Gender-related differences in the coagulofibrinolytic responses and long-term outcomes in patients with isolated traumatic brain injury: A 2-center retrospective study.

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.

Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury.

Traumatic brain injury (TBI) is associated with coagulation/fibrinolysis disorders. We retrospectively evaluated 61 TBI cases transported to hospital within 1 h post-injury. Levels of thrombin-antithrombin III complex (TAT), D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were measured on arrival and 3 h, 6 h, 12 h, 1 day, 3 days and 7 days after injury. Multivariate logistic regression analysis was performed to identify prognostic factors for coagulation and fibrinolysis. Plasma TAT levels peaked at admission and decreased until 1 day after injury. Plasma D-dimer levels increased, peaking up to 3 h after injury, and decreasing up to 3 days after injury. Plasma PAI-1 levels increased up to 3 h after injury, the upward trend continuing until 6 h after injury, followed by a decrease until 3 days after injury. TAT, D-dimer, and PAI-1 were elevated in the acute phase of TBI in cases with poor outcome. Multivariate logistic regression analysis showed that D-dimer elevation from admission to 3 h after injury and PAI-1 elevation from 6 h to 1 day after injury were significant negative prognostic indicators. Post-TBI hypercoagulation, fibrinolysis, and fibrinolysis shutdown were activated consecutively. Hyperfibrinolysis immediately after injury and subsequent fibrinolysis shutdown were associated with poor outcome.

Antithrombin activity levels for predicting long-term outcomes in the early phase of isolated traumatic brain injury.

Coagulopathy management is an important strategy for preventing secondary brain damage in patients with traumatic brain injury (TBI). Antithrombin (AT) is a natural anticoagulant that controls coagulation and inflammation pathways. However, the significance of AT activity levels for outcomes in patients with trauma remains unclear. This study aimed to investigate the relationship between AT activity levels and long-term outcomes in patients with TBI; this was a sub-analysis of a prior study that collected blood samples of trauma patients prospectively in a tertiary care center in Kawaguchi City, Japan. We included patients with isolated TBI (iTBI) aged ≥16 years admitted directly to our hospital within 1 h after injury between April 2018 and March 2021. General coagulofibrinolytic and specific molecular biomarkers, including AT, were measured at 1, 3, 6, 12, and 24 h after injury. We analyzed changes in the AT activity levels during the study period and the impact of the AT activity levels on long-term outcomes, the Glasgow Outcome Scale-Extended (GOSE), 6 months after injury. 49 patients were included in this study; 24 had good neurological outcomes (GOSE 6-8), and 25 had poor neurological outcomes (GOSE 1-5). Low AT activity levels were shown within 1 h after injury in patients in the poor GOSE group; this was associated with poor outcomes. Furthermore, AT activity levels 1 h after injury had a strong predictive value for long-term outcomes (area under the receiver operating characteristic curve of 0.871; 95% CI: 0.747-0.994). Multivariate logistic regression analysis with various biomarkers showed that AT was an independent factor of long-term outcome (adjusted odds ratio: 0.873; 95% CI: 0.765-0.996; p=0.043). Another multivariate analysis with severity scores showed that low AT activity levels were associated with poor outcomes (adjusted odds ratio: 0.909; 95% CI: 0.822-1.010; p=0.063). We demonstrated that the AT activity level soon after injury could be a predictor of long-term neurological prognosis in patients with iTBI.

Neurointensive Care of Traumatic Brain Injury Patients Based on Coagulation and Fibrinolytic Parameter Monitoring.

Coagulopathy, a common complication of traumatic brain injury (TBI), is characterized by a hypercoagulable state developing immediately after injury, with hyperfibrinolysis and bleeding tendency peaking 3 h after injury, followed by fibrinolysis shutdown. Reflecting this timeframe, the coagulation factor fibrinogen is first consumed and then degraded after TBI, its concentration rapidly decreasing by 3 h post-TBI. The fibrinolytic marker D-dimer reaches its maximum concentration at the same time. Hyperfibrinolysis in the acute phase of TBI is associated with poor prognosis via hematoma expansion. In the acute phase, the coagulation and fibrinolysis parameters must be monitored to determine the treatment strategy. The combination of D-dimer plasma level at admission and the level of consciousness upon arrival at the hospital can be used to predict the patients who will "talk and deteriorate." Fibrinogen and D-dimer levels should determine case selection and the amount of fresh frozen plasma required for transfusion. Surgery around 3 h after injury, when fibrinolysis and bleeding diathesis peak, should be avoided if possible. In recent years, attempts have been made to estimate the time of injury from the time course of coagulation and fibrinolysis parameter levels, which has been particularly useful in some cases of pediatric abusive head trauma patients.

Time course of coagulation and fibrinolytic parameters in pediatric traumatic brain injury.

OBJECTIVE: Coagulopathy is a well-recognized risk factor for poor outcomes in patients with traumatic brain injury (TBI). Differences in the time courses of coagulation and fibrinolytic parameters between pediatric and adult patients with TBI have not been defined. METHODS: Patients with TBI and an Abbreviated Injury Scale of the head score ≥ 3, in whom the prothrombin time (PT)-international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen concentration, and plasma D-dimer levels were measured on arrival and at 3, 6, and 12 hours after injury, were retrospectively analyzed. Propensity score-matched analyses were performed to adjust baseline characteristics between pediatric patients (aged < 16 years) and adult patients (aged ≥ 16 years). RESULTS: A total of 468 patients (46 children and 422 adults) were included. Propensity score matching resulted in a matched cohort of 46 pairs. Higher PT-INR and APTT values at 1 to 12 hours after injury and lower fibrinogen concentrations at 1 to 6 hours after injury were observed in the pediatric group compared with the adult group. Plasma levels of D-dimer were elevated in both groups at 1 to 12 hours after injury, but no significant differences were seen between the groups. Multivariate logistic regression analysis of the initial coagulation and fibrinolytic parameters in the pediatric group revealed no prognostic significance of the coagulation parameter values, but elevation of the fibrinolytic parameter D-dimer was an independent negative prognostic factor. CONCLUSIONS: In the acute phase of TBI, pediatric patients were characterized by prolongation of PT-INR and APTT and lower fibrinogen concentrations compared with adult patients, but these did not correlate with outcome. D-dimer was an independent prognostic outcome factor in terms of the Glasgow Outcome Scale in pediatric patients with TBI.

Treatment of Geriatric Traumatic Brain Injury: A Nationwide Cohort Study.

BACKGROUND: Because of the aging of the Japanese population, traumatic brain injuries (TBI) have increased in elderly adults. However, the effectiveness and prognosis of intensive treatment for geriatric TBI have not yet been determined. Thus, we used nationwide data from the Japan Neurotrauma Data Bank (JNTDB) projects to analyze prognostic factors for intensive and aggressive treatments. METHODS: We analyzed 1,879 geriatric TBI cases (age ≥65 years) registered in four JNTDB projects: Project 1998 (P1998) to Project 2015 (P2015). Clinical features, use of aggressive treatment, and 6-month outcomes on the Glasgow Outcome Scale (GOS) were compared among study projects. Logistic regression was used to identify prognostic factors in aggressively treated patients. RESULTS: The percentage of geriatric TBI cases significantly increased with time-P1998: 30.1%; Project 2004 (P2004): 34.6%; Project 2009 (P2009): 43.9%; P2015: 53.6%, p<0.0001). Use of aggressive treatment also significantly increased, from 67.0% in P1998 to 69.3% in P2015 (p<0.0001). Less invasive methods, such as trepanation and normothermic targeted temperature management, were more often chosen for geriatric patients. These efforts resulted in a significant decrease in the 6-month mortality rate, from 76.2% in P1998 to 63.1% in P2015 (p=0.0003), although the percentage of severely disabled patients increased, from 8.9% in P1998 to 11.1% in P2015 (p=0.0003). Intraventricular hemorrhage was the factor most strongly associated with unfavorable 6-month outcomes (OR 3.79, 95% CI 1.78-8.06, p<0.0001). CONCLUSIONS: Less invasive treatments reduced mortality in geriatric TBI but did not improve functional outcomes. Patient age was not the strongest prognostic factor; thus, physicians should consider characteristics other than age.

