Thromboelastometry and organ failure in trauma patients: a prospective cohort study

Major trauma is among the most common causes of death worldwide. Whereas uncontrolled bleeding accounts for 50 to 80% of mortality early following trauma [1],[2], multiple organ failure (MOF) is the most important cause of late mortality after trauma [1],[3]. Traumatic injury induces a hypocoagulable state, as a result of acute traumatic coagulopathy (ATC) accompanied by loss, consumption and dilution of coagulation factors and fibrinolysis. Hypothermia, shock and acidosis further amplify the derangement of the coagulation system [4]. In addition to reduced hemostatic potential, trauma can also induce a hypercoagulable state [5]-[7]. Animal experiments have shown that hypercoagulability can arise within hours of the injury [8], a phenomenon confirmed in humans [5],[9]. However, uniform definitions of hypercoagulability are lacking and effects of this hypercoagulable state after trauma are not fully elucidated, with studies showing conflicting results. An association with adverse events such as an increased risk of venous thromboembolism has been reported [7],[10],[11]. However, early hypercoagulability has also been associated with decreased early mortality, which may suggest that hypercoagulability is a functional response in order to reduce blood loss [9].

In sepsis, it has been demonstrated that hypercoagulability, characterized by the formation of microthrombi with concurrent protein C deficiency and impaired fibrinolysis, contributes to MOF and adverse outcome [12],[13]. Although sepsis and trauma are different entities, the accompanying coagulopathies show similarities and persistent protein C deficiency after trauma is also associated with occurrence of MOF [14],[15]. Shock and hypoperfusion can induce activation of the endothelium and if the patient survives the initial bleeding episode, this can result in a procoagulant state. It is conceivable that therapy of ATC may add to this endogenous response, possibly resulting in an overshoot in coagulation over time, with subsequent enhancement of hypercoagulability and MOF.

Diagnosing hypercoagulability is complex. Thrombin generation tests, or assessment of plasma levels of natural anticoagulants, as protein C, are not readily available for clinical use and not validated to detect hypercoagulability. Thromboelastometry (ROTEM) provides real-time information on all aspects of the coagulation system, including the presence of hypercoagulability [16],[17]. The use of thromboelastometry to diagnose hypocoagulability in trauma has frequently been explored in recent years [18]-[21]. However, reports on the use of ROTEM to detect a hypercoagulable state are scarce.

We aimed to study the incidence of early hypercoagulability in multiple trauma patients and to establish whether hypercoagulability is associated with the occurrence of MOF and mortality. In addition, as transfusion strategies have shifted, we assessed whether transfusion strategy influenced the occurrence of hypercoagulability.

During the study period, 1,245 patients were screened and 1,010 patients were enrolled in the study (Figure 1). For 62 of the patients, no data were available on occurrence of MOF or mortality, therefore, analyses were performed in the remaining 948 patients.

Of these, 776 patients were admitted to the hospital (intensive care unit: n = 318 and ward: n = 458) and 76 were discharged home. Patient characteristics are listed in Table 1. The majority of included patients were males experiencing blunt injury. Median age was 38 years and median ISS was 13 (IQR 8 to 25). Eighteen patients died at admission, nine of them had traumatic brain injury (TBI). Of those who died between 24 hours and 28 days, mortality was 21% in TBI and 3.4% in non-TBI patients.

Hypercoagulability after trauma has been reported using a variety of thrombelastographic (TEG) measurements [5],[7],[9],[25],[26], however, whether TEG and ROTEM results are interchangeable is still under debate [27],[28]. Reported incidences of hypercoagulability diagnosed by TEG range from 11 to 80% [5],[7],[9],[10],[26]. This wide variation can be ascribed to use of different definitions of hypercoagulability, with studies using individual parameters of the thrombelastographic trace [5],[9],[26], a combination of parameters [6],[10] or the use of G as a marker of whole clot strength [7]. Also injury severity and timing of measurements differed among these cohorts. Although our findings are in line with those previously reported in a smaller cohort of trauma patients [26], our observed rates of hypercoagulability were lower compared to a recent evaluation of admission profiles with TEG, most likely due to the use of a more narrow definition of hypercoagulability in this study [9]. With respect to the observed rate of hypocoagulability, our numbers were in line with the previous mentioned TEG study [9], but lower than other reports from the ACIT cohort using ROTEM [29], because only patients needing more than four units of RBC were included.

