title: Valproic acid modulates platelet and coagulation function ex vivo.
abstract: : Trauma-induced coagulopathy is associated with adverse patient outcome. Animal models demonstrate that histone deacetylase inhibitors, such as valproic acid (VPA), improve survival following injury. While in-vivo data suggest that improved survival may in part be because of an attenuation of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI) and hemorrhagic shock (HS). Blood samples were drawn prior to TBI+HS insult (Healthy group) and 2 h following TBI+HS (Shock group). Samples were incubated with VPA or vehicle controls for 1 h. Platelet aggregation was analyzed via impedance aggregometry and coagulation was measured using thromboelastography. Addition of VPA to the healthy blood did not affect platelet aggregation or coagulation parameters. In shock blood, incubation with VPA significantly reduced collagen-(P = 0.050), arachidonic acid-(P = 0.005), and adenosine diphosphate-(P = 0.023) induced platelet aggregation. VPA also significantly increased the clot strength (P = 0.002) and clot formation rate (P = 0.011). This is the first study to investigate the effect of VPA on platelet function ex vivo. Our results suggest that VPA has no effect on normal blood, but it decreases platelet activation and improves clot dynamics (strength and rate of formation) in blood from shocked animals. This suggests that VPA is capable of exerting a selective platelet sparing effect while enhancing the clot integrity.
authors.affiliation: aDepartment of Surgery, University of Michigan Hospital, Ann Arbor, Michigan bDepartment of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio, USA cDepartment of Surgical Gastroenterology dInstitute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Denmark.
authors.forename: Ted
authors.initials: T
authors.lastname: Bambakidis
authors.forename: Simone E
authors.initials: SE
authors.lastname: Dekker
authors.forename: Ihab
authors.initials: I
authors.lastname: Halaweish
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Vahagn C
authors.initials: VC
authors.lastname: Nikolian
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Georgoff
authors.forename: Patryk
authors.initials: P
authors.lastname: Piascik
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Sillesen
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D001930:Brain Injuries / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D012771:Shock, Hemorrhagic / Q000097:blood; D013552:Swine; D013927:Thrombosis; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid