Abstract
BackgroundThe level of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is increased in sepsis and strongly associated with disease severity and mortality. Endothelial activation and damage contribute to both sepsis and trauma pathology. Therefore, this study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome.MethodsProspective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS), transfusions and 30-day mortality were recorded and plasma/serum (sampled a median of 68 min (IQR 48-88) post-injury) was analyzed for sVEGFR1 and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue injury (histone-complexed DNA fragments, hcDNA), endothelial activation and damage (von Willebrand Factor Antigen, Angiopoietin-2, soluble endothelial protein C receptor, syndecan-1, soluble thrombomodulin (sTM)), coagulation activation/inhibition and fibrinolysis (prothrombinfragment 1 + 2, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and inflammation (interleukin-6). Spearman correlations and regression analyses to identify variables associated with sVEGFR1 and its predictive value.ResultsCirculating sVEGFR1 correlated with injury severity (ISS, rho = 0.46), shock (SBE, rho = -0.38; adrenaline, rho = 0.47), tissue injury (hcDNA, rho = 0.44) and inflammation (IL-6, rho = 0.54) (all p < 0.01) but by multivariate linear regression analysis only lower SBE and higher adrenaline and IL-6 were independent predictors of higher sVEGFR1. sVEGFR1 also correlated with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1, rho = 0.67), endothelial cell damage (sTM, rho = 0.66) and activation (Ang-2, rho = 0.31) and hyperfibrinolysis (tPA, rho = 0.39; D-dimer, rho = 0.58) and with activated protein C (rho = 0.31) (all p < 0.01). High circulating sVEGFR1 correlated with high early and late transfusion requirements (number of packed red blood cells (RBC) at 1 h (rho = 0.27, p = 0.016), 6 h (rho = 0.27, p = 0.017) and 24 h (rho = 0.31, p = 0.004) but was not associated with mortality.ConclusionssVEGFR1 increased with increasing injury severity, shock and inflammation early after trauma but only sympathoadrenal activation, hypoperfusion, and inflammation were independent predictors of sVEGFR1 levels. sVEGFR1 correlated strongly with other biomarkers of endothelial activation and damage and with RBC transfusion requirements. Sympathoadrenal activation, shock and inflammation may be critical drivers of endothelial activation and damage early after trauma.
Highlights
Critical illness accompanied by shock is associated with endothelial activation and damage, evidenced by high circulating levels of molecules derived from the endothelium such as adhesion and signaling receptors, glycocalyx constituents and Weibel-Palade body contents [1,2]
We investigated potential drivers of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) and sVEGFR1 interrelations with a broad range of endothelial derived biomarkers indicative of endothelial activation, WeibelPalade body release, endothelial cell damage and glycocalyx degradation/shedding, hypothesizing that the level of sVEGFR1 would increase with trauma severity and with the level of sympathoadrenal activation in accordance with previous finding from our group [4]
SVEGFR1 levels in trauma patients In blood sampled on admission from severely injured trauma patients, high circulating soluble vascular endothelial growth factor (VEGF) receptor 1 levels correlated with high injury severity (ISS; rho = 0.46, p < 0.001), shock (SBE; rho = -0.38, p = 0.001 and adrenaline; rho = 0.47, p < 0.001), high circulating levels of histones/DAMPs and inflammation (IL-6; rho = 0.54, p < 0.001) (Table 2 univariate analysis)
Summary
Critical illness accompanied by shock is associated with endothelial activation and damage, evidenced by high circulating levels of molecules derived from the endothelium such as adhesion and signaling receptors, glycocalyx constituents and Weibel-Palade body contents [1,2]. High circulating Angiopoietin (Ang)-2 [3], syndecan-1 [4,5,6], a glycocalyx constituent [7], and soluble thrombomodulin (sTM) [4,8] are indicators of endothelial activation, glycocalyx degradation and endothelial cell damage, respectively; events that contribute directly to trauma pathology by enhancing vascular permeability, hypocoagulability and hyperfibrionlysis in the circulating blood [9,10,11]. High levels of Ang-2, syndecan-1 and sTM all predict a poor outcome in trauma patients [3,4,6,8] Sepsis is another life threatening condition where endothelial disruption, due in part to hyperinflammation and shock, contributes directly to disease pathology [12,13,14], so high circulating levels of endothelial derived biomarkers here predict a poor clinical outcome [15]. This study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome
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