title: Hemorrhagic transformation after ischemic stroke in animals and humans.
abstract: 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 (<18 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 (>18 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.
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: Glen C
authors.initials: GC
authors.lastname: Jickling
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: DaZhi
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: Boryana
authors.initials: B
authors.lastname: Stamova
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Ander
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Aigang
authors.initials: A
authors.lastname: Lu
authors.affiliation: Department of Neurology, MIND Institute, University of California at Davis, Sacramento, California, USA.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Sharp
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D004789:Enzyme Activation / Q000187:drug effects; D024243:HMGB1 Protein / Q000096:biosynthesis; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015912:Thrombolytic Therapy / Q000379:methods; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D010447:Peptide Hydrolases