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.
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.


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.
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Anesthesiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands.
Simone E
SE
Dekker
Division of Trauma, Emergency Surgery And Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; Department of Surgery, Copenhagen University Hospital, Hillerød, Denmark.
Martin
M
Sillesen
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
Ted
T
Bambakidis
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.
Anuska V
AV
Andjelkovic
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
Guang
G
Jin
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
Baoling
B
Liu
Department of Anesthesiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands.
Christa
C
Boer
Capital Region Blood Bank, University of Copenhagen, Rigshospitalet, Denmark; Department of Surgery, University of Texas Medical School, Centre for Translational Injury Research (CeTIR), Houston, Texas.
Pär I
PI
Johansson
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Emergency Medicine, VU University Medical Center, Amsterdam, the Netherlands.
Durk
D
Linzel
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
Ihab
I
Halaweish
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
Hasan B
HB
Alam
D000818:Animals; D001930:Brain Injuries / Q000097:blood / Q000188:drug therapy*; D023201:CD40 Ligand / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy*; D013552:Swine; D014635:Valproic Acid / Q000008:administration & dosage*
D056572:Histone Deacetylase Inhibitors; D019007:P-Selectin; D023201:CD40 Ligand; D014635:Valproic Acid
Fresh frozen plasma; Hemorrhagic shock; Histone deacetylase inhibitor; Neuroprotection; Platelet activation; Resuscitation; Swine; Traumatic brain injury