PMID- 28538627
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20220805
IS  - 2163-0763 (Electronic)
IS  - 2163-0755 (Print)
IS  - 2163-0755 (Linking)
VI  - 83
IP  - 3
DP  - 2017 Sep
TI  - Early heparin administration after traumatic brain injury: Prolonged cognitive 
      recovery associated with reduced cerebral edema and neutrophil sequestration.
PG  - 406-412
LID - 10.1097/TA.0000000000001590 [doi]
AB  - BACKGROUND: Early administration of unfractionated heparin (UFH) after traumatic 
      brain injury (TBI) reduces early in vivo circulating leukocytes (LEUs) in 
      peri-injury penumbral brain tissue, enhancing cognitive recovery 2 days after 
      injury. It remains unclear how long this effect lasts and if this is related to 
      persistently accumulating LEUs in penumbral brain tissue. We hypothesized that 
      UFH reduces LEU brain tissue sequestration resulting in prolonged cognitive 
      recovery. METHODS: CD1 male mice underwent either TBI by controlled cortical 
      impact (CCI) or sham craniotomy. Unfractionated heparin (75 or 225 U/kg) or 
      vehicle was repeatedly administered after TBI. Neurologic function (Garcia 
      Neurological Test [maximum score = 18]) and body weight loss ratios were 
      evaluated at 24 hours to 96 hours after TBI. Brain and lung wet-to-dry ratios, 
      hemoglobin levels, and brain LEU sequestration (Ly6G immunohistochemistry) were 
      evaluated 96 hours postmortem. Analysis of variance with Bonferroni correction 
      determined significance (p < 0.05). RESULTS: Compared with untreated CCI animals 
      (24 hours, 14.7 +/- 1.0; 48 hours, 15.5 +/- 0.7; 72 hours, 15.0 +/- 0.8; 96 hours, 16.5 
      +/- 0.9), UFH75 (24 hours, 16.0 +/- 1.0, p < 0.01; 48 hours, 16.5 +/- 0.7, p < 0.05; 72 
      hours, 17.1 +/- 0.6, p < 0.01; 96 hours, 17.4 +/- 0.7, p < 0.05) increased cognitive 
      recovery throughout the entire observation period after TBI. At 48 hours, UFH225 
      significantly worsened body weight loss (10.2 +/- 4.7%) as compared with uninjured 
      animals (5.5 +/- 2.9%, p < 0.05). Both UFH75 (60.8 +/- 40.9 PMNs per high-power field 
      [HPF], p < 0.05) and UFH225 (36.0 +/- 17.6 PMNs/HPF, p < 0.01) significantly 
      decreased brain neutrophil sequestration found in untreated CCI animals (124.2 +/- 
      44.1 PMNs/HPF) 96 hours after TBI. Compared with untreated CCI animals (78.8 +/- 
      0.8%), UFH75 (77.3 +/- 0.6%, p = 0.04) reduced cerebral edema to uninjured levels 
      (77.4 +/- 0.6%, p = 0.04 vs. CCI). Only UFH225 (10.6 +/- 1.2 g/dL) resulted in lower 
      hemoglobin than in uninjured animals (13.0 +/- 1.2 g/dL, p < 0.05). CONCLUSIONS: 
      Heparin after TBI reduces tissue LEU sequestration and edema in injured brain for 
      up to 4 days. This is associated with persistent improved cognitive recovery, but 
      only when low-dose UFH is given. Early administration of UFH following TBI may 
      blunt LEU-related cerebral swelling and slow progression of secondary brain 
      injury.
FAU - Nagata, Katsuhiro
AU  - Nagata K
AD  - From the Division of Traumatology, Surgical Critical Care & Emergency Surgery 
      (K.N., Y.S., J.L.P.), Center for Brain Injury and Repair, University of 
      Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department 
      of Neurosurgery (K.N., K.D.B., Y.S., J.C., V.E.J., D.H.S., J.L.P.), Department of 
      Emergency and Critical Care Medicine, Tokyo Medical University Hachioji Medical 
      Center, Tokyo Japan (K.N., Y.S., K.K.); and Sidney Kimmel Medical College at 
      Thomas Jefferson University (J.M.), Philadelphia, Pennsylvania.
FAU - Browne, Kevin D
AU  - Browne KD
FAU - Suto, Yujin
AU  - Suto Y
FAU - Kumasaka, Kenichiro
AU  - Kumasaka K
FAU - Cognetti, John
AU  - Cognetti J
FAU - Johnson, Victoria E
AU  - Johnson VE
FAU - Marks, Joshua
AU  - Marks J
FAU - Smith, Douglas H
AU  - Smith DH
FAU - Pascual, Jose L
AU  - Pascual JL
LA  - eng
GR  - R01 NS092398/NS/NINDS NIH HHS/United States
GR  - R01 NS094003/NS/NINDS NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - J Trauma Acute Care Surg
JT  - The journal of trauma and acute care surgery
JID - 101570622
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Animals
MH  - Brain Edema/*prevention & control
MH  - Brain Injuries, Traumatic/*drug therapy/physiopathology
MH  - Disease Models, Animal
MH  - Heparin/*administration & dosage
MH  - Immunohistochemistry
MH  - Male
MH  - Mice
MH  - Neutrophils
MH  - Recovery of Function
PMC - PMC9351989
MID - NIHMS1824874
COIS- DISCLOSURE The authors declare no conflicts of interest.
EDAT- 2017/05/26 06:00
MHDA- 2017/09/19 06:00
PMCR- 2022/08/04
CRDT- 2017/05/25 06:00
PHST- 2017/05/26 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2017/05/25 06:00 [entrez]
PHST- 2022/08/04 00:00 [pmc-release]
AID - 10.1097/TA.0000000000001590 [doi]
PST - ppublish
SO  - J Trauma Acute Care Surg. 2017 Sep;83(3):406-412. doi: 
      10.1097/TA.0000000000001590.