PLASMINOGEN ACTIVATORS POTENTIATE THROMBIN-INDUCED BRAIN INJURY

Background and Purpose-Evidence suggests that cerebral edema following intracerebral hemorrhage (ICH) results from a mass effect in combinat ion with neurotoxic injury from clot-derived substrates such as thromb in. Thrombolytics can compete for thrombin inhibitors endogenous to th e brain. This study examines the effect of intracerebral infusion of t hrombolytics, tissue plasminogen activator (tPA), and urokinase (uPA), individually and in combination with thrombin. Methods-Various 100 mu L solutions were stereotactically infused into the right basal gangli a of adult male rats. Animals were euthanized 24 hours later, and brai n sections were taken for measurement of water, sodium, and potassium content. Results-Regardless of dose, when infused independently tPA (2 mu g) and uPA (2000 and 5000 Plough units) failed to produce any sign ificant tissue edema compared with vehicle control tissues, However, w hen either thrombolytic was infused concomitantly with thrombin (1 or 5 U), brain water, sodium, and potassium content all demonstrated a po tentiation of thrombin-induced brain injury (P<0.05). In addition, ani mal deaths were significantly greater than expected in animals receivi ng a combination of tPA (2 mu g) and thrombin (5 U) compared with eith er drug alone (P<0.001). Conclusions-This study indicates that brain e dema caused by thrombin can be greatly amplified by the presence of pl asminogen activators, perhaps because the latter compete for naturally occurring thrombin inhibitors. In the context of ICH, our results sug gest that the use of tPA or uPA to lyse clotted blood in brain parench yma may promote edema formation in surrounding tissue.