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.
Highlights
Hemorrhagic transformation (HT) is bleeding into an area of ischemic brain after stroke
We present evidence suggesting that there is a difference between HT that occurs early after stroke compared with HT that is delayed
TPA binding to the platelet-derived growth factor receptor alpha (PDGFRa) on astrocyte end feet increases the blood–brain barrier (BBB) permeability[36] and increased levels of Platelet-derived growth factor-CC (PDGF-CC) are associated with HT in tissue plasminogen activator (tPA)-treated stroke patients[37] (Figure 2)
Summary
Glen C Jickling[1], DaZhi Liu[1], Boryana Stamova[1], Bradley P Ander[1], Xinhua Zhan[1], Aigang Lu2 and Frank R Sharp[1]. 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). Clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers.
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