From the Departments of Surgery, Section of Neurosurgery (B.E.F., R.F.K.,
A.L.B., J.T.H.), Pediatrics (A.L.B.), and Neurology (A.L.B.), University of
Michigan, Ann Arbor, Michigan.
Correspondence to Richard F. Keep, PhD, Department of Surgery (Neurosurgery), University of Michigan, R5605 Kresge I, Ann Arbor, MI 48109-0532. E-mail rkeep{at}umich.edu
Background and Purpose—Evidence
suggests that cerebral edema following intracerebral
hemorrhage (ICH) 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 µL 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
µg) 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 µg) 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.
Henry
Ford Hospital,
Detroit, Michigan
© 1998 American Heart Association, Inc.
Original Contributions
Plasminogen Activators Potentiate Thrombin-Induced Brain Injury
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