We hypothesized that occurrence of hypercoagulability was associated with MOF. However, we observed an opposite effect. Patients showing hypocoagulability within the first 24 hours of admission developed more severe organ failure and had an increased late mortality. This observation is in line with studies demonstrating that hypocoagulability is associated with adverse outcome after trauma and brain injury [23],[30],[31]. We showed that, in addition to individual parameters, G values on admission and 24 hours after admission are predictors for the occurrence of MOF. Of note, G is considered to better represent total clot strength than the individual thrombelastography parameters [7],[16],[23]. Previous studies on ROTEM in trauma patients focused on diagnosing early coagulation abnormalities [20],[32], prediction of transfusion requirements [21],[33] and correction of hypocoagulability [34],[35]. Our data indicate, contrary to our hypothesis, that hypocoagulability detected by ROTEM also has an enhanced risk of adverse late outcome, which confirms previous observations in a smaller cohort [21].

In the current study, patients with hypercoagulability had lower mortality and lower SOFA scores. A similar observation was recently reported in a smaller cohort of trauma patients [9]. Therefore, we hypothesize that early hypercoagulability after trauma is an evolutionary response to prevent exsanguination. Results do not point toward the hypothesis that early hypercoagulability after trauma resembles disseminated intravascular coagulation (DIC) with the formation of microthrombi, thereby contributing to organ failure [15],[36]. The observation that early hypercoagulability after trauma is more prevalent in females is in line with a previous report [5].

Limitations of our study include that we did not systematically look for occurrence of venous thromboembolism as this is a complication of major interest in patients initially surviving major trauma. In addition, only the summary of the SOFA score was collected, hereby we cannot comment on SOFA subgroups. It is also not possible to rule out a contribution of late hypercoagulability to the development of organ failure, as we only assessed ROTEM on admission and after 24 hours. Prolonged hypercoagulability has been linked to increased risk of thromboembolic complications [7],[10],[11]. Also, we did not assess d-dimers and hereby we were not able to correlate ROTEM findings to DIC scores. However, a recent review of pathology samples obtained early after trauma failed to demonstrate microthrombi despite the clinical presence of increased DIC scores [37]. Furthermore, in 40% of admitted patients ROTEM values were not available at 24 hours following trauma, attributed to logistic issues, which could have introduced recruitment bias and contributed to an underestimation of hypercoagulability at this time point. Limited reports have described the coagulopathic changes over time in trauma and a recent small cohort study suggested that hypercoagulability after trauma occurs after 48 hours [38]. Therefore, further research should include serial measurements and a prospective standardized observation of complications after trauma. However, the current data suggest that early hypercoagulability after trauma not only reduces early mortality [9], but also seems to be associated with lower occurrence and severity of MOF and 28-day mortality.

Altogether, this study has identified a significant proportion of patients with hypercoagulability as defined by ROTEM at admission. Further work in larger studies should define the clinical consequences and prognostic value of identifying hypercoagulability, specifically including thromboembolic events, and might assess a role for very early, targeted use of anticoagulants in selected patients. The role of plasma or other blood components in potentially exacerbating the consequences of hypercoagulability is also an area of further research. In this study, patients with hypocoagulability on admission mostly tended to regress to normal values over time and not to hypercoagulability, irrespective of blood product ratio. This is in contrast with studies showing an association between amount of blood products and MOF [39], but is in line with other studies, which suggested that other fluids were more associated with MOF than blood products [40],[41]. Also, there is experimental evidence that FFP preserves endothelial integrity in hemorrhagic shock [42].