Impairment of the blood-brain barrier: a potential surrogate delineating the determinants of cerebral bleeding caused by fibrinolytic drugs.
BACKGROUND
Intracranial bleeding is encountered in some patients with acute myocardial infarction treated with fibrinolytic drugs, and especially in patients with occult cerebral vasculopathy. In order to determine whether pharmacologically induced plasminemia is a determinant, and whether impairment of the blood-brain barrier can serve as a marker of risk, we studied spontaneously hypertensive stroke-prone rats (SHRSP) genetically disposed to cerebral vasculopathy.


METHODS
In order to simulate the induction of plasminemia in patients treated with fibrinolytic drugs for acute myocardial infarction, three intravenous injections of human plasminogen and human tissue-type plasminogen activator (t-PA) were administered to the rats at 2-h intervals (12 mg plasminogen plus 60 micrograms t-PA, 6 mg plus 30 micrograms t-PA, and 0.5 mg plus 2.5 micrograms t-PA), and serial blood samples were assayed for plasmin. One hour after the final intravenous injection, the brain was perfusion-fixed with 4% formaldehyde, and the blood-brain barrier integrity was assessed by localization of immunoglobulin G (IgG) using fluorescein-conjugated goat anti-rat IgG and confocal microscopy.


RESULTS
Transient plasminemia followed each injection of plasminogen and t-PA. Intracranial extravasation of IgG was observed in nine of 11 SHRSP treated with t-PA and plasminogen. None of seven SHRSP injected with vehicle alone exhibited extravasation (chi 2 = 6.37, P = 0.01).


CONCLUSIONS
The results indicate that the blood-brain barrier in SHRSP is susceptible to impairment secondary to pharmacologically induced plasminemia and is predisposed to bleeding. The preparation developed may facilitate the delineation of relative risk of injury to cerebral vessels with thrombolytic therapy.
Absher
P M
PM
Department of Medicine, University of Vermont 05446-2500, USA. pabsher@zoo.uvm.edu
Hendley
E
E
Jaworski
D M
DM
Taatjes
D J
DJ
Sobel
B E
BE
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D010958:Plasminogen / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D005343:Fibrinolytic Agents; D007074:Immunoglobulin G; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin