Rapid breakdown of microvascular barriers and subsequent hemorrhagic transformation after delayed recombinant tissue plasminogen activator treatment in a rat embolic stroke model.
OBJECTIVE
Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after stroke increases risk of hemorrhagic transformation, particularly in areas with blood-brain barrier leakage. Our aim was to characterize acute effects of rtPA administration on the integrity of microvascular barriers.


METHODS
Stroke was induced in spontaneously hypertensive rats by unilateral embolic middle cerebral artery occlusion. Six hours after stroke, rtPA was intravenously administered (n=10). Controls received saline (n=4). Extravasation of the large-diameter contrast agent monocrystalline iron oxide nanocolloid (MION) was assessed with susceptibility contrast-enhanced MRI during rtPA injection. In addition, we performed perfusion MRI and diffusion-weighted MRI. After MRI, 2 hours after rtPA treatment, intracerebral hemorrhage was quantified with a spectrophotometric hemoglobin assay.


RESULTS
Late rtPA treatment resulted in increased hemorrhage volume (8.4+/-1.7 versus 2.9+/-0.9 micro L in controls; P<0.05). In MION-injected animals, during rtPA administration, transverse relaxation rate change (DeltaR2*) increased from 12.4+/-6.0 to 31.6+/-19.2 s(-1) (P<0.05) in areas with subsequent hemorrhage. Significant DeltaR2* changes were absent in nonhemorrhagic areas, in animals without injected MION, and in saline-treated animals. Thrombolytic therapy did not improve perfusion in regions with hemorrhagic transformation (cerebral blood flow index was 22.8+/-19.7% [of contralateral] at 0.5 hours before and 22.4+/-18.0% at 1 hour after rtPA administration).


CONCLUSIONS
The DeltaR2* changes during rtPA delivery in MION-injected animals indicate extravasation of MION, which reflects increased permeability of the blood-brain barrier. This implies that late rtPA treatment rapidly aggravates early ischemia-induced damage to microvascular barriers, thereby enhancing hemorrhagic transformation.
Dijkhuizen
Rick M
RM
Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass, USA. rickd@NMR.MGH.Harvard.edu
Asahi
Minoru
M
Wu
Ona
O
Rosen
Bruce R
BR
Lo
Eng H
EH
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D018450:Disease Progression; D052203:Ferrosoferric Oxide; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D007501:Iron; D008279:Magnetic Resonance Imaging; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010087:Oxides; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects*
D003287:Contrast Media; D010087:Oxides; D011994:Recombinant Proteins; D007501:Iron; D010959:Tissue Plasminogen Activator; D052203:Ferrosoferric Oxide