Abstract
Coagulation function differs by gender, with women being characterized as more hypercoagulable. Even in the early stages of trauma, women have been shown to be hypercoagulable. Several studies have also examined the relationship between gender and the prognosis of trauma patients, but no certain conclusions have been reached. Patients with isolated traumatic brain injury (iTBI) are known to have coagulopathy, but no previous studies have examined the gender differences in detail. This is a retrospective analysis of a prospective registry conducted at 2 centers. The study included adult patients with iTBI enrolled from April 2018 to March 2021. Coagulofibrinolytic markers were measured in each patient at 1 hour, 24 hours, 3 days, and 7 days after injury, and neurological outcomes were assessed with the Glasgow Outcome Scale Extended at 6 months. Subgroup analysis was also performed by categorizing patients into groups according to neurological prognosis or age at 50 years. Males (n = 31) and females (n = 21) were included in the analysis. In males, there was a significant difference in the levels of activated partial thromboplastin time (P = .007), fibrin/fibrinogen degradation products (P = .025), D-dimer (P = .034), α2-plasmin inhibitor (P = .030), plasmin-α2-plasmin inhibitor complex (P = .004) at 1 hour after injury between favorable and unfavorable long-term neurological outcome groups, while in females there was no significant difference in these markers between 2 groups. In the age group under 50 years, there were significant gender differences in fibrinogen (day 3: P = .018), fibrin/fibrinogen degradation products (1 hour: P = .037, day 3: P = .009, day 7: P = .037), D-dimer (day 3: P = .005, day 7: P = .010), plasminogen (day 3: P = .032, day 7: P = .032), and plasmin-α2-plasmin inhibitor complex (day 3: P = .001, day 7: P = .001), and these differences were not evident in the age group over 50 years. There were differences in coagulofibrinolytic markers depending on gender in patients with iTBI. In male patients, aggravation of coagulofibrinolytic markers immediately after traumatic brain injury may be associated with poor neurologic outcome 6 months after injury.
Keywords: gender difference, isolated traumatic brain injury, long-term outcome, trauma-induced coagulopathy
1. Introduction
Women and men have different coagulation functions; women exhibit higher coagulability.[1–3] The effect affects the incidence and prognosis of the disease, and its difference with respect to gender has been demonstrated in arterial thrombotic events such as stroke[4,5] and ischemic heart disease.[6–9] However, gender differences have not been considered when deciding treatment strategies.
Coagulopathy caused by trauma is widely recognized and of great interest to clinicians, with many reviews published in recent years.[10–12] Researchers have investigated the similarity between delivery and trauma in terms of massive hemorrhage and differences in coagulation function concerning gender in patients with trauma; they have shown that women show hypercoagulability in the early stages of trauma.[13–15] Several studies have been conducted on the relationship between gender and prognosis in patients with trauma.[14–19] In patients with trauma, reports have indicated mixed results; some indicate that women have a better prognosis[15,16]; some have the same prognosis,[14,17,18] and some have poorer prognoses.[19] No certain conclusion has been obtained.
Coagulopathy is also present in isolated traumatic brain injury (iTBI) patients without massive bleeding.[20,21] Gender differences in patients with traumatic brain injury (TBI) were reviewed by Gupte R et al, with a detailed description of the relationship between prognosis and gender, with the conclusion that women with TBI tend to exhibit a worse prognosis than men with TBI.[22] However, this review does not mention coagulopathy as a prognostic factor in head injury; no previous study has examined coagulofibrinolytic dynamics in patients with TBI in detail.
This study aimed to examine in detail differences in coagulofibrinolytic responses with respect to gender in patients with TBI.
2. Methods
2.1. Setting
Data for this study were prospectively collected from April 2018 through March 2021 for patients with iTBI visiting 2 medical facilities, Nippon Medical School and Kawaguchi Municipal Medical Center, which are emergency departments that treat patients with the most severe trauma in the medical area. The area and population of the medical area for Nippon Medical School are 64 km2 and 850,000 people, respectively, and that for Kawaguchi Municipal Medical Center are 85 km2 and 800,000 people, respectively.
2.2. Outcomes and definitions
The severity of trauma was assessed by Abbreviated Injury Scale (AIS) and Injury Severity Score. Intensivists and neurointensivists independently evaluated intracranial and extracranial AIS and CT scans at the study institution. The definition of iTBI was AIS ≥ 3 in the head and AIS ≤ 2 in other parts. Patient severity was assessed according to the Acute Physiology and Chronic Health Evaluation II score. The outcomes were assessed using the Glasgow Outcome Scale Extended (GOS-E) 6 months after injury.[23,24] The GOS-E is divided into the following 8 categories: dead, vegetative state, lower body severe disability, upper body severe disability, lower body moderate disability, upper body moderate disability, lower body good recovery, and upper body good recovery. In this study, we defined GOS-E scores 6 to 8 as favorable neurological outcomes and 1 to 5 as unfavorable neurological outcomes. Neurointensivists assessed the GOS-E at the study institution, who, by telephone and mail, contacted patients, patient families, and hospitals to which patients were transferred from our hospital after discharge.
