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(Stroke. 1995;26:1039-1046.)
© 1995 American Heart Association, Inc.

Articles

Intravenous Aspirin Causes a Paradoxical Attenuation of Cerebrovascular Thrombolysis

Presented in part at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics, San Francisco, Calif, July 30-Aug 3, 1993, and published in abstract form in The Pharmacologist. 1993;35:275.

G. Roger Thomas, PhD; Harold Thibodeaux, BS; Carol J. Errett; Martin M. Bednar, MD, PhD; Cordell E. Gross, MD William F. Bennett, PhD

From the Department of Cardiovascular Research, Genentech Inc, South San Francisco, Calif (G.R.T., H.T., C.J.E., W.F.B.), and the Division of Neurosurgery, Vermont Center for Vascular Research, University of Vermont, Burlington (M.M.B., C.E.G.).

Correspondence to G. Roger Thomas, Department of Cardiovascular Research, Genentech Inc, South San Francisco, CA 94080. E mail thomas.roger@gene.com.

Background and Purpose Aspirin treatment is recognized as an advantageous adjunct to thrombolytic agents in myocardial infarct patients. In this study we examined the effects of aspirin on the rate of clot lysis and on the frequency and extent of hemorrhagic transformations in rabbit models of embolic stroke.

Methods Rabbit models of ex vivo platelet aggregation and cutaneous template bleeding times were used to show the anticoagulant effects of aspirin in our experimental paradigm. We monitored tissue-type plasminogen activator (TPA)–induced clot lysis in two rabbit models of embolic stroke by (1) scintigraphically following the dissolution of a ^99mTc-tagged clot or (2) using roentgenography to follow the disappearance of an Sn-tagged clot.

Results In animals pretreated (18 hours) with a single administration of aspirin (1, 5, or 20 mg/kg IV) or 1 mg/kg per day for 3 days, the aggregation response of platelets to collagen (3.3 µg/mL) or arachidonic acid (0.5 mmol/L) was attenuated. High-dose aspirin also increased ear template bleeding time from 1.6 to 2.6 minutes. When aspirin (20 mg/kg) was administered 18 hours before embolism and subsequent lysis with TPA (0.3 mg/kg bolus; 3 mg/kg per hour IV), the pretreatment significantly antagonized the rate and extent of TPA-induced clot lysis by up to 70%. This was confirmed in a second embolic stroke model. The suppression of TPA-induced lysis was reversed by administration of the prostacyclin analogue iloprost (10 µg/kg per hour) directly into the cerebral circulation.

Conclusions We conclude that aspirin reduces the effects of TPA in embolic stroke models. This effect may be the result of a loss of endothelial prostacyclin production since the effect is reversed by iloprost.

Key Words: aspirin • prostaglandins • thrombolytic therapy • rabbits

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