Association of APOE ε4 with progressive hemorrhagic injury in patients with traumatic intracerebral hemorrhage

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  • 1 Department of Neurosurgery and
  • 2 Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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OBJECTIVE

The intracranial hematoma volume in patients with traumatic brain injury is a key parameter for the determination of the management approach and outcome. Apolipoprotein E (APOE) ε4 is reported to be a risk factor for larger hematoma volume, which might contribute to a poor outcome. However, whether APOE ε4 is related to progressive hemorrhagic injury (PHI), a common occurrence in the clinical setting, remains unclear. In this study, the authors aimed to investigate the association between the APOE genotype and occurrence of PHI.

METHODS

This prospective study included a cohort of 123 patients with traumatic intracerebral hemorrhage who initially underwent conservative treatment. These patients were assigned to the PHI or non-PHI group according to the follow-up CT scan. A polymerase chain reaction and sequencing method were carried out to determine the APOE genotype. Multivariate logistic regression analysis was applied to identify predictors of PHI.

RESULTS

The overall frequency of the alleles was as follows: E2/2, 0%; E2/3, 14.6%; E3/3, 57.8%; E2/4, 2.4%; E3/4, 22.8%; and E4/4, 2.4%. Thirty-four patients carried at least one allele of ε4. In this study 60 patients (48.8%) experienced PHI, and the distribution of the alleles was as follows: E2/2, 0%; E2/3, 5.7%; E3/3, 22.8%; E2/4, 2.4%; E3/4, 16.3%; and E4/4, 1.6%, which was significantly different from that in the non-PHI group (p = 0.008). Additionally, the late operation rate in the PHI group was significantly higher than that in the non-PHI group (24.4% vs 11.4%, p = 0.002). Multivariate logistic regression identified APOE ε4 (OR 5.14, 95% CI 2.40–11.62), an elevated international normalized ratio (OR 3.57, 95% CI 1.61–8.26), and higher glucose level (≥ 10 mmol/L) (OR 3.88, 95% CI 1.54–10.77) as independent risk factors for PHI. Moreover, APOE ε4 was not a risk factor for the coagulopathy and outcome of the patients with traumatic intracerebral hemorrhage.

CONCLUSIONS

The presence of APOE ε4, an elevated international normalized ratio, and a higher glucose level (≥ 10 mmol/L) are predictors of PHI. Additionally, APOE ε4 is not associated with traumatic coagulopathy and patient outcome.

ABBREVIATIONS AD = Alzheimer disease; APOE = apolipoprotein E; APTT = activated partial thromboplastin time; CAA = cerebral amyloid angiopathy; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; INR = international normalized ratio; PCR = polymerase chain reaction; PHI = progressive hemorrhagic injury; PLT = platelet count; PT = prothrombin time; TBI = traumatic brain injury.

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Contributor Notes

Correspondence Ting Lei: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. naowai1@tjh.tjmu.edu.cn.

INCLUDE WHEN CITING Published online July 19, 2019; DOI: 10.3171/2019.4.JNS183472.

X. Wan and C. Gan contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Alexander S, Kerr ME, Kim Y, Kamboh MI, Beers SR, Conley YP: Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury. J Neurotrauma 24:790797, 2007

    • Search Google Scholar
    • Export Citation
  • 2

    Ariza M, Pueyo R, Matarín MdelM, Junqué C, Mataró M, Clemente I, : Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. J Neurol Neurosurg Psychiatry 77:11911193, 2006

    • Search Google Scholar
    • Export Citation
  • 3

    Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, : Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512516, 2012

    • Search Google Scholar
    • Export Citation
  • 4

    Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, : Guidelines for the surgical management of traumatic brain injury. Neurosurgery 58 (Suppl 2):S1S62, 2006

    • Search Google Scholar
    • Export Citation
  • 5

    Cepeda S, Gómez PA, Castaño-Leon AM, Martínez-Pérez R, Munarriz PM, Lagares A: Traumatic intracerebral hemorrhage: risk factors associated with progression. J Neurotrauma 32:12461253, 2015

    • Search Google Scholar
    • Export Citation
  • 6

    Dowlatshahi D, Wasserman JK, Momoli F, Petrcich W, Stotts G, Hogan M, : Evolution of computed tomography angiography spot sign is consistent with a site of active hemorrhage in acute intracerebral hemorrhage. Stroke 45:277280, 2014

    • Search Google Scholar
    • Export Citation
  • 7

    Elshourbagy NA, Liao WS, Mahley RW, Taylor JM: Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci U S A 82:203207, 1985

