Current Neurology and Neuroscience Reports

, Volume 2, Issue 1, pp 38–43 | Cite as

Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment

  • Paul A. Lapchak


Hemorrhagic transformation (HT) is a frequent consequence of ischemic stroke that becomes more prevalent after thrombolytic therapy. Despite concerns about safety parameters, thrombolytic drugs remain the first course of action available to clinicians for stroke management. However, recent efforts in preclinical studies have attempted to discover other drugs that can lessen the risk of hemorrhage associated with thrombolytic administration. This review focuses on three classes of pharmacologic agents that have shown some promise in animal models of stroke, and can thus be considered as possible candidates for coadministration with thrombolytics in the treatment of stroke. These include the following: 1) spin trap agents, such as α-phenyl-N-t-butylnitrone (PBN) that scavenge free radicals; 2) matrix metalloproteinase (MMP) inhibitors, such as BB-94, that prevent membrane and vessel remodeling following ischemia; and 3) the novel glycoprotein (GP) IIb/IIIa platelet receptor antagonist SM-20302. Although these drugs affect different mechanisms, the common denominator seemed to be their effectiveness in reducing the incidence of hemorrhage in response to thrombolytic infusion following an embolic stroke.


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References and Recommended Reading

  1. 1.
    Okada Y, Yamaguchi T, Minematsu K, et al.: Hemorrhagic transformation in cerebral embolism. Stroke 1989, 20:598–603.PubMedGoogle Scholar
  2. 2.
    Hornig CR, Bauer T, Simon C, Trittmacher S, Dorndorf W: Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993, 24:465–468.PubMedGoogle Scholar
  3. 3.
    Toni D, Fiorelli M, Bastianello S, et al.: Hemorrhagic transformation of brain infarct: predictability in the first 5 hours from stroke onset and influence on clinical outcome. Neurology 1996, 46:341–345.PubMedGoogle Scholar
  4. 4.
    Brott T, Adams HP, Olinger CP, et al.: Measurements of acute cerebral infarction: A clinical examination scale. Stroke 1989, 20:864–870.PubMedGoogle Scholar
  5. 5.
    Fisher CM, Adams RD: Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropath Exp Neurol 1951, 10:92–93.PubMedGoogle Scholar
  6. 6.
    Mohr JP, Caplan LR, Melski JW: The Harvard cooperative stroke registry: a prospective registry. Neurology 1978, 28:754–762.PubMedGoogle Scholar
  7. 7.
    Lyden PD, Zivin JA: Hemorrhagic transformation after cerebral ischemia: Mechanisms and incidence. Cerebrovasc Brain Met Rev 1993, 5:1–16.Google Scholar
  8. 8.
    Lapchak PA, Chapman DF, Zivin JA: Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 2000, 31:3034–3040.PubMedGoogle Scholar
  9. 9.
    Lapchak PA, Chapman DF, Zivin JA: Pharmacological effects of the spin trap agents N-t-Butyl-Phenylnitrone (PBN) and 2,2,6,6-Tetramethylpiperidine-N-Oxyl (TEMPO) in a rabbit thromboembolic model. Combination studies with the thrombolytic tissue plasminogen activator. Stroke 2001, 32:147–153. Study showing differential effects of two classes of spin trap agents on hemorrhage rate.PubMedGoogle Scholar
  10. 10.
    Rosenberg GA, Navratil M: Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 1997, 48:921–926.PubMedGoogle Scholar
  11. 11.
    delZoppo GJ: Microvascular responses to cerebral ischemia/ inflammation. Ann NY Acad Sci. 1997, 823:132–147.CrossRefGoogle Scholar
  12. 12.
    NINDS rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995, 333:1581–1587.CrossRefGoogle Scholar
  13. 13.
    Wardlaw JM, Warlow CP, Counsell C: Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet 1997, 350:607–614.PubMedCrossRefGoogle Scholar
  14. 14.
    Hacke W, Kaste M, Fieschi C, et al.: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: The European Cooperative Stroke Study (ECASS). JAMA 1995, 274:1017–1025.PubMedCrossRefGoogle Scholar
  15. 15.
