ANTITHROMBIN-III AMELIORATES POST-TBI CEREBRAL LEUKOCYTE MOBILIZATION ENHANCING RECOVERY OF BLOOD BRAIN BARRIER INTEGRITY.

BACKGROUND Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. AT-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 BBB permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial (EC) interactions and leakage at the BBB following TBI. METHODS CD1 mice (n=71) underwent either severe TBI (controlled cortical impact; CCI: 6 m/sec velocity, 1 mm depth and 4 mm diameter) or sham craniotomy (SHAM) and then received either AT-III (250 IU/kg), ENX (1.5mg/kg) or VEH (saline) every 24h. 48 hours post-TBI, cerebral intravital microscopy visualized in-vivo, penumbral microvascular EC-LEU interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight (bw) loss and the Garcia Neurological Test (GNT: 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). AT-III also reduced live BBB leakage (p<0.05). AT-III animals demonstrated the least 48-hour bw loss (8.4 ±1%) vs CCI +VEH (11.4 ± 0.5%, p<0.01). GNT scores were similar among groups. CONCLUSIONS AT-III reduces post-TBI penumbral EC-LEU interactions in the BBB leading to reduced neuro-microvascular permeability. AT-III further reduced body weight loss compared to heparinoid or no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer term neurocognitive recovery after TBI. LEVEL OF EVIDENCE Level II Evidence (Therapeutic / care management).