    • Search Google Scholar
    • Export Citation
  • 8

    Folkerson LE, Sloan D, Cotton BA, Holcomb JB, Tomasek JS, Wade CE: Predicting progressive hemorrhagic injury from isolated traumatic brain injury and coagulation. Surgery 158:655661, 2015

    • Search Google Scholar
    • Export Citation
  • 9

    Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, : Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 52:244248, 1999

    • Search Google Scholar
    • Export Citation
  • 10

    Greenberg SM, Charidimou A: Diagnosis of cerebral amyloid angiopathy: evolution of the Boston criteria. Stroke 49:491497, 2018

  • 11

    Halpern CH, Reilly PM, Turtz AR, Stein SC: Traumatic coagulopathy: the effect of brain injury. J Neurotrauma 25:9971001, 2008

  • 12

    Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI: Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 150:165175, 2008

    • Search Google Scholar
    • Export Citation
  • 13

    Horsburgh K, McCarron MO, White F, Nicoll JA: The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models. Neurobiol Aging 21:245255, 2000

    • Search Google Scholar
    • Export Citation
  • 14

    Isoniemi H, Tenovuo O, Portin R, Himanen L, Kairisto V: Outcome of traumatic brain injury after three decades—relationship to ApoE genotype. J Neurotrauma 23:16001608, 2006

    • Search Google Scholar
    • Export Citation
  • 15

    Jiang Y, Sun X, Gui L, Xia Y, Tang W, Cao Y, : Correlation between APOE -491AA promoter in ε4 carriers and clinical deterioration in early stage of traumatic brain injury. J Neurotrauma 24:18021810, 2007

    • Search Google Scholar
    • Export Citation
  • 16

    Johnson VE, Stewart W, Smith DH: Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat Rev Neurosci 11:361370, 2010

    • Search Google Scholar
    • Export Citation
  • 17

    Juratli TA, Zang B, Litz RJ, Sitoci KH, Aschenbrenner U, Gottschlich B, : Early hemorrhagic progression of traumatic brain contusions: frequency, correlation with coagulation disorders, and patient outcome: a prospective study. J Neurotrauma 31:15211527, 2014

    • Search Google Scholar
    • Export Citation
  • 18

    Kassam I, Gagnon F, Cusimano MD: Association of the APOE-ε4 allele with outcome of traumatic brain injury in children and youth: a meta-analysis and meta-regression. J Neurol Neurosurg Psychiatry 87:433440, 2016

    • Search Google Scholar
    • Export Citation
  • 19

    Laroche M, Kutcher ME, Huang MC, Cohen MJ, Manley GT: Coagulopathy after traumatic brain injury. Neurosurgery 70:13341345, 2012

  • 20

    Liaquat I, Dunn LT, Nicoll JA, Teasdale GM, Norrie JD: Effect of apolipoprotein E genotype on hematoma volume after trauma. J Neurosurg 96:9096, 2002

    • Search Google Scholar
    • Export Citation
  • 21

    Maegele M, Schöchl H, Menovsky T, Maréchal H, Marklund N, Buki A, : Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol 16:630647, 2017

    • Search Google Scholar
    • Export Citation
  • 22

    Nicoll JA, Roberts GW, Graham DI: Apolipoprotein E ε4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med 1:135137, 1995

    • Search Google Scholar
    • Export Citation
  • 23

    Olivecrona M, Wildemyr Z, Koskinen LO: The apolipoprotein E ε4 allele and outcome in severe traumatic brain injury treated by an intracranial pressure-targeted therapy. J Neurosurg 112:11131119, 2010

    • Search Google Scholar
    • Export Citation
  • 24

    Orito K, Hirohata M, Nakamura Y, Yamamoto M, Takeshige N, Aoki T, : Predictive value of leakage signs for pure brain contusional hematoma expansion. J Neurotrauma 35:760766, 2018

    • Search Google Scholar
    • Export Citation
  • 25

    Padgett CR, Summers MJ, Skilbeck CE: Is APOE ε4 associated with poorer cognitive outcome following traumatic brain injury? A meta-analysis. Neuropsychology 30:775790, 2016

    • Search Google Scholar
    • Export Citation
  • 26

    Panenka WJ, Gardner AJ, Dretsch MN, Crynen GC, Crawford FC, Iverson GL: Systematic review of genetic risk factors for sustaining a mild traumatic brain injury. J Neurotrauma 34:20932099, 2017

    • Search Google Scholar
    • Export Citation
  • 27

    Perel P, Arango M, Clayton T, Edwards P, Komolafe E, Poccock S, : Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 336:425429, 2008

    • Search Google Scholar
    • Export Citation
  • 28

    Smith C, Graham DI, Murray LS, Stewart J, Nicoll JA: Association of APOE e4 and cerebrovascular pathology in traumatic brain injury. J Neurol Neurosurg Psychiatry 77:363366, 2006

    • Search Google Scholar
    • Export Citation
  • 29

    Stein SC, Graham DI, Chen XH, Dunn L, Smith DH: Apo E genotype not associated with intravascular coagulation in traumatic brain injury. Neurosci Lett 387:2831, 2005

    • Search Google Scholar
    • Export Citation
  • 30

    Steyerberg EW, Mushkudiani N, Perel P, Butcher I, Lu J, McHugh GS, : Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med 5:e165, 2008

    • Search Google Scholar
    • Export Citation
  • 31

    Thompson AL, Kosior JC, Gladstone DJ, Hopyan JJ, Symons SP, Romero F, : Defining the CT angiography ‘spot sign’ in primary intracerebral hemorrhage. Can J Neurol Sci 36:456461, 2009

    • Search Google Scholar
    • Export Citation
  • 32

    Tian Y, Salsbery B, Wang M, Yuan H, Yang J, Zhao Z, : Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury. Blood 125:21512159, 2015

    • Search Google Scholar
    • Export Citation
  • 33

    Tzioras M, Davies C, Newman A, Jackson R, Spires-Jones T: Invited review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease. Neuropathol Appl Neurobiol 45:327346, 2019

    • Search Google Scholar
    • Export Citation
  • 34

    Wan X, Fan T, Wang S, Zhang S, Liu S, Yang H, : Progressive hemorrhagic injury in patients with traumatic intracerebral hemorrhage: characteristics, risk factors and impact on management. Acta Neurochir (Wien) 159:227235, 2017

    • Search Google Scholar
    • Export Citation
  • 35

    Wan X, Liu S, Wang S, Zhang S, Yang H, Ou Y, : Elderly patients with severe traumatic brain injury could benefit from surgical treatment. World Neurosurg 89:147152, 2016

    • Search Google Scholar
    • Export Citation
  • 36

    Wan X, Zhao K, Wang S, Zhang H, Zeng L, Wang Y, : Is it reliable to predict the outcome of elderly patients with severe traumatic brain injury using the IMPACT prognostic calculator? World Neurosurg 103:584590, 2017

    • Search Google Scholar
    • Export Citation
  • 37

    Weir CJ, McCarron MO, Muir KW, Dyker AG, Bone I, Lees KR, : Apolipoprotein E genotype, coagulation, and survival following acute stroke. Neurology 57:10971100, 2001

    • Search Google Scholar
    • Export Citation
  • 38

    White CL, Griffith S, Caron JL: Early progression of traumatic cerebral contusions: characterization and risk factors. J Trauma 67:508515, 2009

    • Search Google Scholar
    • Export Citation
  • 39

    Willemse-van Son AH, Ribbers GM, Hop WC, van Duijn CM, Stam HJ: Association between apolipoprotein-ε4 and long-term outcome after traumatic brain injury. J Neurol Neurosurg Psychiatry 79:426430, 2008

    • Search Google Scholar
    • Export Citation
  • 40

    Yip AG, McKee AC, Green RC, Wells J, Young H, Cupples LA, : APOE, vascular pathology, and the AD brain. Neurology 65:259265, 2005

  • 41

    Yousuf A, Khursheed N, Rasool I, Kundal V, Jeelani H, Afroze D: Genetic variation of ApoE gene in ethnic Kashmiri population and its association with outcome after traumatic brain injury. J Mol Neurosci 56:597601, 2015

    • Search Google Scholar
    • Export Citation
  • 42

    Yuan F, Ding J, Chen H, Guo Y, Wang G, Gao WW, : Predicting progressive hemorrhagic injury after traumatic brain injury: derivation and validation of a risk score based on admission characteristics. J Neurotrauma 29:21372142, 2012

    • Search Google Scholar
    • Export Citation
  • 43

    Zhou W, Xu D, Peng X, Zhang Q, Jia J, Crutcher KA: Meta-analysis of APOE4 allele and outcome after traumatic brain injury. J Neurotrauma 25:279290, 2008

    • Search Google Scholar
    • Export Citation

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