    Zivin JA: Thrombolytic stroke therapy: Past, present, and future. Neurology 1999, 53:14–19.PubMedGoogle Scholar
  16. 16.
    Simoons ML: Risk-benefit of thrombolysis. Cardiol Clin 1995, 13:339–345.PubMedGoogle Scholar
  17. 17.
    Chopp M, Zhang RL, Zhang ZG, Jiang Q: The clot thickens: thrombolysis and combination therapies. Acta Neurochir Suppl 1999, 73:67–71. Article stressing the importance of drug combination therapy for stroke.PubMedGoogle Scholar
  18. 18.
    del Zoppo GJ, Zuemer H, Harker LA: Thrombolytic therapy in stroke: possibilities and hazards. Stroke 1986, 7:595–607.Google Scholar
  19. 19.
    Grotta JC, Alexandov AV: tPA-associated reperfusion after acute stroke demonstrated by SPECT. Stroke 1998, 29:429–432.PubMedGoogle Scholar
  20. 20.
    Jean WC, Spellman SR, Nussbaum ES, Low WC: Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery 1998, 43:1382–1397.PubMedCrossRefGoogle Scholar
  21. 21.
    Clark RK, Lee EV, White RF, et al.: Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull 1994, 35:387–392.PubMedCrossRefGoogle Scholar
  22. 22.
    Egan R, Lutsep HL, Clark WM, et al.: Open label tissue plasminogen activator for stroke: the Oregon experience. J Stroke Cerebrovasc Dis 1999, 8:287–290.CrossRefPubMedGoogle Scholar
  23. 23.
    Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC: Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 1999, 51:1359–1363.Google Scholar
  24. 24.
    delZoppo GJ, Wagner S, Tagaya M: Trends and future developments in the pharmacological treatment of acute ischaemic stroke. Drugs 1997, 54:9–38.Google Scholar
  25. 25.
    Cheung JY, Bonventre JV, Malis CD, Leaf A: Calcium and ischemic injury. N Engl J Med 1986, 314:1670–1676.PubMedCrossRefGoogle Scholar
  26. 26.
    Rosenberg GA, Cunningham LA, Wallace J, et al.: Immunohistochemistry of matrix metalloproteinases in reperfusion injury to the rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 2001, 893:104–112. Original study implicating matrix metalloproteinases (MMP)-3 and MMP-9 in microvascular damage.PubMedCrossRefGoogle Scholar
  27. 27.
    Facchinetti F, Dawson VL, Dawson TM: Free radicals as mediators of neuronal injury. Cell Mol Neurobiol 1998, 18:667–682.PubMedCrossRefGoogle Scholar
  28. 28.
    Siesjo BK, Siesjo P: Mechanisms of secondary brain injury. Eur J Anaesthesiol 1996, 13:247–268.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakai A, Kuroda S, Kristian T, Siesjo BK: The immunosuppressant drug FK506 ameliorates secondary mitochondrial dysfunction following transient focal cerebral ischemia in the rat. Neurobiol Dis 1997, 4:288–300.PubMedCrossRefGoogle Scholar
  30. 30.
    Floyd RA: Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999, 222:236–245.PubMedCrossRefGoogle Scholar
  31. 31.
    Anderson KM, Ells G, Bonomi P, Harris JE: Free radical spin traps as adjuncts for the prevention and treatment of disease. Med Hypotheses 1999, 52:53–57.PubMedCrossRefGoogle Scholar
  32. 32.
    Hensley K, Carney JM, Stewart CA, et al.: Nitrone-based free radical traps as neuroprotective agents in cerebral ischaemia and other pathologies. Int Rev Neurobiol 1997, 40:299–317.PubMedCrossRefGoogle Scholar
  33. 33.
    Thomas CE, Ohlweiler DF, Carr AA, et al.: Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps. J Biol Chem 1996, 271:3097–3104.PubMedCrossRefGoogle Scholar
  34. 34.
    Peeling J, Yan HJ, Chen SG, Campbell M, Del Bigio MR: Protective effects of free radical inhibitors in intracerebral hemorrhage in rat. Brain Res 1998, 795:63–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Asahi M, Asahi K, Wang X, Lo EH: Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2000, 20:452–457. Preclinical data supporting the development of spin trap agents.PubMedCrossRefGoogle Scholar
  36. 36.
    Hu BR, Liu C, Zivin JA: Reduction of intracerebral hemorrhaging in a rabbit embolic stroke model. Neurology 1999, 53:2140–2145.PubMedGoogle Scholar
  37. 37.
