Fibrinogen Extravasation is Associated with Microglial Activation and Neuronal Loss in Traumatic Brain Injury (P3.177)

Objective: To explore the association between blood brain barrier (BBB) breakdown and fibrinogen extravasation on inflammation and neuronal loss in human traumatic brain injury (TBI). Background: Despite causing significant mortality and morbidity, TBI has no disease-specific treatment. Recent interest has focused on two potential therapeutic targets: the BBB and inflammation. It is not known if BBB damage contributes to inflammation, or if ensuing inflammation is helpful or injurious. We hypothesized that BBB damage, and the leak of fibrinogen, was a significant driver of microglial activation and subsequent neuronal loss. Design/Methods: Five brain regions from 15 acute ( 1 year) sufferers of moderate and severe TBI were compared with 15 age and sex matched controls. For the first time ever in human TBI studies, neuronal density, axonal injury, BBB damage and inflammation were compared quantitatively by means of immunohistochemistry (>1400 tissue sections). Results: Acute TBI resulted in global BBB damage, with significant fibrinogen and IgG extravasation seen in all brain regions. Extravasation of fibrinogen - but not IgG - correlated significantly with microglial activation (r s 0.52 – 0.60, p 0.03) and neuronal loss (r s −0.59 to −0.71, p 0.021). Microglial activation negatively correlated with neuronal density (r s −0.57 to r s −0.78, p 0.013). Trajectory analysis revealed that the areas highest in fibrinogen were also highest in activated microglia and lowest in neuronal density. No correlation was found between plasma protein extravasation, inflammation and axonal injury. In chronic TBI, fibrinogen and IgG extravasation was negligible and limited to cases of post-traumatic epilepsy. Neither protein correlated with inflammation and neuronal or axonal loss. Conclusions: Acute TBI causes widespread BBB damage. The ensuing extravasation of fibrinogen is significantly correlated with microglial activation and neuronal loss. Obtunding fibrinogen’s interaction with microglia may provide a targeted means for decreasing neurotoxic inflammation in acute TBI. Study Supported by: Surgeon General’s Department Thomas Willis Oxford Brain Bank Disclosure: Dr. Jenkins has nothing to disclose.