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(Stroke. 1998;29:563-569.)
© 1998 American Heart Association, Inc.

Original Contributions

Thrombolysis-Related Intracranial Hemorrhage

A Radiographic Analysis of 244 Cases From the GUSTO-1 Trial With Clinical Correlation

James M. Gebel, MD; Cathy A. Sila, MD; Michael A. Sloan, MD; Christopher B. Granger, MD; Kenneth W. Mahaffey, MD; Joseph Weisenberger; Cindy L. Green, MS; Harvey D. White, DSc; Joel M. Gore, MD; W. Douglas Weaver, MD; Robert M. Califf, MD; Eric J. Topol, MD; for the GUSTO-1 Investigators

From the Cleveland Clinic Foundation (Ohio) (J.M.G., C.A.S., J.W., E.J.T.); the University of Maryland Medical Center, Baltimore (M.A.S.); Duke University Medical Center, Durham, NC (C.B.G., K.W.M., C.L.G., R.M.C.); Green Lane Hospital, Auckland, New Zealand (H.D.W.); the University of Massachusetts, Worcester, Mass (J.M.G.); and the University of Washington, Seattle, Wash (W.D.W.).

Correspondence to Cathy A. Sila, MD, Department of Neurology (S-91), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis.

Methods—CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing.

Results—Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002).

Conclusions—Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.

Key Words: cerebral hemorrhage • myocardial infarction • thrombolytic therapy

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Intracranial hemorrhage is an uncommon but serious complication of systemic thrombolysis for acute myocardial infarction. Mortality from such hemorrhages in major trials ranges from 44% to 83%,^{1 2 3 4 5 6 7} with higher ICH rates consistently noted for TPA-treated patients than for SK-treated patients. The emergence of thrombolysis for acute ischemic stroke^{8 9 10 11 12} has increased interest in the character, mechanism, and pathogenesis of thrombolysis-related ICH.

Previous reports of thrombolysis-related ICH have noted a tendency for diversity, multiplicity, and large hemorrhage volumes.^{5 13 14 15} Age, hypertension, low body weight, and elevated fibrin degradation products have been identified as clinical risk factors, and amyloid angiopathy, hypertensive vascular disease, and hemorrhagic transformation of a prior silent cerebral infarct have been reported as underlying neuropathologic causes.^{15 16 17 18 19} The studies from which these reports are based, however, are seriously limited by small case series, lack of consistent clinical or neuroimaging documentation of cerebrovascular complications, and uncommon use of more than one thrombolytic regimen. This article analyzes symptomatic ICH complicating systemic intravenous thrombolysis for acute myocardial infarction in the GUSTO-1 trial, which is unique for its large size, systematic documentation of clinical information, use of four thrombolytic regimens, and protocol recommendation of a neuroimaging study for every stroke patient.

Our first goal was to generate a comprehensive, systematic descriptive analysis of the radiographic features of this ICH population. Our second goal was to create hemorrhage subgroups based on anatomic similarities and to analyze the relationship of both the overall hemorrhage population and each subgroup to selected relevant radiographic features and to clinical and laboratory data from the GUSTO-1 database. We focused on recently reported clinical risk factors for ICH in GUSTO-1,²⁰ including hypertension, age, and time interval between treatment and hemorrhage onset, a newly identified independent predictor of mortality and outcome.²¹ Because hemorrhage volume was also an important independent predictor of mortality in GUSTO-1,²¹ we were especially interested in identifying both radiographic and clinical features that correlated with higher ICH volume and high-volume anatomic subgroups. Finally, because the GUSTO-1 trial employed four different thrombolytic treatment regimens, we explored differences between the clinicoradiographic profiles of each regimen.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient Population
The GUSTO-1 trial randomized 41 021 patients in 1081 hospitals in 15 countries into one of four thrombolytic treatment strategies: SK 1.5 million U over 1 hour with subcutaneous heparin 12 500 U twice daily; SK 1.5 million U over 1 hour with intravenous heparin; accelerated TPA 15 mg bolus, then 0.75 mg/kg (maximum 50 mg) over 30 minutes and 0.5 mg/kg (maximum 35 mg) over 1 hour with intravenous heparin; or combination therapy with TPA 1.0 mg/kg (maximum 90 mg) over 1 hour with 10% given as a bolus and SK 1.0 million U over 1 hour with intravenous heparin. The intravenous heparin regimen consisted of 5000 U given as a bolus, then 1000 U/h for at least 48 hours adjusted to maintain an aPTT of 60 to 85 seconds. Chewable aspirin was given at entry and daily thereafter (160 to 325 mg). Additional details of each treatment regimen and descriptions of patient demographics, study end points, data acquisition, and quality assurance have been published elsewhere,²² as have study definitions and means of reporting adverse cerebrovascular events.²⁰