2.3. Patient
This study included patients with iTBI aged ≥16. Therefore, the following cases were excluded from the analysis: patients ≤15 years of age, patients expected to have a non-head AIS of 3 or higher, patients with insufficient information on time of injury, patients whose first blood test was more than 1 hour after the injury, patients who did not consent to participate in the study, and presence of diseases or drugs that affect coagulation and fibrinolysis parameters such as hepatic failure, anticoagulant medication, and cardiopulmonary arrest prior to admission or on arrival.
2.4. Study design
This study is a retrospective analysis using a prospective registry conducted at 2 facilities (Nippon Medical School and Kawaguchi Municipal Medical Center).
All the patients in the study received the standard care provided to patients with trauma today. Tranexamic acid was administered, and blood transfusions were administered as needed. Burr hole surgery and craniotomy were performed when intracranial decompression was necessary. In addition to general coagulofibrinolytic biomarkers, the following specific molecular biomarkers were assessed: plasminogen (Testzym S PLG, Sekisui Medical Corp., Tokyo, Japan), α2-plasmin inhibitor (α2-PI) (Testzym S APL, Sekisui Medical Corp., Tokyo, Japan), plasmin-α2-plasmin inhibitor complex (PIC) (LPIA-ACE PPI II, LSI Medience Corp., Tokyo, Japan), plasminogen activator inhibitor-1 (LPIA-tPAI test, LSI Medience Corp., Tokyo, Japan), and antithrombin (Revohem AT, Sysmex Corp., Kobe, Japan). These coagulofibrinolytic markers were measured at 1 hour, 24 hour, 3 days, and 7 days after the injury. In the present study, 1 hour after injury was defined as day 0 and 24 hour after injury as day 1.
2.5. Statistical analysis
The patient cohort was divided into men and women and evaluated for pre-injury background, injury status, severity, and coagulofibrinolytic markers at each time point after injury.
In addition, the following 2 subgroup analyses were performed: patients were divided into 2 groups according to the neurological outcome, and the difference between men and women within each group was examined; patients were divided into men and women, and the correlation between neurological outcome and coagulofibrinolytic markers within each group was examined.
Additionally, the patients were divided into 2 more groups, those older than 50 years and those younger than 50, to examine the effect of pre- and post-menopause on coagulation disorders. The age threshold was set based on the mean age of menopause for Japanese women aged 49.33 years.[25] To minimize the influence of patient bias on the results, we used propensity score matching to analyze head injuries and surgical treatment as covariates with a caliper of 0.1 standard deviation.
Data for continuous variables are presented as medians with interquartile ranges. Categorical data are presented as frequencies and percentages. Patient characteristics and outcomes were compared between the 2 groups using the Mann–Whitney U test (for numerical variables), Fisher exact test (for categorical variables), and chi-square tests (for categorical variables). All analyses were performed using the IBM SPSS software (version 25; IBM Japan, Tokyo, Japan). All reported P values were 2-tailed, and the differences were considered statistically significant at P values of <.05.
2.6. Ethical statement
The study protocol was approved by the Institutional Review Board of Hokkaido University Hospital, Kawaguchi Municipal Medical Center and Nippon Medical School (approval numbers are 021-0185, 2018-27 and 30-09-999 in order). Written consent forms were obtained from the participants’ legal guardians or next of kin at the time of study participation.
3. Results
Data were collected for 60 cases during the study period, of which 8 cases were later found not to be iTBI (i.e., the head AIS scores were not 3 or higher) and were excluded from the study. Therefore, we analyzed 52 patients with iTBI (Fig. 1). Table 1 shows the patient background with respect to gender. No significant differences were observed in age, the severity of the head injury, or the outcome between the men (n = 31) and women (n = 21). In addition, no significant differences were observed in vital signs and blood tests except for blood pressure (systolic: P = .038, diastolic: P = .004), hemoglobin (P = .001), and creatinine (P < .001). No significant differences were detected in the estimated glomerular filtration rate between the genders. The proportion of cerebral contusion was higher in the men than in the women (P = .030); more men underwent craniotomy (P = .026).
Figure 1.
Flow chart of study population. AIS = abbreviated injury scale, iTBI = isolated traumatic brain injury.
Table 1.