Age-Related Differences in the Time Course of Coagulation and Fibrinolytic Parameters in Patients with Traumatic Brain Injury.

Coagulopathy and older age are common and well-recognized risk factors for poorer outcomes in traumatic brain injury (TBI) patients; however, the relationships between coagulopathy and age remain unclear. We hypothesized that coagulation/fibrinolytic abnormalities are more pronounced in older patients and may be a factor in poorer outcomes. We retrospectively evaluated severe TBI cases in which fibrinogen and D-dimer were measured on arrival and 3-6 h after injury. Propensity score-matched analyses were performed to adjust baseline characteristics between older patients (the "elderly group," aged ≥75 y) and younger patients (the "non-elderly group," aged 16-74 y). A total of 1294 cases (elderly group: 395, non-elderly group: 899) were assessed, and propensity score matching created a matched cohort of 324 pairs. Fibrinogen on admission, the degree of reduction in fibrinogen between admission and 3-6 h post-injury, and D-dimer levels between admission and 3-6 h post-injury were significantly more abnormal in the elderly group than in the non-elderly group. On multivariate logistic regression analysis, independent risk factors for poor prognosis included low fibrinogen and high D-dimer levels on admission. Posttraumatic coagulation and fibrinolytic abnormalities are more severe in older patients, and fibrinogen and D-dimer abnormalities are negative predictive factors.

A retrospective study of the effect of fibrinogen levels during fresh frozen plasma transfusion in patients with traumatic brain injury.

BACKGROUND: The association between traumatic brain injury (TBI) and coagulopathy is well established. While coagulopathy prophylaxis in TBI involves replenishing coagulation factors with fresh frozen plasma (FFP), its effectiveness is controversial. We investigated the relationship between plasma fibrinogen concentration 3 h after initiating FFP transfusion and outcomes and evaluated the correlation with D-dimer levels at admission. METHODS: We retrospectively examined data from 380 patients with severe isolated TBI with blood samples collected a maximum of 1 h following injury. Plasma fibrinogen and D-dimer concentrations were obtained at admission, and plasma fibrinogen concentration was again assessed 3-4 h following injury. The patients were divided into two groups based on whether or not they received FFP transfusion. Patients were also divided into subgroups according their fibrinogen level: ≥ 150 mg/dL (high-fibrinogen subgroup) or < 150 mg/dL (low-fibrinogen subgroup) 3 h after injury. Demographic, clinical, radiological and laboratory data were compared between these subgroups. RESULTS: Glasgow Outcome Scale (GOS) scores at discharge and 3 months after injury were significantly lower in the FFP transfusion group than in the FFP non-transfusion group. Among patients who received FFP, GOS scores at discharge and 3 months after injury were significantly higher in the high-fibrinogen subgroup than in the low-fibrinogen subgroup. Elevated admission D-dimer predicted subsequent fibrinogen decrease. CONCLUSIONS: In FFP transfusion, fibrinogen level ≥ 150 mg/dL 3 h after injury was associated with better outcomes in TBI patients. Assessing the admission D-dimer and tracking the fibrinogen are crucial for optimal coagulopathy prophylaxis in TBI patients.

Feasibility and Safety of Intravascular Temperature Management for Severe Heat Stroke: A Prospective Multicenter Pilot Study.

