fibrin and Brain-Injuries

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

Vitronectin (VN), one of the serum proteins, is known to be involved in the regulation of blood coagulation, fibrinolysis, and cell migration. It has been proposed that the regulation of fibrinolysis by VN promotes the blood-brain barrier (BBB) recovery from brain injuries such as traumatic injury and subarachnoid hemorrhage. The effects of VN on fibrinolysis in the injured brain remain unclear, however. We examined the effects of VN on the fibrinolytic system in the stab-wounded cerebral cortex of VN-knockout (KO) mice. First, hemorrhage and recovery from BBB breakdown in the wounded regions were assessed by serum immunoglobulin G (IgG) extravasation. The level of IgG extravasation increased 3-7 days after the stab wound (D3-7) in the cortex of VN-KO mice, compared with that in wild type mice, indicating that VN deficiency inhibited the recovery from BBB breakdown. The VN deficiency decreased fibrin fiber deposition at D1-3, suggesting that VN deficiency tilts the balance between fibrinogenesis and fibrinolysis toward fibrinolysis. Next, the effects of VN deficiency on the fibrinolytic factors were analyzed in the stab-wounded cortex. The VN deficiency impaired the activity of plasminogen activator inhibitor-1, an inhibitor of the fibrinolytic system, at D3-5. Further, VN deficiency up-regulated the mRNA and protein expression levels of tissue-type plasminogen activator, and urokinase-type plasminogen activator. These results demonstrate that VN contributes to the regulation of the fibrinolytic system and recovery from BBB breakdown in the wounded brain.

Topics: Animals; Blood-Brain Barrier; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Fibrin; Fibrinolysis; Head Injuries, Penetrating; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; RNA, Messenger; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vitronectin

Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries.

Topics: Animals; Brain Injuries; Crotalus; Disease Models, Animal; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematoma; Hemorrhage; International Normalized Ratio; Intraoperative Complications; Male; Prothrombin Time; Rats; Rats, Sprague-Dawley; Snake Venoms

Persistent intracerebral hemorrhage (ICH) is a major cause of death and disability after traumatic brain injury (TBI) for which no medical treatment is available. Delayed bleeding is often ascribed to consumptive coagulopathy initiated by exposed brain tissue factor. We examined an alternative hypothesis, namely, that marked release of tissue-type plasminogen activator (tPA) followed by delayed synthesis and release of urokinase plasminogen activator (uPA) from injured brain leads to posttraumatic bleeding by causing premature clot lysis. Using a murine model of severe TBI, we found that ICH is reduced in tPA(-/-) and uPA(-/-) mice but increased in PAI-1(-/-) mice compared with wild-type (WT) mice. tPA(-/-), but not uPA(-/-), mice developed a systemic coagulopathy post-TBI. Tranexamic acid inhibited ICH expansion in uPA(-/-)mice but not in tPA(-/-) mice. Catalytically inactive tPA-S(481)A inhibited plasminogen activation by tPA and uPA, attenuated ICH, lowered plasma d-dimers, lessened thrombocytopenia, and improved neurologic outcome in WT, tPA(-/-), and uPA(-/-) mice. ICH expansion was also inhibited by tPA-S(481)A in WT mice anticoagulated with warfarin. These data demonstrate that protracted endogenous fibrinolysis induced by TBI is primarily responsible for persistent ICH and post-TBI coagulopathy in this model and offer a novel approach to interrupt bleeding.

Topics: Animals; Antifibrinolytic Agents; Brain; Brain Injuries; Cerebral Hemorrhage; Fibrin; Fibrinolysis; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Mutation; Plasminogen; Plasminogen Activator Inhibitor 1; Protein Binding; Time Factors; Tissue Plasminogen Activator; Tranexamic Acid; Urokinase-Type Plasminogen Activator

In this study the authors' aim was to assess whether fibrin matrix could act as an injectable, valuable scaffold in bone marrow stromal cell (BMSC) transplantation for injured CNS tissue.. Both clotting time and 3D structure of fibrin matrix were analyzed with various concentrations of fibrinogen and CaCl(2). The BMSCs were harvested from green fluorescent protein-transgenic mice and cultured. A cortical lesion was produced in rats by application of a very cold rod to the right cerebral hemisphere. The BMSCs, fibrin matrix, or BMSC-fibrin matrix complex was transplanted into the lesion though a small bur hole 7 days after the insult. Using immunohistochemical analysis, the authors evaluated the survival, migration, and differentiation of the transplanted cells 4 weeks after transplantation.. Based on in vitro observations, the concentrations of fibrinogen and CaCl(2) were fixed at 2.5 mg/ml and 2 microM in animal experiments, respectively. Fibrin matrix almost completely disappeared 4 weeks after transplantation. However, immunohistochemical analysis revealed that fibrin matrix exclusively enhanced the retention of the transplanted cells within the lesion, migration toward the lesion boundary zone, and differentiation into the neurons and perivascular cells.. Injectable fibrin matrix enhanced the survival, migration, and differentiation of the BMSCs transplanted into the cortical lesion in rats. The authors believe that it is one of the promising candidates for a potential, minimally invasive scaffold for CNS disorders. The present findings strongly suggest that such a strategy of tissue engineering could be a therapeutic option for CNS regeneration in patients with CNS injuries.

