Antithrombin III ameliorates post-traumatic brain injury cerebral leukocyte mobilization enhancing recovery of blood brain barrier integrity.

BACKGROUND: Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS: CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS: Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION: Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.

Ability of Fibrin Monomers to Predict Progressive Hemorrhagic Injury in Patients with Severe Traumatic Brain Injury.

BACKGROUND: Progressive hemorrhagic injury (PHI) is common in patients with severe traumatic brain injury (TBI) and is associated with poor outcomes. TBI-associated coagulopathy is frequent and has been described as risk factor for PHI. This coagulopathy is a dynamic process involving hypercoagulable and hypocoagulable states either one after the other either concomitant. Fibrin monomers (FMs) are a direct marker of thrombin action and thus reflect coagulation activation. This study sought to determine the ability of FM to predict PHI after severe TBI. METHODS: We conducted a prospective, observational study including all severe TBI patients admitted in the trauma center. Between September 2011 and September 2016, we enrolled patients with severe TBI into the derivation cohort. Between October 2016 and December 2018, we recruited the validation cohort on the same basis. Study protocol included FM measurements and standard coagulation test at admission and two computed tomography (CT) scans (upon arrival and at least 6 h thereafter). A PHI was defined by an increment in size of initial lesion (25% or more) or the development of a new hemorrhage in the follow-up CT scan. Multivariate logistic regression analysis was applied to identify predictors of PHI. RESULTS: Overall, 106 patients were included in the derivation cohort. Fifty-four (50.9%) experienced PHI. FM values were higher in these patients (151 [136.8-151] vs. 120.5 [53.3-151], p < 0.0001). The ROC curve demonstrated that FM had a fair accuracy to predict the occurrence of PHI with an area under curve of 0.7 (95% CI [0.6-0.79]). The best threshold was determined at 131.7 µg/ml. In the validation cohort of 54 patients, this threshold had a negative predictive value of 94% (95% CI [71-100]) and a positive predictive value of 49% (95% CI [32-66]). The multivariate logistic regression analysis identified 2 parameters associated with PHI: FM ≥ 131.7 (OR 6.8; 95% CI [2.8-18.1]) and Marshall category (OR 1.7; 95% CI [1.3-2.2]). Coagulopathy was not associated with PHI (OR 1.3; 95% CI [0.5-3.0]). The proportion of patients with an unfavorable functional neurologic outcome at 6-months follow-up was higher in patients with positive FM: 59 (62.1%) versus 16 (29.1%), p < 0.0001. CONCLUSIONS: FM levels at admission had a fair accuracy to predict PHI in patients with severe TBI. FM values ≥ 131.7 µg/ml are independently associated with the occurrence of PHI.

Prognostic role of D-dimer level upon admission in patients with traumatic brain injury.

BACKGROUND: The aim of this study was to evaluate the prognostic role of D-dimer level upon admission in patients with traumatic brain injury (TBI) through performing a meta-analysis. METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE were searched for potential eligible literature. The study characteristics and relevant data were extracted. Poor functional outcome was defined according to the Glasgow Outcome Scale (GOS ≤3). Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the predictive value of D-dimer for progressive hemorrhagic injury (PHI) and poor functional outcome at 3 months (3M GOS ≤3) in patients with TBI. RESULTS: Eleven studies with 2761 patients were included. Eight studies examined the predictive role of higher D-dimer level for the risk of PHI, and the pooled OR was 1.72 (95% CI, 1.23-2.42). Three studies examined the predictive role of higher D-dimer level for the risk of 3M GOS ≤3, and the pooled OR was 2.00 (95% CI, 0.87-4.59). Significant between-study heterogeneities were observed, and sensitivity analyses and subgroup analyses were performed. No significant publication bias was found. CONCLUSIONS: In conclusion, in patients with TBI, higher D-dimer level upon admission was associated with higher risk of PHI, yet no significant relationship was found between D-dimer level and the risk of 3M GOS ≤3. In the future, this readily available marker could help identify patients at risk and tailor management of these patients, thus reducing PHI and improving outcome.

Differences in Neuropeptide Y Secretion Between Intracerebral Hemorrhage and Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Neuropeptide Y (NPY) is one of the most potent endogenous vasoconstrictors, and its contribution to the multifactorial cascade of cerebral vasospasm due to nontraumatic subarachnoid hemorrhage (SAH) is not yet fully understood. This experimental study compared the hemorrhage-specific course of NPY secretion into cerebrospinal fluid (CSF) and into plasma between 2 groups: patients with SAH and patients with basal ganglia hemorrhage (BGH) or cerebellar hemorrhage (CH) over the first 10 days after hemorrhage. MATERIALS AND METHODS: Seventy-nine patients were prospectively included: SAH patients (n=66) (historic population) and intracerebral hemorrhage patients (n=13). All patients received an external ventricular drain within 24 hours of the onset of bleeding. CSF and plasma were drawn daily from day 1 to day 10. The levels of NPY were determined by means of competitive enzyme immunoassay. The CSF samples of 29 patients (historic population) who had undergone spinal anesthesia due to orthopedic surgery served as the control group. RESULTS: NPY levels in CSF were significantly higher in the 2 hemorrhage groups than in the control group. However, the 2 hemorrhage groups showed significant differences in NPY levels in CSF (SAH mean, 0.842 ng/mL vs. BGH/CH mean, 0.250 ng/mL; P<0.001) as well as in the course of NPY secretion into CSF over the 10-day period. NPY levels in plasma did not differ significantly among SAH, BGH/CH, and controls. CONCLUSIONS: Our findings support the hypothesis that excessive release of NPY into CSF but not into plasma is specific to aneurysmal SAH in the acute period of 10 days after hemorrhage. In BGH/CH, CSF levels of NPY were also increased, but the range was much lower.

Plasma copeptin level predicts acute traumatic coagulopathy and progressive hemorrhagic injury after traumatic brain injury.

Higher plasma copeptin levels correlate with poor clinical outcomes after traumatic brain injury. Nevertheless, their links with acute traumatic coagulopathy and progressive hemorrhagic injury are unknown. Therefore, we aimed to investigate the relationship between plasma copeptin levels, acute traumatic coagulopathy and progressive hemorrhagic injury in patients with severe traumatic brain injury. We prospectively studied 100 consecutive patients presenting within 6h from head trauma. Progressive hemorrhagic injury was present when the follow-up computerized tomography scan reported any increase in size or number of the hemorrhagic lesion, including newly developed ones. Acute traumatic coagulopathy was defined as an activated partial thromboplastic time greater than 40s and/or international normalized ratio greater than 1.2 and/or a platelet count less than 120×10(9)/L. We measured plasma copeptin levels on admission using an enzyme-linked immunosorbent assay in a blinded fashion. In multivariate logistic regression analysis, plasma copeptin level emerged as an independent predictor of progressive hemorrhagic injury and acute traumatic coagulopathy. Using receiver operating characteristic curves, we calculated areas under the curve for progressive hemorrhagic injury and acute traumatic coagulopathy. The predictive performance of copeptin was similar to that of Glasgow Coma Scale score. However, copeptin did not obviously improve the predictive value of Glasgow Coma Scale score. Thus, copeptin may help in the prediction of progressive hemorrhagic injury and acute traumatic coagulopathy after traumatic brain injury.

Association between peripheral oxidative stress and white matter damage in acute traumatic brain injury.

The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.

Platelet activation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage.

