Katsuhiro Nagata1, Kenichiro Kumasaka, Kevin D Browne, Shengjie Li, Jesse St-Pierre, John Cognetti, Joshua Marks, Victoria E Johnson, Douglas H Smith, Jose L Pascual. 1. 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.
Abstract
BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: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). RESULTS: 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. CONCLUSIONS: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: Aric F Logsdon; Brandon P Lucke-Wold; Ryan C Turner; Jason D Huber; Charles L Rosen; James W Simpkins Journal: Compr Physiol Date: 2015-07-01 Impact factor: 9.090
Authors: J R Weber; K Angstwurm; T Rosenkranz; U Lindauer; D Freyer; W Bürger; C Busch; K M Einhäupl; U Dirnagl Journal: J Cereb Blood Flow Metab Date: 1997-11 Impact factor: 6.200
Authors: D H Smith; H D Soares; J S Pierce; K G Perlman; K E Saatman; D F Meaney; C E Dixon; T K McIntosh Journal: J Neurotrauma Date: 1995-04 Impact factor: 5.269
Authors: Stuart Glassner; Karan Srivastava; Paul Cofnas; Brian Deegan; Peter Demaria; Rimsky Denis; Enrique Ginzburg Journal: Rambam Maimonides Med J Date: 2013-01-30
Authors: Mackenzie C Morris; Farzaan Kassam; Aron Bercz; Nadine Beckmann; Fabian Schumacher; Erich Gulbins; Amy T Makley; Michael D Goodman Journal: J Surg Res Date: 2019-07-03 Impact factor: 2.192
Authors: Ruchira M Jha; Bradley J Molyneaux; Travis C Jackson; Jessica S Wallisch; Seo-Young Park; Samuel Poloyac; Vincent A Vagni; Keri L Janesko-Feldman; Keito Hoshitsuki; M Beth Minnigh; Patrick M Kochanek Journal: J Neurotrauma Date: 2018-06-06 Impact factor: 5.269
Authors: Katsuhiro Nagata; Kevin D Browne; Yujin Suto; Kenichiro Kumasaka; John Cognetti; Victoria E Johnson; Joshua Marks; Douglas H Smith; Jose L Pascual Journal: J Trauma Acute Care Surg Date: 2017-09 Impact factor: 3.697
Authors: Yujin Suto; Katsuhiro Nagata; Syed M Ahmed; Christina Jacovides; Kevin D Browne; John Cognetti; Maura T Weber; Victoria E Johnson; Ryan Leone; Lewis J Kaplan; Douglas H Smith; Jose L Pascual Journal: J Trauma Acute Care Surg Date: 2018-08 Impact factor: 3.697
Authors: Sarah Thompson; Beatriz Martínez-Burgo; Krishna Mohan Sepuru; Krishna Rajarathnam; John A Kirby; Neil S Sheerin; Simi Ali Journal: Int J Mol Sci Date: 2017-08-03 Impact factor: 5.923
Authors: Andre Bredthauer; Manuel Kopfmueller; Michael Gruber; Sophie-Marie Pfaehler; Karla Lehle; Walter Petermichl; Timo Seyfried; Diane Bitzinger; Andreas Redel Journal: Cardiovasc Ther Date: 2020-04-25 Impact factor: 3.023
Authors: Mohamed ElSaadani; Syed M Ahmed; Christina Jacovides; Alfonso Lopez; Victoria E Johnson; Lewis J Kaplan; C William Schwab; Douglas H Smith; Jose L Pascual Journal: J Trauma Acute Care Surg Date: 2021-02-01 Impact factor: 3.313
Authors: Katsuhiro Nagata; Yujin Suto; John Cognetti; Kevin D Browne; Kenichiro Kumasaka; Victoria E Johnson; Lewis Kaplan; Joshua Marks; Douglas H Smith; Jose L Pascual Journal: J Trauma Acute Care Surg Date: 2018-05 Impact factor: 3.697