Amplification mechanisms in platelet activation and arterial thrombosis.
Platelets react with different intensities to a large variety of agonists (e.g. 5-hydroxytryptamine, ADP, thrombin, thromboxane A2). In vitro, low concentrations of 'weak' agonists such as 5-hydroxytryptamine markedly enhance the platelet functional response in terms of aggregation, release of intragranular products and arachidonic acid metabolites to otherwise ineffective concentrations of other agonists. This type of amplification takes place at an early, postreceptor stage of the platelet activation cascade, with the turnover of inositol phospholipids and the increase in free cytoplasmic intracellular Ca2+ concentrations. Mutual amplification, rather than the single potency of each, also determines the contribution by platelet agonists to thrombogenesis in vivo. Indeed, in various animal models and, to some extent, in man, a pharmacological blockade of the platelet 5-HT2 serotonergic (e.g. ketanserin) or thromboxane A2/prostaglandin endoperoxide receptor (e.g. ridogrel) and manipulation of arachidonic acid metabolism (e.g. cyclo-oxygenase inhibition with aspirin or thromboxane A2 synthetase inhibition with ridogrel), when applied together, are more effective in preventing extensive platelet activation and arterial thrombotic occlusion and in improving the efficacy of thrombocytic agents (speed up of thrombolysis and prevention of thrombotic re-occlusion after lysis) than when the same compounds are applied separately. These observations suggest that an amplification between 5-hydroxytryptamine and thromboxane A2, for example, as platelet agonists is causally involved in arterial thrombus formation.
De Clerck
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FF
Department of Haematology, Janssen Research Foundation, Beerse, Belgium.
Janssen
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PA
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000502:physiology; D006801:Humans; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D012701:Serotonin / Q000502:physiology; D013927:Thrombosis / Q000209:etiology*; D013928:Thromboxane A2 / Q000502:physiology
D001095:Arachidonic Acids; D016718:Arachidonic Acid; D012701:Serotonin; D013928:Thromboxane A2