The paradoxical thrombogenic effect of aspirin in experimental thrombosis

Zimmerman, Rainer; Thiessen, Molly E.W.; Mörl, H; Weckesser, G.

doi:10.1016/0049-3848(79)90228-7

Cited by 17 publications

(6 citation statements)

References 14 publications

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“…In consequence the results described by Zimmermann et al [27], concerning a para doxical effect of single doses of 100 mg ASA/ kg or of an enhanced antithrombotic effect of repeated ASA doses in rabbits, could not be confirmed in this model. Nafazatrom in a dose of 10 mg/kg i.v.…”

Section: Discussioncontrasting

confidence: 38%

Laser-Induced Thrombi in Rat Mesenteric Vessels and Antithrombotic Drugs

Weichert¹,

Pauliks²,

Breddin³

1983

Pathophysiol Haemos Thromb

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A method to induce microthrombi in small mesenteric arteries (ø 15–25 μm) has been developed to study platelet reactions and to investigate antithrombotic drugs. A high power water immersion interference contrast system, based on a Leitz Orthoplan microscope, was used. In Nembutal-anesthetized male Wistar rats and in fawn hooded bleeder rats, vascular lesions were produced with a Hadron-512-Ruby-bio-laser or with a Coherent CR-2 supergraphite ion laser (Argon laser). The ruby laser produced intravascular precipitates consisting of proteins and erythrocytes which usually stuck to the vessel wall and on which platelets immediately adhered, transformed with pseudopode formation and formed loose aggregates. The Argon laser induced vascular damage, usually without intravascular heat precipitates which also led to platelet adhesion, transformation and aggregation. Fibrin threads rarely formed in the early platelet thrombi. Thrombus formation was significantly reduced in this model by dipyridamole (10 mg/kg orally), by Ditazole (50 mg/kg orally), heparin (100 IU/kg i.v.), Molsidomine (50 mg/kg orally), Nafazatrom (Bay G 6575, 10 mg/kg i.v. and orally), Ticlopidine (100 and 200 mg/kg orally) and Tioxaprofen (EMD 26644, 10 mg/kg orally). Thrombus formation was also significantly reduced in fawn hooded bleeder rats.

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Section: Discussioncontrasting

confidence: 38%

Laser-Induced Thrombi in Rat Mesenteric Vessels and Antithrombotic Drugs

Weichert¹,

Pauliks²,

Breddin³

1983

Pathophysiol Haemos Thromb

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“…However, prior studies have reported a thrombogenic effect with aspirin in rabbits only with doses five times higher than those used in our study. 21 - 29 In addition, we found no evidence of increased thrombosis on our postmortem examinations. To our knowledge, our study is the first experimental stroke study to assess the cerebral hemorrhagic risk of aspirin.…”

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confidence: 57%

Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits.

Clark

Madden

Lyden

et al. 1991

Stroke

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We studied the incidence of cerebral hemorrhage in an animal model of embolic stroke to determine the safety of aspirin, heparin, and tissue plasminogen activator therapies. We occluded the middle cerebral arteries of rabbits with labeled blood clots and administered either tissue plasminogen activator, heparin, aspirin, tissue plasminogen activator plus aspirin, tissue plasminogen activator plus heparin, or saline at various times after stroke. Compared to saline controls, both the aspirin-only and the tissue plasminogen activator-plus-aspirin groups had a significantly higher incidence of cerebral hemorrhage, whereas the heparin and tissue plasminogen activator combination groups did not. We conclude that aspirin antiplatelet therapy alone may increase the risk of hemorrhagic infarction, whereas heparin or tissue plasminogen activator therapy appears to be relatively safe. (Stroke 1991;22:872-876) T he recent availability of pharmacologic quantities of the thrombolytic agent tissue plasminogen activator (t-PA) has stimulated renewed clinical interest in thrombolytic therapy for stroke. Tissue plasminogen activator acts on plasminogen predominantly in the presence of fibrin, thus limiting its activity to the accessible surface of the clot. 1 -2 By producing less systemic depletion of fibrinogen and other clotting factors than other thrombolytic agents, t-PA may confer less risk of cerebral hemorrhage.We previously have used large and small clot experimental embolic stroke models to demonstrate efficacy of t-PA therapy without finding a significant increase in cerebral hemorrhage rate or severity. -6Animal studies by other investigators using t-PA have produced similar results.7 " 11 However, the risk of cerebral hemorrhage associated with clinical t-PA thrombolysis remains a concern. Data from the Received December 14, 1990; accepted March 28, 1991. Thrombolysis in Myocardial Infarction Trial and other cardiac thrombolysis studies indicate a 0-5% incidence of "spontaneous" cerebral hemorrhage. 12" 16 Initial results from two multicenter acute t-PA stroke trials recently completed also show a 40% (Acute Stroke Study Group Trial-Burroughs Wellcome) rate of cerebral hemorrhagic infarction and a 5% (National Institutes of Health Trial) rate of intracerebral hematoma. 1718A potential explanation for the difference in cerebral hemorrhage rates between the experimental and clinical studies is the concurrent use of anticoagulant or antiplatelet therapies in the clinical populations. Because the concurrent use of heparin or aspirin may be indicated to prevent vessel reocclusion after thrombolysis, and given that the majority of high-risk patients may be on aspirin before their stroke, an understanding of the risk of their concurrent use with t-PA is critical. To assess the cerebral hemorrhagic potential of t-PA with aspirin or heparin, we undertook the present study using an animal model of embolic occlusion of the middle cerebral artery.

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“…5 Thrombogenic effects of aspirin have been demonstrated experimentally, particularly at high doses, and possibly relate to inhibition of endothelially derived prostacyclin synthesis or, in some patients, increase in platelet adhesiveness. [13][14][15][16] Hypo- thetically, a separate and competing effect of aspirin to enhance thrombosis would be detectable in low-risk patients, in contrast to those with manifest vascular disease, in which the antiplatelet effect dominates. Aspirin in doses that reduce systemic prostacyclin appear to inhibit intrinsic thrombolytic mechanisms, 17,18 possibly by interference with nitric oxide synthase.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Use and Incident Stroke in the Cardiovascular Health Study

Kronmal

Hart

Talbert

et al. 1998

Stroke

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Background and Purpose-Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. Methods-We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. Results-Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative riskϭ1.6; 95% confidence interval [CI], 1.2 to 2.2; Pϭ0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (PϽ0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (Pϭ0.003). Conclusions-Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials. (Stroke. 1998;29:887-894.)

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The paradoxical thrombogenic effect of aspirin in experimental thrombosis

Cited by 17 publications

References 14 publications

Laser-Induced Thrombi in Rat Mesenteric Vessels and Antithrombotic Drugs

Laser-Induced Thrombi in Rat Mesenteric Vessels and Antithrombotic Drugs

Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits.

Aspirin Use and Incident Stroke in the Cardiovascular Health Study

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