Baseline characteristics of patients with isolated traumatic brain injury.
| Female (n = 21) | Male (n = 31) | P value | |
|---|---|---|---|
| Age, yr | 77.0 (48.0–83.0) | 61.0 (40.5–76.0) | .097 |
| Cause of injury | .397 | ||
| Traffic accident, n (%) | 13 (61.9) | 16 (51.6) | |
| Fall, n (%) | 6 (28.6) | 6 (19.4) | |
| Others, n (%) | 2 (9.5) | 9 (29.0) | |
| Types of head injuries | |||
| Acute subdural hematoma, n (%) | 16 (76.2) | 23 (74.2) | .421 |
| Acute epidural hematoma, n (%) | 2 (9.5) | 7 (22.6) | .222 |
| Cerebral contusion, n (%) | 15 (71.4) | 29 (93.5) | .030 |
| Traumatic subarachnoid hemorrhage, n (%) | 19 (90.5) | 29 (93.5) | .683 |
| Skull fracture | 12 (57.1) | 23 (74.2) | .198 |
| Vital signs upon arrival | |||
| Glasgow coma scale | 11 (6–14) | 10 (6–14) | .932 |
| Anisocoria, n (%) | 5 (23.8) | 10 (32.3) | .509 |
| Systolic blood pressure (mm Hg) | 137.0 (118.0–159.0) | 157.0 (137.0–174.0) | .038 |
| Diastolic blood pressure (mm Hg) | 78.0 (69.0–98.0) | 98.0 (86.5–110.0) | .004 |
| Heart rate (/min) | 88.0 (77.0–100.0) | 86.0 (76.5–105.0) | .926 |
| Respiratory rate (/min) | 22.0 (19.0–26.0) | 21.0 (19.0–27.0) | .779 |
| Body temperature (°C) | 35.9 (35.3–36.3) | 36.0 (35.6–36.5) | .341 |
| Blood test results upon arrival | |||
| pH | 7.410 (7.374–7.453) | 7.390 (7.359–7.419) | .102 |
| Lactate (mmol/L) | 2.0 (1.6–2.3) | 2.89 (1.62–4.38) | .149 |
| White blood cell (103/µL) | 10.8 (7.4–12.2) | 10.2 (8.1–11.2) | .695 |
| Red blood cell (104/µL) | 390 (365–421) | 429.0 (379.0–494.5) | .061 |
| Hemoglobin (g/dL) | 11.7 (10.9–12.2) | 13.5 (11.9–14.8) | .001 |
| Creatinine (mg/dL) | 0.56 (0.47–0.67) | 0.83 (0.76–1.02) | <.001 |
| eGFR (mL/min/1.73m2) | 82.5 (62.1–103.6) | 75.2 (55.3–88.7) | .075 |
| APACHE II score | 14.0 (12.0–20.5) | 14.0 (8.8–20.5) | .603 |
| Injury severity score | 25.0 (16.0–25.0) | 25.0 (24.0–25.0) | .267 |
| Abbreviated injury scale of head | 5.0 (4.0–5.0) | 5.0 (4.0–5.0) | .170 |
| Treatment | |||
| Burr holes (%) | 8 (38.1) | 9 (29.0) | .494 |
| Craniotomy (%) | 5 (23.8) | 17 (54.8) | .026 |
| Tranexamic acid (%) | 4 (19.0) | 8 (25.8) | .570 |
| Red blood cell transfusion (Unit) | 0 (0–0) | 0 (0–4) | .398 |
| Fresh frozen plasma transfusion (Unit) | 0 (0–0) | 0 (0–9) | .251 |
| Glasgow Outcome Scale Extended | 6.0 (3.0-8.0) | 5.0 (2.0–7.0) | .264 |
| Unfavorable neurological outcome (n, %) | 10 (47.6) | 18 (58.1) | .458 |
Data presented as median (25th–75th percentile), percentage or numbers.
APACHE II = acute physiology and chronic health evaluation II, eGFR = estimated glomerular filtration rate.
In the overall patient cohort, plasminogen (P = .041) and plasminogen activator inhibitor-1 (P = .046) exhibited significant gender differences at 1 hour after injury (Table 2).
Table 2.
Results of coagulofibrinolytic markers 1 hour after the injury.
| Female (n = 21) | Male (n = 31) | P value | |
|---|---|---|---|
| Platelet counts (109/L) | 204 (185–283) | 201 (169–244) | .490 |
| PT ratio | 1.03 (0.97–1.06) | 1.05 (1.00–1.13) | .668 |
| APTT (s) | 25.2 (24.2–29.9) | 27.2 (25.2–30.7) | .918 |
| Fibrinogen (g/L) | 2.12 (1.72–2.64) | 2.02 (1.65–2.68) | .473 |
| FDP (mg/L) | 69.9 (31.5–182.1) | 111.2 (47.8–287.4) | .143 |
| D-dimer (μg/mL) | 20.7 (9.3–51.4) | 31.3 (15.2–59.7) | .205 |
| Plasminogen (%) | 90.5 (76.3–99.0) | 88.5 (80.5–97.8) | .041 |
| α2-PI (%) | 87.0 (77.0–97.0) | 87.0 (70.0–99.0) | .991 |
| PIC (μg/mL) | 6.3 (2.5–12.6) | 10.0 (5.3–25.1) | .673 |
| PAI-1 (ng/mL) | 16.5 (11.3–26.8) | 22.5 (14.0–32.0) | .046 |
| Antithrombin (%) | 92.0 (76.0–100.0) | 84.0 (78.0–91.0) | .860 |
Data presented as median (25th–75th percentile).
