RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke
Article first published online: 10 SEP 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 2, pages 232–240, August 2013
How to Cite
Jickling, G. C., Ander, B. P., Stamova, B., Zhan, X., Liu, D., Rothstein, L., Verro, P., Khoury, J., Jauch, E. C., Pancioli, A. M., Broderick, J. P. and Sharp, F. R. (2013), RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke. Ann Neurol., 74: 232–240. doi: 10.1002/ana.23883
- Issue published online: 24 SEP 2013
- Article first published online: 10 SEP 2013
- Accepted manuscript online: 7 MAR 2013 06:15AM EST
- Manuscript Accepted: 1 MAR 2013
- Manuscript Revised: 19 FEB 2013
- Manuscript Received: 20 SEP 2012
- NIH . Grant Numbers: NS056302 , NS075035 , NS079153
Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood–brain barrier is a central feature of HT pathogenesis, and leukocytes may contribute to this process. We sought to determine whether ischemic strokes that develop HT have differences in RNA expression in blood within 3 hours of stroke onset prior to treatment with thrombolytic therapy.
Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA was assessed by microarray analysis. Strokes that developed HT (n = 11) were compared to strokes without HT (n = 33) and controls (n = 14). Genes were identified (corrected p < 0.05, fold change ≥|1.2|), and functional analysis was performed. RNA prediction of HT in stroke was evaluated using cross-validation, and in a second stroke cohort (n = 52).
Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic therapy. A panel of 6 genes could predict strokes that later developed HT with 80% sensitivity and 70.2% specificity. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase-9; a shift in transforming growth factor-β signaling involving SMAD4, INPP5D, and IRAK3; and a disruption of coagulation factors V and VIII.
Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of the identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk. Ann Neurol 2013;74:232–240