Abstract
-
Objective
To identify relationships between skull fracture (SF) and hyperfibrinolysis (HF) among patients with isolated traumatic brain injury (TBI).
-
Methods
This was a retrospective cohort study based on a nationwide neurotrauma database in Japan. Adult patients with isolated TBI (head Abbreviated Injury Scale [AIS] >2, any other AIS <3) and who were registered in the multicenter neurotrauma registry from 2015 to 2017 were included. To examine the relationship between SF and HF, we conducted multivariable logistic regression analyses to calculate the adjusted odds ratios (aORs) with their 95% confidence intervals (CIs) for HF. HF was defined as a D-dimer level ≥38 mg/L on arrival based on a previous study.
-
Results
A total of 335 patients were enrolled and the median age of the cohort was 64 years (interquartile range, 44–76 years). HF was observed in 161 patients (48.1%). The association of SF with HF yielded an aOR of 4.78 (95% CI, 2.71–8.42) compared to non-SF in multivariable logistic regression analysis. In addition, the associations of skull base fracture, skull vault fracture, and combination of skull base and vault fracture with HF yielded the corresponding aORs of 3.60 (95% CI, 1.20–10.81), 4.99 (95% CI, 2.63–9.44), and 4.84 (95% CI, 2.41–9.72), respectively, relative to non-SF.
-
Conclusion
This multicenter observational study demonstrated the association of SF with HF in patients with isolated TBI.
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Keywords: Traumatic brain injury; Skull fracture; Hyperfibrinolysis; Coagulopathy; D-dimer
Capsule Summary
What is already known
Hyperfibrinolysis (HF), indicated by elevated D-dimer levels, is a well-established complication in trauma-induced coagulopathy and is associated with traumatic brain injury (TBI). Skull fractures (SFs) are often observed in TBI and may indicate severe brain tissue injury. Prior studies have suggested a relationship between SF and coagulopathy, but no studies have explicitly reported an association between SF and HF.
What is new in the current study
This multicenter cohort study demonstrates a significant independent association between SF and HF in patients with isolated TBI. Specifically, the presence of skull vault fractures, skull base fractures, or a combination of both, was found to be strongly associated with elevated D-dimer levels on admission. These findings suggest that SF may serve as an early predictor of HF, providing valuable information for trauma management strategies.
INTRODUCTION
Trauma patients often suffer from coagulopathy, which can result in mortality resulting from the trauma [
1–
4]. Hyperfibrinolysis (HF), characterized by elevated D-dimer levels, is a well-recognized manifestation of trauma-induced coagulopathy [
3,
5–
9]. In the case of traumatic brain injury (TBI), D-dimer levels not only reflect HF but also serve as an important prognostic indicator [
10,
11]. HF is a critical factor in TBI as it is associated with the progression of intracranial hemorrhage and poorer prognosis [
12]. However, the extent to which different types of morphology in TBI are correlated with HF remains unclear.
Skull fractures (SFs) are commonly observed in TBI and may be an objective indicator of the severity of head impact and primary brain injury, as they occur when force is sufficient to cause skull fracture [
13,
14]. Brain tissue injury-induced release of tissue factor has been implicated in promoting HF [
1,
5,
15–
17]. TBI with SF may result in more severe brain tissue damage than TBI alone. Previous research has shown an independent relationship between SF and prognosis [
18], and another report indicates that D-dimer levels are associated with SF in pediatric TBI [
19]. In a previous study, we found that depressed SF was associated with severe hypofibrinogenemia, which means SF may induce HF and cause fibrinogen depletion in TBI settings [
20]. However, no studies have explicitly reported an association between SF and HF.
We hypothesize that the presence of SF is correlated with HF, and early detection and intervention of HF in TBI are crucial. Therefore, it is necessary to investigate this relationship to improve the quality of trauma care. In this study we investigated the relationship between SF and elevated D-dimer levels in patients with TBI on admission and determine the relationships between injury morphology and HF.
METHODS
Ethics statement
Permission to analyze the Japan Neurotrauma Data Bank (JNTDB) database was obtained from the Japan Society of Neurotraumatology before starting this study. The study protocol was approved by the Institutional Ethics Review Board of Yamaguchi University (No. H26-36), which was the core hospital of this registry. The requirement for patient consent was waived because only anonymized data were used. This study was conducted in compliance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines [
21].