Topics: Absorbable Implants; Animals; Bone Marrow Transplantation; Brain Injuries; Calcium Chloride; Cell Differentiation; Cell Movement; Cell Survival; Fibrin; Green Fluorescent Proteins; Male; Mice; Mice, Transgenic; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stromal Cells; Tissue Scaffolds; Treatment Outcome

Although coagulopathy is known to be the major contributor to a poor outcome of traumatic brain injury (TBI), the mechanisms that trigger coagulation abnormalities have not been studied in detail. We undertook a prospective observational study at a neurosurgical ICU (NICU) in a university hospital. We examined 11 patients with severe isolated TBI, at admittance to the hospital and during the next 3 days. We collected cerebrovenous blood samples from a jugular bulb catheter, arterial blood, and cerebrospinal fluid (CSF) samples. We measured concentrations of thrombin-antithrombin complex (TAT), fibrin D-dimer (DD), prothrombin fragment 1 + 2 (F1 + 2), interleukin-6 (IL-6), and complement complex (C5b-9). All patients had some degree of consumption coagulopathy at the study start and a tendency to thrombocytopenia during the next few days. Levels of DD (3.6 +/- 2.7 mg/L), TAT (86 +/- 72 microg/L) and F1 + 2 (5.9 +/- 6.8 nmol/L) were significantly increased shortly after the trauma compared to reference values, with considerable transcranial gradients for TAT (49 microg/L) and F1 + 2 (3.2 nmol/L). Compared to controls, IL-6 levels were increased more than a hundredfold in both blood (283 +/- 192 ng/L) and CSF (424 +/- 355 ng/L) samples, with a transcranial gradient at the study start (107 ng/L). C5b-9 levels were moderately increased in blood samples, 270 +/- 114 microg/L, versus controls, 184 +/- 39 (p < 0.05). We conclude that activation of the coagulation system takes place during the passage of blood through the damaged brain, and is already evident hours after the trauma. IL-6 and activation of the complement system (C5b-9) co-vary with hemostatic parameters in TBI patients.

Topics: Accidents; Adult; Antithrombins; Biomarkers; Blood Coagulation Disorders; Blood Coagulation Tests; Brain Injuries; Complement Membrane Attack Complex; Female; Fibrin; Glasgow Coma Scale; Humans; Inflammation; Interleukin-6; International Normalized Ratio; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Thrombin

The current study was designed to evaluate the effects of basic fibroblast growth factor (bFGF) on human BMSC (hBMSC) transplantation-mediated neural regeneration in traumatic brain injury (TBI). Fibrin gel was used as a delivery vehicle to release bFGF locally in the TBI sites in a controlled manner. To test this hypothesis, hBMSCs suspended in fibrin gel containing bFGF were transplanted to rat TBI sites. Transplantation of hBMSCs suspended in fibrin gel without bFGF served as a control. hBMSC transplantation and bFGF treatment showed enhanced neural tissue regeneration than that of the control. The infarction volume and apoptotic activity of the transplanted hBMSCs were significantly decreased, and functional outcomes were significantly improved in the hBMSC transplantation and bFGF treatment group than in the control group. This study demonstrates that bFGF significantly enhances histological and functional recovery when used in hBMSC transplantation therapy in TBI.

Topics: Animals; Brain Injuries; Combined Modality Therapy; Drug Carriers; Fibrin; Fibroblast Growth Factor 2; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Nerve Regeneration; Rats; Rats, Sprague-Dawley; Stromal Cells; Treatment Outcome

Secondary thrombosis may contribute to cerebral ischemia caused by traumatic brain injury (TBI). In this study, we sought to investigate the temporal and spatial profiles of intravascular thrombosis and to evaluate the effect of atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor, on thrombosis after TBI. Young male Wistar rats weighing 350-400 g were subjected to controlled cortical impact injury, and were sacrificed at 1 and 4 h, and 1, 3, 8, and 15 days after TBI (5 rats/time point), respectively. For the evaluation of the effects of atorvastatin on intravascular thrombosis, rats were subjected to TBI, and subsequently atorvastatin (1 mg/kg) was orally administered starting 1 day after TBI and then daily until sacrifice at 3, 8, and 15 days after TBI (5 rats/time point). Before sacrifice of animals, blood was withdrawn and employed for the measurement of von Willibrand factor and platelet activity using enzyme-linked immunoabsorbant assay (ELISA). Brain tissues were prepared for histological analysis. The data show that (1) delayed thrombosis is present in the lesion boundary zone and in the hippocampal CA3 region, starting at 1-4 h, peaking at 1-3 days, and then declining at 8 and 15 days after TBI; (2) intravascular thrombosis also occurs in the other areas of cortex, striatum, and corpus callosum, but with a scattered distribution; (3) delayed thrombi are composed of platelets, fibrin, and vWF; and (4) reduction of the plasma vWF level and platelet activity by atorvastatin decreases delayed thrombosis after TBI. These data suggest that atorvastatin reduces intravascular thrombosis attributed to hemostatic disturbances caused by TBI.

Topics: Animals; Atorvastatin; Blood Coagulation Factors; Brain; Brain Injuries; Disease Models, Animal; Fibrin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Thrombosis; Male; Pyrroles; Rats; Rats, Wistar; Time Factors

Several mechanisms are involved in the development of secondary ischemic brain damage, including microthrombi formation, which is thought to play a prominent role. Ninety-four autopsy cases were macro- and microscopically examined by specific staining for fibrin, 74 of which showed cortical contusion after a craniocerebral trauma. Twenty cases with no neurological pathology were used as controls. Traumatic cases comprised 52 males and 22 females, with a mean age of 48 years; most cases died in the first 48 h. The total number of fibrinous microthrombi in a slice of each hemisphere was determined. The mean number of microthrombi found in contused hemisphere was 152 (37-283), with 88 in the contralateral hemisphere (21-139) as compared to 13 (0-27) in control cases. Differences were statistically significant. Globular microthrombi or "shock bodies" (2-60 micro diameter) were present in five cases. Enhanced presence of microthrombi in contused brain areas, higher incidence in young people, an increase in the amount of microthrombi up to the 9th day after injury and involvement of the contralateral hemisphere free of contusion foci were all demonstrated. Microthrombi would therefore seem to be one of the central secondary events after brain trauma to bear in mind when designing treatment strategies.

Topics: Adolescent; Adult; Aged; Autopsy; Brain; Brain Injuries; Child; Child, Preschool; Female; Fibrin; Functional Laterality; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Rheology; Skull; Survival Analysis; Time Factors

Cortical biopsies of eight patients with craniocerebral trauma complicated with subdural or epidural hematoma were examined with the transmission electron microscope. The patients showed post-traumatic neurobehavioural disorders and moderate or severe vasogenic brain edema. The capillary wall displayed increased vacuolar and vesicular endothelial transport, basement membrane thickening and vacuolization and swollen astrocytic end-feet. Pericapillary and parenchymatous hemorrhages were also observed. The extracellular space appeared considerably enlarged with presence of proteinaceous hematogenous edema fluid and fibrinous organization. Pyramidal and non-pyramidal neurons showed intracellular edema featured by irregular enlargement of rough endoplasmic reticulum, nuclear envelope and Golgi apparatus. The myelinated axons exhibited clear or black type axoplasmic degeneration, varicose fiber swelling, myelin sheath distortion, formation of myelin ovoids and increased amount of oligodendroglial ad-axonal layer. The dendrites also showed clear or dark and beaded shape degeneration. Synaptic degeneration was characterized by swollen and shrunken pre- and postsynaptic endings, clumping, enlargement and depletion of synaptic vesicles, synaptic membrane complex disassembly and detachment of glial ensheathment. Perivascular and perineuronal astrocytes appeared remarkably swollen. Phagocytic astrocytes were also found. Oligodendrocytes displayed hydropic and reactive changes. Reactive oligodendrocytes induced myelinolysis. The brain barrier dysfunction, the vasogenic and cytotoxic edema and the subsequent neuronal and neuroglial cell reactive and degeneration processes might represent the morphological substrate responsible for the post-traumatic neurobehavioural disorders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Behavioral Symptoms; Blood-Brain Barrier; Brain Edema; Brain Injuries; Capillaries; Cerebral Cortex; Female; Fibrin; Humans; Male; Microscopy, Electron; Middle Aged; Nerve Degeneration; Neurocognitive Disorders

Although fibrin adhesives are popular in the field of neurosurgery, the medical literature is devoid of study elucidating their effects on the brain tissue. To study the safety of applying fibrin glue to the brain and to explore new surgical potentialities, we implanted soft pellets made of fibrin glue into the brains of Wistar rat. Following 6 h and 3, 7 and 14 days post-implantation survival, the brains were removed and paraffin sections were processed for hematoxylin-eosin staining, as well as immunohistochemistry for microtubule-associated protein (MAP-1A) and glial fibrillary acidic protein. The changes in the neuronal and glial elements and also the numbers of inflammatory and endothelial cells in the vicinity of implanted fibrin glue pellets were compared with those of gelfilm pellets. The results demonstrated that topical application of fibrin glue to the brain causes significantly enhanced local accumulation of mononuclear cells and promoted angiogenesis close to the wound while not affecting the neuronal and glial elements. These findings suggest that fibrin glue can be considered as a safe supportive material for intradural procedures directly involving the brain tissue.

