Hemorrhagic Transformation and Microvascular Integrity during Focal Cerebral Ischemia/Reperfusion

Hamann, Gerhard F.; Okada, Yasushi; Zoppo, Gregory J. del

doi:10.1097/00004647-199611000-00036

Cited by 265 publications

(188 citation statements)

References 25 publications

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“…This led the authors to postulate that later development of HT probably resulted from early ischemic damage to the endothelium. More recent studies by Hamann et al support this view, noting that reperfusion of ischemic tissue caused structural damage to the basal lamina (BL), an important part of the BBB complex (33,34). They concluded that this loss of BL structure in conjunction with breakdown of the extracellular matrix was probably necessary for the extravasation of plasma including proteins and, at later times, the formed elements of blood such as platelets and RBCs.…”

Section: Discussionmentioning

confidence: 99%

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Knight

Nagesh

Nagaraja³

et al. 2005

Magnetic Resonance in Med

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Pathologic changes in brain tissue during and after stroke may lead to injury of the blood-brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T 1 and T 2 , and magnetization transfer (MT) related parameters (T 1sat , K for and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n ‫؍‬ 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) by MRI and 14 C-␣-aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia-injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T 1sat in the caudate-putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/ contralateral T 1sat ratio > 1.6 demarcates leakage of small molecules such as Gd-DTPA and AIB across the BBB. Key words: Gd-DTPA; hemorrhagic transformation; magnetization transfer; MRI; rt-PA; stroke Thrombolysis using recombinant tissue plasminogen activator (rt-PA) has proven to be an effective intervention for the treatment of acute ischemic stroke (1), but the risk of hemorrhagic transformation (HT) following such treatment remains an obstacle to widespread usage of thrombolytic agents. To illustrate this risk, the probability of symptomatic HT increases significantly during the first 36 h after stroke onset in patients receiving rt-PA (6.4% vs. 0.6% in placebo-treated patients), and 61% of the patients with symptomatic HT die within 3 months (1). Studies performed using animal stroke models show similar findings with increased risk of HT associated with thrombolytics (2-5). In view of these complications with thrombolytic therapy, it is important to develop diagnostic imaging techniques that reliably identify tissue regions that are prone to HT and to obtain such data when deciding on a treatment protocol.One of the possible imaging techniques is computed tomography (CT). The sensitivity of CT for detection of early ischemic damage remains controversial because a significant proportion of stroke patients show negative acute CT images but go on to develop large infarcts (6). Although it is the standard diagnostic test for extant cerebral bleeding, CT has a limited capacity to predict HT in ischemic stroke (7). An early report from the NINDS rt-PA Stroke Trial showed only a 57% efficiency for the prediction of symptomatic HT based on early CT findings (1). A more recent retrospective analysis of CT films from the trial adjusted the data for group imbalances in several baseline clinical features and found that early ischemic changes were not predictive of clinical deterioration at 24 h or of symptomatic intracerebral hemorrhage (i.e., death) at 90 days (8). It may be that high...

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Section: Discussionmentioning

confidence: 99%

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Knight

Nagesh

Nagaraja³

et al. 2005

Magnetic Resonance in Med

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“…Several preclinical studies and biomarker analyses have suggested that neuroinflammatory markers are linked to blood‐brain barrier (BBB) breakdown and HT risk 11, 31, 32, 33. Disruption of the BBB has been shown to be associated with neuroinflammation following ischemic injury,32 and hemorrhagic transformation has been reported as a maker of BBB breakdown 33. The ligand for ST2, IL‐33, is hypothesized to serve as an acute inflammatory signaling molecule that participates in maintaining barrier function and integrity 34.…”

Section: Discussionmentioning

confidence: 99%

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Wolcott

Batra

Bevers

et al. 2017

Ann Clin Transl Neurol

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Objective ST2 is a member of the toll‐like receptor superfamily that can alter inflammatory signaling of helper T‐cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke.MethodsWe measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0‐2 and 3‐6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan–Meier survival analysis and receiver operating characteristic curves.Results646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2–12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7–49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9–55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54–5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58–8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40–37.44, P = 0.039).InterpretationSoluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke.

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“…It is known that the integrity of the cerebral microvasculature is provided mainly by 2 differing anatomical and functional barriers, ie, the blood-brain barrier (BBB) and basal lamina. 15 The BBB is represented by the interendothelial cell tight junctions. The basal lamina consists of a network of type IV collagen and laminin polymer connected by entactin and serves as a structural barrier to the extravasation of cellular blood elements.…”

Section: Discussionmentioning

confidence: 99%

Contrast Enhancement and Contrast Extravasation on Computed Tomography After Intra-Arterial Thrombolysis in Patients With Acute Ischemic Stroke

Yoon

Seo

Kim

et al. 2004

Stroke

151

161

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Background and Purpose-The goal of this study was to determine the CT findings and clinical consequences of contrast enhancement and contrast extravasation on CT scans obtained after intra-arterial thrombolytic therapy for treatment of acute ischemic stroke. Methods-Sixty-two patients were treated with intra-arterial thrombolysis. All patients underwent nonenhanced CT scans immediately and 24 hours after thrombolytic therapy. Contrast enhancement was defined as a hyperdense lesion that disappeared on a 24-hour follow-up CT scan. Contrast extravasation was defined as a hyperdense lesion with maximum Hounsfield unit Ͼ90 that persisted on a follow-up CT scan. We evaluated the differences in the clinical and radiological data between 3 groups: contrast enhancement, contrast extravasation, and control groups. Results-Contrast enhancement was found in 14 of 62 patients (22.6%); contrast extravasation was seen in 7 (11.3%).Compared with the control group, the contrast enhancement group had a lower recanalization grade (64.3% versus 34.1%, Pϭ0.048) and a lower incidence of hemorrhagic transformation (14.3% versus 43.9%, Pϭ0.047). The contrast extravasation group had a higher incidence of both hemorrhage (100% versus 43.9%, Pϭ0.006) and symptomatic hemorrhage (100% versus 14.6%, PϽ0.001) than the control group. Poor outcomes were more frequent in the contrast extravasation group (100% versus 38.9%, Pϭ0.003) than the control group. Conclusions-Contrast enhancement on CT scans obtained after intra-arterial thrombolysis is usually not associated with hemorrhagic complications. However, contrast extravasation is highly associated with parenchymatous hematoma and should be considered a negative prognostic sign.

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Hemorrhagic Transformation and Microvascular Integrity during Focal Cerebral Ischemia/Reperfusion

Cited by 265 publications

References 25 publications

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

Contrast Enhancement and Contrast Extravasation on Computed Tomography After Intra-Arterial Thrombolysis in Patients With Acute Ischemic Stroke

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