Aspirin and agents acting on the cyclo-oxygenase pathway
Aspirin irreversibly inhibits cyclo-oxygenase by acetylation of amino acids that are next to the active site. In platelets, this is the rate limiting step in synthesis of thromboxane A2, and inhibition occurs in the megakaryocyte so that all budding platelets are dysfunctional. Because platelets are unable to regenerate fresh cyclo-oxygenase in response, the effect of aspirin remains as long as the lifespan of the platelet (generally about 10 days). A severe weakness of aspirin is that its specificity for cyclo-oxygenase means it has little effect on other pathways of platelet activation. Thus aspirin fails to prevent aggregation induced by thrombin and only partially inhibits that induced by ADP and high dose collagen. Antithrombotic doses used in clinical trials have varied widely from less than 50 mg to over 1200 mg/day, with no evidence of any difference in clinical efficacy. Absorption is over 80% with extensive presystemic metabolism to salicylic acid. Only the parent acetylsalicylic acid has any significant effect on platelet function.
Adverse effects of aspirin include haemorrhage, hypersensitivity and skin rashes, alopecia, and purpura. Sulfinpyrazone also inhibits cyclo-oxygenase (thus producing an aspirin-like state), but is reversible, and also inhibits serotonin uptake by platelets. Iloprost is a prostacyclin analogue that exerts its effects by promoting vasodilatation and inhibiting platelet aggregation induced by ADP, thereby opposing the effects of thromboxane A2.
Dipyridamole
Dipyridamole inhibits phosphodiesterase, thus preventing the inactivation of cyclic AMP, intraplatelet levels of which are increased, resulting in reduced activation of cytoplasmic second messengers. However, it may also exert its effect in other ways, such as stimulating prostacyclin release and inhibiting thromboxane A2 formation. The influence of this drug on these pathways causes reduced platelet aggregability and adhesion in vitro with increased platelet survival in vivo. Its effect is relatively short lasting, and repeated dosing or slow release preparations are needed to achieve 24 hour inhibition of platelet function.
Clopidogrel and Ticlopidine
These thienopyridine derivatives inhibit platelet aggregation induced by agonists such as platelet activating factor and collagen, and also dramatically reduce the binding of ADP to a platelet surface purinoreceptor. The mechanism of this inhibitory action seems to be independent of cyclo-oxygenase. There is also impairment of the platelet response to thrombin, collagen, fibrinogen, and von Willebrand factor. The peak action on platelet function occurs after several days of oral dosing. Adverse effects include evidence of bone marrow suppression, in particular leucopenia, especially with ticlopidine.
Other receptor blockers
Signal transduction generally occurs when specific receptors on the surface are occupied by ligands such as ADP, leading to structural modification of the glycoprotein IIb/IIIa receptor on the surface of the platelet. This is the commonest receptor on the platelet surface and represents the final common pathway for platelet aggregation, resulting in crosslinking of platelets. After intravenous administration of glycoprotein IIb/IIIa receptor inhibitors such as abciximab, platelet aggregation is 90% inhibited within two hours, but function recovers over the course of two days.
The major adverse effect is haemorrhage, and concurrent use of oral anticoagulants is contraindicated. Eptifibatide is a cyclic heptapeptide that mimics the part of the structure of fibrinogen that interacts with glycoprotein IIb/IIIa. Thus it is a fraction of the size of abciximab and is targeted at the same structure on the platelet surface. Clinical trials with oral glycoprotein IIb/IIIa receptor inhibitors have been disappointing, with no beneficial effects seen and even some evidence of harm.
Aspirin irreversibly inhibits cyclo-oxygenase by acetylation of amino acids that are next to the active site. In platelets, this is the rate limiting step in synthesis of thromboxane A2, and inhibition occurs in the megakaryocyte so that all budding platelets are dysfunctional. Because platelets are unable to regenerate fresh cyclo-oxygenase in response, the effect of aspirin remains as long as the lifespan of the platelet (generally about 10 days). A severe weakness of aspirin is that its specificity for cyclo-oxygenase means it has little effect on other pathways of platelet activation. Thus aspirin fails to prevent aggregation induced by thrombin and only partially inhibits that induced by ADP and high dose collagen. Antithrombotic doses used in clinical trials have varied widely from less than 50 mg to over 1200 mg/day, with no evidence of any difference in clinical efficacy. Absorption is over 80% with extensive presystemic metabolism to salicylic acid. Only the parent acetylsalicylic acid has any significant effect on platelet function.
Adverse effects of aspirin include haemorrhage, hypersensitivity and skin rashes, alopecia, and purpura. Sulfinpyrazone also inhibits cyclo-oxygenase (thus producing an aspirin-like state), but is reversible, and also inhibits serotonin uptake by platelets. Iloprost is a prostacyclin analogue that exerts its effects by promoting vasodilatation and inhibiting platelet aggregation induced by ADP, thereby opposing the effects of thromboxane A2.
Dipyridamole
Dipyridamole inhibits phosphodiesterase, thus preventing the inactivation of cyclic AMP, intraplatelet levels of which are increased, resulting in reduced activation of cytoplasmic second messengers. However, it may also exert its effect in other ways, such as stimulating prostacyclin release and inhibiting thromboxane A2 formation. The influence of this drug on these pathways causes reduced platelet aggregability and adhesion in vitro with increased platelet survival in vivo. Its effect is relatively short lasting, and repeated dosing or slow release preparations are needed to achieve 24 hour inhibition of platelet function.
Clopidogrel and Ticlopidine
These thienopyridine derivatives inhibit platelet aggregation induced by agonists such as platelet activating factor and collagen, and also dramatically reduce the binding of ADP to a platelet surface purinoreceptor. The mechanism of this inhibitory action seems to be independent of cyclo-oxygenase. There is also impairment of the platelet response to thrombin, collagen, fibrinogen, and von Willebrand factor. The peak action on platelet function occurs after several days of oral dosing. Adverse effects include evidence of bone marrow suppression, in particular leucopenia, especially with ticlopidine.
Other receptor blockers
Signal transduction generally occurs when specific receptors on the surface are occupied by ligands such as ADP, leading to structural modification of the glycoprotein IIb/IIIa receptor on the surface of the platelet. This is the commonest receptor on the platelet surface and represents the final common pathway for platelet aggregation, resulting in crosslinking of platelets. After intravenous administration of glycoprotein IIb/IIIa receptor inhibitors such as abciximab, platelet aggregation is 90% inhibited within two hours, but function recovers over the course of two days.
The major adverse effect is haemorrhage, and concurrent use of oral anticoagulants is contraindicated. Eptifibatide is a cyclic heptapeptide that mimics the part of the structure of fibrinogen that interacts with glycoprotein IIb/IIIa. Thus it is a fraction of the size of abciximab and is targeted at the same structure on the platelet surface. Clinical trials with oral glycoprotein IIb/IIIa receptor inhibitors have been disappointing, with no beneficial effects seen and even some evidence of harm.
Contraindications to aspirin
Absolute
- Active gastrointestinal ulceration
- Hypersensitivity
- Thrombocytopenia
Relative
- History of ulceration or dyspepsia
- Children under 12 years old
- Bleeding disorders
- Warfarin treatment
Edited by:
GREGORY Y H LIP
Professor of cardiovascular medicine and director, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham.
ANDREW D BLANN
Senior lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham.
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