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Intrathecal Fibrinolytic Therapy after Subarachnoid Hemorrhage: Dosage Study in a Primate Model and Review of the Literature

Published online by Cambridge University Press:  18 September 2015

J.M. Findlay ,
B.K.A. Weir ,
K. Kanamaru ,
M. Grace ,
P. Gordon ,
R. Baughman  and
A. Howarth
J.M. Findlay*
Affiliation:
Division of Neurosurgery, Genentech Inc., San Francisco
B.K.A. Weir
Affiliation:
Division of Neurosurgery, Genentech Inc., San Francisco
K. Kanamaru
Affiliation:
Division of Neurosurgery, Genentech Inc., San Francisco
M. Grace
Affiliation:
Department of Surgery, Genentech Inc., San Francisco
P. Gordon
Affiliation:
Division of Hematology, Genentech Inc., San Francisco
R. Baughman
Affiliation:
Department of Pharmacological Sciences, Genentech Inc., San Francisco
A. Howarth
Affiliation:
Division of Neurosurgery, Genentech Inc., San Francisco
*
Division of Neurosurgery, 2D 1.02 Mackenzie Health Sciences Centre, 8440 - 112 Street, Edmonton, Alberta, Canada T6G 2B7
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Abstract:

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Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P<0.05) reduction of lumen caliber in the clotside internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 16 , Issue 1 , February 1989 , pp. 28 - 40
Copyright
Copyright © Canadian Neurological Sciences Federation 1989

References

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