The data were obtained from the JNTDB dataset, which contains information collected from 33 hospitals across Japan from April 2015 to March 2017. The JNTDB is a nationwide, multicenter, prospective, observational trauma registry. The data were compiled by administrators based on in-hospital electronic medical charts. Detailed descriptions of the JNTDB have been published previously [
22,
23]. The following patients were included in the JNTDB: (1) all age groups; (2) patients with a Glasgow Coma Scale (GCS) score of 8 or less at the time of admission or who deteriorated to a GCS score of 8 or less during the clinical course; and (3) patients who underwent neurosurgical intervention as treatment for trauma (including trepanation but excluding surgery for chronic subdural hematoma). Details of the JNTDB are provided in
Suppl. 1.
Adult trauma patients (≥16 years) registered in the JNTDB dataset with 1,345 patients were considered eligible for inclusion. We included patients with isolated TBI, defined as head Abbreviated Injury Scale (AIS) >2 and any other AIS <3. We excluded patients younger than 16 years and those who developed cardiac arrest on arrival at the hospital. We also excluded patients who had received antithrombotic therapy before the injury, those who were transported more than 3 hours after injury, and those who were transported via other hospitals. Moreover, we excluded patients with missing information on the D-dimer level.
Data collection, variables, and potential bias
We collected and described the following clinical information from the JNTDB: sex, age, time of transport, vital signs (systolic blood pressure, heart rate, body temperature) and GCS score at hospital arrival, AIS of the head, Injury Severity Score (ISS), and in-hospital mortality. We also collected imaging studies for the presence of SF, which was subdivided into skull base fracture (base-SF), skull vault fracture (vault-SF), and merging both fractures (both-SF), type of intracranial injury and thickness or diameter of hematoma (subdural hematoma, epidural hematoma, cerebral contusion, subarachnoid hemorrhage [SAH], intraventricular hemorrhage [IVH]), Trauma Coma Data Bank (TCDB) classification (diffuse injury I–II, diffuse injury III–IV, evacuated/nonevacuated mass), and ISS. The AIS, ISS, and TCDB classification details are described in
Suppl. 2. The TCDB classification is divided into diffuse injury I to IV, evacuated mass, and nonevacuated mass [
24,
25]. These were further categorized as diffuse injury I and II, diffuse injury III and IV, evacuated mass, and nonevacuated mass for analysis. In addition, we collected coagulation parameters, including D-dimer, on arrival.
We defined HF as a D-dimer level ≥38 mg/L on arrival, based on a previous multicenter study in Japan reported by Hayakawa et al. [
7]. Therefore, we defined the presence or absence of HF using two groups: HF(+) (D-dimer ≥38 mg/L) and HF(–) (D-dimer <38mg/L).
We described the patient characteristics and distribution of patients with and without SF (SF and non-SF groups). We defined the two groups as the explanatory variable and the presence of HF as the objective variable. We performed logistic regression analyses to generate crude odds ratios (ORs) for HF(+) with SF, along with their 95% confidence intervals (CIs), compared to non-SF. For potential confounders,we included sex, age, GCS, type of intracranial injury, and TCDB classification as covariates and performed multivariable logistic regression analyses to calculate the adjusted ORs (aORs) of the groups with and without SF with their 95% CIs. Further, we also performed subgroup analysis to identify any associations with HF. Statistical results were calculated as point estimates with their 95% CIs. Statistical significance was defined as the absence of a 95% CI overlap with the null effect value (OR=1). All statistical analyses were performed using JMP Pro ver. 17 (SAS Institute Inc).
Subgroup analysis
We divided the cohort into a nonelderly group (<65 years) and an elderly group (≥65 years) and evaluated D-dimer levels and HF in each subgroup. This was done to examine how SF might be affected by differences in D-dimer levels according to age as reported in a previous study [
26].
We performed five additional sensitivity analyses to confirm the robustness of our results. Because the definition of HF by D-dimer level is unclear, we performed a sensitivity analysis using different cutoff values. Logistic regression analysis was performed using D-dimer >50 mg/L, which we used as the cutoff for severe HF in our previous study [
20]. Considering the complex pathophysiology of coagulopathy in TBI, we conducted an additional analysis in which HF was defined as fibrinogen <150 mg/dL, rather than using D-dimer as the sole criterion. Fibrinogen decreases in TBI due to depletion caused by HF [
20,
27,
28]. Intracranial hematoma was assessed as a binary value of presence or absence in the main analysis, but a continuous variable of hematoma size (thickness and diameter) was used as a confounding variable. To further eliminate the influence of torso trauma, a logistic regression analysis was performed on the cohort that further excluded those with AIS of 2 trauma to other parts of the body other than the head. Logistic analysis was performed by adding ISS, which has been shown to be associated with coagulopathy in TBI, to the variables [
29].
