Hemorrhage after thrombolysis

Neumann-Haefelin, T., et al., Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke, 2006. 37(10) p. 2463-6. 

TrouiUas P, von Kummer R (2006) Classification and pathogenesis of cerebral hemorrhages after thrombolysis in ischemic stroke. Stroke 37 556-561... 

Singer OC, Humpich MC, Fiehler J et al (2008) Risk for symptomatic intracerebral hemorrhage after thrombolysis assessed by diffusion-weighted magnetic resonance imaging. Ann Neurol 63 52-60... 

Singer OC, KurreW, Humpich MC et al (2009) Risk assessment of symptomatic intracerebral hemorrhage after thrombolysis using DWI-ASPECTS. Stroke 40 2743-2748... 

TABLE 4.2 Management of Symptomatic Intracerebral Hemorrhage after Intraarterial Thrombolysis. 

Kase CS, Furlan AJ, Wechsler LR, Higashida RT, Rowley HA, Hart RG, Molinari GF, Frederick LS, Roberts HC, Gebel JM, Sila CA, Schulz GA, Roberts RS, Gent M. Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke the PROACT n trial. Neurology 2001 57 1603-1610. 

Retrospective analysis of CT scans has suggested that early signs of extensive infarction on CT, corresponding to a very poor ASPECTS score of < 2 (Weir et al. 2006) are associated with 85% mortality without thrombolysis and poor outcome, including hemorrhagic transformation, after thrombolysis (von Kummer et al. 1994, 1997 Hacke et al. 1998 Dzialowski et al. 2006). These observations have led to the introduction of the one-third rule, that is, patients with signs of infarction of greater than one-third of the middle cerebral artery... 

ECASS I, a double-blind placebo-controlled trial of IV thrombolysis administered within 6 h of stroke onset, was performed from 1992 to 1994 and involved 620 patients at 75 centers in 14 European countries [1, 39]. hi this smdy, patients with initial CT findings of greater than one-third MCA territory hypodensity or snlcal effacement were shown to have an increased risk of fatal intraparenchymal hemorrhage after treatment (Fig. 3.4). Because of this, these findings are considered by some to be contraindications to thrombolytic therapy [10, 35, 36, 39,40]. However, it is controversial... 

Swap, C., et al. Degree of oligemia by perfusion-weighted CT and risk of hemorrhage after lA thrombolysis, in Stroke -Proceedings of the 27th International Conference on Stroke and Cerebral Circulation. 2002. San Antonio, TX. 

Hjort, N., et al., MRI detection of early blood-brain barrier disruption parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis. Stroke, 2008. 39(3) p. 1025-8. 

Most of the studies that have addressed the hypothesis that the diffusion-perfusion mismatch can be used to select patients for thrombolysis have done so indirectly, by using the existence of the mismatch to widen, rather than replace the temporal window for treatment. The traditional 3-h window is based on several early clinical trials, in which thrombolysis was effective when administered to patients who were last seen without symptoms less than 3 h before treatment [69], but did not improve in outcomes when admiifistered after up to 5 [70] or 6 [71, 72] hours after onset. These studies did not use DWI or PWI, requiring only a noncontrast head CT examination to exclude the possibility of hemorrhage before thrombolysis could be initiated. A subsequent trial, which also did not incorporate DWI or PWI, found that thrombolysis could be effective up to 4.5 h, and this result has been used to widen the therapeutic window to 4.5 h at some centers [73]. 

M15. Montaner, J., Molina, C. A., Monasterio, J., et al.. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107, 598-603 (2003). 

However, several important studies have shown that intravenous thrombolysis may be beneficial more than 3 hours after stroke onset, provided that only patients with a significant diffusion-perfusion mismatch are treated. In one such smdy, Ribo et al. found that patients with a significant diffusion-perfusion mismatch could be treated safely and effectively in the 3-6-hour time period. In phase II of the desmo-teplase in acute stroke (DIAS) trial, patients with diffusion-perfusion mismatch were treated with desmoteplase up to 9 hours after stroke onset, and showed better outcomes than patients given placebo, with only a minimal incidence of symptomatic hemorrhage. Similar success was achieved in the same time window by the dose escalation study of desmoteplase in acute ischemic stroke (DEDAS). ... 

Greer DM, Koroshetz WJ, Cullen S, Gonzalez RG, Lev MH. Magnetic resonance imaging improves detection of intracerebral hemorrhage over computed tomography after intra-arterial thrombolysis. Stroke 2004 35 491 95. 

Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embohc focal ischemia in rats. Stroke 2002 33 831-836. 

E Role in therapy Thrombolytic agents currently licensed for the treatment of AMI in the United States include streptokinase, tissue plasminogen activator, anistreplase, reteplase, and tenecteplase. TNKase and alteplase have similar clinical efficacy for thrombolysis after myocardial infarction (i.e., similar mortality and intracranial hemorrhage rates). However, advantages of TNKase include ease and rapidity of administration, longer half-life, greater fibrin specificity, and lower noncerebral bleeding rates. Reteplase shares some characteristics of tenecteplase (e.g., similar half-life, rapid onset, and ease of administration). 

Gore JM, Sloan M, Price TR, Randall AM, Bovill E, Collen D, Forman S, Knatterud GL, Sopko G, Terrin ML. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, phase 11, pilot and clinical trial. Circulation 1991 83(2) 448-59. 

In the ECASS II and ECASS III trials, in an attempt to control for confounding variables, lower doses of rt-PA were used than in the ECASS I trial, and patients with greater than one-third MCA territory hypodensities were excluded from the study, which resulted in very low symptomatic hemorrhage rates in patients treated with rt-PA up to 4.5 h after stroke onset [49, 50]. In a more recent IA thrombolysis study, patients with a baseline ASPECTS >7 - implying less extensive MCA hypodensities on NCCT - had significantly more independent functional outcomes at 90 days than did patients with baseline ASPECTS <7 [51]. 

The results of the 2008 European Cooperative Acute Stroke Study (ECASS 111) expanded the 3-h time window for IV thrombolysis and revealed that although safe and effective up to 4.5 h after stroke onset, treatment benefits roughly one-half as many patients as those treated within 3 h [2, 158, 159]. Hence, the ratio between the hemorrhagic risk of treatment and the potential clinical benefit of treatment becomes a more critical consideration as the time window for therapy is expanded with newer IV and lA techniques. It is the mismatch between the size of the infarct core (proportional to hemorrhagic risk) and the size of the ischemic penumbra (proportional to potentially salvageable tissue), as determined by CTP, that provides an imaging measure of this risk-to-benefit ratio. Evidence suggests that core/penumbra mismatch may persist up to 24 h in some patients [160,161]. 

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