Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock

Simone E. Dekker, Martin Sillesen, Ted Bambakidis, Anuska V. Andjelkovic, Guang Jin, Baoling Liu, Christa Boer, Pär I. Johansson, Durk Linzel, Ihab Halaweish, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)312-318
Number of pages7
JournalJournal of Surgical Research
Volume190
Issue number1
DOIs
StatePublished - Jul 2014
Externally publishedYes

Keywords

  • Fresh frozen plasma
  • Hemorrhagic shock
  • Histone deacetylase inhibitor
  • Neuroprotection
  • Platelet activation
  • Resuscitation
  • Swine
  • Traumatic brain injury

ASJC Scopus subject areas

  • Surgery

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