Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients

Kaźmierski, Radosław; Michalak, Sławomir; Wencel-Warot, Agnieszka; Nowinski, Wiesław L.

doi:10.1212/wnl.0b013e31826e9a83

Cited by 110 publications

(111 citation statements)

References 39 publications

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“…41 The role of TJPs in early HT is unclear since one study found intact TJPs at 24 hours after stroke 74 whereas a human study found increased blood levels of TJPs to be predictive of HT. 75 Early Hemorrhagic Transformation: Role of Other Leukocyte Factors Though leukocyte-derived MMPs appear to be one mediator of early HT, additional leukocyte-derived molecules have been implicated. 76 We examined mRNA expression in blood within 3 hours of ischemic stroke onset in humans before administration of tPA.…”

Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

449

369

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Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (o18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (418 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

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Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

449

369

View full text Add to dashboard Cite

show abstract

“…S-100 Protein: Measurement of serum S-100 protein levels in the first 10 days after stroke onset helps to predict long term clinical outcome and final infarct size [102]. The level of S-100 protein independently predicts HT before rtPA treatment, however with too low diagnostic accuracy to be useful in the preselection of patients for rtPA therapy [104,105].…”

Section: Blood Markers Nsementioning

confidence: 99%

“…MMP-9 and neutrophil levels are elevated in the cerebrospinal fluid as well. Since rtPA itself promotes neutrophil degranulation, a peak of MMP-9 elevation can be detected 30 minutes after rtPA administration as well [105][106][107].…”

Section: Mmp-9 Levelmentioning

confidence: 99%

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Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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The better understanding of the diverse mechanisms leading to the hemorrhagic transformation of an ischemic stroke is the crucial point in the prevention of this altogether common phenomenon. The different individual risk factors include the anatomical variability of collateral blood supply, age, genetics, body weight, etiology of the occlusion, side of the occluded vessel, renal status, stroke severity, history of high serum glucose or hypertension and hypertension or hyperglycemia at the onset of the stroke, ferritin level, INR, antiplatelet usage or the platelet count etc. All these might contribute to the process of hemorrhagic transformation. These risk factors have been identified by retrospective epidemiological studies and are useful to identify patients who are at high risk for hemorrhagic conversion and help the decision between conservative, thrombolytic or more advanced treatments such as thrombectomy. The modulations of potential molecular targets participating in the process seem to be promising in animal models, but human trials are lacking the breakthrough success so far, both in extending the time frame of the thrombolysis and in replacing the recombinant tissue plasminogen activator (rtPA) as thrombolytic agent.So far, the careful preselection of patients eligible for thrombolytic therapy is the best way to prevent hemorrhagic transformation. The intensive research in the field revealing small but important molecular details are continuously contributing to the better understanding of hemorrhagic transformation with the intention of finding new agents that co-administrated to the rtPA or completely replacing that could decrease the risk of secondary bleeding.The aim of this review is to give comprehensive insight into the process of hemorrhagic transformation of ischemic stroke, starting with basic overview of the penumbra concept and the collateral supply followed by discussion of the recanalisation-reperfusion-hemorrhagic transformation process after vessel occlusion also highlighting the importance of timing and ratio of recanalisation spontaneously and in case of thrombolytic agent administration. We overview the risk factors of hemorrhagic transformation, which may be helpful to physicians to identify high risk patients before rtPA administration. The last part of the work is dealing with future therapeutic possibilities based on the so far revealed molecular mechanisms of hemorrhagic transformation. With the aim to assess the rate and influencing factors on the recanalisation and reperfusion rate 381 patients with large-vessel occlusion was investigated. The patient group involved ones treated with rtPA or treated conservatively. Partial or complete recanalisation was achieved in 121 out of 210 (58%) patients after intravenous rtPA administration. The recanalisation success was more likely if the patient had atrial fibrillation [4] -maybe because cardioembolic clots consists more fibrin and are more likely to reopen by plasmin proteolysis than thrombosis of an atherosclerotic plaq...

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“…The level of NSE in CSF reaches its peak on the third day after cerebral ischemia in rats, and is positively correlated with the final infarction volume [6]. The up-regulation of NSE level in serum lags behind that in brain tissue for 2 hours in permanent cerebral ischemia model [7,8]. Myelin basic protein (MBP) is an important myelin structural protein.…”

Section: Introductionmentioning

confidence: 99%

To Optimize the Therapeutic Dose and Time Window of Picroside II in Cerebral Ischemic Injury in Rats by Orthogonal Test

Huang¹,

Sun²,

Wang³

et al. 2013

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The paper aims to optimize the therapeutic dose and time window of picroside II by orthogonal test in cerebral ischemic injury in rats. The forebrain ischemia models were established by bilateral common carotid artery occlusion (BCCAO) methods. The successful models were randomly divided into sixteen groups according to orthogonal experimental design and treated by injecting picroside II intraperitonenally at different ischemic time with different dose. The concentrations of neuron-specific enolase (NSE), neuroglial marker protein S100B and myelin basic protein (MBP) in serum were determined by enzyme linked immunosorbent assay to evaluate the therapeutic effect of picroside II in cerebral ischemic injury. The results indicated that best therapeutic time window and dose of picroside II in cerebral ischemic injury were ischemia 1.5 h with 20 mg/kg body weight according to the concentrations of NSE, S100B and MBP in serum. It is concluded that according to the principle of lowest therapeutic dose with longest time window, the optimized therapeutic dose and time window are injecting picroside II intraperitonenally with 20 mg/kg body weight at ischemia 1.5 h in cerebral ischemic injury in rats.

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Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients

Abstract: Analyzing serum levels of TJ proteins, like CLDN5, OCLN, and CLDN5/ZO1 ratio, as well as S100B and VEGF, is an effective way to screen for clinical deterioration caused by HT in ischemic stroke patients, both within and after the IV thrombolysis time window.

Cited by 110 publications

References 39 publications

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Hemorrhagic transformation of ischemic stroke

To Optimize the Therapeutic Dose and Time Window of Picroside II in Cerebral Ischemic Injury in Rats by Orthogonal Test

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