Simone E Dekker1, Martin Sillesen2, Ted Bambakidis3, Anuska V Andjelkovic4, Guang Jin3, Baoling Liu3, Christa Boer5, Pär I Johansson6, Durk Linzel7, Ihab Halaweish3, Hasan B Alam8. 1. Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Anesthesiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands. 2. 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. 3. Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. 4. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan. 5. Department of Anesthesiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands. 6. 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. 7. Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Emergency Medicine, VU University Medical Center, Amsterdam, the Netherlands. 8. Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
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.
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.
Authors: Simone E Dekker; Vahagn C Nikolian; Martin Sillesen; Ted Bambakidis; Patrick Schober; Hasan B Alam Journal: J Neurosci Res Date: 2017-07-25 Impact factor: 4.164
Authors: Andrew R Mayer; Andrew B Dodd; Meghan S Vermillion; David D Stephenson; Irshad H Chaudry; Denis E Bragin; Andrew P Gigliotti; Rebecca J Dodd; Benjamin C Wasserott; Priyank Shukla; Rachel Kinsler; Sheila M Alonzo Journal: Neurosci Biobehav Rev Date: 2019-06-27 Impact factor: 8.989
Authors: Paul Vulliamy; Lucy Z Kornblith; Matthew E Kutcher; Mitchell J Cohen; Karim Brohi; Matthew D Neal Journal: Platelets Date: 2020-01-27 Impact factor: 3.862
Authors: Pieter H Sloos; Paul Vulliamy; Cornelis van 't Veer; Anirban Sen Gupta; Matthew D Neal; Karim Brohi; Nicole P Juffermans; Derek J B Kleinveld Journal: Transfusion Date: 2022-06-24 Impact factor: 3.337
Authors: Jordan Todd; Vimala N Bharadwaj; Kimberly Nellenbach; Seema Nandi; Emily Mihalko; Connor Copeland; Ashley C Brown; Sarah E Stabenfeldt Journal: J Biomed Mater Res B Appl Biomater Date: 2021-06-11 Impact factor: 3.368