Hemorrhage Classification, Location, and Radiographic Features Analyzed
All available brain CT scans of the 268 patients classified by the GUSTO-1 Stroke Review Committee²⁰ as having ICH were reviewed by at least one principal investigator (J.M.G., C.A.S., or M.A.S.). Images were assessed for quality and hemorrhage margin clarity. Imaging characteristics were classified as completely as image quality permitted. The number of hemorrhage foci was noted, and the largest was classified as the primary hemorrhage. ICH were categorized as intraparenchymal (IPH), subdural (SDH), intraventricular (IVH), or subarachnoid (SAH). Classification of each hematoma location was based on the epicenter of the hematoma as either lobar (right or left frontal, parietal, temporal, or occipital), thalamic, basal ganglia/internal capsule, cerebellar (vermis or hemispheric), or brain stem (midbrain, pons, or medulla). For patients with more than one neuroimaging study, only the first study demonstrating the hemorrhage of interest was incorporated into our data analysis.

Radiographic characteristics for each hematoma were defined as follows (Figure): "confluent" refers to a hematoma of predominantly uniform CT attenuation, whereas "mottled" refers to a hematoma of mixed, heterogeneous CT attenuation. As defined in this analysis, the terms "confluent" and "mottled" are mutually exclusive. "Blood/fluid level" refers to the presence of at least one distinct area of hematoma containing an area of low CT attenuation above and high CT attenuation below a discrete line of separation, irrespective of its overall confluent versus mottled appearance. "Hypodense" refers to a "hematoma" of predominately low CT attenuation and includes specifically all hypodense brain lesions classified as hemorrhages (rather than infarcts with hemorrhagic conversion) by the GUSTO-1 Stroke Review Committee, the committee having final say in the classification of all adverse neurological events occurring in the GUSTO-1 trial. We included these rare lesions in our data analysis to maintain consistency between our study and others previously reported using the same determinations of this committee. Although a proportion of infarcts with hemorrhagic conversion may have been classified as hemorrhages, hypodense lesions represented such a small fraction (<3%) of the analysis population that any impact of such error, if present, would be negligible in the context of the far greater number of lesions with typical high attenuation. Mass effect features listed in Table 1 were noted. Herniation was classified as subfalcial, downward transtentorial, and/or upward transtentorial. Intraventricular hemorrhage was graded and defined as follows: "mild," defined as blood present in either the third ventricle or less than one third of one lateral ventricle; "moderate," defined as blood in either greater than two thirds of one lateral ventricle or less than half of both lateral ventricles; or "severe," defined as blood completely filling one lateral ventricle or more than half of both lateral ventricles.²³ Similarly, hydrocephalus was graded and defined as follows: "mild," defined as a prominent third ventricle or one dilated lateral ventricle; "moderate," defined as either a dilated third ventricle and one dilated lateral ventricle, or two moderately dilated lateral ventricles; or "severe," defined as two grossly dilated lateral ventricles.²³ Preexisting brain lesions were noted when possible, including cortical or lacunar infarct, periventricular leukomalacia or "white matter change," brain atrophy, or underlying mass lesion.

View larger version (154K): [in this window] [in a new window]   Figure 1. Characteristic radiographic hematoma features: confluence (top left), mottled appearance (top right), blood/fluid level (bottom right), and hypodensity (bottom left). See text for definitions.