BACKGROUND: Traumatic brain injury (TBI) and hemorrhage are the leading causes of trauma-related mortality. Both TBI and hemorrhage are associated with coagulation disturbances, including platelet dysfunction. We hypothesized that platelet dysfunction could be detected early after injury, and that this dysfunction would be associated with early activation, as measured by circulating levels of platelet activation markers. METHODS: A total of 33 swine were allocated to TBI and hypotension (n = 27, TBI and volume-controlled 40% blood loss) or controls (n = 6, anesthesia and instrumentation only). Animals in the TBI/Hemorrhage group were left hypotensive, defined as mean arterial pressure of 35 mm Hg, for 2 hours. Blood samples were drawn at baseline and 3 minutes and 15 minutes following injury as well as following 2 hours of shock. Samples were analyzed for platelet aggregation using impedance aggregometry with agonists collagen, arachidonic acid, and adenosine diphosphate (ADP) and thromboelastography (TEG) and circulating levels of platelet activation markers transforming growth factor-ß (TGF-ß), CD40 ligand, and sP-selectin. RESULTS: Platelet ADP aggregation was significantly lower in the TBI/Hemorrhage group when compared with the control group 15 minutes following injury (62.4 vs. 80.4 U, p = 0.03) as well as following 2 hours of hypotension (59.9 vs. 73.5 U, p < 0.01). The latter was associated with lower TEG measured clot strength (TEG-MA, 74.1 vs. 79.4 mm, p = 0.05). No difference in collagen or arachidonic acid aggregation was observed. TGF-ß levels were significantly higher in the TBI/Hemorrhage group following 2 hours of hypotension (1,764 vs. 1,252 pg/mL, p = 0.01). No differences in CD40 ligand or sP-selectin levels were observed. CONCLUSION: In this combined model of TBI and hemorrhage, a significantly lower ADP-induced platelet aggregation was detected 15 minutes following injury that was further aggravated during the 2-hour shock period. This dysfunction was associated with an increase in platelet activation marker TGF-ß.

Traumatic brain injury-associated coagulopathy.

Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI.

Ability of S100B to predict severity and cranial CT results in children with TBI.

OBJECTIVES: To evaluate the ability of S100B to predict severity of TBI and abnormal cranial CT results for children with TBI. METHODS: This is a secondary analysis of a previously established cohort of consecutive patients presenting to the emergency department with TBI limited to children <19 years of age, who arrived within 6 hours of injury, received a cranial CT scan and consented to blood drawn for S100B. RESULTS: A total of 109 children were included in this cohort. The mean S100B levels were higher in children with moderate/severe TBI as compared to children with mild TBI based GCS score (0.281 µg L(-1), 95%CI = 0.101, 0.461 vs 0.053, 95%CI = 0.010, 0.095). S100B levels were significantly elevated in children following TBI with abnormal cranial CT as compared to children with a normal cranial CT (0.210 µg L(-1), SD = 0.313 vs 0.036 µg L(-1), SD = 0.046, p = 0.03). Area under the curve for S100B was also significant (0.72, 95%CI = 0.58, 0.86) for prediction of abnormal cranial CT for children with TBI. S100B did not predict abnormal cranial CT for children following TBI with a GCS of 15 (AUC = 0.53, 95%CI = 0.36, 0.71). CONCLUSIONS: For children following TBI, S100B appears to predict severity of TBI; however, it may not be clinically useful as an independent screening test to select children with mild TBI who need a cranial CT.

Alcohol binge before trauma/hemorrhage impairs integrity of host defense mechanisms during recovery.