    Folbergrova J, Zhao Q, Katsura K, Siesjö BK: N-tert-butyl-alphaphenylnitrone improves recovery of brain energy state in rats following transient focal ischemia. Proc Natl Acad Sci USA 1995, 92:5057–5061.PubMedCrossRefGoogle Scholar
  38. 38.
    Kuroda S, Katsura K, Hillered L, et al.: Delayed treatment with a-phenyl-N-tert-butyl nitrone (PBN) attenuates secondary mitochondrial dysfunction after transient focal cerebral ischemia in the rat. Neurobiol Dis 1996, 3:149–157.PubMedCrossRefGoogle Scholar
  39. 39.
    Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK: Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1999, 19:788–787.Google Scholar
  40. 40.
    Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ: Neuroprotective effects of the novel brain-penetrating antioxidant U-101033E and the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN). Exp Brain Res 2000, 130:60–66.PubMedCrossRefGoogle Scholar
  41. 41.
    Nakashima M, Niwa M, Iwai T, Uematsu T: Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat. Free Radical Biol Med 1999, 26:722–729.CrossRefGoogle Scholar
  42. 42.
    Schulz JB, Panahian N, Chen YI, et al.: Facilitation of postischemic reperfusion with alpha-PBN: assessment using NMR and Doppler flow techniques. Am J Physiol 1997, 272:H1986-H1995.PubMedGoogle Scholar
  43. 43.
    Schaefer CF, Janzen EG, West MS, Poyer JL, Kosanke SD: Blood chemistry changes in the rat induced by high doses of nitronyl free radical spin traps. Free Radical Biol Med 1996, 21:427–436.CrossRefGoogle Scholar
  44. 44.
    Chen GM, Bray TM, Janzen EG, McCay PB: Excretion, metabolism and tissue distribution of a spin trapping agent, alpha-phenyl-N-tert-butyl-nitrone (PBN) in rats. Free Radical Res Comm 1990, 9:317–323.CrossRefGoogle Scholar
  45. 45.
    Rosenberg GA: Matrix metalloproteinases in brain injury. J. Neurotrauma 1995, 12:833–842.PubMedGoogle Scholar
  46. 46.
    Romanic AM, Madri JA: Extracellular matrix-degrading proteinases in the nervous system. Brain Pathol 1994, 4:145–156.PubMedGoogle Scholar
  47. 47.
    Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC: Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 1998, 29:1020–1030.PubMedGoogle Scholar
  48. 48.
    Zask A, Levin JI, Killar LM, Skotnicki JS: Inhibition of matrix metalloproteinases: structure based design. Curr Pharm Des 1996, 2:624–661.Google Scholar
  49. 49.
    Gearing AJ, Beckett P, Christodoulou M, et al.: Processing of tumour necrosis factor-a precursor by metalloproteinases. Nature 1994, 370:555–557.PubMedCrossRefGoogle Scholar
  50. 50.
    Yamamoto M, Hirayama R, Naruse K, et al.: Structure-activity relationship of hydroxamate-based inhibitors on membranebound Fas ligand and TNF-alpha processing. Drug Des Discov 1999, 16:119–130.PubMedGoogle Scholar
  51. 51.
    McGeehan GM, Becherer JD, Bast RC Jr, et al.: Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature 1994, 370:558–561.PubMedCrossRefGoogle Scholar
  52. 52.
    Black RA, Durie FH, Otten-Evans C, et al.: Relaxed specificity of matrix metalloproteinases (MMPS) and TIMP insensitivity of tumor necrosis factor-alpha (TNF-alpha) production suggest the major TNF-alpha converting enzyme is not an MMP. Biochem Biophys Res Comm 1996, 225:400–405.PubMedCrossRefGoogle Scholar
  53. 53.
    Dayer JM, Beutler B, Cerami A: Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985, 162:2163–2168.PubMedCrossRefGoogle Scholar
  54. 54.
    Mun-Bryce S, Rosenberg GA: Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 1998, 18:1163–1172.PubMedCrossRefGoogle Scholar
  55. 55.
    Rosenberg GA, Estrada EY, Dencoff JE, Stetler-Stevenson WG: Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 1995, 703:151–155.PubMedCrossRefGoogle Scholar
  56. 56.
    Barone FC, Arvin B, White RF, et al.: Tumor necrosis factoralpha. A mediator of focal ischemic brain injury. Stroke 1997, 28:1233–1244.PubMedGoogle Scholar
  57. 57.
    Lukes A, Mun-Brice S, Lukes M, Rosenberg GA: Extracellular matrix degradation by metalloproteinases and central nervous system diseases. Mol Neurobiol 1999, 19:267–284.PubMedGoogle Scholar
