Skip to main content
SpringerLink
Log in

Intracranial Hemorrhage: Mechanisms of Secondary Brain Injury

  • Chapter
  • First Online:
Intracerebral Hemorrhage Research

Part of the book series: Acta Neurochirurgica Supplementum ((NEUROCHIRURGICA,volume 111))

Abstract

ICH is a disease with high rates of mortality and morbidity, with a substantial public health impact. Spontaneous ICH (sICH) has been extensively studied, and a large body of data has been accumulated on its pathophysiology. However, the literature on traumatic ICH (tICH) is limited, and further investigations of this important topic are needed. This review will highlight some of the cellular pathways in ICH with an emphasis on the mechanisms of secondary injury due to heme toxicity and to events in the coagulation process that are common to both sICH and tICH.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Narayan RK, Maas AI, Servadei F, Skolnick BE, Tillinger MN, Marshall LF (2008) Progression of traumatic intracerebral hemorrhage: a prospective observational study. J Neurotrauma 25:629–639

    Article  PubMed  Google Scholar 

  2. White CL, Griffith S, Caron JL (2009) Early progression of traumatic cerebral contusions: characterization and risk factors. J Trauma 67:508–514, discussion 514–505

    Article  PubMed  Google Scholar 

  3. Park JH, Park SW, Kang SH, Nam TK, Min BK, Hwang SN (2009) Detection of traumatic cerebral microbleeds by susceptibility-weighted image of MRI. J Korean Neurosurg Soc 46:365–369

    Article  PubMed  Google Scholar 

  4. Wu HM, Huang SC, Hattori N, Glenn TC, Vespa PM, Hovda DA, Bergsneider M (2004) Subcortical white matter metabolic changes remote from focal hemorrhagic lesions suggest diffuse injury after human traumatic brain injury. Neurosurgery 55:1306–1315, discussion 1316–1307

    Article  PubMed  Google Scholar 

  5. Immonen RJ, Kharatishvili I, Grohn H, Pitkanen A, Grohn OH (2009) Quantitative MRI predicts long-term structural and functional outcome after experimental traumatic brain injury. Neuroimage 45:1–9

    Article  PubMed  Google Scholar 

  6. Narayan RK, Maas AI, Marshall LF, Servadei F, Skolnick BE, Tillinger MN (2008) Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial. Neurosurgery 62:776–786, discussion 786–778

    Article  PubMed  Google Scholar 

  7. Chang EF, Claus CP, Vreman HJ, Wong RJ, Noble-Haeusslein LJ (2005) Heme regulation in traumatic brain injury: relevance to the adult and developing brain. J Cereb Blood Flow Metab 25:1401–1417

    Article  PubMed  CAS  Google Scholar 

  8. Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:629–652

    Article  PubMed  CAS  Google Scholar 

  9. Sharp FR, Massa SM, Swanson RA (1999) Heat-shock protein protection. Trends Neurosci 22:97–99

    Article  PubMed  CAS  Google Scholar 

  10. O’Brien PJ, Little C (1969) Intracellular mechanisms for the decomposition of a lipid peroxide. II. Decomposition of a lipid peroxide by subcellular fractions. Can J Biochem 47:493–499

    Article  PubMed  Google Scholar 

  11. Zhao X, Song S, Sun G, Strong R, Zhang J, Grotta JC, Aronowski J (2009) Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 29:15819–15827

    Article  PubMed  CAS  Google Scholar 

  12. Wang X, Mori T, Sumii T, Lo EH (2002) Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33:1882–1888

    Article  PubMed  CAS  Google Scholar 

  13. Keep RF, Xiang J, Ennis SR, Andjelkovic A, Hua Y, Xi G, Hoff JT (2008) Blood-brain barrier function in intracerebral hemorrhage. Acta Neurochir Suppl 105:73–77

    Article  PubMed  CAS  Google Scholar 

  14. Thiex R, Tsirka SE (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus 22:E6

    Article  PubMed  Google Scholar 

  15. Bhasin RR, Xi G, Hua Y, Keep RF, Hoff JT (2002) Experimental intracerebral hemorrhage: effect of lysed erythrocytes on brain edema and blood-brain barrier permeability. Acta Neurochir Suppl 81:249–251

