Kara Jo Swafford, MD

García-Yébenes I, García-Culebras A, Peña-Martínez C, Fernández-López D, Díaz-Guzmán J, Negredo P, et al. Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice. Stroke. 2018

Oxidative stress, activation of proteases and infiltration of circulating white cells are involved in short-term blood brain barrier (BBB) damage and hemorrhagic transformation (HT) after acute ischemic stroke. Iron can generate toxic reactive oxygen species associated with injury to the BBB after cerebral ischemia that may also increase HT. Some clinical studies found an increased risk of HT in the setting of iron overload. García-Yébenes, et al investigated whether iron overload increases the risk of HT with tPA in a murine model of ischemic stroke and sought to elucidate the mechanisms involved.

Mice were fed either a standard or iron-supplemented diet (iron overload group). After thromboembolic middle cerebral artery (MCA) occlusion, mice were given tPA after 20 minutes, 1 hour or 3 hours. Mice in a sham group (MCA exposed but not occluded) were given either saline or tPA. Serum and brain samples were collected to measure markers of oxidative stress, activation of matrix metalloproteinase (MMP)-9 and neutrophil infiltration. Recanalization rates after tPA infusion, infarct volume and HT were assessed.

Despite earlier recanalization, there was increased oxidative stress, induction of MMP-9 and neutrophil infiltration in the iron overload group, which also had increased infarct volume, suggesting that excess iron accelerates ischemic injury. Moreover, iron overload was associated with more severe HT. The precise mechanisms underlying these effects are unclear. It is suspected that elevated iron may cause platelet dysfunction, accelerating thrombolysis after tPA. This beneficial effect of reperfusion is reduced by an associated increase in tissue damage. Further studies are needed to investigate iron-associated injury in ischemic stroke patients. If corroborated, the findings may be relevant when deciding to administer tPA to patients with elevated serum iron levels, such as those with hemochromatosis, thalassemia or diabetes mellitus.