α2-PI = α2 plasmin inhibitor, APTT = activated partial thromboplastin time, FDP = fibrin/fibrinogen degradation products, PIC = plasmin-α2 plasmin inhibitor complex, PAI-1, plasminogen activator inhibitor 1, PT = prothrombin time.
Results of subgroup analysis at 1 hour after injury are shown in Figure 2. A significant association was observed between abnormal coagulofibrinolytic markers and poor neurological outcomes in men. Men with poor neurological outcome showed predominantly higher activated partial thromboplastin time (APTT) (P = .007), fibrin/fibrinogen degradation products (FDP) (P = .025), D-dimer (P = .034), and PIC (P = .031) levels at 1 hour after injury and predominantly lower α2-PI (P = .030) levels than those with good neurological outcome. Detailed analysis results of each coagulofibrinolytic marker up to 7 days after injury are shown in Tables S1 and S2, Supplemental Digital Content, http://links.lww.com/MD/I433. Gender differences were observed for the following coagulofibrinolytic markers: fibrinogen (day 1: P = .018, day 3: P = .001, day 7: P = .011), plasminogen (day 7: P = .001), α2-PI (day 7: P = .006), and PIC (day 7: P = .030) in the group with the favorable neurological outcome and for prothrombin time ratio (day 7: P = .020), D-dimer (day 3: P = .019), and PIC (day 3: P = .008) in the group with the unfavorable neurological outcome (Table S1, Supplemental Digital Content, http://links.lww.com/MD/I433).
Figure 2.
Values of general coagulofibrinolytic markers at 1 hour after injury according to gender and neurological outcome. Each box shows unfavorable neurological outcomes in men, favorable neurological outcomes in men, favorable neurological outcomes in women, and unfavorable neurological outcome in women in order from the lightest color. α2-PI = α2-plasmin inhibitor, APTT = activated partial thromboplastin time, FDP = fibrin/fibrinogen degradation products, PAI-1 = plasminogen activator inhibitor-1, PIC = plasmin-α2-plasmin inhibitor complex.
Table 3 shows the additional analysis results for examining the effect of menopause. At least one significantly different coagulofibrinolytic marker is shown in Table 3, and the other markers are omitted. This analysis requires consideration that the number of premenopausal women is low and that the women are significantly older than the men in the over-50 age group; nevertheless, significant gender differences were observed in fibrinogen (day 3: P = .018), FDP (day 0: P = .037, day 3: P = .009, day 7: P = .037), D-dimer (day 3: P = .005, day 7: P = .010), plasminogen (day 3: P = .032, day 7: P = .032), and PIC (day 3: P = .001, day 7: P = .001) in the age group under 50 years. These differences were not evident in the age group over 50 years (Table 3).
Table 3.
Differences in coagulofibrinolytic markers in cohorts under or over 50 years of age.
| Under 50 years old | Over 50 years old | |||||
|---|---|---|---|---|---|---|
| Female (n = 6) | Male (n = 12) | P value | Female (n = 15) | Male (n = 19) | P value | |
| Age, yr | 29.0 (23.3–37.0) | 37.0 (31.5–41.3) | .250 | 80.0 (74.0–83.0) | 74.0 (62.5–80.5) | .017 |
| APACHE II score | 11.5 (8.5–14.5) | 10.0 (6.5–17.3) | .820 | 16.0 (14.0–22.0) | 17.5 (12.3–24.3) | .846 |
| Injury severity score | 15.0 (10.3–22.8) | 23.8 (25.0–25.0) | .180 | 16.0 (25.0–25.0) | 24.0 (25.0–25.0) | .784 |
| Abbreviated injury scale of head | 3.5 (3.0–4.8) | 4.8 (5.0–5.0) | .102 | 4.0 (5.0–5.0) | 4.0 (5.0–5.0) | .758 |
| Unfavorable neurological outcome (n, %) | 2 (33.3) | 3 (25.0) | .561 | 8 (53.3) | 15 (78.9) | .112 |