    PubMed  CAS  Google Scholar 

  16. Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Baranano DE, Dore S, Poss KD, Snyder SH (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1:152–157

    Article  PubMed  CAS  Google Scholar 

  17. Regan RF, Chen J, Benvenisti-Zarom L (2004) Heme oxygenase-2 gene deletion attenuates oxidative stress in neurons exposed to extracellular hemin. BMC Neurosci 5:34. doi:10.1186/1471-2202-5-34

    Article  PubMed  Google Scholar 

  18. Rogers B, Yakopson V, Teng ZP, Guo Y, Regan RF (2003) Heme oxygenase-2 knockout neurons are less vulnerable to hemoglobin toxicity. Free Radic Biol Med 35:872–881

    Article  PubMed  CAS  Google Scholar 

  19. Baranano DE, Rao M, Ferris CD, Snyder SH (2002) Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA 99:16093–16098

    Article  PubMed  CAS  Google Scholar 

  20. Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G (2004) Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg 100:672–678

    Article  PubMed  CAS  Google Scholar 

  21. Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89:991–996

    Article  PubMed  CAS  Google Scholar 

  22. Wada T, Oara H, Watanabe K, Kinoshita H, Yachi A (1970) Autoradiographic study on the site of uptake of the haptoglobin-hemoglobin complex. J Reticuloendothel Soc 8:185–193

    PubMed  CAS  Google Scholar 

  23. Allison AC, Rees WA (1957) The binding of haemoglobin by plasma proteins (haptoglobins); its bearing on the renal threshold for haemoglobin and the aetiology of haemoglobinuria. Br Med J 2:1137–1143

    Article  PubMed  CAS  Google Scholar 

  24. Wang Y, Kinzie E, Berger FG, Lim SK, Baumann H (2001) Haptoglobin, an inflammation-inducible plasma protein. Redox Rep 6:379–385

    Article  PubMed  CAS  Google Scholar 

  25. Buehler PW, Abraham B, Vallelian F, Linnemayr C, Pereira CP, Cipollo JF, Jia Y, Mikolajczyk M, Boretti FS, Schoedon G, Alayash AI, Schaer DJ (2009) Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification. Blood 113:2578–2586

    Article  PubMed  CAS  Google Scholar 

  26. Stein SC, Smith DH (2004) Coagulopathy in traumatic brain injury. Neurocrit Care 1:479–488

    Article  PubMed  Google Scholar 

  27. Keimowitz RM, Annis BL (1973) Disseminated intravascular coagulation associated with massive brain injury. J Neurosurg 39:178–180

    Article  PubMed  CAS  Google Scholar 

  28. Morel N, Morel O, Petit L, Hugel B, Cochard JF, Freyssinet JM, Sztark F, Dabadie P (2008) Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury. J Trauma 64:698–704

    Article  PubMed  Google Scholar 

  29. Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF (2007) Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma 63:1254–1261, discussion 1261–1252

    Article  PubMed  CAS  Google Scholar 

  30. Halpern CH, Reilly PM, Turtz AR, Stein SC (2008) Traumatic coagulopathy: the effect of brain injury. J Neurotrauma 25:997–1001

    Article  PubMed  Google Scholar 

  31. Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB (2008) Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab 28:1761–1770

    Article  PubMed  Google Scholar 

  32. Sugawara T, Jadhav V, Ayer R, Chen W, Suzuki H, Zhang JH (2009) Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats. Stroke 40:1530–1532

    Article  PubMed  Google Scholar 

  33. Morel O, Morel N, Freyssinet JM, Toti F (2008) Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses. Platelets 19:9–23

    Article  PubMed  CAS  Google Scholar 

  34. Kai Y, Maeda Y, Sasaki T, Kanaide H, Hirano K (2008) Basic and translational research on proteinase-activated receptors: the role of thrombin receptor in cerebral vasospasm in subarachnoid hemorrhage. J Pharmacol Sci 108:426–432