OBJECTIVES: Heat stroke is a life-threatening condition with high mortality and morbidity. Although several cooling methods have been reported, the feasibility and safety of treating heat stroke using intravascular temperature management are unclear. This study evaluated the efficacies of conventional treatment with or without intravascular temperature management for severe heat stroke. DESIGN: Prospective multicenter study. SETTING: Critical care and emergency medical centers at 10 tertiary hospitals. PATIENTS: Patients with severe heat stroke hospitalized during two summers. INTERVENTIONS: Conventional cooling with or without intravascular temperature management. MEASUREMENTS AND MAIN RESULTS: Cooling efficacy, Sequential Organ Failure Assessment score, occurrence rate of serious adverse events, and prognosis based on the modified Rankin Scale and Cerebral Performance Category. Patient outcomes were compared between five centers that were prospectively assigned to perform conventional cooling (control group: eight patients) and five centers that were assigned to perform conventional cooling plus intravascular temperature management (intravascular temperature management group: 13 patients), based on equipment availability. Despite their higher initial temperatures, all patients in the intravascular temperature management group reached the target temperature of 37°C within 24 hours, although only 50% of the patients in the control group reached 37°C (p < 0.01). The intravascular temperature management group also had a significant decrease in the Sequential Organ Failure Assessment score during the first 24 hours after admission (4.0 vs 1.5; p = 0.04). Furthermore, the intravascular temperature management group experienced fewer serious adverse events during their hospitalization, compared with the control group. The percentages of favorable outcomes at discharge and 30 days after admission were not statistically significant. CONCLUSIONS: The combination of intravascular temperature management and conventional cooling was safe and feasible for treating severe heat stroke. The results indicate that better temperature management may help prevent organ failure. A large randomized controlled trial is needed to validate our findings.

Subarachnoid Aneurysmal Hemorrhage Associated with Coarctation of the Aorta: Case Report and Review of the Literature.

Intracranial aneurysms (IAs) that undergo rupture causing subarachnoid hemorrhage (SAH), are common in young patients with coarctation of the aorta (CoA), but rarer in middle-aged and elderly patients. The pathogenesis of IAs associated with CoA remains unclear. We report the case of a 50-year-old woman who presented with SAH. On evaluation, six IAs were distributed among the anterior communicating artery (ACoA) (ruptured), distal segments of both anterior cerebral arteries (ACA), the left internal carotid artery (ICA), the bifurcation of the left middle cerebral artery (MCA)/MCA early branch, and the inferior trunk of the left MCA. CoA was also diagnosed. The ruptured ACoA IA, and two other unruptured IAs, were successfully clipped during emergency surgery. Postoperative intensive care was instituted to avoid cerebral vasospasm and renal or spinal cord ischemia. During the same hospitalization, the remaining three IAs were clipped at a second surgery. She was discharged with slight cognitive impairment eighty days after admission. Subsequently, she underwent elective treatment for the CoA. According to the literature, IAs associated with CoA have a higher tendency to involve the ACoA than IAs without CoA. Moreover, adult CoA patients tend to have multiple IAs, considered to be due to hypertension associated with CoA, as well as genetic predisposition. In CoA patients, ruptured IAs should be treated as early as possible before correction of the CoA. Close postoperative observation with management of cerebral vasospasm, renal or spinal cord ischemia, and respiratory compromise in the perioperative period is vital.

Age-related differences in fibrinolytic parameters in patients with acute traumatic brain injury.

BACKGROUND: Coagulopathy and old age have been associated with poor outcomes in traumatic brain injury (TBI) patients; however, the relationships of coagulopathy and age with the acute phase of TBI remain unclear. We hypothesized that coagulation/fibrinolytic abnormalities are more severe in older patients in the acute phase of TBI and may explain, in part, their poor outcome. METHODS: We analyzed the relationship between coagulation/fibrinolytic parameters and age in the acute phase of TBI by retrospectively evaluating 274 patients with initial blood samples obtained no more than 1 hour after injury. Measurement of platelet count, prothrombin time, activated partial thromboplastin time, plasma levels of fibrinogen, and D-dimer was done in the emergency department on arrival as well as 3, 6, and 12 hours following injury. Values were compared between patients aged 16-55 years (group 1) and those aged older than 55 years (group 2) with an Abbreviated Injury Score (AIS)-head of 3-5 to identify any relationship between these parameters and age. RESULTS: When groups 1 and 2 were matched for AIS-head, plasma levels of D-dimer in group 2 were significantly higher than those in group 1 from hospital admission to 12 hours after injury. The Glasgow Outcome Scale scores at 3 months post-injury of group 2 with AIS 4 and 5 were significantly lower than those of group 1 (both P < 0.0001). CONCLUSIONS: Fibrinolytic abnormalities are more severe in older acute-phase TBI patients, which may be a factor associated with their poor prognosis.

