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
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