    Article  PubMed  CAS  Google Scholar 

  35. Xi G, Reiser G, Keep RF (2003) The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J Neurochem 84:3–9. doi:10.1046/j.1471-4159.2003.01268.x [pii]

    Article  PubMed  CAS  Google Scholar 

  36. Akopov S, Sercombe R, Seylaz J (1996) Cerebrovascular reactivity: role of endothelium/platelet/leukocyte interactions. Cerebrovasc Brain Metab Rev 8:11–94

    PubMed  CAS  Google Scholar 

  37. Auer LM, Leber K, Sayama I (1985) Effect of serotonin and its antagonist ketanserin on pial vessels. J Cereb Blood Flow Metab 5:517–522

    Article  PubMed  CAS  Google Scholar 

  38. Muhonen MG, Robertson SC, Gerdes JS, Loftus CM (1997) Effects of serotonin on cerebral circulation after middle cerebral artery occlusion. J Neurosurg 87:301–306

    Article  PubMed  CAS  Google Scholar 

  39. Khalil Z, Helme RD (1990) Serotonin modulates substance P-induced plasma extravasation and vasodilatation in rat skin by an action through capsaicin-sensitive primary afferent nerves. Brain Res 527:292–298. doi:0006-8993(90)91149-B [pii]

    Article  PubMed  CAS  Google Scholar 

  40. Gecse A, Kis B, Mezei Z, Telegdy G (1999) Effects of inflammatory neuropeptides on the arachidonate cascade of platelets. Int Arch Allergy Immunol 118:166–170

    Article  PubMed  CAS  Google Scholar 

  41. Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908

    Article  PubMed  CAS  Google Scholar 

  42. Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–376

    Article  PubMed  CAS  Google Scholar 

  43. Stern M, Savill J, Haslett C (1996) Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta 3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am J Pathol 149:911–921

    PubMed  CAS  Google Scholar 

  44. Lee PY, Pearce FL (1990) Histamine secretion from mast cells stimulated with bradykinin. Agents Actions 30:67–69

    Article  PubMed  CAS  Google Scholar 

  45. Ishikawa M, Zhang JH, Nanda A, Granger DN (2004) Inflammatory responses to ischemia and reperfusion in the cerebral microcirculation. Front Biosci 9:1339–1347

    Article  PubMed  CAS  Google Scholar 

  46. Gregersen R, Lambertsen K, Finsen B (2000) Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 20:53–65

    Article  PubMed  CAS  Google Scholar 

  47. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155. doi:10.1002/glia.10161

    Article  PubMed  Google Scholar 

  48. Stoll G, Schroeter M, Jander S, Siebert H, Wollrath A, Kleinschnitz C, Bruck W (2004) Lesion-associated expression of transforming growth factor-beta-2 in the rat nervous system: evidence for down-regulating the phagocytic activity of microglia and macrophages. Brain Pathol 14:51–58

    Article  PubMed  CAS  Google Scholar 

  49. Min KJ, Yang MS, Kim SU, Jou I, Joe EH (2006) Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci 26:1880–1887

    Article  PubMed  CAS  Google Scholar 

  50. Wang J, Tsirka SE (2005) Tuftsin fragment 1–3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 36:613–618

    Article  PubMed  CAS  Google Scholar 

  51. Mander P, Borutaite V, Moncada S, Brown GC (2005) Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res 79:208–215

    Article  PubMed  CAS  Google Scholar 

  52. Khan M, Sekhon B, Giri S, Jatana M, Gilg AG, Ayasolla K, Elango C, Singh AK, Singh I (2005) S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. J Cereb Blood Flow Metab 25:177–192

    Article  PubMed  CAS  Google Scholar 

  53. Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W (2002) Minocycline delays disease onset and mortality in a transgenic model of ALS. NeuroReport 13:1067–1070

    Article  Google Scholar 

  54. Canolle B, Masmejean F, Melon C, Nieoullon A, Pisano P, Lortet S (2004) Glial soluble factors regulate the activity and expression of the neuronal glutamate transporter EAAC1: implication of cholesterol. J Neurochem 88:1521–1532. doi:10.1046/j.1471-4159.2003.02301.x [pii]