RESULTS
Patient characteristics
The study flowchart is shown in
Fig. 1. Of 1,345 patients enrolled in the JNTDB, 335 patients were included in the analysis: 202 (60.3%) in the SF group and 133 (39.7%) in the non-SF group. Patient characteristics and clinical data are described in
Table 1. More than two-thirds of the patients were male (68.7%), and the median age was 64 years (interquartile range [IQR], 44–76 years). Median GCS score of the patients was 7 (IQR, 4–10). The median D-dimer level was 34.6 mg/L (IQR, 11.2–87.7 mg/L).
The characteristics of patients according to HF(+) or HF(–) are described in
Suppl. 3. The boxplot of D-dimer levels by each SF is described in
Fig. 2. The overall incidence of HF(+) was 48.1% (n=161). The association of SF with HF(+) yielded aORs of 4.78 (95% CI, 2.71–8.42), relative to non-SF in multivariable logistic regression analysis (
Fig. 3). Multivariable logistic regression analyses of the association of base-, vault-, and both-SF with HF(+) yielded the corresponding aORs of 3.60 (95% CI, 1.20–10.81), 4.99 (95% CI, 2.63–9.44), and 4.84 (95% CI, 2.41–9.72), respectively, relative to non-SF (
Fig. 3). Crude ORs and aORs of other covariates are described in
Suppl. 4. The distribution of D-dimer values and HF evaluated in the nonelderly and elderly group subgroups is shown in
Suppl. 5, and the logistic regression analysis results are shown in
Table 2.
The results of the sensitivity analysis are shown in
Table 3. For sensitivity analysis 4, 73 cases with AIS of 2 at any other injury site were excluded, and 262 cases were deemed eligible for analysis. Sensitivity analysis results were similar to those of the main analysis.
DISCUSSION
In this multicenter study including 33 hospitals, patients with SF showed a clear independent association with high D-dimer levels, a finding suggestive of HF. Furthermore, HF was more frequently observed across various SF morphologies, including vault fractures, and a significant association with HF was consistently demonstrated across all SF types compared to the non-SF group.
Our study has several strengths. First, the results of our study were novel: there are few reports that SF is associated with HF, and even fewer reports that it depends on the extent of SF. In a previous study, we reported that SF was associated with in-hospital mortality. It is independently associated with intracranial injury, but we could not attribute this to HF [
18]. Another multicenter study reported that the presence of vault-SF was associated with the occurrence of talk and die, and an association is suggested if talk and die is interpreted as being due to increased intracranial hematoma caused by HF. However, no coagulation parameters were reported in the previous study [
30]. As described above, although previous reports suggested an association with HF, none explicitly demonstrated it, making the present study results novel.
Second, the results of this study, which are robust to multiple sensitivity analyses using a nationwide Japanese multicenter database, are likely to have high internal validity. The results remained robust after adjusting for possible confounding associated with coagulopathy, such as the degrees of intracranial injury and multiple trauma [
2,
31]. In a previous single-center study we reported that SF, especially depressed SF, were associated with severe HF, but our previous study was small [
20]. Therefore, we believe that the current results have high internal validity beyond the limitations of previous studies.
Third, our findings have important clinical implications. When SF is identified on computed tomography (CT), the possibility of HF should be considered, as should additional coagulation testing or periodic coagulation monitoring. In Japan, coagulation testing is commonly performed in hospitals for patients with TBI, but this practice is not universal. Given that coagulation parameters in TBI can fluctuate over time, follow-up coagulation testing after the initial assessment should be considered in certain cases. Identifying SF, especially vault-SF, on CT might serve as a prompt to assess coagulation status, potentially aiding in the early detection and management of HF. Furthermore, the timing of surgery may require careful consideration in SF cases, particularly in relation to HF. If emergency surgery is required due to signs of impending brain herniation, immediate intervention is unavoidable. However, in cases where there is sufficient time before surgery, stabilizing coagulation status, such as through hemostatic management or transfusion therapy, could be an option. Given the potential for HF in SF patients, preoperative coagulation assessment may provide useful information for surgical planning and perioperative management.
By integrating these considerations into clinical practice, our findings offer insights that could help refine management strategies for TBI with SF.
