1 Department of Gastroinstestinal Surgery, Nordsjællands Hospital, The Capital Region of Denmark2 Anæstesi- og operationsklinikken HOC, HovedOrtoCentret Rigshospitalet, Rigshospitalet, The Capital Region of Denmark3 Klinisk Immunologisk Afdeling. Blodbanken og Vævstypelaboratoriet, Diagnostisk Center, Rigshospitalet, The Capital Region of Denmark4 University of Michigan5 Kirurgisk Gastroenterologisk Klinik, Abdominal Centre, Rigshospitalet, The Capital Region of Denmark6 University of Michigan Hospital7 VU University Medical Center
BACKGROUND: We have previously shown that resuscitation with fresh frozen plasma (FFP) in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS) decreases the size of the brain lesion, and that addition of a histone deacetylase inhibitor, valproic acid (VPA), provides synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. MATERIALS AND METHODS: Ten swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were left in shock for 2 h before resuscitation with either FFP or FFP + VPA (300 mg/kg). Serum levels of platelet activation markers transforming growth factor beta, CD40 L, P-selectin, and platelet endothelial cell adhesion molecule (PECAM) 1 were measured at baseline, postresuscitation, and after a 6-h observation period. Platelet activation markers were also measured in the brain whole cell lysates and immunohistochemistry. RESULTS: Circulating P-selectin levels were significantly higher in the FFP + VPA group compared with the FFP alone group (70.85 ± 4.70 versus 48.44 ± 7.28 ng/mL; P < 0.01). Likewise, immunohistochemistry data showed elevated P-selectin in the VPA treatment group (22.30 ± 10.39% versus 8.125 ± 3.94%, P < 0.01). Serum sCD40L levels were also higher in the FFP + VPA group (3.21 ± 0.124 versus 2.38 ± 0.124 ng/mL; P < 0.01), as was brain sCD40L levels (1.41 ± 0.15 versus 1.22 ± 0.12 ng/mL; P = 0.05). Circulating transforming growth factor beta levels were elevated in the FFP + VPA group, but this did not reach statistical significance (11.20 ± 1.46 versus 8.09 ± 1.41 ng/mL; P = 0.17). Brain platelet endothelial cell adhesion molecule 1 levels were significantly lower in the FFP + VPA group compared with the FFP group (5.22 ± 2.00 pg/mL versus 7.99 ± 1.13 pg/mL; P = 0.03). CONCLUSIONS: In this clinically relevant large animal model of combined TBI + HS, the addition of VPA to FFP resuscitation results in an early upregulation of platelet activation in the circulation and the brain. The previously observed neuroprotective effects of VPA may be due to a conservation of platelet function as measured by a higher platelet activation response after resuscitation.
Journal of Surgical Research, 2014, Vol 190, Issue 1, p. 312-8
Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.