Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity.

Levin, Richard I.; Harpel, Peter C.; Weil, Deborah; Chang, T S; Rifkin, Daniel B.

doi:10.1172/jci111454

Cited by 62 publications

(5 citation statements)

References 56 publications

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“…It is also of interest that several studies employing the prophylactic use of aspirin for stroke prevention in "low-risk" patients have reported either no benefit or an increase in stroke incidence. 27,28 These studies correlate well with earlier clinical observations that aspirin possesses antifibrinolytic 29 and/or thrombogenic 30 effect(s).…”

supporting

confidence: 78%

Antiplatelet Therapy in Acute Cerebral Ischemia

Bednar

Gross

1999

Stroke

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Background-Improved recognition of stroke signs and symptoms has paralleled the development of pharmacological strategies that may be examined to reduce stroke mortality and morbidity. Presently, tissue plasminogen activator is the only therapy that significantly improves outcome in acute stroke, with no agent demonstrating a significant reduction in mortality. Summary of Review-Antiplatelet agents are a heterogenous class of drugs that have been successfully used for more than 2 decades in secondary stroke prevention. These agents include aspirin, with or without dipyridamole, and more recently, the adenosine antagonists ticlopidine and clopidogrel. However, studies of the use of antiplatelet agents within 48 hours of the ictus have examined only aspirin. Only 1 study, the Multicentre Acute Stroke Trial-Italy (MAST-I), entered patients within 6 hours of the ictus. These data suggest that an improvement in mortality may be related to the speed of administration. No significant adverse events were noted with early antiplatelet monotherapy. However, MAST-I did note a significant increase in early mortality in patients receiving aspirin plus streptokinase, a finding not adequately explained by an increase in the intracranial hemorrhage rate. Conclusions-The use of antiplatelet therapy in acute stroke, clinical or experimental, has only recently received attention.It is likely that the use of antiplatelet agents for acute stroke therapy will be less restrictive than that currently seen for thrombolytics. Future studies should include an examination of those agents that have previously demonstrated efficacy in secondary stroke prevention, most notably, aspirin. The recognition that all platelet stimuli share a final common pathway that is dependent on the surface glycoprotein IIb/IIIa (fibrinogen) receptor has resulted in the development of various agents which block this receptor and are currently the focus for clinical trials. The role of nitric oxide in stroke therapy will depend on minimizing the hypotensive side effects of this agent. Stroke models are needed to provide preliminary data on the efficacy of antiplatelet therapy, especially as relates to the interaction of antiplatelet agents with thrombolytics. (Stroke. 1999;30:887-893.)

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supporting

confidence: 78%

Antiplatelet Therapy in Acute Cerebral Ischemia

Bednar

Gross

1999

Stroke

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“…However, in a recent study on healthy human volunteers, aspirin (650 mg given orally both 18 and 2 hr before blood collection) inhibited the rise in vascular plasminogen activity after venous occlusion. 42 Similarly a decrease in fibrinolysis induced by both cellular and plasmatic factors after ingestion of 1 g of aspirin per day for 4 days had been reported. 43 Recently Roncaglioni et al 4 These considerations should be borne in mind when analyzing the results of clinical trials combining aspirin and oral anticoagulants.…”

mentioning

confidence: 66%

Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction.

Gaetano¹,

Cerletti²,

Dejana³

et al. 1985

Circulation

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The current dispute over the effects of "low" vs "high"doses of aspirin should take into consideration the pharmacokinetics of this drug. In fact, different pharmaceutical formulations of aspirin may deliver little or no aspirin to the systemic blood. This was the case, for instance, in healthy volunteers taking 320 mg of compressed aspirin or 800 mg of enteric-coated aspirin. In all instances thromboxane B2 generation in serum was fully inhibited. Platelet cyclooxygenase might therefore be effectively acetylated by exposure to aspirin in the portal circulation, whereas vascular cyclooxygenase could be spared. Thus aspirin formulations ensuring complete first-pass deacetylation should be sought rather than "low" or "high" doses of unspecified aspirin formulations. Regardless of the type and dose of aspirin administered, salicylate is formed and accumulates in the circulation. It may antagonize the effects of aspirin on cyclooxygenase, at least in acute conditions. As an example, after administration of 1 g of salicylate to healthy volunteers, when plasma levels of the drug were about 75 ,ug/ml, the effect of 40 mg iv aspirin (given 40 min later) on platelet cyclooxygenase and aggregation was significantly diminished. In contrast, in patients undergoing saphenectomy, the same dose of salicylate (1 g) gave plasma drug levels of about 25 ,ug/ml; salicylate was unable to prevent the inhibitory effect on platelets of 40 mg iv aspirin (given 1 hr later) but did act on vascular prostacyclin. Thus the combination of salicylate with aspirin at an appropriate dose and blood level ratio may result in almost complete dissociation of the drug's effect on platelets and vessels in man. Because the studies outlined in this review address only the short-term outcome of the salicylate-aspirin interaction, the possibility should be tested that inactivation of cyclooxygenase would occur after long-term administration of salicylate-aspirin. A pharmacokinetic approach to the "aspirin dilemma" should also consider the possibility that salicylate and/or its metabolites (e.g., gentisic acid) may interfere with lipoxygenase activity, synthesis of the prothrombin complex coagulation factors, and fibrinolysis. Circulation 72, No. 6, 1185No. 6, -1193No. 6, , 1985 Aspirin, salicylate, and inhibition of platelet aggregation and cyclooxygenase activity. Aspirin inhibits platelet aggregation and the concomitant release reaction.I4 This exciting discovery, made more than 15 years ago, was characterized by three main facts: (1) aspirin was active in man at oral doses as low as 150 mg (about 2 mg/kg), (2) its effects were long lasting (at least 24 to 48 hr), and (3) salicylate, the main metabolite of aspirin, was virtually inactive. The last two observations suggested that the effect of aspirin on platelets was the result of irreversible acetylation. Consequently, the salicylate moiety of aspirin was considered irrelevant for the drug's action on platelets.

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“…5 The well-known mechanism of aspirin as a permanent inactivator of both forms of cyclooxygenase, the first enzyme in the biosynthetic pathway of prostanoids, is the basis of its prevention of thrombotic vascular events 6 and the chemoprevention of cancer. 7 Aspirin has been shown to be effective in both sexes in many secondary-prevention trials. 6 Although there are no reports suggesting that the molecular pharmacology of aspirin differs between the sexes, the pharmacodynamics do differ: concentrations of salicylate are higher in women than in men after identical doses of aspirin, and platelets from women and men who have ingested aspirin show different responses when tested in vitro.…”

mentioning

confidence: 99%

The Puzzle of Aspirin and Sex

Levin

2005

N Engl J Med

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Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity.

Cited by 62 publications

References 56 publications

Antiplatelet Therapy in Acute Cerebral Ischemia

Antiplatelet Therapy in Acute Cerebral Ischemia

Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction.

The Puzzle of Aspirin and Sex

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