| Fibrinogen day 0 (g/L) | 2.45 (2.21–2.77) | 2.02 (1.64–2.31) | .053 | 1.69 (1.62–2.32) | 2.22 (1.98–2.50) | .706 |
| Fibrinogen day 1 (g/L) | 3.00 (2.58–3.49) | 2.99 (2.93–4.01) | .125 | 2.55 (2.29–2.79) | 3.07 (2.79–3.80) | .254 |
| Fibrinogen day 3 (g/L) | 3.63 (3.22–4.12) | 4.27 (3.59–6.16) | .018 | 3.57 (2.82–4.42) | 5.11 (4.03–5.62) | .046 |
| Fibrinogen day 7 (g/L) | 4.55 (4.51–6.24) | 5.27 (4.13–6.93) | .067 | 4.31 (3.48–5.80) | 5.01 (3.89–6.50) | .029 |
| FDP day 0 (mg/L) | 62.5 (29.9–145.4) | 90.3 (37.2–418.1) | .037 | 107.0 (65.0–320.8) | 111.2 (32.2–242.7) | .274 |
| FDP day 1 (mg/L) | 11.6 (7.3–19.2) | 14.2 (5.2–18.0) | .279 | 26.0 (13.5–53.0) | 9.3 (6.6–18.3) | .786 |
| FDP day 3 (mg/L) | 10.7 (6.6–15.5) | 6.2 (5.4–7.4) | .009 | 8.6 (3.2–10.7) | 5.1 (4.1–6.0) | .631 |
| FDP day 7 (mg/L) | 21.8 (13.3–27.5) | 15.6 (11.6–27.6) | .037 | 13.4 (8.4–21.3) | 11.5 (8.8–-20.2) | 1.000 |
| D-dimer day 0 (μg/mL) | 17.5 (6.9–54.2) | 33.4 (11.0–66.3) | .180 | 29.3 (20.8–81.2) | 30.6 (9.9–44.1) | .391 |
| D-dimer day 1 (μg/mL) | 8.3 (3.7–14.8) | 6.6 (3.4–13.2) | .067 | 17.6 (10.3–45.1) | 7.1 (4.7–11.6) | .928 |
| D-dimer day 3 (μg/mL) | 5.3 (3.4–7.2) | 3.4 (2.0–4.5) | .005 | 6.0 (2.0–8.2) | 3.0 (1.9–4.1) | .231 |
| D-dimer day 7 (μg/mL) | 14.3 (6.5–20.4) | 8.0 (5.2–12.2) | .010 | 8.4 (4.8–13.8) | 6.0 (4.3–10.6) | .467 |
| Plasminogen day 0 (%) | 96.0 (77.0–100.0) | 90.5 (78.3–101.8) | .133 | 84.0 (76.3–99.0) | 89.5 (84.3–107.5) | .261 |
| Plasminogen day 1 (%) | 86.0 (70.3–89.0) | 87.0 (75.0–102.0) | .151 | 78.0 (74.3–84.8) | 83.0 (77.3–85.3) | .458 |
| Plasminogen day 3 (%) | 97.5 (77.5–113.8) | 99.5 (83.8–102.0) | .032 | 83.0 (77.5–98.3) | 100.0 (87.0–111.3) | .899 |
| Plasminogen day 7 (%) | 119.0 (102.3–130.5) | 125.5 (116.8–134.0) | .032 | 116.0 (100.0–127.0) | 122.0 (108.0–149.0) | .531 |
| PIC day 0 (μg/mL) | 7.1 (2.6–7.5) | 5.0 (2.4–23.0) | .212 | 11.2 (7.0–27.9) | 9.5 (5.3–16.4) | .526 |
| PIC day 1 (μg/mL) | 1.0 (0.7–1.2) | 0.6 (0.5–0.9) | .083 | 0.9 (0.7–1.6) | 1.0 (0.6–1.4) | .905 |
| PIC day 3 (μg/mL) | 1.6 (1.4–2.0) | 0.8 (0.6–1.6) | .001 | 1.0 (0.7–1.2) | 1.1 (0.7–1.1) | .403 |
| PIC day 7 (μg/mL) | 1.7 (1.5–3.1) | 1.7 (1.4–2.7) | .001 | 1.7 (1.4–2.2) | 1.9 (1.2–2.5) | .277 |
One hour after injury was defined as day 0 and 24 h after injury as day 1. Data presented as median (25th–75th percentile).
APACHE II = acute physiology and chronic health evaluation II, FDP = fibrin/fibrinogen degradation products, PIC = plasmin-α2 plasmin inhibitor complex.
In the propensity matching analysis with matched patient backgrounds, gender differences were observed for fibrinogen (day 1: P = .041, day 3: P = .041), plasminogen (day 0: P = .025), and PIC (day 3: P = .029, day 7: P = .048), showing the same trend as in the main analysis (Table S3, Supplemental Digital Content, http://links.lww.com/MD/I433).
4. Discussion
This study evaluated gender-specific differences in coagulofibrinolytic markers after injury in patients with iTBI. The overall patient population showed gender-related differences in several coagulofibrinolytic markers. Men with poor neurological outcomes showed abnormal coagulofibrinolytic changes 1 hour after injury, suggesting that abnormal coagulofibrinolytic responses may lead to poor neurological outcomes. In contrast, women showed less prominent coagulofibrinolytic changes 1 hour after injury; additionally, abnormal coagulofibrinolytic responses may not be associated with neurologic outcomes, unlike in men. Premenopausal women showed a significant difference in coagulofibrinolytic markers compared to men.
