Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice
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2018-06-13
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Background and Purpose—Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological
therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy
is limited by the risk of hemorrhagic transformation (HT)—the main complication of ischemic stroke. Our aim is to
establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent
this devastating complication.
Methods—Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy
at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix
metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and
edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration,
4-hydroxynonenal, and matrix metalloproteinase-9 staining).
Results—Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration.
Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced
serum matrix metalloproteinase-9 increase, and enhanced basal serum lipid peroxidation. High iron increased brain lipid
peroxidation at most times and neutrophil infiltration at the latest time studied.
Conclusions—Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of
tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis.
Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must
be performed to confirm our results.
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García-Yébenes I, García-Culebras A, Peña-Martínez C, Fernández-López D, Díaz-Guzmán J, Negredo P, Avendaño C, Castellanos M, Gasull T, Dávalos A, Moro MA, Lizasoain I. Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice. Stroke. 2018 Sep;49(9):2163-2172. doi: 10.1161/STROKEAHA.118.021540. PMID: 30018160.