RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke

Ann Neurol. 2013 Aug;74(2):232-40. doi: 10.1002/ana.23883. Epub 2013 Sep 10.


Objective: 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.

Methods: 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).

Results: 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.

Interpretation: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Brain Ischemia / blood*
  • Brain Ischemia / complications
  • Brain Ischemia / genetics
  • Cerebral Hemorrhage / blood
  • Cerebral Hemorrhage / etiology
  • Cerebral Hemorrhage / genetics
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Multicenter Studies as Topic
  • Predictive Value of Tests
  • RNA, Messenger / blood*
  • Randomized Controlled Trials as Topic
  • Stroke / blood*
  • Stroke / complications
  • Stroke / genetics
  • Time Factors


  • RNA, Messenger