Key Points
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Despite progress in antiplatelet therapy, a large amount of unmet clinical need continues to exist. According to current estimates, >60 million people in the United States alone have one or more forms of cardiovascular disease and a high proportion of these individuals are at an increased risk of arterial thrombosis.
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Antithrombotics are the most rapidly growing sector of the cardiovascular market, with sales around US $9.1 billion in 2001 that are forecast to grow to US $22 billion by the year 2007. One of the major factors underpinning this growth is the rapid increase in sales of the antiplatelet drug clopidogrel, which are increasing by an average of 65% per year at present.
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Although aspirin reduces acute vascular events in approximately 25% of patients with vascular disease, the residual risk remains high, justifying the need to develop more effective antithrombotic agents or use combination antiplatelet therapies.
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An important lesson that has emerged from numerous antithrombotic trials is that increased antithrombotic potency per se does not necessarily guarantee enhanced clinical benefit and that, in general, potent antithrombotic approaches must be reserved for high-risk patient populations.
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Bleeding represents the most important factor influencing long-term compliance and overall clinical benefit of antithrombotic therapy. The key concern regarding all existing antithrombotic drugs relates to their therapeutic window. Ideally, antithrombotic approaches should target one or more processes that are crucial for pathological thrombosis, but which are less important for haemostasis. Despite intensive effort, major progress in this area has been limited.
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Novel antithrombotic approaches are likely to evolve from an improved understanding of the mechanisms regulating thrombus formation. In this context, there have been considerable recent advances, largely gained from the development of novel experimental techniques enabling real-time analysis of arterial thrombus formation in vivo.
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The factors contributing to an exaggerated platelet response at sites of atherosclerotic plaque rupture are multifactorial: the net result of changes in platelet reactivity; plaque thrombogenicity; rheological disturbances and the breakdown of the normal control mechanisms dampening platelet activation.
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Future advances in antiplatelet therapy are likely to derive from improvements in the understanding of the molecular events regulating thrombogenesis. In this context, the determination of factors specifically promoting an exaggerated platelet response at sites of atherosclerotic plaque rupture could provide a rational basis for the design and development of novel antiplatelet agents with improved efficacy/side-effect profiles.
Abstract
The central importance of platelets in the development of arterial thrombosis and cardiovascular disease is well established. No other single cell type is responsible for as much morbidity and mortality as the platelet and, as a consequence, it represents a major target for therapeutic intervention. The growing awareness of the importance of platelets is reflected in the increasing number of patients receiving antiplatelet therapy, a trend that is likely to continue in the future. There are, however, significant drawbacks with existing therapies, including issues related to limited efficacy and safety. The discovery of a 'magic bullet' that selectively targets pathological thrombus formation without undermining haemostasis remains elusive, although recent progress in unravelling the molecular events regulating thrombosis has provided promising new avenues to solve this long-standing problem.
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Acknowledgements
The authors wish to thank Drs Zaverio Ruggeri, Christian Gachet, Hatem Salem and Francois Lanza, as well as other members of the authors' laboratory for valuable comments.
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FURTHER INFORMATION
Glossary
- BLEEDING TIME
-
The time taken for cessation of bleeding from a standardized injury, which is used to test for platelet abnormalities (acquired and congenital) and also for von Willebrand's disease.
- THERAPEUTIC WINDOW
-
The dose (or concentration) range between the minimum effective dose (concentration) and the minimum toxic dose (concentration).
- RHEOLOGICAL ENVIRONMENT
-
The blood-flow characteristics operating within defined areas of the vasculature.
- THROMBOTIC THROMBOCYTOPAENIC PURPURA
-
A rare microvascular thrombotic disorder associated with low platelet count, fever, neurological and renal impairment and micro-angiopathic haemolytic anaemia.
- DIATHESIS
-
A permanent (hereditary or acquired) condition that predisposes the affected individual to certain diseases.
- THROMBOCYTOPAENIA
-
A decrease in platelet count, defined in humans as less than 150 × 109 per l, which results in the potential for increased bleeding.
- PHARMACOPHORE
-
The ensemble of steric and electronic features that are necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.
- CAROTID ENDARTERECTOMY
-
A surgical procedure that removes atherosclerotic plaque from the walls of the carotid arteries in an attempt to reduce the risk of stroke or transient ischaemic attack.
- PERCUTANEOUS CORONARY INTERVENTION
-
A group of techniques that can relieve coronary artery narrowing. The techniques include balloon angioplasty, laser angioplasty and implantation of intracoronary stents and other catheter devices.
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Jackson, S., Schoenwaelder, S. Antiplatelet therapy: in search of the 'magic bullet'. Nat Rev Drug Discov 2, 775–789 (2003). https://doi.org/10.1038/nrd1198
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DOI: https://doi.org/10.1038/nrd1198
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