Hemorrhagic Transformation of Cerebral Infarction – Possible Mechanisms

Summary

To analyse the risk/benefit of cerebral thrombolysis the role of hemorrhagic transformation, either as clinically silent hemorrhagic infarction or disastreous parenchymal hemorrhage, is crucial. Thrombolysis in acute ischemic stroke increases the risk of severe, life-threatening hemorrhagic complications by up to 10 times compared to controls. In this paper, previous proposed concepts for the development of intracerebral hemorrhage and hemorrhagic transformation are presented. The role of the cerebral microvasculature will be emphasized. In experimental focal cerebral ischemia a significant loss of basal lamina components of the cerebral microvessels has been demonstrated. This loss in vessel wall integrity is associated with the development of petechial hemorrhage. The mechanisms for this microvascular damage may include plasmin-generated laminin degradation, matrix metalloproteinases activation, transmigration of leukocytes through the vessel wall, and other processes. We propose that attenuation of the microvascular integrity loss with subsequent reduction in hemorrhage is theoretically possible 1) by an improvement in the definition of an individual time window of therapy (by means of imaging techniques), 2) by a biochemical quantification of the basal lamina damage to avoid dangerous interventions, and 3) by pharmacological strategies to protect the basal lamina during thrombolysis.

Key words

Hemorrhagic transformation - intracerebral hemorrhage - cerebral infarction - thrombolysis - microvasculature

• References

• 1 Hacke W, Kaste M, Fieschi C. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The european cooperative acute stroke study (ECASS). JAMA 1995; 274: 1017-25.
• 2 The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581-7.
• 3 The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28: 2109-18.
• 4 Donnan GA, Davis SM, Chambers BR. et al. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996; 276: 961-66.
• 5 Hommel M, Boissel JP, Cornu C. et al. Termination of trial of streptokinase in severe acute ischemic stroke (letter). Lancet 1995; 345: 578-9.
• 6 Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischemic stroke. Lancet 1995; 346: 1509-607.
• 7 Pessin M, del Zoppo GJ, Estol C. Thrombolytic agents in the treatment of stroke. Clin Neuropharmacol 1990; 13: 271-89.
• 8 Charcot JM, Bouchard C. Nouvelles recherches sur la pathologenie de rhemorrhagie cerebrale. Arch Physiol (Paris) 1868; 1: 110-127 643-675, 725-34.
• 9 Ellis AG. The pathogenesis of spontaneous cerebral hemorrhage. Proc Pathol Soc 1909; 12: 197-201.
• 10 Pick L. Uber die sogenannten miliaren Aneurysmen der HirngefaBe. Berl Wiss Wschr 1910; 47: 325-329 382-6.
• 11 Ross Russell RW. Observations on intracerebral aneurysms. Brain 1963; 86: 425-32.
• 12 Cole FM, Yates PO. The occurence and significance of intracerebral microaneurysms. J Pathol Bacteriol 1967; 93: 393-401.
• 13 Fisher CM. Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30: 536-50.
• 14 Schwartz P. Die Arten der Schlaganfalle des Gehirns und ihre Entstehung. In: Monographien Neurologie. Berlin: Springer; 1930
• 15 Fisher CM, Adams RD. Observation on brain embolism with special reference to mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951; 10: 92-4.
• 16 Globus JH, Epstein JA. Massive cerebral hemorrhage: spontaneous and experimentally induced. J Neuropathol Exp Neurol 1953; 12: 107-31.
• 17 Meyer JS. Importance of ischemic damage to small vessels in experimental cerebral infarction. J Neuropathol Exp Neurol 1958; 17: 577-85.
• 18 Risau W, Wolburg H. Development of the blood-brain-barrier. TINS 1990; 13: 174-8.
• 19 Risau W, Hallmann R, Albrecht U. et al. Brain astrocytes induce the expression of an early cell surface marker for the blood-brain-barrier specific endothelium. EMBO J 1986; 5: 3179-83.
• 20 Hamann GF, Okada Y, Fitridge R, del Zoppo GJ. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 1995; 26: 2120-6.
• 21 Wagner S, Tagya M, Koziol JA. et al. Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by alpha 6-beta 4 integrin during focal cerebral ischemia/reperfusion. Stroke 1997; 28: 858-65.
• 22 Hamann GF, Okada Y, del Zoppo GJ. Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab 1996; 16: 1373-8.
• 23 Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 1994; 144: 855-61.
• 24 Heo JH, Lucero J, Abumiya T, Koziol J, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab, submitted.
• 25 Rosenberg GA, Navratil M, Barone F, Feuerstein G. Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 1996; 16: 360-6.
• 26 del Zoppo GJ, Okada Y, Hamann GF. et al. Mechanisms of fibrinolysis-associated hemorrhagic transformation. In: Yamaguchi T, Mori E, Minematsu K. et al. (eds.) Thrombolytic therapy in acute ischemic stroke III. Tokyo: Springer; 1995: 254-66.
• 27 Brun A, Fredriksson K, Gustafson L. Pure subcortical aterosclerotic encephalopathy (Binswanger disease): a clinicopathological study. Cerebrovasc Dis 1992; 2: 87-92.
• 28 Vinters HV, Wang ZZ, Secor DL. Brain parenchymal and microvascular amyloid in Alzheimer's disease. Brain Pathol 1996; 6: 179-95.
• 29 von Kummer R, Allen KL, Holle R. et al. Acute stroke: usefulness of early Ct findings before thrombolytic therapy. Radiology 1997; 205: 327-33.