BACKGROUND: Alcohol abuse, both chronic and acute, is a known modulator of immune function and is associated with increased incidence of traumatic injury. Previously, we demonstrated that acute alcohol intoxication before hemorrhagic shock impairs hemodynamic and neuroendocrine counterregulation, suppresses early lung proinflammatory cytokine expression, and increases mortality from infection during recovery. In the present study, we examined the impact of a 3-day alcohol binge on host responses during trauma/hemorrhage (T x Hem) and following overnight recovery. METHODS: Chronically catheterized, adult male Sprague-Dawley rats were administered an intragastric bolus of alcohol (5 g/kg; 30% w/v) or isocaloric dextrose solution for 3 consecutive days, followed by a 2.5 g/kg dose on day 4 before undergoing full-thickness muscle-crush and fixed pressure (approximately 40 mmHg) hemorrhage and fluid resuscitation (2.4 x total blood volume removed). RESULTS: Alcohol-binge produced a 16% decrease in basal mean arterial blood pressure (MABP), reduced the total blood loss required to reach and to sustain MABP of 40 mmHg, markedly blunted the increase in circulating epinephrine and norepinephrine (20-fold and 3-fold, respectively) levels, and increased immediate mortality from T x Hem. Consistent with our previous reports, significant up-regulation in lung and spleen tumor necrosis factor (TNF)-alpha and interleukin (IL)-1alpha expression was observed immediately following T x Hem and fluid resuscitation. Only the T x Hem-induced increase in lung TNF-alpha was prevented by binge alcohol administration. Following overnight recovery, significant lipopolysaccharide (LPS)-stimulated release of TNF-alpha, IL-1alpha, IL-6, and IL-10 was observed in cells isolated from blood and the alveolar and pleural compartments from all experimental groups. While T x Hem did not prevent LPS-induced release of TNF-alpha, IL-1alpha, IL-6, or IL-10 at 6 or 24 hours, alcohol binge suppressed TNF-alpha, IL-1 and IL-6 release, without altering IL-10 response in cells isolated from blood and pleural compartment. No significant modulation of alveolar macrophage response was observed following alcohol binge and T x Hem. CONCLUSIONS: These results indicate that a 3-day alcohol binge results in hemodynamic instability associated with attenuated neuroendocrine activation and increased mortality during T x Hem as well as sustained suppression of the proinflammatory cytokine response of blood and pleural-derived cells to a "second-hit" inflammatory challenge. As a result, we speculate that the net shift toward an anti-inflammatory state may contribute to enhanced susceptibility to infection during the recovery period.

[Uncontrollable bleeding in a patient with head trauma treated with blood component therapy guided by thromboelastography]. / Ukontrollabel blødning hos en patient med hovedtraume behandlet med blodkomponentterapi vejledt af tromboelastografi.

This is a case report concerning a patient with traumatic uncontrolled bleeding. The patient was admitted with a severe head injury and facial fractures. During neurosurgery, the bleeding became life-threatening and there was a request for recombinant factor VIIa therapy (NovoSeven). Before the treatment, thromboelastography was performed. This showed platelet insufficiency, and after infusion of platelets, the bleeding was under control and there was no longer a need for recombinant factor VIIa therapy. We therefore recommend thromboelastography to evaluate coagulation status before treatment with recombinant factor VIIa.

Traumatic brain injury in anticoagulated patients.

BACKGROUND: Coumadin is widely used in the elderly population. Despite its widespread use, little is known about its effect on the outcome of elderly traumatic brain-injured patients. This study was undertaken to describe the outcomes of such a cohort. METHODS: Clinical material was identified from a Level I trauma center prospective head injury database, and a database obtained from the American College of Surgeons Committee on Trauma Verification and Review Committee from 1999 to 2002. Both databases contain many relevant variables, including age, sex, Glasgow Coma Scale (GCS) score, mechanism of injury, Injury Severity Score, International Normalized Ratio (INR), computed tomography (CT) findings, operative procedure, time to operating room, complications, length of stay, and outcome at hospital discharge. RESULTS: For patients with GCS scores less than 8, average INR was 6.0, with almost 50% having an initial value greater than 5.0. Overall mortality was 91.5%. For the 77 patients with GCS scores of 13 to 15, average INR was 4.4. Overall mortality for this group was 80.6%. A subset of patients deteriorated to a GCS score of less than 10 just hours after injury, despite most having normal initial CT scans. Mortality in this group was 84%. CONCLUSIONS: All patients on warfarin should have an INR performed, and a CT scan should be done in most anticoagulated patients. All supratherapeutically anticoagulated patients, as well as any anticoagulated patient with a traumatic CT abnormality, should be admitted for neurologic observation and consideration given to short term reversal of anticoagulation. Routine repeat CT scanning at 12 to 18 hours or when even subtle signs of neurologic worsening occur is a strong recommendation. A multi-institutional, prospective trial using these guidelines would be a first step toward demonstrating improved outcomes in the anticoagulated patient population after head trauma.