Previous studies have shown that various coagulofibrinolytic markers are prognostic predictors of iTBI.[26–29] The present study showed prolonged APTT, high D-dimer, FDP, and low α2-PI values in men with iTBI presenting poor outcomes, suggesting that coagulopathy immediately after trauma may be associated with poor neurological outcomes in men. These findings are supported by previous studies that show that prolonged APTT and elevated D-dimer within the first hour after injury correlate with poor prognosis.[30–32]
The additional analysis suggested that differences in coagulofibrinolysis after iTBI with respect to gender occur mostly in the age group under 50 years old (Table 3). In premenopausal women, hypercoagulability occurs after trauma, and it has been shown to protect against the development of early coagulopathy after trauma.[33] This effect is prevalent early, up to 24 hour after injury.[13] Estrogen is a known procoagulant, and hormone-induced hypercoagulability may affect the response to hemorrhage and critical injury in premenopausal women.[34,35] In patients with trauma, this mechanism is hypothesized to involve regulation of the immune response[36]; however, the details are not well understood.
In the present study, among the coagulation-fibrinolysis markers, fibrinogen showed a significant gender-related difference up to day 7 after injury (Table 3 and Tables S1 and S3, Supplemental Digital Content, http://links.lww.com/MD/I433). In the early stages of trauma, fibrinogen consumption increases; however, its synthesis remains constant and available levels are very low.[37,38] DIC with hyperfibrinolysis in the early stages of trauma is a poor prognostic factor in patients with trauma.[39] European guidelines suggest that fibrinogen levels should be maintained at >1.5 to 2.0 g/L in patients with severe trauma.[40] In patients with TBI, fibrinogen is an independent prognostic factor for clinical outcomes, and maintaining fibrinogen levels at 2.5 to 3 g/L may improve prognosis.[41] However, currently, no reports focus on fibrinogen levels and gender in patients with trauma. Although studies have been conducted on the relationship between gender and prognosis in patients with trauma,[14–19] they have not been conclusive. Previous studies have reported that prognosis varies by gender depending on the severity of TBI (women show worse prognosis in mild and moderate TBI).[22] In the current study, a significant gender-related difference was observed for fibrinogen in patients with favorable neurological prognosis; however, a further detailed analysis was not possible because of the limited number of cases.
This study provides important data as it evaluated coagulopathy immediately after iTBI and long-term neurological outcomes. The main pathogenesis of trauma-induced coagulopathy is disseminated intravascular coagulopathy (DIC) with or without brain injury.[42] In patients with trauma, DIC with hyperfibrinolytic phenotype in the early phase of trauma, contributing to the exacerbation of hemorrhage, is converted to DIC with the thrombotic phenotype in the sub-acute phase of trauma, contributing to a high rate of multiple organ dysfunction[43]; similar changes occur in patients with iTBI.[20] Additionally, patients with iTBI presenting DIC have a higher mortality rate than those without DIC.[20] Therefore, this study did not assess remote-phase fibrinolysis suppression and organ damage. However, the severe coagulofibrinolytic changes confirmed in men in the early phase may be associated with poor long-term outcomes through the expansion of intracranial hemorrhage and organ damage.
The results of the current study suggested that men with significant abnormalities in coagulofibrinolytic markers immediately after injury were more likely to have a poor neurological outcome, unlike women. Currently, transfusion strategies for patients with trauma are not different according to gender; however, more aggressive intervention may be necessary for men with aggravated coagulofibrinolytic markers immediately after iTBI. This is a retrospective study in which patients were classified and evaluated according to prognosis; prospective studies with sufficient cases are needed further to clarify gender differences in coagulofibrinolysis in patients with TBI.
4.1. Limitation
The number of patients in this study was limited. In a few analyses, the number of premenopausal patients was particularly small, resulting in statistical instability. In this study, we did not collect information on the patient’s menstruation or the use of hormonal agents. In addition, 7 patients in this study died by day 7, which may have caused a survival bias.
In conclusion, differences in coagulofibrinolytic markers were observed for gender in patients with iTBI. In men, aggravation of coagulofibrinolytic markers immediately after TBI may be associated with poor neurologic outcomes 6 months after injury. The difference in coagulation-fibrinolysis markers between men and women was more pronounced in the age group below 50 years, suggesting that female hormones may influence the pathogenesis of coagulopathy in patients with iTBI. In the future, gender may need to be considered when deciding appropriate treatment strategies for coagulopathy in iTBI.
Acknowledgment
We would like to thank Editage (https://www.editage.jp/) for English language editing.
Author contributions
Conceptualization: Takeshi Wada.
Data curation: Ryuta Nakae, Yu Fujiki, Takahiro Kanaya, Yasuhiro Takayama, Go Suzuki, Yasutaka Naoe.
Formal analysis: Takumi Tsuchida.
Investigation: Takumi Tsuchida, Takeshi Wada, Ryuta Nakae.
Methodology: Takumi Tsuchida.
Supervision: Takeshi Wada, Ryuta Nakae, Yasuhiro Takayama, Shoji Yokobori.
Writing – original draft: Takumi Tsuchida.
Writing – review & editing: Takeshi Wada, Ryuta Nakae, Yu Fujiki, Takahiro Kanaya, Yasuhiro Takayama, Go Suzuki, Yasutaka Naoe, Shoji Yokobori.
