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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purified thrombin from an exogenous source is a hemostatic agent commonly used in neurosurgical procedures. The toxicity of thrombin in the brain, however, has not been examined. This study was performed to assess the effect of thrombin on brain parenchyma, using the formation of brain edema as an indicator of injury. Ten microliters of test solution was infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later, and the extent of brain edema and ion content were measured. Concentrations of human thrombin as low as 1 U/microliter resulted in a significant increase in brain water content. Rats receiving 10 U/microliters had a mortality rate of 33% compared to no mortality in the groups receiving smaller doses. Thrombin-induced brain edema was inhibited by a specific and potent thrombin inhibitor, hirudin. A medical grade of bovine thrombin commonly used in surgery also caused brain edema when injected at a concentration of 2 U/microliters. Edema formation was prevented by another highly specific thrombin inhibitor, N alpha-(2-Naphthalenesulfonylglycyl)-4-DL-phenylalaninepiperidid e (alpha-NAPAP). Thrombin-induced brain edema was accompanied by increases in brain sodium and chloride contents and a decrease in brain potassium content. Changes in brain ions were inhibited by both hirudin and alpha-NAPAP, corresponding to the inhibition of brain water accumulation. This study shows that thrombin causes brain edema when infused into the brain at concentrations as low as 1 U/microliter, an amount within the range of concentrations used for topical hemostasis in neurosurgery.
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PMID:Intracerebral infusion of thrombin as a cause of brain edema. 749 Jun 19

The causes and characteristics of the brain edema which forms adjacent to an acute intracerebral hemorrhage (ICH) have not been explored thoroughly. This study was designed to examine the edema process in rat brain provoked by two different blood clot components. An intracerebral clot was produced by stereotactic injection of 100 microl of either blood (bICH) or cryoprecipitate/thrombin (pICH) into the right caudate nucleus. Water, Na+, K+, and Cl- contents were measured at 0, 4.24, 48, and 72 h after instillation of the clot. During the first 24 h, the water content of the ipsilateral caudate nucleus and cortex gradually increased in both groups. By 48 h brain edema was more severe in the bICH compared to that with pICH in the ipsilateral basal ganglia and cortex. The edema formation was accompanied by significant increase in sodium and chloride, as well as a decrease in potassium content by 48 h and sustained to 72 h. These results suggest that both blood and plasma clots can cause brain edema, but a plasma clot is less damaging than a blood clot in the immediate vicinity of the mass.
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PMID:The effects of blood or plasma clot on brain edema in the rat with intracerebral hemorrhage. 797 48

Thrombin and two different types of control solutions (buffer and albumin) were continuously infused into the rat caudoputamen by an osmotic minipump. Routine histological studies with immunohistochemistry using antibodies for BrdU, GFAP, vimentin and laminin were carried out to assess infiltration of inflammatory cells, formation of edema, cell proliferation, and reactivity of astrocytes and mesenchymal cells. The number of inflammatory cells, number of BrdU positive cells, area and number of vimentin positive astrocytes, and the area of GFAP-positive reactive astrocytes were quantitatively analyzed. In the thrombin group, pale tissue foci due to spongiosis were observed together with infiltration of inflammatory cells, proliferation of mesenchymal cells, and increase of vimentin positive astrocytes which was significantly different from the control groups. The results suggest that thrombin plays an important role in inflammation, brain edema and reactive gliosis following CNS injury.
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PMID:A novel aspect of thrombin in the tissue reaction following central nervous system injury. 797 64

The mechanism by which intracerebral hemorrhage leads to the formation of brain edema is unknown. This study assesses the components of blood to determine if any are toxic to surrounding brain. Various solutions were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; brain edema and ion contents were measured. Whole blood caused an increase in brain water content and ion changes consistent with brain edema. Concentrated blood cells, serum from clotted blood, and plasma from unclotted blood all failed to provoke edema formation when infused directly into the brain. On the other hand, activation of the coagulation cascade by adding prothrombinase to plasma did produce brain edema. The edema response to whole blood could be prevented by adding a specific thrombin inhibitor, hirudin, to the injected blood. This study indicates that thrombin plays an important role in edema formation from an intracerebral blood clot.
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PMID:Edema from intracerebral hemorrhage: the role of thrombin. 861 42

