Abstract
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.
Similar content being viewed by others
References and Recommended Reading
Okada Y, Yamaguchi T, Minematsu K, et al.: Hemorrhagic transformation in cerebral embolism. Stroke 1989, 20:598–603.
Hornig CR, Bauer T, Simon C, Trittmacher S, Dorndorf W: Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993, 24:465–468.
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.
Brott T, Adams HP, Olinger CP, et al.: Measurements of acute cerebral infarction: A clinical examination scale. Stroke 1989, 20:864–870.
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.
Mohr JP, Caplan LR, Melski JW: The Harvard cooperative stroke registry: a prospective registry. Neurology 1978, 28:754–762.
Lyden PD, Zivin JA: Hemorrhagic transformation after cerebral ischemia: Mechanisms and incidence. Cerebrovasc Brain Met Rev 1993, 5:1–16.
Lapchak PA, Chapman DF, Zivin JA: Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 2000, 31:3034–3040.
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.
Rosenberg GA, Navratil M: Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 1997, 48:921–926.
delZoppo GJ: Microvascular responses to cerebral ischemia/ inflammation. Ann NY Acad Sci. 1997, 823:132–147.
NINDS rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995, 333:1581–1587.
Wardlaw JM, Warlow CP, Counsell C: Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet 1997, 350:607–614.
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.
Zivin JA: Thrombolytic stroke therapy: Past, present, and future. Neurology 1999, 53:14–19.
Simoons ML: Risk-benefit of thrombolysis. Cardiol Clin 1995, 13:339–345.
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.
del Zoppo GJ, Zuemer H, Harker LA: Thrombolytic therapy in stroke: possibilities and hazards. Stroke 1986, 7:595–607.
Grotta JC, Alexandov AV: tPA-associated reperfusion after acute stroke demonstrated by SPECT. Stroke 1998, 29:429–432.
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.
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.
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.
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.
delZoppo GJ, Wagner S, Tagaya M: Trends and future developments in the pharmacological treatment of acute ischaemic stroke. Drugs 1997, 54:9–38.
Cheung JY, Bonventre JV, Malis CD, Leaf A: Calcium and ischemic injury. N Engl J Med 1986, 314:1670–1676.
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.
Facchinetti F, Dawson VL, Dawson TM: Free radicals as mediators of neuronal injury. Cell Mol Neurobiol 1998, 18:667–682.
Siesjo BK, Siesjo P: Mechanisms of secondary brain injury. Eur J Anaesthesiol 1996, 13:247–268.
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.
Floyd RA: Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999, 222:236–245.
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.
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.
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.
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.
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.
Hu BR, Liu C, Zivin JA: Reduction of intracerebral hemorrhaging in a rabbit embolic stroke model. Neurology 1999, 53:2140–2145.
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.
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.
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.
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.
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.
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.
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.
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.
Rosenberg GA: Matrix metalloproteinases in brain injury. J. Neurotrauma 1995, 12:833–842.
Romanic AM, Madri JA: Extracellular matrix-degrading proteinases in the nervous system. Brain Pathol 1994, 4:145–156.
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.
Zask A, Levin JI, Killar LM, Skotnicki JS: Inhibition of matrix metalloproteinases: structure based design. Curr Pharm Des 1996, 2:624–661.
Gearing AJ, Beckett P, Christodoulou M, et al.: Processing of tumour necrosis factor-a precursor by metalloproteinases. Nature 1994, 370:555–557.
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.
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.
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.
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.
Mun-Bryce S, Rosenberg GA: Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 1998, 18:1163–1172.
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.
Barone FC, Arvin B, White RF, et al.: Tumor necrosis factoralpha. A mediator of focal ischemic brain injury. Stroke 1997, 28:1233–1244.
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.
Rosenberg GA: Ischemic brain edema. Prog Cardiovasc Dis 1999, 42:209–216.
Califf RM: Glycoprotein IIb/IIIa blockade and thrombolytics: early lessons from the SPEED and GUSTO IV trials. Am Heart J 1999, 138:S12-S15.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lincoff AM, Califf RM, Topol EJ: Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease. J Am Coll Cardiol 2000, 35:1103–1115.
Blankenship JC: Bleeding complications of glycoprotein IIb-IIIa receptor inhibitors. Am Heart J 1999, 138:287–296.
Juran NB: Minimizing bleeding complications of percutaneous coronary intervention and glycoprotein IIb-IIIa antiplatelet therapy. Am Heart J 1999, 138:297–306.
Madan M, Blankenship JC, Berkowitz SD: Bleeding complications with platelet glycoprotein IIb/IIIa receptor antagonists. Curr Opin Hematol 1999, 6:334–341.
Vahdat B, Canavy I, Fourcade L, et al.: Fatal cerebral hemorrhage and severe thrombocytopenia during abciximab treatment. Catheter Cardiovasc Intervent 2000, 49:177–180.
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.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lapchak, P.A. Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep 2, 38–43 (2002). https://doi.org/10.1007/s11910-002-0051-0
Issue Date:
DOI: https://doi.org/10.1007/s11910-002-0051-0