(P-HC-8) Temporal Effects of Prothrombin Complex Concentrate and Anti-thrombin III in Modulation of Traumatic Brain Injury Induced Blood Brain Barrier Permeability and Hemorrhage

Background/Case Studies:

Background: Traumatic brain injury (TBI) is the leading cause of mortality and morbidity. Secondary sequelae are blood-brain barrier (BBB) disruption, inflammation, intracranial hemorrhage (ICH), coagulopathy, and edema. Recent clinical trials have demonstrated the beneficial effects of early plasma resuscitation in the patient population.

Study

Design/Methods:

Aims: The aim of this study was to evaluate the effects of Prothrombin Complex Concentrate ( PCC-Beriplex) and its components on TBI induced vascular dysfunction.
Methods: In vitro, the transendothelial electrical resistance of brain microvascular endothelial cell monolayers after treatment with both products with an electric cell-substrate impedance sensing assay. In vivo analysis of the effects of PCC (Beriplex) and Anti-Thrombin III (Kybernin) were evaluated in a controlled cortical impact model of TBI in C57Bl/6J mice. A 3mm piston impacted the exposed cortex at a velocity of 4.5 mm/s, depth of 1.2 mm, and with a dwell time of 300 ms. This led to a moderate-severe injury severity. Therapies were delivered intravenously at either 40 minutes or 2 hours post-injury to mimic a pre-hospital and hospital setting. BBB permeability was measured via measurement of a 10kD dextran fluorescent dye. ICH, inflammation and gliosis in the brain were measured by immunohistochemistry and were evaluated at 3 days post-injury.

Results/Findings:

Results: In vitro, Thrombin induced disruption of brain endothelial cell barrier permeability was reduced in the presence of Beriplex (25IU/kg and 50IU/kg), Kybernin, and Protein S. In TBI mice, increased BBB permeability at 3 days post-injury, was attenuated after a single dose of Beriplex (50IU/kg) or Kybernin (0.7IU/kg) delivered at 40 minutes, but not at 2 hours post-injury, compared to saline treated mice. Treatment with Beriplex but not Kybernin at 40 minutes post-injury reduces ICH compared to saline-treated mice.

Conclusions:

Conclusion: Temporal and divergent protective effects of PCC and Anti-thrombin III were observed in a murine model of TBI on BBB permeability and ICH. PCC attenuates both ICH and BBB permeability and Anti-thrombin III is a potent regulator of BBB permeability, suggesting that both PCC and Anti-thrombin III may serve a purpose in treating TBI patients with cerebral edema and ICH early after injury.