Plasminogen activators potentiate thrombin-induced brain injury.
OBJECTIVE
Evidence suggests that cerebral edema following intracerebral hemorrhage (i.c.h.) results from a mass effect in combination with neurotoxic injury from clot-derived substrates such as thrombin. Thrombolytics can compete for thrombin inhibitors endogenous to the brain. This study examines the effect of intracerebral infusion of thrombolytics, tissue plasminogen activator (tPA), and urokinase (uPA), individually and in combination with thrombin.


METHODS
Various 100 microL solutions were stereotactically infused into the right basal ganglia of adult male rats. Animals were euthanized 24 hours later, and brain sections were taken for measurement of water, sodium, and potassium content.


RESULTS
Regardless of dose, when infused independently tPA (2 micrograms) and uPA (2000 and 5000 Plough units) failed to produce any significant tissue edema compared with vehicle control tissues. However, when either thrombolytic was infused concomitantly with thrombin (1 or 5 U), brain water, sodium, and potassium content all demonstrated a potentiation of thrombin-induced brain injury (P < 0.05). In addition, animal deaths were significantly greater than expected in animals receiving a combination of tPA (2 micrograms) and thrombin (5 U) compared with either drug alone (P < 0.001).


CONCLUSIONS
This study indicates that brain edema caused by thrombin can be greatly amplified by the presence of plasminogen activators, perhaps because the latter compete for naturally occurring thrombin inhibitors. In the context of ICH, our results suggest that the use of tPA or uPA to lyse clotted blood in brain parenchyma may promote edema formation in surrounding tissue.
Figueroa
B E
BE
Department of Surgery, University of Michigan, Ann Arbor 48109-0532, USA.
Keep
R F
RF
Betz
A L
AL
Hoff
J T
JT
D000818:Animals; D001479:Basal Ganglia / Q000098:blood supply; D001522:Behavior, Animal / Q000187:drug effects; D001784:Blood Gas Analysis; D001794:Blood Pressure; D001929:Brain Edema / Q000139:chemically induced* / Q000401:mortality; D002540:Cerebral Cortex / Q000098:blood supply; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000401:mortality; D004357:Drug Synergism; D007839:Functional Laterality / Q000502:physiology; D006490:Hemostatics / Q000494:pharmacology*; D007477:Ions; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014867:Water / Q000032:analysis
D006490:Hemostatics; D007477:Ions; D014867:Water; D013917:Thrombin; D010959:Tissue Plasminogen Activator