Traumatic brain injury (TBI) is one of the leading causes of death and disability, with more than 10 million people hospitalized for TBI every year (1). Although primary damage to the brain is inevitable, secondary injuries are potentially avoidable and can affect the therapeutic interventions and outcomes of patients with TBI. TBI-associated coagulopathy is widely recognized as a risk factor for secondary brain damage and contributes to poor clinical outcomes. Two meta-analyses reported that the overall prevalence of TBI-associated coagulopathy was 32.7–35.2%, and a strong association was confirmed between the incidence of coagulopathy and poor outcomes (2, 3). TBI-associated coagulopathy contributes to poor outcomes in both hypocoagulability, leading to the expansion of intracranial hemorrhage, and hypercoagulability, leading to secondary cerebral ischemia due to intravascular thrombosis in the injured brain (4–8). Therefore, elucidation of the pathophysiology of TBI-induced coagulopathy may contribute to improving the outcomes of TBI patients, but no consensus has been reached thus far.

Disseminated intravascular coagulation (DIC) is acknowledged as the primary pathophysiological mechanism of trauma-induced coagulopathy (TIC), which is caused by multiple factors, such as anemia, hemodilution, hypothermia, acidosis, hemorrhagic shock, and serious trauma itself (9). Coagulopathy that occurs in patients with TBI is consistent with the definition of DIC proposed by the International Society on Thrombosis and Haemostasis: the activation of coagulation with the loss of localization and damage to the microvasculature (10, 11). Previous studies have clearly demonstrated consumption coagulopathy and disseminated microvascular thrombosis formation in the brain and other organs, which is the pathophysiology of DIC itself (12, 13).

A recent consensus statement from the International Society on Thrombosis and Haemostasis described that TIC is driven by two distinct and synergic insults: hypovolemic shock due to blood loss and extensive tissue disruption (14). However, it is unclear whether this concept can be applied to patients with TBI, since these patients do not suffer substantial blood loss, indicating that they are less likely to develop hemorrhagic shock.

Therefore, this study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing the coagulofibrinolytic changes in isolated TBI (iTBI) with those in non-TBI trauma, and to determine the associated factors, particularly shock-related factors such as blood pressure and serum lactate levels. To gain a deeper insight into the pathomechanisms of TBI-induced coagulopathy, coagulofibrinolytic changes were compared between iTBI patients with and without DIC, and the clinical significance of DIC diagnosis in patients with iTBI was evaluated.

This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing the coagulofibrinolytic changes in iTBI patient with those in non-TBI trauma patients, to determine the associated factors, and to identify the clinical significance of DIC diagnosis in patients with iTBI. In the present study, similar requirements for massive transfusion and in-hospital mortality were observed between iTBI and non-TBI patients with a similar severity of trauma. The changes in the levels of coagulofibrinolytic biomarkers were also identical between the groups. The lactate levels in the iTBI group were positively correlated with DIC scores but not with blood pressure. Moreover, the ISS was an independent predictor of DIC development in patients with iTBI. iTBI patients with DIC showed a significantly higher requirement for emergency surgery for TBI, and a higher incidence of massive transfusion than did those without DIC. DIC development was significantly associated with poor hospital survival, and DIC scores at 0 h were predictive of in-hospital mortality. In patients with iTBI with DIC, marked thrombin and plasmin generation was confirmed.

Although numerous mechanisms that are potentially associated with coagulopathy after TBI have been suggested, we previously demonstrated that the main pathomechanism of TIC, with or without TBI, is DIC (19–21). DIC is characterized by increased thrombin generation and subsequent consumption coagulopathy due to damage-associated molecular patterns derived from injured cells and tissues (22). That is, DIC is caused by trauma itself (23). However, another theory advocates that TBI alone does not cause early coagulopathy (24) and that coagulopathy occurs only in patients with shock-induced profound acidosis and high lactate concentrations (25–27). The results of the present study indicated no correlation between lactate levels and systolic blood pressure (Figure 3B) in iTBI patients, but the positive correlation between lactate levels and DIC score (Figure 3D) in those patients implies that the increase in lactate levels in TBI patients is caused by DIC-mediated secondary tissue hypoperfusion rather than by hypotension due to hemorrhagic shock. The results demonstrated that ISS was an independent predictor of pathological coagulofibrinolytic changes, namely DIC, in iTBI patients (Table 2), which also supports the concept that TIC is caused by trauma itself, with or without shock (23). The current results revealed similar coagulofibrinolytic changes, characterized by DIC with hyperfibrinolysis, between iTBI and non-TBI (Figures 1, 2), which was in line with the findings of a previous study (28).

iTBI patients with DIC had a higher requirement for massive transfusion and emergency surgery and had a higher in-hospital mortality than did those without DIC (Table 5). In addition, the DIC score in the iTBI group immediately after arrival to the hospital was predictive of in-hospital mortality (Figure 4B). Similar results have been reported not only in the setting of iTBI (2, 3), but also in other trauma settings (29). These results suggest the importance of DIC diagnosis in severely injured patients with or without TBI.

