Triggers and mediators of hemorrhagic transformation in cerebral ischemia

Mol Neurobiol. 2003 Dec;28(3):229-44. doi: 10.1385/MN:28:3:229.


Intracerebral hemorrhagic transformation is a multifactorial phenomenon in which ischemic brain tissue converts into a hemorrhagic lesion with blood-vessel leakage, extravasation, and further brain injury. It has been estimated that up to 30-40% of all ischemic strokes undergo spontaneous hemorrhagic transformation, and this phenomenon may become even more prevalent with the increasing use of thrombolytic stroke therapy. An emerging conceptual model suggests that the loss of microvascular integrity and disruption of neurovascular homeostasis connects the experimental findings of blood-cell extravasation to brain injury after hemorrhage. In this short article, we examine mechanisms related to reperfusion injury and oxidative stress, leukocyte infiltration, vascular activation, and dysregulated extracellular proteolysis as potential triggers of hemorrhagic transformation. Perturbations in cell-cell and cell-matrix signaling within the hypothesized neurovascular unit may ultimately lead to neuroinflammation and apoptotic-like cell death in the parenchyma. Further investigations into the molecular mediators of hemorrhagic transformation may reveal new therapeutic targets for this clinically complex problem.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Blood-Brain Barrier / physiology
  • Brain Ischemia / complications*
  • Brain Ischemia / physiopathology*
  • Cerebral Hemorrhage / etiology*
  • Cerebral Hemorrhage / physiopathology*
  • Extracellular Fluid / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Microcirculation / metabolism
  • Microcirculation / pathology
  • Microcirculation / physiopathology
  • Reperfusion Injury / etiology
  • Reperfusion Injury / physiopathology


  • Inflammation Mediators