View this table: [in this window] [in a new window]   Table 1. Frequency of Studied Radiographic Features

Method of Hematoma Volume Estimation
The volume of each IPH, SDH, IVH, and surrounding edema was determined with the use of computer-assisted volumetric analysis (proprietary software, Center for Computer Assisted Neurosurgery, Cleveland Clinic Foundation, run on Sun Microsystems SparkStation I). Each slice containing hematoma was traced by a single technician (J.P.W.), modeled after the technique reported by Hier et al.²⁴

Creation of Location-Based Hemorrhage Subgroups
The large number and diversity of available hemorrhages allowed the creation of anatomic subgroups as anticipated, which are defined in Table 2. The term "deep" hemorrhage in this table refers specifically to IPH centered in the putamen, thalamus, internal capsule, brain stem, or cerebellum, ie, those anatomic locations characteristic of "spontaneous" hypertensive hemorrhage.

View this table: [in this window] [in a new window]   Table 2. Definitions of Anatomic Subgroups of Intracranial Hemorrhage

Correlation of Radiographic Features With Clinical Variables
Neuroimaging data were combined with hemorrhage volume, as shown in Table 3, and with clinical data from the GUSTO database, as shown in Tables 4, 5, 6, and 7. Mortality and outcome analysis in our study population are the focus of a separate companion report, which identifies total hemorrhage volume as the only radiographic feature independently predictive of outcome in a multivariate logistic regression model analysis.²¹

View this table: [in this window] [in a new window]   Table 3. Relationship of Radiographic Features to Hemorrhage Volume

View this table: [in this window] [in a new window]   Table 4. Relationship of Treatment Regimen to Total ICH Volume

View this table: [in this window] [in a new window]   Table 5. Relationship of Time to Onset of ICH Symptoms After Treatment to Total ICH Volume

View this table: [in this window] [in a new window]   Table 6. Relationship of Hemorrhage Type to Time Interval From Treatment to Hemorrhage Occurrence (Grouped by Quartile)

View this table: [in this window] [in a new window]   Table 7. Relationship of Hemorrhage Type to Selected Clinical Data

Statistical Methods
Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by the median and 25th and 75th percentiles or the mean and SD for continuous variables. The ² test and Fisher's exact test were used to assess relations among the categorical variables of interest, while the Wilcoxon rank-sum test and the Kruskal-Wallis test were used to assess differences among groups of continuous variables. The correlation coefficient was used to measure the degree of linear association between two continuous variables. The correlation is constrained to lie in the interval (-1, 1), with an absolute value of 1 showing perfect correlation. Regression analysis was also used to evaluate the relation between two quantitative variables. A value of P.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Availability of Imaging Studies
CT scans of the brain were available for 249 (93%) of 268 patients classified as having hemorrhagic stroke. Four studies were excluded for lack of hemorrhage and one was reclassified as a hemorrhagic conversion of a cerebral infarct, leaving 244 patients. Of these 244 scans, 213 (87.3%) were of sufficient quality to classify every desired radiographic feature. The median total hemorrhage volume (25th, 75th percentile) for all ICH was 72 mL (39, 118), for all IPH was 48 mL (21, 85), and for all SDH was 88 mL (41, 111).

Hemorrhage Type and Location
IPH, either single or multiple, was the most common lesion (80.8%), followed by IPH plus SDH (15.2%), SDH only (2.9%), and IVH only (1.2%). Hematoma location was predominately lobar (77%), followed by cerebellar, capsular/putaminal, thalamic, and brain stem (Table 8). IVH, present in 48.9%, was graded as mild in 54.3%, moderate in 31.0%, and severe in 14.7% of cases. SAH was present in 11.4% of cases.

View this table: [in this window] [in a new window]   Table 8. Anatomic Distribution of Individual IPH

Radiographic Features
Mass effect was evident in 87.7% of cases and correlated with hematoma volume (Table 3). Herniation was observed in 103 cases (43.1%) and Duret's hemorrhage (brain stem hemorrhage secondary to completed transtentorial herniation) in 11 cases. The two most common features of IPH were confluence (79.4%) and the presence of blood/fluid level (81.5%). Median hemorrhage volume was significantly higher in cases complicated by hydrocephalus and IVH. Additionally, median volume of hematomas with a blood/fluid level was nearly double (79 mL) that of those without such a level (44 mL) (P<.001), and mottled hematomas were of significantly higher volume than confluent hematomas. Notably, only 112 of 298 individual hematomas had identifiable perihematoma edema (37.6%), with a median (25th, 75th percentile) volume of only 9 mL (5, 16) (range, 0 to 93 mL). Identifiable edema volume was substantially higher in those hematomas without a blood/fluid level (12 mL [6, 26]) than those with such a level (8 mL [5, 15]) (P=.1764 for difference between absolute edema volumes), a difference that becomes more striking when one considers that the former hematomas were half the volume of the latter (edema versus hematoma volume ratio of 0.273 [27.3%] for hematomas without blood/fluid level versus 0.101 [10.1%] for hematomas with such a level). Edema volume did not correlate with timing of hemorrhage (P=.605 by regression analysis). Preexisting lesions were noted in 43.8% of studies, including brain atrophy, periventricular leukomalacia, cortical infarct, and lacunar infarct (Table 1). Total hemorrhage volume was lower if preexisting lesions were observed (Table 3).

Relationship of Clinical Data to Hemorrhage Volume
DBP at enrollment (P=.018) and first recorded DBP (P=.014) correlated linearly to hemorrhage volume. More significantly, however, total hemorrhage volume in the combination treatment group (TPA+SK+intravenous heparin) was significantly higher than for other regimens (P=.034) (Table 4). Median total hemorrhage volume was 63 mL (33, 99) in those under age 63, the youngest age quartile, versus 95 mL (40, 147) in those over age 76, the oldest age quartile, and a linear correlation between total hemorrhage volume and increasing age was observed (P=.005 by regression analysis). Median overall time to ICH symptom onset after treatment was 14 (8, 30) hours, and hemorrhages occurring within this time were significantly larger than those occurring thereafter (P=.008) (Table 5). Median time from symptom onset to neuroimaging was 3 hours, and neither volumes nor other radiographic features of hemorrhages occurring within this time interval differed significantly from those occurring thereafter. There were no significant correlations between hemorrhage volume and anticoagulation, as measured by 6-, 12-, or 24-hour aPTT values or highest aPTT values before neurological change.

Correlation of Clinical and Radiographic Features to Hemorrhage Location
IVH most commonly complicated solitary deep IPH (group 2; 60%) and least commonly complicated SDH (groups 3 and 5; 17% and 28%, respectively). Total hemorrhage volumes were greatest in those with SDH and least for those with solitary deep IPH (Table 7).

Entry blood pressure criteria were strict in the GUSTO-1 protocol. Thus, there were no significant differences between subgroups in first recorded and trial entry DBP or SBP. However, there was a significant difference in highest recorded mean SBP before onset of neurological symptoms between subgroups, with the highest pressures occurring in the solitary deep IPH subgroup (P=.016 versus all other subgroups combined). A significant difference was observed between time from treatment to hemorrhage symptom onset, with symptoms occurring sooner in those patients with multifocal hemorrhage (groups 4 and 5) versus those with unifocal hemorrhage (groups 1, 2, and 3) (P=.002) (Table 5). This is in contradistinction to the median time from symptom onset to neuroimaging of 3 hours for all ICH patients, which did not differ significantly between subgroups. Finally, patients with SDH were more likely to have had syncope within the 48 hours before enrollment (P=.006) and facial or head trauma within 2 weeks of enrollment (P=.026) (Table 7). There were no significant differences observed in median age, body weight, aPTT values, or treatment regimen between subgroups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The GUSTO-1 trial provided a unique opportunity to analyze the diverse spectrum of ICH complicating coronary thrombolysis with its large size, systematic documentation of clinical information, use of multiple treatment regimens, and protocol recommendations of a neuroimaging study and additional clinical information for every patient with a stroke. Although two thirds of the hemorrhages were solitary and supratentorial, the remainder were subdural, infratentorial, and multifocal. The high frequency of IVH and SAH observed highlights the tendency of these hemorrhages to decompress across multiple intracranial compartments. Their large size is reflected in the high median absolute volume of 72 mL as well as the frequency of radiographic features of mass effect and herniation. Although the presence of a blood/fluid level is distinctly uncommon in spontaneous IPH, it was present in 82% of the hematomas in this series. Perihemorrhage edema was minimal in most cases, but especially so in those hematomas with a blood/fluid level.

A prior history of stroke was an exclusion criterion for entry into GUSTO-1, yet we identified remote lacunar and cortical infarcts in 16 cases with ICH, presumably clinically silent. However, our ability to observe such preexisting lesions was often limited by large hemorrhage size and resultant obliteration of remaining brain tissue, which is the most likely explanation for the lower hemorrhage volumes observed in patients with preexisting lesions. The true frequency of such lesions is therefore probably higher than that we were able to observe. Although massive hemorrhagic transformation of an underlying infarct has been reported as an additional mechanism of postthrombolytic ICH, the frequency of observed silent cerebral infarcts is similar to that seen in patients presenting with an initial ischemic stroke and more likely reflects the multifocal nature of atherosclerotic vascular disease in these patients.²⁵ Since neuroimaging was not obtained on GUSTO-1 patients without cerebrovascular complications, we were unable to explore this possibility further and cannot discount the possibility that hemorrhagic transformation of acute (presumably cardioembolic) infarct represents a significant proportion of such hemorrhages and in particular those few of "hypodense" appearance. Such an instance has in fact been reported and pathologically confirmed in the literature.²⁵ Likewise, we could not ascertain the frequency of asymptomatic ICH in the GUSTO-1 patient population, again because only patients with symptomatic adverse neurological events were imaged by protocol recommendation.

As anticipated, mass effect features, hydrocephalus, and the presence of IVH correlated with higher hemorrhage volume. However, this study also identified a newly observed association between higher hemorrhage volume and hematoma characteristics of a blood/fluid level and mottled appearance. The total hemorrhage volumes (median, 72 mL) observed in this study are at least twice that reported for nonanticoagulant-related spontaneous IPH.²⁶ The large volumes and hematoma characteristics of mottling and blood/fluid levels suggest the presence of ongoing fibrinolysis within such hematomas. The observation that perihematoma edema was minimal, particularly in those hematomas with blood/fluid levels, would be consistent with this hypothesis since animal models have linked the development of perihematoma edema to the diffusion of serum proteins liberated through thrombin-mediated activation of the clotting cascade.^{27 28 29} Multifocal ICH was seen in 30% of cases in this study, whereas spontaneous multifocal hemorrhage is rare. Reported causes include multiple underlying mass lesions (neoplastic or vascular malformation), vasculitides, venous sinus thrombosis, coagulopathies, or amyloid angiopathy,^{2 13 30 31 32 33} but in none of these processes does the frequency approach the rate observed in our study. The observation that such hemorrhages (subgroups 4 and 5) occurred much earlier after treatment than unifocal ICHs (groups 1, 2, and 3) again supports that their pathogenesis is linked to thrombolysis-related coagulopathy.

As previously reported,^{20 22} the overall frequency of symptomatic intracranial hemorrhage in GUSTO-1 was 0.65%, with treatment regimen–specific rates of 0.47% for SK with subcutaneous heparin, 0.57% for SK with intravenous heparin, 0.74% for accelerated TPA with intravenous heparin, and 0.94% for SK with both accelerated TPA and intravenous heparin. The observed correlations between increasing treatment regimen potency and both increased hemorrhage risk and volume further support thrombolysis-related coagulopathy as an important factor in the genesis and expansion of these hemorrhages. The timing of hemorrhage also appears to be important. As previously reported, the mean time from treatment to ICH was 17.5 hours for SK-treated patients, 10 hours for TPA-treated patients, and 13 hours for the combination (TPA+SK) group (P=.0113).²⁰ In this analysis, although ICHs occurring within the median time of 13.5 hours after treatment were significantly larger than those occurring thereafter, those occurring within the 8- to 13-hour quartile after treatment were largest. This observation cannot be explained by significant differences in time from symptom onset to imaging between patients in this quartile versus the others, since there were none, and as such most probably results from a combination of the differing mean times from treatment to hemorrhage onset for each regimen, the differing rates of hemorrhage between each regimen, and the differing median volumes of hemorrhage associated with each regimen. It is noteworthy, however, that earlier hemorrhage occurrence correlated with higher 30-day mortality independently of hemorrhage volume in GUSTO-1 in the multivariate analysis performed by Sloan et al,²¹ suggesting that additional factors (perhaps the brain's inability to accommodate a more rapidly expanding and acute mass as well as a more slowly expanding, subacute mass) are operative.

As in other reports,^{6 15 16 17 21 34 35 36} advanced age correlated strongly with hemorrhage risk but in this analysis also significantly correlated with increased hemorrhage volume (P=.005). Amyloid angiopathy is also associated with advanced age and has been reported as an underlying factor for both spontaneous and postthrombolytic lobar IPH.^{14 18 19 30 37 38 39 40} Unfortunately, because autopsy and surgical pathologic data were not available, we cannot speculate further on the relative importance of underlying amyloid angiopathy as a risk factor for hemorrhage in the elderly.

Hypertension has been noted to increase the risk of postthrombolytic ICH in many^{15 16 17 34 37} but not all^{6 35} reports. Although there were statistically significant differences of 2 mm DBP and 8 mm SBP between enrollment blood pressure of all ICH patients versus their non-ICH GUSTO counterparts,²⁰ this modest difference is impractical for clinical use and probably reflects the strict blood pressure entry criteria and treatment required by the GUSTO-1 protocol. However, a history of hypertension was most frequent in and actual SBPs at symptom onset were highest in those patients whose hemorrhages occurred in the deep locations characteristic of spontaneous hypertensive hemorrhages (subgroup 2), suggesting that hypertension acts as a significant cofactor in the pathogenesis of these hemorrhages.

Another noteworthy clinicoradiographic observation is the disproportionate frequency of facial or head trauma within 2 weeks of treatment or syncope within 2 days of treatment in patients with postthrombolytic SDH. Although the relationship of head trauma to SDH pathogenesis is well established,^{13 34} the association observed in this study reinforces that any prior traumatic vascular lesion, even if clinically asymptomatic, is a risk factor for developing this high-volume, high-mortality lesion. This conclusion is cautiously made, however, since there is no way to account for whether bias in history taking existed for this subgroup.

In conclusion, this study represents the largest descriptive analysis of neuroimaging features with clinical correlation performed on postthrombolytic ICH to date. We identified relationships between higher hemorrhage volume and the radiographic features of presence of hematoma characteristics of a blood/fluid level (P<.001) or mottled appearance (P=.05), hydrocephalus (P<.001), and IVH (P=.022) and clinical factors of advanced age (P=.005) and time interval from treatment to symptom onset (P=.008). We conclude that thrombolysis-related coagulopathy is the most important identifiable factor in the pathogenesis of postthrombolytic ICH, but its interaction with other factors may determine the ICH subtype and manifestation of hemorrhage. Hypertension (P=.016) appears to be a cofactor in the genesis of solitary deep IPH, and recent head trauma (P=.026) or syncope (P=.006) plays a significant role in SDH.

	Selected Abbreviations and Acronyms

 

aPTT = activated partial thromboplastin time DBP = diastolic blood pressure GUSTO-1 = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries ICH = intracranial hemorrhage IPH = intraparenchymal hemorrhage IVH = intraventricular hemorrhage SAH = subarachnoid hemorrhage SBP = systolic blood pressure SDH = subdural hemorrhage SK = streptokinase TPA = tissue plasminogen activator

	Acknowledgments

 
This study was funded by Genentech (South San Francisco, Calif), Bayer (New York, NY), CIBA-Corning (Medfield, Mass), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France).

Received September 30, 1997; revision received December 22, 1997; accepted December 22, 1997.

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