fibrin and Brain-Injuries--Traumatic

Several studies have demonstrated the clinical utility of tranexamic acid (TXA) for use in trauma patients presenting with significant hemorrhage. Tranexamic acid is an antifibrinolytic that inhibits plasminogen activation, and plasmin activity has been shown to mitigate blood loss and reduce all-cause mortality in the absence of adverse vascular occlusive events. Recent clinical developments indicate TXA is safe to use in patients with concomitant traumatic brain injury (TBI); however, the prehospital effects are not well understood. Importantly, TXA has been associated with seizure activity. Therefore, this study sought to evaluate the effects of early administration of TXA on neurological recovery and electroencephalogram (EEG) abnormalities following penetrating TBI with concomitant hypoxemia and hemorrhagic shock. We hypothesized that early administration of TXA will provide hemodynamic stabilization and reduce intracerebral hemorrhage, which will result in improved neurological function. To test this hypothesis, Sprague-Dawley rats received a unilateral, frontal penetrating ballistic-like brain injury by inserting a probe into the frontal cortex of the anesthetized rat. Five minutes following brain injury, animals underwent 30 min of respiratory distress and 30 min of hemorrhage. Upon completion of the hemorrhage phase, animals received the initial dose of drug intravenously over 10 min after which the prehospital phase was initiated. During the prehospital phase, animals received autologous shed whole blood as needed to maintain a MAP of 65 mm Hg. After 90 min, "in-hospital" resuscitation was performed by administering the remaining shed whole blood providing 100% oxygen for 15 min. Upon recovery from surgery, animals were administered their second dose of vehicle or TXA intravenously over 8 h. Tranexamic acid induced an early improvement in neurologic deficit, which was statistically significant compared with vehicle at 24, 48, and 72 h at three doses tested. Analysis of cerebral hemoglobin content and intracerebral lesion progression revealed 100 mg/kg provided the optimal effects for improvement of neuropathology and was continued for determination of adverse treatment effects. We observed no exacerbation of cerebral thrombosis, but TXA treatment caused an increased risk of EEG abnormalities. These results suggest that TXA following polytrauma with concomitant brain injury may provide mild neuroprotective effects by preventing lesion progression

Topics: Animals; Antifibrinolytic Agents; Brain Injuries; Brain Injuries, Traumatic; Electroencephalography; Fibrin; Head Injuries, Penetrating; Hemorrhage; Multiple Trauma; Rats; Rats, Sprague-Dawley; Tranexamic Acid

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.

Topics: Adolescent; Adult; Age Factors; Aged; Blood Coagulation; Brain Injuries, Traumatic; Cohort Studies; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Injury Severity Score; Male; Middle Aged; Young Adult

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Topics: Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; Capillary Permeability; Cerebral Cortex; Cognition; Fibrin; Hippocampus; Hypertension; Interleukins; Male; Rats; Rats, Inbred SHR; Tumor Necrosis Factor-alpha

The neuroprotective effects of mesenchymal stem cells (MSCs) have been reported in rodent and in preliminary clinical studies. MSCs are usually transplanted to patients by systemic infusion. However, only a few of the infused MSCs are delivered to the brain because of pulmonary trapping and the blood-brain barrier. In this study, MSCs were topically applied to the site of traumatic brain injury (TBI) and the neuroprotective effects were assessed.. TBI was induced in Sprague-Dawley (SD) rats with an electromagnetically controlled cortical impact device after craniotomy was performed between the bregma and lambda, 1 mm lateral to the midline. We applied 1.5 million MSCs, derived from the adipose tissue of transgenic green fluorescent protein (GFP)-SD rats, to the exposed cerebral cortex at the injured site. The MSCs were held in position by a thin layer of fibrin. Neurological function in the test (n = 10) and control (n = 10) animals was evaluated using the rotarod test, the water maze test, and gait analysis at different time points.. Within 5 days following topical application, GFP-positive cells were found in the brain parenchyma. These cells co-expressed with markers of Glial fibrillary acidic protein (GFAP), nestin, and NeuN. There was less neuronal death in CA1 and CA3 of the hippocampus in the test animals. Neurological functional recovery was significantly improved.. Topically applied MSCs can migrate to the injured brain parenchyma and offer neuroprotective effects.

Topics: Administration, Topical; Animals; Animals, Genetically Modified; Antigens, Nuclear; Behavior, Animal; Brain; Brain Injuries, Traumatic; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Disease Models, Animal; Fibrin; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Male; Maze Learning; Mesenchymal Stem Cell Transplantation; Nerve Tissue Proteins; Nestin; Rats; Rats, Sprague-Dawley; Recovery of Function; Rotarod Performance Test