BACKGROUND Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU–endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.

TXA after TBI, improves rodent BBB integrity and neurological recovery but only if administered early after injury. Late TXA administration increases rolling leukocyte mobilization to the penumbra.

BACKGROUND:Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS:Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS:Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01).Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05). CONCLUSION:Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI.

Beta blockade in severe traumatic brain injury has shown improvements in survival and recovery after injury. This paper demonstrates in a series of in vivo and ex vivo experiments a potential mechanism for this benefit using a live rodent TBI model.