Effect of delayed argatroban treatment on intracerebral hemorrhage-induced edema in the rat

  • Takuji Kitaoka
  • Y. Hua
  • G. Xi
  • S. Nagao
  • J. T. Hoff
  • R. F. Keep
Conference paper
Part of the Acta Neurochirurgica Supplements book series (NEUROCHIRURGICA, volume 86)


Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH) induced edema formation. However, the time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Nor is it known whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding. This study examines whether a thrombin inhibitor, argatroban, can reduce edema formation following intracerebral infusion of 100 μl of blood in the rat, the therapeutic time window for argatroban, and whether argatroban promotes rebleeding. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours. The systemic administration of argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema formation. There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours. Our data suggest argatroban may be an effective therapy for ICH-induced edema.


Intracerebral hemorrhage thrombin edema argatroban 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Carney OH, Redin W, McCroskey L (1992) Role of highaffinity thrombin receptors in postclotting cellular effects of thrombin. Sem Thrombosis Hemost 18: 91–103CrossRefGoogle Scholar
  2. 2.
    Choudhri TF, Hoh BL, Solomon RA, Connolly ES, Pinsky DJ (1997) Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice. Stroke 28: 2296–2302PubMedCrossRefGoogle Scholar
  3. 3.
    Fujii Y, Tanaka R, Takeuchi S, Koike T, Minakawa T, Sasaki O (1994) Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 80: 51–57PubMedCrossRefGoogle Scholar
  4. 4.
    Gebel JM, Brott TG, Sila CA, Tomsick TA, Jauch E, Salisbury S, Khoury J, Miller R, Pancioli A, Duldner JE, Topol EJ, Broderick JP (2000) Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke 31: 596–600PubMedCrossRefGoogle Scholar
  5. 5.
    Gong C, Boulis N, Qian J, Turner DE, Hoff JT, Keep RF (2001) Intracerebral hemorrhage-induced neuronal death. Neurosurgery 48: 875–882PubMedGoogle Scholar
  6. 6.
    Hursting MJ, Alford KL, Becker JC, Brooks RL, Joffrion JL, Knappenberger GO, Kogan PW, Kogan TP, McKinney AA, Schwarz RP Jr (1997) Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost 23: 503–516PubMedCrossRefGoogle Scholar
  7. 7.
    Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T (1996) Enlargement of spontaneous intracerebral hemorrhage: Incidence and time course. Stroke 27: 1783–1787PubMedCrossRefGoogle Scholar
  8. 8.
    Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT (1995) Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 83: 1045–1050PubMedCrossRefGoogle Scholar
  9. 9.
    Lee KR, Betz AL, Kim S, Keep RF, Hoff JT (1996)The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage. Acta Neurochir (Wien) 138: 396-40CrossRefGoogle Scholar
  10. 10.
    Lee KR, Kawai N, Kim S, Sagher O, Hoff JT (1997) Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. J Neurosurg 86: 272–278PubMedCrossRefGoogle Scholar
  11. 11.
    Lee KR, Colon G, Betz AL, Keep RF, Kim S, Hoff JT (1996) Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 84: 91–96PubMedCrossRefGoogle Scholar
  12. 12.
    Mutch NJ, Robbie LA, Booth NA (2000) Human thrombi contain an abundance of active thrombin. Throm Hemost 86: 1028–1034Google Scholar
  13. 13.
    Nishino A, Suzuki M, Ohtani H, Motohashi O, Umezawa K, Nagura H, Yoshimoto T (1993) Thrombin may contribute to the pathophysiology of central nervous system injury. J Neurotrauma 10: 167–179PubMedCrossRefGoogle Scholar
  14. 14.
    Ojemann RG, Mohr JP (1976) Hypertensive brain hemorrhage. Clin Neurosurg 23: 220–244PubMedGoogle Scholar
  15. 15.
    Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M (1990) Collagenase-induced intracerebral hemorrhage in rats. Stroke 21: 801–807PubMedCrossRefGoogle Scholar
  16. 16.
    Schwarz RP, Becker J-C, Brooks RL, Hursting MJ, Joffrion JL, Knappenberger GO, Kogan TP, Kogan PW, McKinney AA (1997) The preclinical and clinical pharmacology of Novastan (Argatroban): a small-molecule, direct thrombin inhibitor. Clin Appl Thrombosis/Hemostasis 3: 1–15CrossRefGoogle Scholar
  17. 17.
    Xi G, Wagner KR, Keep RF, Hua Y, de Courten-Myers GM, Broderick JP, Brotl TG, Hoff JT, Muizelaar JP (1998) Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 29: 2580–2586PubMedCrossRefGoogle Scholar
  18. 18.
    Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurgery 89: 991–996CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2003

Authors and Affiliations

  • Takuji Kitaoka
    • 1
    • 3
  • Y. Hua
    • 1
  • G. Xi
    • 1
  • S. Nagao
    • 3
  • J. T. Hoff
    • 1
  • R. F. Keep
    • 1
    • 2
  1. 1.Department of NeurosurgeryUniversity of MichiganAnn ArborUSA
  2. 2.Department of PhysiologyUniversity of MichiganAnn ArborUSA
  3. 3.Department of Neurological SurgeryKagawa Medical UniversityKagawaJapan

Personalised recommendations