Topics: Adhesives; Animals; Astrocytes; Brain; Brain Injuries; Drug Implants; Endothelium, Vascular; Fibrin; Gelatin; Inflammation; Male; Microtubule-Associated Proteins; Neovascularization, Pathologic; Neurons; Neutrophils; Rats; Rats, Wistar

To test the hypothesis that hypercoagulability after brain trauma was related to the severity of injury and also to outcome, new coagulation markers were used in 20 patients with isolated brain trauma. In addition to routine coagulation tests, soluble fibrin (SF), D-dimer, and antithrombin (AT) levels were assessed. Thirteen of 20 patients had a Glasgow coma score (GCS) of < or = 7 on admission and severe disability (SD) or worse on the Glasgow outcome scale (GOS). Eight patients had a very bad outcome [GOS = dead (D) or vegetative (V)]. All patients had increased SF levels (ref. < 15 nmol/L) at admission. Six patients with SF < 50 nmol/L had a good outcome with moderate disability (MD) or better. Patients with increasingly higher SF levels had a worse outcome: Three of five patients with SF 50 to 150 nmol/L were severely disabled (SD) or worse; four of six patients with SF > 150 nmol/L remained vegetative (V) or died (D). Four of the six patients with the highest D-dimer levels at admission remained vegetative (V) or died (D). Six of 13 patients with a significant drop in AT levels had a bad outcome (D or V) whereas only two of seven patients without AT consumption did poorly. Routine coagulation studies were often pathologic, i.e., reduced platelet count, but there was no relation to outcome. Increased SF and D-dimer levels at admission followed by a secondary decrease in AT concentration and platelets seem to be good markers of the posttraumatic hypercoagulation often seen after brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Coagulation Disorders; Brain Injuries; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Partial Thromboplastin Time; Prognosis; Prothrombin Time; Severity of Illness Index; Solubility

Axonal regeneration of septal cholinergic neurons was examined after lesion of the septohippocampal pathway of the adult rat and implantation of tubes containing peripheral cellular or acellular substrates. After empty tube implantation, no regenerated structures were observed in the conduit. However, after implanting tubes filled with sections of predegenerated sciatic nerves or a fibrin-fibronectin-containing matrix provided by peripheral regeneration chambers, numerous regenerated axons were detected 6 weeks after the operation. At the electron microscopic level, regenerated axons were observed in the grafted sciatic nerves in contact with Schwann cells but also in contact with astrocytes which were able to migrate and send processes into the graft. After fibrin-fibronectin-containing-matrix implantation, the regenerated structure between septum and hippocampus was composed mainly of fibroblasts, astrocytes, and regenerated axons associated to these central glial cells.

Topics: Acetylcholine; Animals; Astrocytes; Axons; Brain Injuries; Cell Movement; Fibrin; Fibronectins; Hippocampus; In Vitro Techniques; Nerve Regeneration; Neurons; Peripheral Nerves; Rats; Rats, Wistar; Sciatic Nerve; Septum Pellucidum

Topics: Afibrinogenemia; Blood Coagulation Disorders; Blood Coagulation Tests; Brain Injuries; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Fibrin; Fibrinogen; Humans; Plasma Substitutes

Three cases with intracranial lesions developed evidence of disseminated intravascular coagulation which was confirmed at necropsy. The factors engendering this state, including release of potent thromboplastin from neural tissue are discussed and the danger of this intermediary mechanism of disease increasing the mortality of intracranial disease is demonstrated. Careful haematological investigation of all patients with intracranial disease is therefore advised, especially if they manifest evidence of a bleeding tendency.

Topics: Adult; Blood Cell Count; Blood Platelets; Brain Abscess; Brain Injuries; Cerebral Cortex; Cerebral Hemorrhage; Child; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Hemoglobinometry; Humans; Kidney; Male; Necrosis; Prothrombin Time; Thrombin

Topics: Brain Injuries; Disseminated Intravascular Coagulation; Fibrin; Humans

Topics: Abortion, Criminal; Accidents, Traffic; Adult; Animals; Brain; Brain Injuries; Cerebral Hemorrhage; Embolism, Air; Female; Fibrin; Forensic Medicine; Heart Ventricles; Humans; Injections; Intracranial Embolism and Thrombosis; Male; Middle Aged; Pregnancy; Rabbits