title: Unfractionated heparin after TBI reduces in vivo cerebrovascular inflammation, brain edema and accelerates cognitive recovery.
abstract: Severe traumatic brain injury (TBI) may increase the risk of venous thromboembolic complications; however, early prevention with heparinoids is often withheld for its anticoagulant effect. New evidence suggests low molecular weight heparin reduces cerebral edema and improves neurological recovery after stroke and TBI, through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post-TBI. We hypothesized that UFH after TBI reduces cerebral edema by reducing LEU-mediated inflammation and improves neurological recovery.
  
  
  
  CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. UFH (75 U/kg or 225 U/kg) or vehicle (VEH, 0.9% saline) was administered 2, 11, 20, 27, and 34 hours after TBI. At 48 hours, pial intravital microscopy through a craniotomy was used to visualize live brain LEUs interacting with endothelium and microvascular fluorescein isothiocyanate-albumin leakage. Neurologic function (Garcia Neurological Test, GNT) and body weight loss ratios were evaluated 24 and 48 hours after TBI. Cerebral and lung wet-to-dry ratios were evaluated post mortem. ANOVA with Bonferroni correction was used to determine significance (p < 0.05).
  
  
  
  Compared to positive controls (CCI), both UFH doses reduced post-TBI in vivo LEU rolling on endothelium, concurrent cerebrovascular albumin leakage, and ipsilateral cerebral water content after TBI. Additionally, only low dose UFH (75 U/kg) improved GNT at both 24 and 48 hours after TBI. High dose UFH (225 U/kg) significantly increased body weight loss above sham at 48 hours. Differences in lung water content and blood pressure between groups were not significant.
  
  
  
  UFH after TBI reduces LEU recruitment, microvascular permeability, and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery whereas higher UFH may worsen functional recovery. Further study is needed to determine if this is caused by increased bleeding from injured brain with higher UFH doses.
authors.affiliation: From the Division of Traumatology, Surgical Critical Care & Emergency Surgery (K.N., J.S-P., J.L.P.) and Department of Neurosurgery, Center for Brain Injury and Repair (K.D.B., J.C., V.E.J., D.H.S., J.L.P.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Sidney Kimmel Medical College at Thomas Jefferson University (J.M.), Philadelphia, Pennsylvania; Department of Neurosurgery (S.L.), Qianfoshan Hospital, Shandong University, Jinan, China; and Department of Emergency and Critical Care Medicine (K.K.), Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kumasaka
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Browne
authors.forename: Shengjie
authors.initials: S
authors.lastname: Li
authors.forename: Jesse
authors.initials: J
authors.lastname: St-Pierre
authors.forename: John
authors.initials: J
authors.lastname: Cognetti
authors.forename: Joshua
authors.initials: J
authors.lastname: Marks
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Johnson
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Smith
authors.forename: Jose L
authors.initials: JL
authors.lastname: Pascual
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control* / Q000523:psychology; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000523:psychology / Q000628:therapy*; D002199:Capillary Permeability; D003071:Cognition; D004195:Disease Models, Animal; D006493:Heparin / Q000627:therapeutic use*; D036904:Leukocyte Rolling; D008297:Male; D051379:Mice
chemical_list: D000925:Anticoagulants; D006493:Heparin