Cited by 220Intracerebral and Subarachnoid Hemorrhage ResearchBarrier Structure and Function StudiesTraumatic Brain Injury and Neurovascular Disturbances

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Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

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Keep, Richard F, Zhou, Ningna, Xiang, Jianming, Andjelkovic, Anuska V, Hua, Ya, Xi, Guohua·2014·Fluids and Barriers of the CNS

DOI 10.1186/2045-8118-11-18PMC PMC4130123

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Abstract

This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood-brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer's disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.

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Figure 1 Photomicrographs showing both sides of serial coronal sections (thickness approximately 5 mm) containing hematoma (#) and edematous white matter (*) 24 hours after blood infusion in a pig brain frozen in situ. Perihematomal edema is present as blue-staining translucent regions in white matter adjacent to the hematoma. Evans blue staining is observed throughout the ipsilateral white matter and is indicative of increased BBB permeability and vasogenic edema development. Figure/legend reprinted with permission from Journal of Neurosurgery[11].CC BY · PubMed Central

Figure 2 Flair magnetic resonance imaging in a patient at day 1 after ICH. Note the marked edema (#) surrounding the hematoma (*).CC BY · PubMed Central

Figure 3 Hematoxylin & eosin staining of a section from the brain of a patient with cerebral cavernous malformation (type CCM3). Note the multiple blood vessels with little or no intervening parenchymal tissue. Scale bar = 200 μm.CC BY · PubMed Central

Figure 4 The underlying cause of secondary BBB dysfunction appears to differ in ICH (A) from cerebral ischemia (B). In ICH, evidence indicates a major role for the presence of blood components in brain parenchyma activating a number of pathways (cell injury, receptor-mediated signaling and inflammation) leading to BBB dysfunction. In contrast, in cerebral ischemia, the initiating cause of injury is the lack of oxygen and glucose supply to the brain. Delayed restoration of blood flow can also induce BBB dysfunction (reperfusion injury). With ischemic injury, there are a number of factors that can enhance the BBB dysfunction. Thus, for example, hyperglycemia and tissue plasminogen activator (tPA) both can result in hemorrhage after reperfusion. Less is known about factors that enhance secondary BBB dysfunction in ICH.CC BY · PubMed Central

Figure 5 During hematoma resolution after ICH, there is phagocytosis of erythrocytes by invading macrophages/microglia. Hematoxylin & eosin stained section from a pig ICH model (described in [10]) at day 7 after blood injection. Note the phagocytes engulfing erythrocytes (*) and the production of hemosiderin, a breakdown product of hemoglobin (yellow staining).CC BY · PubMed Central

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Authors: Keep, R. F., Zhou, N., Xiang, J., Andjelkovic, A. V., Hua, Y., & Xi, G.
Affiliations: University of Michigan (US)
Corresponding author: Keep, Richard F
ORCID: Keep, Richard F
Zhou, Ningna
Xiang, Jianming
Andjelkovic, Anuska V
Hua, Ya
Xi, Guohua
Venue: Fluids and Barriers of the CNS
Publisher: Springer Science and Business Media LLC
Published: 2014
Volume: 11
Issue: 1
Pages: 18
ISSN: 2045-8118 (ISSN-L)
DOI: 10.1186/2045-8118-11-18
PMC: PMC4130123
OpenAlex: W2103156349
Cited by: 220
References: 144
Citations by year: 2026: 22 · 2025: 20 · 2024: 17 · 2023: 19 · 2022: 23 · 2021: 18 · 2020: 29 · 2019: 17 · 2018: 9 · 2017: 24 · 2016: 12 · 2015: 9 · 2014: 1
FWCI: 2.10
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Fluids and Barriers of the CNS (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Deep Blue (University of Michigan) (submittedVersion)
Funders: National Institutes of Health (NS073959, NS079157)
National Institute of Neurological Disorders and Stroke (R21NS075757, R01NS034709, R21NS084049, R01NS079157)
Topics: Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords: intracerebral hemorrhage, blood-brain barrier dysfunction, hematoma expansion, vascular disruption, thrombin, hemoglobin, iron, neuroinflammation, iron chelation, hematoma evacuation, hypertension, vascular malformations, coagulopathy, Alzheimer's disease, secondary hemorrhage

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Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

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