The present study confirms that trauma patients present a spectrum of different coagulopathies that can be identified by TEG and demonstrates that hypercoagulable trauma patients are older and have higher fibrinogen level and platelet count. Furthermore, increasing injury severity was associated with increased shock, sympathoadrenal activation, tissue injury, platelet activation, protein C activation (higher activated PC, lower non-activated PC), hyperfibrinolysis and reduced fibrinogen and FXIII levels. Finally, in the most severely injured patients (highest ISS group), adrenaline and sCD40L were independently negatively associated with maximum clot strength and platelet count alone was only associated with clot strength after adjusting for platelet activation level (sCD40L).
Trauma is a leading cause of death and disability worldwide and hemorrhage is responsible for the majority of potentially preventable deaths. Death due to exsanguination occurs early (50% within 2 hours) after the injury  emphasizing that immediate diagnosis of existing coagulopathies by TEG/ROTEM is of critical importance to enable goal-directed therapy early in the resuscitation phase [12, 14].
In accordance with previous studies [1, 6–11] TEG identified a spectrum of different coagulopathies in trauma patients, with hypercoagulability being the most frequent  and in this study associated with high age and high fibrinogen level and platelet count. In contrast to some previous studies [6, 11], but consistent with others , no difference in injury severity between patients with normal and hypercoagulable TEG was found. Though not statistically significant, it is notable that no hypercoagulable patients were massively transfused or had ACT according to APTT/INR, a finding in accordance with previous studies . Furthermore, it is notable that the hypercoagulable and normal patients had comparable mortality despite a considerably higher age in the hypercoagulable group. It is tempting to speculate that a hypercoagulable response to moderate (survivable) trauma may be optimal from an evolutionary perspective by promoting hemostasis. Given this, the hypocoagulability and/or hyperfibrinolysis that may accompany severe (unsurvivable) injury may reflect a less well adapted exaggerated response to excessive systemic endothelial activation and damage along with extremely low flow and hypoperfusion .
The low prevalence of hyperfibrinolysis is in accordance with previous findings in trauma patients [1, 7–9], but we found a lower than expected prevalence of hypocoagulability [1, 6]. The latter may be due to the relatively low number of severely injured and/or shocked patients in the present study, which may also explain the low prevalence of patients with ACT according to APTT and INR. Though the 15% prevalence of ACT in the present study is within the range previously reported in other trauma studies (from 10-34%) , this relatively low proportion of patients with ACT should be taken into account when interpreting the results from the present study.
Though we lacked statistical power to compare patients with hypocoagulability or hyperfibrinolysis to patients with a normal TEG, the high level of sympathoadrenal activation, tissue injury, platelet activation, PC activation and tPA release in the patient with primary hyperfibrinolysis concurs with the biomarker profile expected to yield hyperfibrinolysis [3, 4, 20]. However, this finding reported here needs to be confirmed in a larger study powered to investigate biomarkers in patients with hypocoagulable or hyperfibrinolytic TEG profiles.
Increasing injury severity was associated with lower fibrinogen levels and importantly also with lower FXIII levels and higher prevalence of patients with ACT according to APTT or INR. The association between injury severity and fibrinogen, APTT and INR is well established [3, 4] whereas the negative association between ISS and FXIII has not been described previously, despite an established association between low FXIII levels and increased bleeding following e.g., cardiac surgery and neurosurgery . In accordance with previous studies, higher ISS was also associated with evidence of increased sympathoadrenal activation, tissue injury [18, 19], PC activation and hyperfibrinolysis [3, 4, 18, 19]. In contrast to previous studies of ACT reporting solely on decreases in non-activated PC as indirect evidence of PC activation [3, 4], the present study is to our knowledge the first to directly demonstrate enhanced PC activation with increasing injury severity, evidenced by increased activated PC in the highest ISS groups, occurring along with a previously described decline in non-activated PC in these patients.
Though not statistically significant, the TEG profile changed towards reduced R time and increased fibrinolysis with increasing injury severity, a finding also in accordance with previous findings [6–8].
Maximum clot strength is a strong predictor of bleeding and transfusion requirements in trauma patients [6, 10, 11, 29], explaining why we investigated variables independently associated with this. In the two lower ISS groups, the fibrinogen level and platelet count were both independently associated with clot strength, in accordance with previous findings [6, 7, 23, 29]. Importantly, we found that the variables independently associated with clot strength changed with injury severity so that platelet count only remained independently associated with clot strength in the highest ISS group after adjusting for the platelet activation level (sCD40L). Based on this finding it could be speculated that trauma induced platelet activation (and ensuing release of sCD40L) may result in downstream platelet exhaustion or hypo responsiveness so the platelets left could not adequately support clot formation. Alternatively, the finding may simply reflect that adequately activated platelets were consumed in vivo upon clot formation leaving in the circulation (and collected upon blood sampling) platelets with lower hemostatic potential. The finding emphasizes that changes observed in the blood may optimally be interpreted from a systems biology perspective taking into account the condition of the vascular endothelium (activated, damaged, leaky etc.) surrounding the circulating blood and hence critically influencing the composition of both the circulating and sampled blood . Whichever explanation, the notion that severe trauma may result in platelet exhaustion is in accordance with previous thoughts  and in accordance with a recent study of platelet function in trauma patients reporting on low platelet reactivity assessed by both Multiplate and by the platelet component of viscoelastic tests (ROTEM) in patients with highest ISS and non-survivors . Finally, it should be noted that the fibrinogen values included in the statistical model in the present study may not adequately reflect fibrin polymerization (and hence functional contribution to clot strength) since optical measurements of circulating fibrinogen levels not always simply reflect fibrin polymerization.
Importantly, we also found that the adrenaline level was negatively independently associated with clot strength only in the highest ISS group indicating that excessive sympathoadrenal activation may negatively influence hemostasis. We recently proposed  and demonstrated  that progressive increases in adrenaline levels in trauma patients promote a switch from hypercoagulability towards hypocoagulability and hyperfibrinolysis due to the influence of adrenaline on the vascular endothelium [19, 20]. The finding here supports this notion and emphasizes that the sympathoadrenal activation following trauma may contribute directly to the early coagulopathy observed in trauma patients.
Whether the different contribution of fibrinogen and platelets to TEG clot strength in patients with high vs. low injury severity reflects that these patients would benefit from different resuscitation strategies with e.g., FFP/fibrinogen/cryoprecipitate pool vs. platelets cannot be answered from the present explorative study but should be investigated in a randomized clinical trial powered to answer this question.
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 and patients with hypocoagulable or hyperfibrinolytic TEG profiles, included in the present study increases the risk of introducing a type II error, emphasizing that the reported findings should be confirmed in a larger cohort of patients. Finally, exclusion of patients based on pre-hospital fluid administration (> 2,000 ml) could theoretically have introduced a bias by excluding the most severely injured and bleeding patients, which should be taken into account. However, in 2004 our Trauma Centre introduced Hemostatic Control Resuscitation and abandoned colloids along with a general consensus of restrictive pre-hospital crystalloid fluid resuscitation so extremely few patients admitted to our Trauma Centre in the study period and today were resuscitated with > 2,000 ml fluids pre-hospital and no patients received colloids.