In this study, sympathoadrenal activation, hypoperfusion and inflammation were independently associated with high circulating sVEGFR1 levels early after trauma and sVEGFR1 correlated positively with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1), endothelial cell damage (sTM) and Weibel-Palade body degranulation (tPA, Ang-2). High sVEGFR1 levels correlated with high early and late transfusion requirements but did not associate with mortality.
Tissue trauma undoubtedly contributes directly to endothelial injury in trauma, but the concurrent excessive sympathoadrenal activation [4, 25], hypoperfusion  and inflammation  present in shocked trauma patients also induce systemic endothelial activation and damage [9, 10]. Hypoxia is a potent inducer of endothelial activation  and catecholamines also induce active release of procoagulant and profibrinolytic factors from the endothelium [28, 29] and in high concentrations, they directly damage the endothelium [9, 30, 31] in accordance with the recent finding that high circulating adrenaline early after trauma is independently associated with high syndecan-1 levels . In line with this, the present study found that high circulating adrenaline was independently associated with high sVEGFR1, even after adjusting for injury severity, hcDNA, hypoperfusion and inflammation. Though the level of VEGF is reported unchanged and unaffected by injury severity and shock early after trauma , the finding here that sVEGFR1 increased with increasing injury severity, shock and inflammation suggests that the bioavailability of VEGF may change early after trauma. Notably, patients with sTBI had lower circulating sVEGFR1 as compared to non-sTBI trauma patients. The potential (patho)physiologic effects, if any, of these findings however remains to be determined.
In accordance with previous studies reporting of strong interrelations between different endothelial biomarkers in trauma  and sepsis , sVEGFR1 correlated with other endothelial derived biomarkers in this study. Importantly, sVEGFR1 was strongly positively correlated with both syndecan-1 and sTM, biomarkers of endothelial glycocalyx degradation/shedding and endothelial cell damage, respectively, and both carrying prognostic value in trauma patients [4, 6, 8]. Also, sVEGFR1 correlated with Ang-2 and tPA, which are both Weibel-Palade constituents  and inducers of fibrinolysis and enhanced vascular permeability, and with activated protein C, a potent natural anticoagulant and inducer of fibrinolysis. Considering Ang-2, this is increased early after trauma and associated with poor clinical outcome . Ang-2 is expressed almost exclusively by endothelial cells and is induced dramatically and released instantaneously from Weibel-Palade bodies upon endothelial activation [17, 29, 32] and its release results in rapid (autocrine) destabilization of the endothelium which, through endothelial activation and increased vascular permeability, triggers an inflammatory response [17, 32].
Despite the interrelation between sVEGFR1 and other endothelial activation and damage biomarkers in accordance with the finding in sepsis by Shapiro et al , sVEGFR1 did not associate with mortality as observed in sepsis. Whether this is due to a type II error due to the low number of subjects investigated in the present study or reflects biologic differences between the trauma and sepsis populations remains to be determined.
Given the finding that sVEGFR1 correlated with transfusion requirements, it should be emphasized that all biochemistry variables and biomarkers were measured in arrival blood samples taken before administration of any blood products and hence sampled before any potential introduction of bias (e.g., content of sVEGFR1 in blood products). Though sVEGFR1 correlated with transfusion requirements, it did not correlate with any TEG variables.
It may seem counterintuitive that active release of endothelial derived molecules in the most severely injured and potentially bleeding trauma patients promotes progressive hypocoagulability in the circulating blood [4, 10, 11, 25, 33–36] through induction of endogenous anticoagulation (activated protein C, sTM), hyperfibrinolysis (tPA, activated protein C) [8, 11] and heparinization (glycocalyx shedding) [4, 9, 37]. We recently hypothesized that this progressive hypocoagulability, from a systems biology perspective, reflects an evolutionary adapted response that counterbalances the progressively more damaged and procoagulant endothelium in order to keep the microcirculation open . Furthermore, several of the endothelial derived molecules that promote hypocoagulability exert potent antiinflammatory and cytoprotective functions [13, 38–40] that may ultimately generate at survival advantage in injured individuals . In addition to progressive hypocoagulability, severe trauma is associated with increased vascular permeability which, in part, may result from downstream effects of glycocalyx degradation [42, 43] and Ang-2 release [17, 32]. In a context without resuscitation (from an evolutionary perspective) the increase in vascular permeability may generate a survival advantage since the rapid shift of volume from the intra- to the extra-vascular compartment in a bleeding subject may both lower blood pressure and contain fluid within the body for latter mobilization if the subject survives, which seems favorable as compared to bleeding out a large un-replaceable intravascular volume. Such response (or a more exaggerated one) may, however, not generate the same survival benefit in a context with aggressive volume resuscitation and life support in severely injured individuals and this may explain the consistent finding that the highest levels of several endothelial derived molecules are negatively associated with outcome in trauma [3–6, 8].
The results presented here are subject to the limitations inherent to observational studies and, thereby, do not allow independent evaluation of the cause-and-effect relationship suggested. Furthermore, the low number of subjects, and especially the low number of severely injured patients, included in the present study increases the risk of introducing a type II error and the multiple testing increases the risk of a type I error, emphasizing that the reported findings should be confirmed in a larger cohort of patients.