Time Course of Coagulation and Fibrinolytic Parameters in Patients with Traumatic Brain Injury.

Traumatic brain injury (TBI) has long been associated with coagulopathy; however, the time course of coagulation/fibrinolytic parameters in the acute phase of TBI remains unclear. The purpose of the study was to analyze the time course of coagulation/fibrinolytic parameters in the acute phase of TBI and to elucidate parameter relationships to prognosis. We retrospectively evaluated 234 patients with severe isolated TBI with initial blood samples obtained no more than 1 h after injury. Platelet count, prothrombin time, activated partial thromboplastin time (aPTT), plasma levels of fibrinogen, and D-dimer were measured on arrival in the emergency department and 3, 6, and 12 h after injury. Multivariate logistic regression analysis was performed to identify risk factors for poor prognosis at each time point. From hospital admission to 12 h after injury, an elevated D-dimer level was a significant negative prognostic indicator (admission: p < 0.0001; 3 h after injury: p = 0.0005; 6 h after injury: p = 0.005; 12 h after injury: p = 0.0009). An upward trend of aPTT on admission and 3 h after injury was also a significant negative prognostic indicator (admission: p = 0.0011; 3 h after injury: p = 0.013). On multivariate logistic regression analysis, which included all initial variables, independent risk factors for poor prognosis included older age (p = 0.0005), low Glasgow Coma Scale score (p < 0.0001), high Abbreviated Injury Score (p = 0.015), aPTT >30.2 sec (p = 0.019), and elevated D-dimer level (p = 0.0005). We concluded that D-dimer is the best coagulation/fibrinolytic parameter to monitor for prediction of outcome.

Cerebral endothelial injury in severe head injury: the significance of measurements of serum thrombomodulin and the von Willebrand factor.

Thrombomodulin (TM), which is located in the surface of the endothelium in the arteries, veins, and capillaries of major organs such as the brain, lungs, liver, kidneys, skeletal muscles, and gastrointestinal tract, is one of several indicators of endothelial injury. Von Willebrand factor (vWf), which is synthesized by endothelial cells, is also an endothelial specific glycoprotein. The serum level of vWf increases in response to various stimuli without endothelial injury. An elevated serum level of vWf may suggest endothelial activation in severe head injury. We hypothesize that the degree of cerebral endothelial activation or injury depends on the type of head injury and that measuring the TM and vWf is useful for predicting delayed traumatic intracerebral hematoma (DTICH), produced by weakness of the vessel wall, occuring either as a direct or indirect effect of head injury. The values of vWf in focal brain injury (ranging from 332.5 +/- 52.8% to 361.7 +/- 86.2%) were significantly higher than those in diffuse axonal injury from 2 h to 7 days after the injury occurred (ranging from 201.6 +/- 59.5% to 242.5 +/- 51.7%). The serum level of TM in focal brain injury (ranging from 3.84 +/- 1.54 to 4.12 +/- 1.46 U/mL) was higher than that in diffuse axonal injury (ranging from 2.96 +/- 0.63 to 3.67 +/- 1.70 U/mL), but these differences were not statistically significant. In patients with DTICH, TM was significantly higher than in patients without DTICH (p < 0.01). The results of our study demonstrate that the degree of endothelial activation in focal brain injury was significantly higher than in diffuse brain injury. In addition, the serum level of TM in patients with DTICH was significantly higher than in patients without DTICH. These findings suggest that cerebral tissue injury is often accompanied by cerebral endothelial activation, and that these two phenomena should be distinguished from each other. The levels of serum TM and vWf appear to be good indicators of the cerebral endothelial injury and of endothelial activation in severe head injury.