The present study revealed marked thrombin generation with lower levels of antithrombin in iTBI patients, particularly those with DIC (Figure 5). Previous studies confirmed such thrombin generation after iTBI, as evaluated by the high levels of the thrombin–antithrombin complex, prothrombin fragment 1 + 2, fibrinopeptide A, and fibrin monomers (28, 30, 31). High levels of soluble tissue factors have also been found (30, 32). Injury to the blood–brain barrier, caused by direct cerebral vascular disruption, potentially releases brain tissue factors into systemic circulation (5, 33). Tissue factors exposed to blood bind extensively to factor VIIa, followed by the initiation of the extrinsic coagulation pathway and subsequent consumption coagulopathy (23). Massive thrombin generation due to the activation of coagulation may lead to the consumption of anticoagulant factors, such as antithrombin and protein C, followed by further activation of coagulation. These changes contribute to hypercoagulability inside the vessels, leading to intravascular microthrombosis in the brain and other organs, and hypocoagulability outside the vessels due to consumptive coagulopathy, leading to the progression of intracranial hemorrhage (34).

This study demonstrated marked plasmin generation with lower levels of antiplasmin in iTBI and these changes were prominent in iTBI patients with DIC (Figure 6). Hyperfibrinolysis after trauma is caused by the release of tissue-type plasminogen activator (t–PA) from the endothelial Weibel-Palade bodies due to traumatic shock-induced tissue hypoperfusion (22). However, patients with iTBI with high lactate levels had no low blood pressure (Figure 3B), and similar results were reported previously (35). These results indicate that increases in lactate levels are not caused by low blood pressure-related hypoperfusion, but by DIC-induced tissue-hypoperfusion. That is, high lactate levels in iTBI with coagulopathy are a result rather than a cause of TIC. Instead of traumatic shock-induced tissue hypoperfusion, the direct release of t-PA from injured brain tissue has been acknowledged as another explanation of hyperfibrinolysis in patients with iTBI (11). A previous study demonstrated that endogenous t-PA increases the lysis of plasma clots and contributes to intracerebral hemorrhage after TBI (36).

Several limitations of our study need to be considered. First, although the present dataset was prospectively collected, causal relationships could not be defined because of the retrospective study design and missing values. Second, this study included a small number of patients. Third, we did not distinguish types of TBI (e.g., acute subdural hematoma, traumatic subarachnoid hemorrhage, and contusion), which may affect the pathology and severity of TBI-induced coagulopathy. Fourth, although more patients received tranexamic acid in the iTBI group than in the non-TBI group, the effects of tranexamic acid on the levels of coagulation and fibrinolysis-related markers were not determined. Fifth, bias may exist in trauma types in the non-TBI group, as suggested by the finding that many patients in this group had severe thoracic injury. Finally, this was a single nationwide study conducted in a developed country, which may have limited the global generalization of the results.

The present study demonstrated similar coagulofibrinolytic changes between iTBI and non-TBI patients, which are consistent with DIC. Marked generation of thrombin and plasmin was confirmed in iTBI patients, and these changes were more prominent in iTBI patients with DIC. The development of DIC in patients with iTBI was associated with a poor survival outcome, and DIC scores immediately after hospital arrival could predict in-hospital death. Therefore, the diagnosis of DIC in the early phase of trauma is important for predicting the outcome of severely injured patients, including those with iTBI.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved under the condition that written informed consent was obtained from the patient or next of kin by the JAAM and the Ethics Committee of each hospital (JAAM, 2014-01; Hokkaido University Graduate School of Medicine, Head institute of the FORECAST group, 014-0307). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

TW analyzed the study results, interpreted the data, and drafted the manuscript. AS checked the statistical methods and results. AS, SG, KY, SFujis, DS, SK, HO, TA, TM, JS, JK, NT, RT, KT, SS, YSh, TN, KO, YSa, AH, SFujim, YU, and YO planned the study, decided the methods, developed a web-based registration system, discussed the results, and critically revised the manuscript. All authors have read and approved the final version of the manuscript.

This study was supported by the Japanese Association for Acute Medicine (JAAM, 2014-01). This work was also supported in part by JSPS KAKENHI (Grant-in-Aid (C) 2020, 20K09260).

AS reported receiving personal fees from CSL Behring outside of the submitted work. SG reported receiving personal fees from Asahi Kasei Pharma America Inc. and Asahi Kasei Pharma Japan Inc. outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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