In this study, higher D-dimer values were found in the SF group. Furthermore, prothrombin time/international normalized ratio and activated partial thromboplastin time were similar between the two groups, but fibrinogen was lower in the SF group compared to non-SF. Since previous studies have reported an inverse relationship between D-dimer and fibrinogen in TBI, the present study also showed a characteristic trend in trauma-induced coagulopathy [
32,
33]. There was no difference in surgical treatment in HF(+) compared to HF(–), but there were differences in neurological outcomes and in-hospital mortality, suggesting poor prognosis. This study included a larger number of older adults than previous studies conducted in the United States and Europe [
34,
35]. In Japan, the increase in head trauma among the elderly has become a social problem, and our results reflect the aging of the Japanese society [
36]. Furthermore, subgroup analysis by age showed that D-dimer levels were higher in the elderly group than in the nonelderly group, and the frequency of HF(+) was higher, confirming the differences in D-dimer levels by age reported in previous studies, as well as in the present study [
26]. Furthermore, the OR of HF(+) was higher in the elderly group than in the nonelderly group.
In general, tissue injury activates the coagulation system in the early stages of trauma by releasing tissue factors and damage-associated molecular patterns (DAMPs); tissue factor complexes with factor VIIa to activate the coagulation system, and DAMPs stimulate inflammatory pathways by releasing multiple mediators. Thrombin production and the formation of fibrin from fibrinogen result in the uncontrolled activation of the coagulation system and the accumulation of large amounts of fibrin, resulting in consumptive coagulopathy [
37]. Furthermore, in head trauma, large amounts of tissue plasminogen activator (tPA) are released from the injured endothelial cells, causing so-called primary fibrinolysis that leads to plasminogen activation [
38]; HF has also been reported to be associated with increased tPA levels, and is exacerbated by the loss of α2 plasmin inhibitor [
39]. After plasminogen activation, plasmin causes cleavage of crosslinked fibrin polymers, leading to formation of fibrin degradation products (secondary fibrinolysis), which in turn causes elevated D-dimer. In this study, D-dimer was used as a surrogate marker for HF. Elevated D-dimer levels, a degradation product of stabilized fibrin that reflects secondary fibrinolysis, may be useful and convenient for representing HF because they result from the degradation of fibrin by plasmin, regardless of a marked increase in free tPA levels or α2-antiplasmin consumption. It should be noted, however, that HF in trauma is a complex mechanism that cannot be expressed by D-dimer alone, as discussed above.
In the present study, we postulated that two mechanisms explain why SF is associated with a high D-dimer, a surrogate finding for HF. First, direct injury from an impact that results in an SF causes severe tissue injury to the brain. The release of tissue factors due to brain tissue injury has been associated with trauma-induced coagulopathy, including HF, and an association between brain tissue injury and high D-dimer levels has also been reported [
27]. In fact, as shown in
Suppl. 3, findings suggestive of primary brain injuries, such as cerebral contusion, SAH, and IVH, were associated with HF. These findings suggest an association between brain tissue injury and HF. Here, SF reflects the magnitude of the impact to the head and can be considered an objective indicator of impact [
18,
40]. This impact may result in a degree of brain tissue damage not depicted on CT and thus may have shown an independent association even after adjusting for confounding of intracranial injury. Furthermore, because vault-SF was strongly associated with HF in the subgroup analysis of this study, it may be concluded that the brain area immediately below the tissue injury is larger than the base-SF [
41]. Based on these findings, we hypothesized that microscopic tissue injury from the impact causing SF might reflect HF.
Second, we considered the possibility that SF is associated with high D-dimer levels. Previous studies have reported that high D-dimer levels are associated with extremity, rib, and pelvic fractures, and they have shown a trend toward higher levels with larger skeletal injuries [
42,
43]. Such trends also suggest that they are an indicator of trauma severity [
43]. In pediatric head trauma, D-dimer has received attention as a potential screening tool to avoid CT, based on reports that low D-dimer levels can negate SF [
44,
45]. Although the detailed mechanism has not been elucidated, it is conceivable that these high D-dimer levels may be caused by endothelial damage to the interplate vessels and periosteal damage due to skull injury, which may be involved in HF. Previous basic studies using a mouse model of TBI have reported that SF induces inflammatory cytokines and that fractures are more likely to induce neuroinflammation than soft tissue injuries [
46]. Based on the above, we hypothesized that SF may induce HF, resulting in high D-dimer levels.
We believe these two mechanisms are intertwined based on the available evidence. In particular, the fact that the present study showed a robust association even in analyses adjusted for detailed confounding by the morphology of intracranial injury supports the possibility that the latter, damage to the skull, pericranium, and other structures, may be more related to HF. In summary, our study's findings and proposed mechanisms are interesting and are supported by previous studies, but further research may be necessary to fully understand the pathogenesis of this relationship.
