Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke.
Reperfusion therapy with tissue plasminogen activator (tPA) is a rational therapy for acute ischemic stroke. Properly titrated use of tPA improves clinical outcomes. However, there is also an associated risk of hemorrhagic transformation after tPA therapy. Emerging data now suggest that some of these potentially neurotoxic side effects of tPA may be due to its signaling actions in the neurovascular unit. Besides its intended role in clot lysis, tPA is also an extracellular protease and signaling molecule in brain. tPA mediates matrix remodeling during brain development and plasticity. By interacting with the NMDA-type glutamate receptor, tPA may amplify potentially excitotoxic calcium currents. At selected concentrations, tPA may be vasoactive. Finally, by augmenting matrix metalloproteinase (MMP) dysregulation after stroke, tPA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood-brain barrier leakage, edema, and hemorrhage. Understanding these pleiotropic actions of tPA may reveal new therapeutic opportunities for combination stroke therapy.
Wang
Xiaoying
X
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass, USA.
Tsuji
Kiyoshi
K
Lee
Sun-Ryung
SR
Ning
MingMing
M
Furie
Karen L
KL
Buchan
Alastair M
AM
Lo
Eng H
EH
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002543:Cerebral Hemorrhage / Q000209:etiology*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010960:Plasminogen Activators / Q000009:adverse effects / Q000494:pharmacology*; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9