Supplementary Material
Abbreviations:
- AIS
- abbreviated injury scale
- APTT
- activated partial thromboplastin time
- DIC
- disseminated intravascular coagulopathy
- FDP
- fibrin/fibrinogen degradation products
- GOS-E
- Glasgow Outcome Scale Extended
- iTBI
- isolated traumatic brain injury
- PIC
- plasmin-α2-plasmin inhibitor complex
- TBI
- traumatic brain injury
Supplemental Digital Content is available for this article.
The authors have no funding and conflicts of interest to disclose.
Written consent forms were obtained from the participants’ legal guardians or next of kin at the time of study participation.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Tsuchida T, Wada T, Nakae R, Fujiki Y, Kanaya T, Takayama Y, Suzuki G, Naoe Y, Yokobori S. Gender-related differences in the coagulofibrinolytic responses and long-term outcomes in patients with isolated traumatic brain injury: A 2-center retrospective study. Medicine 2023;102:6(e32850).
Contributor Information
Takumi Tsuchida, Email: t.tsuchida@frontier.hokudai.ac.jp.
Ryuta Nakae, Email: nakae@nms.ac.jp.
Yu Fujiki, Email: siam1999@nms.ac.jp.
Takahiro Kanaya, Email: t-kanaya@nms.ac.jp.
Yasuhiro Takayama, Email: ccm2199@yahoo.co.jp.
Go Suzuki, Email: g.suzuki417@gmail.com.
Yasutaka Naoe, Email: ynaoe1120@mac.com.
Shoji Yokobori, Email: shoji@nms.ac.jp.
References
- [1].Scarpelini S, Rhind SG, Nascimento B, et al. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res. 2009;42:1210–7. [DOI] [PubMed] [Google Scholar]
- [2].Gorton HJ, Warren ER, Simpson NA, et al. Thromboelastography identifies sex-related differences in coagulation. Anesth Analg. 2000;91:1279–81. [DOI] [PubMed] [Google Scholar]
- [3].Hobson AR, Qureshi Z, Banks P, et al. Gender and responses to aspirin and clopidogrel: insights using short thrombelastography. Cardiovasc Ther. 2009;27:246–52. [DOI] [PubMed] [Google Scholar]
- [4].Roy-O’Reilly M, McCullough LD. Sex differences in stroke: the contribution of coagulation. Exp Neurol. 2014;259:16–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Martínez-Sánchez P, Fuentes B, Fernández-Domínguez J, et al. Young women have poorer outcomes than men after stroke. Cerebrovasc Dis. 2011;31:455–63. [DOI] [PubMed] [Google Scholar]
- [6].Greenland P, Reicher-Reiss H, Goldbourt U, et al. In-hospital and 1-year mortality in 1,524 women after myocardial infarction. Comparison with 4,315 men. Circulation. 1991;83:484–91. [DOI] [PubMed] [Google Scholar]
- [7].Malacrida R, Genoni M, Maggioni AP, et al. A comparison of the early outcome of acute myocardial infarction in women and men. The Third international study of infarct survival collaborative group. N Engl J Med. 1998;338:8–14. [DOI] [PubMed] [Google Scholar]
- [8].Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National Registry of myocardial infarction 2 Participants. N Engl J Med. 1999;341:217–25. [DOI] [PubMed] [Google Scholar]
- [9].Simon T, Mary-Krause M, Cambou JP, et al. Impact of age and gender on in-hospital and late mortality after acute myocardial infarction: increased early risk in younger women: results from the French nation-wide USIC registries. Eur Heart J. 2006;27:1282–8. [DOI] [PubMed] [Google Scholar]
- [10].Gando S, Hayakawa M. Pathophysiology of trauma-induced coagulopathy and management of critical bleeding requiring massive transfusion. Semin Thromb Hemost. 2016;42:155–65. [DOI] [PubMed] [Google Scholar]
- [11].Moore HB, Gando S, Iba T, et al. Defining trauma-induced coagulopathy with respect to future implications for patient management: communication from the SSC of the ISTH. J Thromb Haemost. 2020;18:740–7. [DOI] [PubMed] [Google Scholar]
- [12].Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers. 2021;7:30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Schreiber MA, Differding J, Thorborg P, et al. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma. 2005;58:475–80. discussion 8081. [DOI] [PubMed] [Google Scholar]
- [14].Smith A, Duchesne J, Marturano M, et al. Does gender matter: a multi-institutional analysis of viscoelastic profiles for 1565 trauma patients with severe hemorrhage. Am Surg. 2022;88:512–8. [DOI] [PubMed] [Google Scholar]
- [15].Coleman JR, Moore EE, Samuels JM, et al. Trauma resuscitation consideration: sex matters. J Am Coll Surg. 2019;228:760–768e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Deitch EA, Livingston DH, Lavery RF, et al. Hormonally active women tolerate shock-trauma better than do men: a prospective study of over 4000 trauma patients. Ann Surg. 2007;246:447–55. discussion 5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Magnotti LJ, Fischer PE, Zarzaur BL, et al. Impact of gender on outcomes after blunt injury: a definitive analysis of more than 36,000 trauma patients. J Am Coll Surg. 2008;206:984–91. discussion 9192. [DOI] [PubMed] [Google Scholar]
