Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury

Consecutive patients with traumatic brain injury who were admitted to the emergency department (ED) from June 2000 to March 2016 were eligible for inclusion in the present study. Patients with severe iTBI who were admitted to the ICU were included in the present study. Exclusion criteria were as follows: missing data, ≤ 8 years of age, cardiac arrest and resuscitation, severe injuries to other parts of the body and cervical spinal cord injury. Our Institutional Review Board approved this study and waived informed consent.

We retrospectively conducted a systematic review of the computer-based medical records of these patients to provide baseline data and DIC-related parameters. The platelet count, prothrombin time, prothrombin time ratio, fibrinogen, antithrombin, FDP, D-dimer and lactate levels were measured at four time points within 24 hours after admission to the ED: Time Point 01, immediately after to 4 hours after arrival at the ED; Time Point 02, 4–8 hours after arrival; Time Point 03, 8–16 hours after arrival; and Time Point 04, 16–24 hours after arrival. The day 0 data showed the worst maximal values (highest or lowest) of these four measurement time points. The day 0 data were used for classifying patients with or without DIC and for determining the phenotype.

Severe isolated traumatic brain injury (iTBI) was defined according to the Abbreviated Injury Scale (AIS) as follows: AIS of the head and neck ≥ 3 and AIS of other body parts ≤ 2. The Injury Severity Score (ISS) was used to evaluate the degree of the injury. In the present study, brain damage was defined as cerebral contusion with or without hematoma and subdural hematoma with cerebral contusion. The severity of the patient’s condition and organ dysfunction was assessed by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Sequential Organ Failure Assessment (SOFA) score [21], respectively. The systemic inflammatory response syndrome (SIRS) score was calculated according to the formula established in the American College of Chest Physicians/Society of Critical Care Medicine consensus conference [22]. DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC diagnosis criteria based on the day 0 data [1, 23]. DIC and overt DIC were diagnosed based on total scores of ≥ 4 and ≥ 5, respectively. We referred to the criteria of Asakura [11] for the definition of the DIC phenotype. Hyperfibrinolysis was defined as an FDP level ≥ 100 μg/ml, and the FDP/D-dimer ratio was used as a surrogate marker of fibrin(ogen)olysis [11]. Tissue hypoperfusion was defined as a blood lactate level ≥ 4 mmol/L based on the Surviving Sepsis Campaign Guidelines 2012 [24]. The outcome measure was the rate of all-cause hospital mortality.

The results were shown as the median and interquartile range. The IBM SPSS software program (version 24.0 for MAC OSX; IBM Japan, Tokyo, Japan) was used for all of the analyses. The Kruskal–Wallis test was used for comparison among three groups, while the Mann–Whitney U test and the chi-square test were used for comparisons between two groups. The dependent and the independent variables were evaluated by logistic regression analysis (the backward stepwise method based on likelihood) and the odds ratios and 95% confidence intervals were shown. The prediction of hospital death was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Survival curves during hospital stay were analyzed by the Kaplan–Meier method using a log-rank test for comparison. p < 0.05 was considered to indicate statistical significance.

During the study period, a total of 335 trauma patients with brain injury presented to the ED. After the exclusion of ineligible patients and patients with incomplete data, patients with cervical spinal cord injury in whom the AIS of the head and neck was ≥ 3 were further excluded. Finally, 92 eligible patients with iTBI were identified. The patients were divided into the DIC (n = 45) and non-DIC (n = 47) groups based on the JAAM DIC scoring system (Fig. 1).

Table 1 presents the demographic data of the patients. Although the ISS and AIS were distributed evenly between the two groups, the APACHE II scores of the DIC patients were higher. All of the DIC patients developed SIRS with higher SOFA scores and required greater volume of blood transfusion, leading to a significantly worse outcome in comparison to the non-DIC patients. It is important to note that the mean blood pressures of the two groups at arrival to the ED were ≥ 90 mmHg and that only 5 patients required catecholamine, which suggests a low incidence of hemorrhagic shock in both groups of the patients. The use of tranexamic acid was evenly distributed between the two groups. No patients received an infusion or transfusion in the prehospital setting because emergency medical service personnel are not permitted perform transfusion and the infusion of Ringer’s lactate solution is only allowed for patients with a severe worsening of hypovolemic shock.

The DIC patients continuously showed significantly lower platelet counts, more prolonged prothrombin time ratios and lower levels of fibrinogen and antithrombin immediately after arrival at the ED (Time Point 01) until Time Point 04, and on day 0 in comparison to non-DIC patients (Fig. 2). The DIC patients also showed persistently higher levels of FDP and D-dimer in comparison to the non-DIC patients (Fig. 3). In addition, the FDP/D-dimer ratios of the DIC patients were significantly higher than those of the non-DIC patients (Fig. 4). These results suggest consumption coagulopathy, insufficient anticoagulation by antithrombin and increased fibrin(ogen)olysis in DIC patients. The numbers of patients at each time point are presented in Additional file 1: Table S1.

The DIC patients were subdivided into those with (n = 17) and without (n = 28) hyperfibrinolysis based on their FDP levels (Table 2). The DIC patients’ fibrinolysis marker levels are presented in Table 3, which shows that the levels of FDP and D-dimer of the DIC patients with hyperfibrinolysis were extremely high in comparison to those without hyperfibrinolysis. The ISS of the two groups was identical; however, the patients with hyperfibrinolysis had higher DIC, APACHE II and SOFA scores and underwent transfusion with higher volumes of red blood cell concentrates in comparison to the patients without hyperfibrinolysis. The FDP/D-dimer ratios of the patients with hyperfibrinolysis were markedly higher than non-DIC patients (Fig. 4). Based on these results, DIC with hyperfibrinolysis is considered equivalent to DIC with the fibrinolytic phenotype, which is associated with fibrin(ogen)olysis, hemorrhage and organ dysfunction. DIC with hyperfibrinolysis was associated with a higher mortality rate (58.9%) in comparison to DIC without hyperfibrinolysis (10.7%).

Stepwise logistic regression analyses confirmed that the DIC and APACHE II scores are independent predictors of patients’ death (Table 4). The ROC curves further showed the significant discriminative performance of the DIC and APACHE II scores for predicting death in iTBI patients (Fig. 5). These results are important because the DIC score showed good discriminative power for predicting the outcome in comparison to the APACHE II score, which is known as a superior predictor of death in various kinds of critical illness. The Kaplan–Meier curves showed that DIC, especially DIC diagnosed by the ISTH scoring system and DIC with hyperfibrinolysis, significantly affected the survival rate of patients with iTBI (Fig. 6). Table 5 shows that the DIC score and the existence of hyperfibrinolysis further influenced the death in DIC patients.

Despite the fact that the two groups showed the same mean blood pressures on arrival at the ED, the DIC patients, especially those with hyperfibrinolysis, showed a higher prevalence of hypoperfusion and significantly higher lactate levels (Fig. 3, Tables 1 and 3). However, the lactate levels were not found to be an independent predictor of hyperfibrinolysis by the stepwise logistic regression analyses (odds ratio, 1.335; 95% confidence interval, 0.991–1.798; p = 0.058) (Table 5). In addition, neither hypoperfusion nor brain damage predicted hyperfibrinolysis in DIC patients.