The coagulation cascade has a potential role in brain edema formation due to intracerebral hemorrhage. In this study blood and other solutions were injected stereotactically into the right basal ganglia in rats. Twenty-four hours following injection, brain water and ion contents were measured to determine the amount of brain edema. Intracerebral blood resulted in an increase in brain water content. The amount of brain edema surrounding the intracerebral hematoma was reduced by a thrombin inhibitor N alpha-(2-Naphthalenesulfonylglycyl)-4-amidino-DL-phenylalaninep iperidide, (alpha-NAPAP) infused into the hematoma after the clot had been allowed to solidify. The inhibitor did not alter the actual size of the clot mass. An artificial clot composed of fibrinogen, thrombin, and styrene microspheres also produced brain edema. A fibrin clot led to edema formation even in the absence of mass effect provided by the microspheres. The single component responsible for production of brain edema in all these models was thrombin. The edema was formed in response to a fibrinogen-independent pathway. These results indicate that the coagulation cascade is involved in brain edema that develops adjacent to an intracerebral hematoma.
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PMID:The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage. 873 89

Previous work from this laboratory has shown that injection of thrombin into rat basal ganglia causes brain edema. This study investigates the effect on rat brain of thrombin-soaked gelatin sponge (used for intraoperative hemostasis in clinical situations) at a concentration similar to that used in humans. Three models were developed to evaluate this effect. In the first model, a gelatin sponge soaked with vehicle or thrombin (100 U/cm3) was placed on the intact pia of the right frontal lobe in rats without cortical lesions. In the second model, frontal cortex was excised (3 mm3) and the exposed brain was cauterized with electrocoagulation. Gelatin sponge was soaked with vehicle or thrombin (1000, 100, 10, or 1 U/cm3) and placed in the lesion site. In the third model, hirudin, a specific thrombin antagonist, was added to the thrombin-soaked gelatin sponge and placed in a similar cortical lesion to determine if the observed effects were specific to thrombin. The dose-response range for thrombin was determined qualitatively by magnetic resonance (MR) imaging and quantitatively by brain edema formation 24 hours after exposure. We found no edema in the cortically intact rats. The rats given cortical lesions developed significant edema when subjected to 1000, 100, and 10 U/cm3 thrombin as seen on MR imaging and at 100 and 10 U/cm3 thrombin as revealed by wet/dry weight and ion studies of brain tissue. Topical hirudin prevented thrombin-induced edema. It is concluded that thrombin-soaked gelatin sponges cause or enhance significant brain edema in rats at concentrations typically used for human neurosurgery.
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PMID:Thrombin-soaked gelatin sponge and brain edema in rats. 2366 25

Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin, and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.
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PMID:Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. 901 Apr 29

The coagulation cascade plays an important role in brain edema formation caused by intracerebral blood. In particular, thrombin produces brain injury via direct brain cell toxicity. Seizures and increased cerebral electrical activity are commonly associated with intracerebral blood and are possible effects of thrombin leading to cell injury in the brain. In this study, artificial clots containing concentrations of thrombin found in hematomas were infused intracerebrally in rats. The animals were observed clinically for seizure activity, behavior, and neurological deficits. Several animals underwent video electroencephalographic (EEG) monitoring during intracerebral infusion and for 30 minutes postinfusion. All animals were killed 24 hours after injection, and brain water and ion contents were measured to determine the amount of brain edema. Clinically, thrombin produced focal motor seizures in all animals. None of the control animals or those receiving N[alpha]-(2-Naphthalenesulfonyl-glycyl)-4-amidino-DL-phenylalanine -piperidide (alpha-NAPAP), a thrombin inhibitor added to the thrombin, showed clinical evidence of seizures. Of the rats undergoing EEG monitoring, all animals receiving thrombin showed electrical evidence of seizure activity, whereas none of the control animals exhibited seizure activity. There was no evidence of seizure activity on EEG monitoring when alpha-NAPAP was injected along with the thrombin. In addition, the artificial clots containing thrombin produced agitation and a circling tendency in the rats, along with brain edema. These results indicate that the coagulation cascade is involved in seizure production and increased brain electrical activity, which contribute to the neurological deficits and brain edema formation that are seen with intracerebral hemorrhage.
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PMID:Seizures induced by intracerebral injection of thrombin: a model of intracerebral hemorrhage. 920 68

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.
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PMID:Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion. 972 98

Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
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PMID:Effect of intracerebral and subdural hematomas on energy-dependent transport across the blood-brain barrier. 1059 21


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