- [18].Croce MA, Fabian TC, Malhotra AK, et al. Does gender difference influence outcome? J Trauma. 2002;53:889–94. [DOI] [PubMed] [Google Scholar]
- [19].Brown JB, Cohen MJ, Minei JP, et al. Characterization of acute coagulopathy and sexual dimorphism after injury: females and coagulopathy just do not mix. J Trauma Acute Care Surg. 2012;73:1395–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Nakae R, Murai Y, Morita A, et al. Coagulopathy and traumatic brain injury: overview of new diagnostic and therapeutic strategies. Neurol Med Chir (Tokyo). 2022;62:261–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Gupte R, Brooks W, Vukas R, et al. Sex differences in traumatic brain injury: what we know and what we should know. J Neurotrauma. 2019;36:3063–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Jennett B, Snoek J, Bond MR, et al. Disability after severe head injury: observations on the use of the Glasgow outcome scale. J Neurol Neurosurg Psychiatry. 1981;44:285–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow outcome scale and the extended Glasgow outcome scale: guidelines for their use. J Neurotrauma. 1998;15:573–85. [DOI] [PubMed] [Google Scholar]
- [25].Kono S, Sunagawa Y, Higa H, et al. Age of menopause in Japanese women: trends and recent changes. Maturitas. 1990;12:43–9. [DOI] [PubMed] [Google Scholar]
- [26].MacLeod JB, Lynn M, McKenney MG, et al. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55:39–44. [DOI] [PubMed] [Google Scholar]
- [27].Sun Y, Wang J, Wu X, et al. Validating the incidence of coagulopathy and disseminated intravascular coagulation in patients with traumatic brain injury—analysis of 242 cases. Br J Neurosurg. 2011;25:363–8. [DOI] [PubMed] [Google Scholar]
- [28].Van Beek JG, Mushkudiani NA, Steyerberg EW, et al. Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24:315–28. [DOI] [PubMed] [Google Scholar]
- [29].Allard CB, Scarpelini S, Rhind SG, et al. Abnormal coagulation tests are associated with progression of traumatic intracranial hemorrhage. J Trauma. 2009;67:959–67. [DOI] [PubMed] [Google Scholar]
- [30].Nakae R, Takayama Y, Kuwamoto K, et al. Time course of coagulation and fibrinolytic parameters in patients with traumatic brain injury. J Neurotrauma. 2016;33:688–95. [DOI] [PubMed] [Google Scholar]
- [31].Fujiwara G, Okada Y, Sakakibara T, et al. 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. [DOI] [PubMed] [Google Scholar]
- [32].Solla DJF, de Amorim RLO, Kolias AG, et al. Incremental prognostic value of coagulopathy in addition to the crash score in traumatic brain injury patients. Neurocrit Care. 2021;34:130–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Pommerening MJ, Schwartz DA, Cohen MJ, et al. Hypercoagulability after injury in premenopausal females: a prospective, multicenter study. Surgery. 2014;156:439–47. [DOI] [PubMed] [Google Scholar]
- [34].Duhl AJ, Paidas MJ, Ural SH, et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol. 2007;197:457.e1–457.e21. [DOI] [PubMed] [Google Scholar]
- [35].Levi M, Middeldorp S, Büller HR. Oral contraceptives and hormonal replacement therapy cause an imbalance in coagulation and fibrinolysis which may explain the increased risk of venous thromboembolism. Cardiovasc Res. 1999;41:21–4. [DOI] [PubMed] [Google Scholar]
- [36].Gee AC, Sawai RS, Differding J, et al. The influence of sex hormones on coagulation and inflammation in the trauma patient. Shock. 2008;29:334–41. [DOI] [PubMed] [Google Scholar]
- [37].Martini WZ, Chinkes DL, Pusateri AE, et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab. 2005;289:E930–4. [DOI] [PubMed] [Google Scholar]
- [38].Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg. 2007;246:831–5. [DOI] [PubMed] [Google Scholar]
- [39].Sawamura A, Hayakawa M, Gando S, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124:608–13. [DOI] [PubMed] [Google Scholar]
- [40].Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [41].Lv K, Yuan Q, Fu P, et al. Impact of fibrinogen level on the prognosis of patients with traumatic brain injury: a single-center analysis of 2570 patients. World J Emerg Surg. 2020;15:54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Gando S, Shiraishi A, Wada T, et al. A multicenter prospective validation study on disseminated intravascular coagulation in trauma-induced coagulopathy. J Thromb Haemost. 2020;18:2232–44. [DOI] [PubMed] [Google Scholar]
- [43].Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19:72. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.