BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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.
Authors: Ryan J Barrett; Rahat Hussain; William M Coplin; Samera Berry; Penelope M Keyl; Daniel F Hanley; Robert R Johnson; J Ricardo Carhuapoma Journal: Neurocrit Care Date: 2005 Impact factor: 3.210
Authors: Jun Zhang; Robert F Groff; Xiao-Han Chen; Kevin D Browne; Jason Huang; Eric D Schwartz; David F Meaney; Victoria E Johnson; Sherman C Stein; Rasmus Rojkjaer; Douglas H Smith Journal: Exp Neurol Date: 2008-01-05 Impact factor: 5.330
Authors: Bo Chen; Beth Friedman; Qun Cheng; Phil Tsai; Erica Schim; David Kleinfeld; Patrick D Lyden Journal: Stroke Date: 2009-11-05 Impact factor: 7.914