    Article  PubMed  CAS  Google Scholar 

  55. Sercombe R, Dinh YR, Gomis P (2002) Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol 88:227–249

    Article  PubMed  CAS  Google Scholar 

  56. Uemura Y, Sugimoto T, Okamoto S, Handa H, Mizuno N (1987) Changes of neuropeptide immunoreactivity in cerebrovascular nerve fibers after experimentally produced SAH. Immunohistochemical study in the dog. J Neurosurg 66:741–747

    Article  PubMed  CAS  Google Scholar 

  57. Fein JM, Flor WJ, Cohan SL, Parkhurst J (1974) Sequential changes of vascular ultrastructure in experimental cerebral vasospasm. Myonecrosis of subarachnoid arteries. J Neurosurg 41:49–58

    Article  PubMed  CAS  Google Scholar 

  58. Mayberg MR, Okada T, Bark DH (1990) The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg 72:626–633

    Article  PubMed  CAS  Google Scholar 

  59. Gomis P, Kacem K, Sercombe C, Seylaz J, Sercombe R (2000) Confocal microscopic evidence of decreased alpha-actin expression within rabbit cerebral artery smooth muscle cells after subarachnoid haemorrhage. Histochem J 32:673–678

    Article  PubMed  CAS  Google Scholar 

  60. Yamamoto Y, Bernanke DH, Smith RR (1990) Accelerated non-muscle contraction after subarachnoid hemorrhage: cerebrospinal fluid testing in a culture model. Neurosurgery 27:921–928

    Article  PubMed  CAS  Google Scholar 

  61. Grossetete M, Phelps J, Arko L, Yonas H, Rosenberg GA (2009) Elevation of matrix metalloproteinases 3 and 9 in cerebrospinal fluid and blood in patients with severe traumatic brain injury. Neurosurgery 65:702–708

    Article  PubMed  Google Scholar 

  62. Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI, Kim JM, Kim M, Roh JK (2007) Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther 322:1051–1058

    Article  PubMed  CAS  Google Scholar 

  63. Simard JM, Kilbourne M, Tsymbalyuk O, Tosun C, Caridi J, lvanova S, Keledjian K, Bochicchio E, Gerzanich V (2009) Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain confusion. J Neurotrauma 26(12): 2257–2267

    Article  PubMed  CAS  Google Scholar 

  64. Armin SS, Colohan AR, Zhang JH (2006) Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century. Neurol Res 28:445–452

    Article  PubMed  Google Scholar 

  65. Armin SS, Colohan AR, Zhang JH (2008) Vasospasm in traumatic brain injury. Acta Neurochir Suppl 104:421–425

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroprotection Research Laboratory, Massachusetts General Hospital, Boston, MA, USA

    Josephine Lok, Wendy Leung & Eng H. Lo

  2. Department of Pediatrics, Pediatric Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA

    Josephine Lok, Wendy Leung, Sarah Murphy & Natan Noviski

  3. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    William Butler

  4. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Eng H. Lo

  5. Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

    Eng H. Lo

Authors
  1. Josephine Lok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wendy Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natan Noviski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Josephine Lok .

Editor information

Editors and Affiliations

  1. , Neurosurgery, Physiology, Loma Linda University, Campus Street 11041, Loma Linda, 92530, USA

    John Zhang

  2. School of Medicine, Dept. Neurosurgery, Loma Linda University, Anderson St. 11234, Loma Linda, 92354, California, USA

    Austin Colohan

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag/Wien

About this chapter

Cite this chapter

Lok, J., Leung, W., Murphy, S., Butler, W., Noviski, N., Lo, E.H. (2011). Intracranial Hemorrhage: Mechanisms of Secondary Brain Injury. In: Zhang, J., Colohan, A. (eds) Intracerebral Hemorrhage Research. Acta Neurochirurgica Supplementum, vol 111. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0693-8_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-0693-8_11

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-0692-1

  • Online ISBN: 978-3-7091-0693-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation