD 19), and the median ISS was 25 (IQR 12–34). There was a significant association between cfDNA levels and both syndecan-1 and thrombomodulin levels (both p<0.001). This was independent of all covariates except for ISS, which significantly correlated with cfDNA levels. 50 ng/ml change in syndecan-1 and 1 ng/ml change in thrombomodulin corresponded to 15% and 20% increases in cfDNA levels respectively (both p<0.001). Patients who died had significantly higher prehospital and in-hospital cfDNA levels (both p<0.05).ConclusionsRaised cfDNA levels are associated with markers of endotheliopathy following trauma, and are associated with mortality. This relationship is present within the first hour of injury, and a change in one biomarker level is reflected by similar changes in the others. These findings are in keeping with the hypothesis that circulating DNA and endothelial injury share a common pathway following trauma.
Highlights
Cell-free deoxyribonucleic acid is defined as extracellular DNA present within the circulation
There was a significant association between Cell-free deoxyribonucleic acid (cfDNA) levels and both syndecan-1 and thrombomodulin levels
Raised cfDNA levels are associated with markers of endotheliopathy following trauma, and are associated with mortality
Summary
Cell-free deoxyribonucleic acid (cfDNA) is defined as extracellular DNA present within the circulation It consists of a combination of nuclear and mitochondrial DNA (mtDNA) that enters the circulation following cell necrosis [1], tissue injury, and the generation of extracellular traps by activated immune cells such as neutrophils [2] and monocytes [3]. The former is a transmembrane heparan sulfate proteoglycan that forms part of the endothelial glycocalyx, and the latter is an integral membrane protein present on the surface of endothelial cells throughout the circulation Raised levels of these biomarkers are associated with coagulopathy [14, 15, 17, 18], inflammation [15], poor microcirculatory flow[19], organ failure[20], and mortality [15,16,17]. The current study aimed to analyse the association between cfDNA and biomarkers of endotheliopathy in a cohort of trauma patients, and whether raised levels of cfDNA were associated with poorer clinical outcomes
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