Human Recombinant Factor VIIa is Neuroprotective in a Model of Traumatic Brain Injury and Secondary Hypoxemia

摘要

Factor VII (FVII) circulates in plasma as a zymogen until it is exposed to tissue factor (TF). When bound to TF, activated FVII (FVIIa) initiates the extrinsic coagulation cascade that results in the formation of a polymerized fibrin clot. In the untraumatized brain, TF is physically isolated from FVII. However, traumatic brain injury (TBI) frequently results in the disruption of the vascular endothelium and resultant exposure of FVII to subendothelial TF. Recent evidence suggests that proinflammatory cytokines(IL-1, IL-6,TNFa) can induce the upregulation of TF. Since these cytokines also have been implicated in the inflammatory response to TBI, it is conceivable that, in the traumatized brain, treatment with recombinant (r) FVIIa might exacerbate injury-induced coagulopathy. In an effort to evaluate this hypothesis. rats were trained to execute a visual discrimination and locate the submerged platform in a Morris water maze (MWM) before being subjected to moderate parasaggittal fluid percussion injury (FPI) immediately followed by 30 min of 10% of O2. Ten min before FPI, rats were injected IV with 4 mg/kg of human rFVIIa; clotting and factor assays revealed that this was a hemostatically active dose. Visual discrimination performance was continuously recorded for two weeks after FPI and on day 7 after FPI, retention was tested in the MWM. After a two-week recovery period, brains were perfusion fixed and processed for histological evaluation. Contrary to our expectation, preliminary findings revealed that FPI reduced neuronal cell density and disrupted the pyramidal and granule cells of the dentate gyrus less in rats treated with rFVIIa than in rats treated with vehicle. Furthermore, visual discrimination accuracy was reduced less and recovered more rapidly and the mean retention score was larger for rats treated with rFVIIa than for rats treated with vehicle. Thus, rather than revealing a therapeutic complication, these preliminary findings agree with recent data.