  58. 58.
    Rosenberg GA: Ischemic brain edema. Prog Cardiovasc Dis 1999, 42:209–216.PubMedCrossRefGoogle Scholar
  59. 59.
    Califf RM: Glycoprotein IIb/IIIa blockade and thrombolytics: early lessons from the SPEED and GUSTO IV trials. Am Heart J 1999, 138:S12-S15.PubMedCrossRefGoogle Scholar
  60. 60.
    Abumiya T, Fitridge R, Mazur C, et al.: Integrin aIIbb3 inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 2000, 31:1402–1410. New method to increase cerebral vessel patency.PubMedGoogle Scholar
  61. 61.
    Rebello SS, Huang J, Shiu WJ, et al.: Pharmacokinetics and pharmacodynamics of SM-20302, a GPIIb/IIIa receptor antagonist, in anesthetized dogs. J Cardiovasc Pharmacol 1998, 32:485–494.PubMedCrossRefGoogle Scholar
  62. 62.
    Horisawa S, Kaneko M, Ikeda Y, Ueki Y, Sakurama T: Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a photochemically induced thrombosis model in guinea pigs. Thrombosis Res 1999, 94:227–234.CrossRefGoogle Scholar
  63. 63.
    Huang J, Rebello SS, Rosenberg LA, et al.: Temporary and partial inhibition of platelets by SM-20302 prevents coronary artery thrombosis in a chronic canine model. Eur J Pharmacol 1999, 366:203–213.PubMedCrossRefGoogle Scholar
  64. 64.
    Horisawa S, Kaneko M, Sakurama T: SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist, exhibits a wide therapeutic window in a newly developed hemorrhage model in mice. Thromb Haemost 1999, 82:1743–1748.PubMedGoogle Scholar
  65. 65.
    Lapchak PA, Araujo DM, Song D, Zivin JA. The nonpeptide GPIIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator (tPA)-induced intracerebral hemorrhage following a thromboembolic stroke. Stroke 2001, in press.Google Scholar
  66. 66.
    Lapchak PA, Araujo DM: Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. CNS Drugs 2001, in press.Google Scholar
  67. 67.
    Bowes MP, Zivin JA, Thomas GR, Thibodeaux H, Fagan SC: Acute hypertension, but not thrombolysis, increases the incidence and severity of hemorrhagic transformation following experimental stroke in rabbits. Exp Neurol 1996, 141:40–46.PubMedCrossRefGoogle Scholar
  68. 68.
    Topol EJ, Easton JD, Amarenco P, et al.: Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Am Heart J 2000, 139:927–933.PubMedCrossRefGoogle Scholar
  69. 69.
    Lincoff AM, Califf RM, Topol EJ: Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease. J Am Coll Cardiol 2000, 35:1103–1115.PubMedCrossRefGoogle Scholar
  70. 70.
    Blankenship JC: Bleeding complications of glycoprotein IIb-IIIa receptor inhibitors. Am Heart J 1999, 138:287–296.PubMedCrossRefGoogle Scholar
  71. 71.
    Juran NB: Minimizing bleeding complications of percutaneous coronary intervention and glycoprotein IIb-IIIa antiplatelet therapy. Am Heart J 1999, 138:297–306.PubMedCrossRefGoogle Scholar
  72. 72.
    Madan M, Blankenship JC, Berkowitz SD: Bleeding complications with platelet glycoprotein IIb/IIIa receptor antagonists. Curr Opin Hematol 1999, 6:334–341.PubMedCrossRefGoogle Scholar
  73. 73.
    Vahdat B, Canavy I, Fourcade L, et al.: Fatal cerebral hemorrhage and severe thrombocytopenia during abciximab treatment. Catheter Cardiovasc Intervent 2000, 49:177–180.CrossRefGoogle Scholar
  74. 74.
    Ali A, Patil S, Grady KJ, Schreiber TL: Diffuse alveolar hemorrhage following administration of tirofiban or abciximab: a nemesis of platelet glycoprotein IIb/IIIa inhibitors. Catheter Cardiovasc Intervent 2000, 49:181–184.CrossRefGoogle Scholar
  75. 75.
    Larrue V, von Kummer R, Muller A, Bluhmki E: Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator. Stroke 2001, 32:438–441. Clinical study dealing with side effects of tissue plasminogen activator.PubMedGoogle Scholar

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© Current Science Inc 2002

Authors and Affiliations

  • Paul A. Lapchak
    • 1
  1. 1.Department of NeuroscienceUniversity of CaliforniaLa JollaUSA

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