Our study has several limitations. First, we were unable to evaluate HF using detailed coagulation/fibrinolysis parameters. In this study, HF was assessed only by D-dimer and fibrinogen, but in reality, a complex mechanism involving not only secondary fibrinolysis but also tissue-type plasminogen activator release may be involved. In addition, parameters reported in previous studies, such as information on α2-plasmin inhibitor, plasmin-α2-plasmin inhibitor complex, and other parameters obtained by thromboelastometry, were not available for this study [
29,
47–
49]. Although we believe that D-dimer and fibrinogen are important parameters, the results of this study may have been more interesting if such coagulation/fibrinolysis data had been added. Second, while we were able to quantify certain factors, such as hematoma volume, as continuous variables in the sensitivity analysis, SAH and IVH could only be assessed qualitatively due to lack of data. Additionally, detailed intracranial injury assessment using magnetic resonance imaging was not included, making it unclear whether microbleeds or diffuse axonal injury were present. These factors are potential confounders. However, the results of this study remain robust and are unlikely to change. Furthermore, although we analyzed SF by classifying it into base and vault fractures, information on specific fracture patterns, such as depressed or comminuted fractures, was not available. More detailed information on injury morphology could have allowed for further discussion and analysis. Although we attempted to quantify complicated injury morphology as much as possible and to adjust for confounding, including sensitivity analysis, SAH and IVH were not quantified. A detailed intracranial injury assessment with magnetic resonance imaging was not included. Thus, findings of microbleeds or diffuse axonal injury were not clear. These findings would be potential confounders. However, the results of this study are robust and may not change. Third, since the registry did not specify whether D-dimer was collected, the initial practice policy of each hospital likely influenced the data. Excluding patients with missing data may introduce selection bias, such as a skew toward certain institutions or a tendency to include more severe cases.
In this study, we observed an independent association between SF and high D-dimer levels, suggesting an association with HF. We also found that all types of SF were independently associated with an increased risk of HF.
NOTES
-
Author contributions
Conceptualization: GF; Data curation: NS; Formal analysis: GF; Investigation: NS; Writing–original draft: GF; Writing–review & editing: NS. All authors read and approved the final manuscript.
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Conflicts of interest
The authors have no conflicts of interest to declare.
-
Funding
The authors received no financial support for this study.
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Data availability
Data analyzed in this study are available from the Japan Neurotrauma Data Bank. The data are not publicly accessible as they were used under license for this study. However, they are available from the corresponding author upon reasonable request, with permission from the Japan Society of Neurotraumatology.
Supplementary materials
Suppl. 2.
Explanations of Abbreviated Injury Scale, Injury Severity Score, and the Trauma Coma Data Bank classifications.
ceem-24-344-Suppl-2.pdf
Suppl. 4.
Crude ORs and adjusted ORs with 95% CIs for each confounding factor (sex, age, GCS, type of intracranial injury, TCDB classification) for HF.
ceem-24-344-Suppl-4.pdf
Suppl. 5.
D-dimer values and HF with and without skull fracture in each subgroup divided by age.
ceem-24-344-Suppl-5.pdf
Fig. 1.Flowchart of the patient selection. JNTDB, Japan Neurotrauma Data Bank; AIS, Abbreviated Injury Scale; TBI, traumatic brain injury; SF, skull fracture. a)The sum exceeds the total because some individuals met more than one criterion.
Fig. 2.Boxplot of D-dimer levels in each skull fracture (SF) group. (A) Non-SF and SF groups. (B) Non-SF and subgroups of SF (skull base fracture [base-SF], skull vault fracture [vault-SF], and merging both fractures [both-SF]).
Fig. 3.Forest plot of adjusted odds ratios (aORs) for hyperfibrinolysis (HF) in each skull fracture (SF) group (adjusted for sex, age, Glasgow Coma Scale, type of intracranial injury, the Trauma Coma Data Bank classification). SF in the main analysis includes all types of SF (skull base fracture [base-SF], skull vault fracture [vault-SF], and merging both fractures [both-SF]).
Table 1.Characteristics of the study participants
Table 1.
|
Characteristic |
Total (n=335) |
SF group (n=202) |
Non-SF group (n=133) |
|
Sex |
|
|
|
|
Male |
230 (68.7) |
143 (70.8) |
87 (65.4) |
|
Female |
105 (31.3) |
59 (29.2) |
46 (34.6) |
|
Age (yr) |
64 (44–76) |
63 (43–73) |
66 (43–78) |
|
Transport time (min) |
40 (30–52) |
40 (30–52) |
43 (30–56) |
|
Heart rate (bpm) |
86 (74–101) |
87 (74–101) |
86 (74–99) |
|
Systolic blood pressure (mmHg) |
151 (130–178) |
149 (127–177) |
157 (136–180) |
|
Body temperature (°C) |
36.2 (35.8–36.7) |
36.1 (35.8–36.5) |
36.4 (36–37.0) |
|
GCS score |
7 (4–10) |
7 (4–11) |
6 (4–8) |
|
Type of hematoma |
|
|
|
|
Subdural hematoma |
172 (51.3) |
98 (48.5) |
74 (55.6) |
|
Epidural hematoma |
54 (16.1) |
46 (22.8) |
8 (6.0) |
|
Contusion |
54 (16.1) |
40 (19.8) |
14 (10.5) |
|
Type of intracranial injury |
|
|
|
|
Subarachnoid hemorrhage |
262 (78.2) |
178 (88.1) |
84 (63.2) |
|
Intraventricular hemorrhage |
52 (15.5) |
34 (16.8) |
18 (13.5) |
|
Type of SF |
|
|
|
|
Base fracture |
18 (5.4) |
18 (8.9) |
0 (0) |
|
Vault fracture |
105 (31.3) |
105 (52.0) |
0 (0) |
|
Base and vault fracture |
79 (23.6) |
79 (39.1) |
0 (0) |
|
TCDB classification |
|
|
|
|
Diffuse injury Ⅰ–Ⅱ |
78 (23.2) |
35 (17.3) |
43 (32.3) |
|
Diffuse injury Ⅲ–Ⅳ |
31 (9.3) |
22 (10.9) |
9 (6.8) |
|
Evacuated and nonevacuated mass |
226 (67.5) |
145 (71.8) |
81 (60.9) |
|
Injury Severity Score |
25 (16–25) |
25 (16–25) |
25 (16–25) |
|
Coagulation parameter |
|
|
|
|
PT-INR |
1.05 (0.99–1.14) |
1.06 (0.99–1.15) |
1.05 (0.98–1.13) |
|
APTT (sec) |
28.5 (24.9–33.1) |
28.6 (24.7–33.8) |
28.4 (25.4–32.3) |
|
Fibrinogen (mg/dL) |
233 (178–296) |
214 (168–274) |
258 (195–320) |
|
D-dimer (mg/L) |
34.6 (11.2–87.7) |
48.8 (22.9–225.2) |
17.9 (5.6–45.6) |
|
Surgical procedure |
241 (71.9) |
155 (76.7) |
86 (64.7) |
|
Outcome |
|
|
|
|
In-hospital mortality |
106 (31.6) |
75 (37.1) |
31 (23.3) |
|
GOS poora) at discharge |
219 (65.4) |
129 (63.9) |
90 (67.7) |
|
HF(+) |
161 (48.1) |
122 (60.4) |
39 (29.3) |
Table 2.Crude ORs and aORs for hyperfibrinolysis of multivariable logistic regression analysis in each subgroup divided by age
Table 2.
|
Variable |
Crude OR (95% CI) |
aORa) (95% CI) |
|
Nonelderly subgroup (<65 yr) |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
3.39 (1.62–7.08) |
4.08 (1.71–9.74) |
|
Elderly subgroup (≥65 yr) |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
5.84 (2.96–11.5) |
6.05 (2.67–13.7) |
Table 3.Crude ORs and aORs of multivariable logistic regression analysis in the sensitivity analysis
Table 3.
|
Variable |
Crude OR (95% CI) |
aORa) (95% CI) |
|
Sensitivity analysis 1 |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
3.51 (2.14–5.77) |
4.29 (2.39–7.70) |
|
Sensitivity analysis 2 |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
1.83 (0.94–3.55) |
2.37 (1.11–5.10) |
|
Sensitivity analysis 3 |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
3.68 (2.30–5.87) |
5.28 (2.99–9.33) |
|
Sensitivity analysis 4 |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
4.00 (2.36–6.78) |
5.12 (2.69–9.77) |
|
Sensitivity analysis 5 |
|
|
|
Non-SF |
Reference |
Reference |
|
SF |
3.68 (2.30–5.87) |
5.17 (2.87–9.29) |
REFERENCES
- 1. Maegele M. Coagulopathy after traumatic brain injury: incidence, pathogenesis, and treatment options. Transfusion 2013;53 Suppl 1:28S-37S.
- 2. Samuels JM, Moore EE, Silliman CC, et al. Severe traumatic brain injury is associated with a unique coagulopathy phenotype. J Trauma Acute Care Surg 2019;86:686-93.
- 3. Gando S, Wada H, Thachil J; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 2013;11:826-35.
- 4. Kaufman HH, Hui KS, Mattson JC, et al. Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury. Neurosurgery 1984;15:34-42.
- 5. Kushimoto S, Kudo D, Kawazoe Y. Acute traumatic coagulopathy and trauma-induced coagulopathy: an overview. J Intensive Care 2017;5:6.
- 6. Zhang J, Jiang R, Liu L, Watkins T, Zhang F, Dong JF. Traumatic brain injury-associated coagulopathy. J Neurotrauma 2012;29:2597-605.
- 7. Hayakawa M, Maekawa K, Kushimoto S, et al. High D-dimer levels predict a poor outcome in patients with severe trauma, even with high fibrinogen levels on arrival: a multicenter retrospective study. Shock 2016;45:308-14.
- 8. Kutcher ME, Cripps MW, McCreery RC, et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma Acute Care Surg 2012;73:87-93.
- 9. Tian HL, Chen H, Wu BS, et al. D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases. Neurosurg Rev 2010;33:359-66.
- 10. Fujiwara G, Okada Y, Sakakibara T, Yamaki T, Hashimoto N. The association between D-dimer levels and long-term neurological outcomes of patients with traumatic brain injury: an analysis of a nationwide observational neurotrauma database in Japan. Neurocrit Care 2022;36:483-91.
- 11. Fujiwara G, Murakami M, Maruyama D, Murakami N. Optic nerve sheath diameter as a quantitative parameter associated with the outcome in patients with traumatic brain injury undergoing hematoma removal. Acta Neurochir (Wien) 2023;165:281-7.
- 12. Zhang J, He M, Song Y, Xu J. Prognostic role of D-dimer level upon admission in patients with traumatic brain injury. Medicine (Baltimore) 2018;97:e11774.
- 13. Haut RC, Wei F. Biomechanical studies on patterns of cranial bone fracture using the immature porcine model. J Biomech Eng 2017;139.
- 14. Sahoo D, Deck C, Yoganandan N, Willinger R. Development of skull fracture criterion based on real-world head trauma simulations using finite element head model. J Mech Behav Biomed Mater 2016;57:24-41.
- 15. Yasui H, Donahue DL, Walsh M, Castellino FJ, Ploplis VA. Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury. Am J Physiol Lung Cell Mol Physiol 2016;311:L74-86.
- 16. Tian Y, Salsbery B, Wang M, et al. Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury. Blood 2015;125:2151-9.
- 17. Nekludov M, Mobarrez F, Gryth D, Bellander BM, Wallen H. Formation of microparticles in the injured brain of patients with severe isolated traumatic brain injury. J Neurotrauma 2014;31:1927-33.
- 18. Fujiwara G, Okada Y, Ishii W, et al. Association of skull fracture with in-hospital mortality in severe traumatic brain injury patients. Am J Emerg Med 2021;46:78-83.
- 19. Berger RP, Fromkin J, Rubin P, Snyder J, Richichi R, Kochanek P. Serum D-dimer concentrations are increased after pediatric traumatic brain injury. J Pediatr 2015;166:383-8.
- 20. Fujiwara G, Murakami M, Ishii W, et al. Effectiveness of administration of fibrinogen concentrate as prevention of hypofibrinogenemia in patients with traumatic brain injury with a higher risk for severe hyperfibrinolysis: single center before-and-after study. Neurocrit Care 2023;38:640-9.
- 21. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007;147:573-7.
- 22. Suehiro E, Fujiyama Y, Koizumi H, Suzuki M. Directions for use of intracranial pressure monitoring in the treatment of severe traumatic brain injury using data from the Japan Neurotrauma Data Bank. J Neurotrauma 2017;34:2230-4.
- 23. Tokutomi T, Miyagi T, Ogawa T, et al. Age-associated increases in poor outcomes after traumatic brain injury: a report from the Japan Neurotrauma Data Bank. J Neurotrauma 2008;25:1407-14.
- 24. Maas AI, Hukkelhoven CW, Marshall LF, Steyerberg EW. Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors. Neurosurgery 2005;57:1173-82.
- 25. Marshall LF, Marshall SB, Klauber MR, et al. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma 1992;9 Suppl 1:S287-92.
- 26. Nakae R, Fujiki Y, Takayama Y, et al. Age-related differences in the time course of coagulation and fibrinolytic parameters in patients with traumatic brain injury. Int J Mol Sci 2020;21:5613.
- 27. Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021;7:30.
- 28. Dong JF, Zhang F, Zhang J. Detecting traumatic brain injury-induced coagulopathy: what we are testing and what we are not. J Trauma Acute Care Surg 2023;94(1S Suppl 1):S50-5.
- 29. Wada T, Shiraishi A, Gando S, et al. Pathophysiology of coagulopathy induced by traumatic brain injury is identical to that of disseminated intravascular coagulation with hyperfibrinolysis. Front Med (Lausanne) 2021;8:767637.
- 30. Shibahashi K, Sugiyama K, Okura Y, Hoda H, Hamabe Y. Multicenter retrospective cohort study of "talk and die" after traumatic brain injury. World Neurosurg 2017;107:82-6.
- 31. Franschman G, Greuters S, Jansen WH, et al. Haemostatic and cranial computed tomography characteristics in patients with acute and delayed coagulopathy after isolated traumatic brain injury. Brain Inj 2012;26:1464-71.
- 32. Xu DX, Du WT, Li X, Wu ZX, Yu GF. D-dimer/fibrinogen ratio for the prediction of progressive hemorrhagic injury after traumatic brain injury. Clin Chim Acta 2020;507:143-8.
- 33. Nakae R, Yokobori S, Takayama Y, et al. A retrospective study of the effect of fibrinogen levels during fresh frozen plasma transfusion in patients with traumatic brain injury. Acta Neurochir (Wien) 2019;161:1943-53.
- 34. Steyerberg EW, Wiegers E, Sewalt C, et al. Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurol 2019;18:923-34.
- 35. McCrea MA, Giacino JT, Barber J, et al. Functional outcomes over the first year after moderate to severe traumatic brain injury in the prospective, longitudinal TRACK-TBI study. JAMA Neurol 2021;78:982-92.
- 36. Yokobori S, Saito K, Sasaki K, et al. Treatment of geriatric traumatic brain injury: a nationwide cohort study. J Nippon Med Sch 2021;88:194-203.
- 37. Gando S. Tissue factor in trauma and organ dysfunction. Semin Thromb Hemost 2006;32:48-53.
- 38. Chapman MP, Moore EE, Moore HB, et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 2016;80:16-25.
- 39. Barrett CD, Moore HB, Vigneshwar N, et al. Plasmin thrombelastography rapidly identifies trauma patients at risk for massive transfusion, mortality, and hyperfibrinolysis: a diagnostic tool to resolve an international debate on tranexamic acid? J Trauma Acute Care Surg 2020;89:991-8.
- 40. Fujiwara G, Okada Y, Shiomi N, Sakakibara T, Yamaki T, Hashimoto N. Derivation of coagulation phenotypes and the association with prognosis in traumatic brain injury: a cluster analysis of nationwide multicenter study. Neurocrit Care 2024;40:292-302.
- 41. Boldsen JL, Milner GR, Weise S. Cranial vault trauma and selective mortality in medieval to early modern Denmark. Proc Natl Acad Sci U S A 2015;112:1721-6.
- 42. Liu C, Song Y, Zhao J, et al. Elevated D-dimer and fibrinogen levels in serum of preoperative bone fracture patients. Springerplus 2016;5:161.
- 43. Johna S, Cemaj S, O'Callaghan T, Catalano R. Effect of tissue injury on D-Dimer levels: a prospective study in trauma patients. Med Sci Monit 2002;8:CR5-8.
- 44. Nozawa M, Mishina H, Tsuji S, Takayama JI. Low plasma D-dimer predicts absence of intracranial injury and skull fracture. Pediatr Int 2020;62:22-8.
- 45. Langness S, Ward E, Halbach J, et al. Plasma D-dimer safely reduces unnecessary CT scans obtained in the evaluation of pediatric head trauma. J Pediatr Surg 2018;53:752-7.
- 46. Zvejniece L, Stelfa G, Vavers E, et al. Skull fractures induce neuroinflammation and worsen outcomes after closed head injury in mice. J Neurotrauma 2020;37:295-304.
- 47. Bugaev N, Como JJ, Golani G, et al. Thromboelastography and rotational thromboelastometry in bleeding patients with coagulopathy: practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg 2020;89:999-1017.
- 48. Baksaas-Aasen K, Gall LS, Stensballe J, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med 2021;47:49-59.
- 49. Takahashi H, Urano T, Takada Y, Nagai N, Takada A. Fibrinolytic parameters as an admission prognostic marker of head injury in patients who talk and deteriorate. J Neurosurg 1997;86:768-72.
