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  • Review Article
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Scientific and therapeutic advances in antiplatelet therapy

Nature Reviews Drug Discovery volume 2, pages 15–28 (2003)Cite this article

Key Points

  • Although the platelet was once considered to be merely a passive participant in the coagulation cascade, it is now recognized as an active synthesizer of humoral factors that potentiate both clot formation and inflammation.

  • For several decades, antiplatelet therapy centered on the thromboxane pathway and its inhibition by aspirin, and aspirin remains the background template therapy for acute ischaemic syndromes, as well as for secondary prevention.

  • However, despite the wealth of data that support the use of aspirin, and indeed the data that suggest it should be more widely prescribed, aspirin remains a suboptimal antiplatelet agent, as evidenced clinically by the fact that even patients who are taking aspirin may nevertheless sustain a thrombotic event.

  • Drugs have been developed to improve on the template of aspirin therapy; the glycoprotein IIb/IIIa inhibitors and the thienopyridines have been extensively studied.

  • The glycoprotein IIb/IIIa receptor is an integrin found in high concentration on the platelet membrane, and is often referred to as the final common pathway of platelet aggregation. The evidence supporting the utility of intravenous GPIIb/IIIa inhibition in percutaneous coronary intervention is overwhelming.

  • In contrast to the favourable data obtained for the intravenous GPIIb/IIIa inhibitors, results with oral GPIIb/IIIa inhibitors have been disappointing. This showed that our understanding of GPIIb/IIIa inhibition was not as deep as believed. Indeed, it could be that this class of agents has a potential dark side, perhaps due to sub-therapeutic levels of drug leading to platelet activation and/or inflammation.

  • So, although the intravenous GPIIb/IIIa inhibitors represent a major therapeutic advance, it is unlikely that there will be any further development or refinement of these agents.

  • Clopidogrel, and its predecessor ticlopidine, are thienopyridines that act by antagonising the receptors for adenosine 5′-diphosphate, which have key roles in platelet activation, shape change and aggregation.

  • Clopidogrel represents a major advance in antiplatelet therapy. In the CAPRIE trial, an 8.7% relative risk reduction in vascular death, ischaemic stroke or myocardial infarction was found with clopidogrel versus aspirin. Subset analyses of the CAPRIE study have demonstrated that the benefits of clopidogrel over aspirin are amplified in high-risk patients.

  • Although it is clear that clopidogrel is more effective than aspirin alone, dual antiplatelet pathway inhibition is more than additive in preventing thrombus formation. Several trials are planned or are ongoing with dual antiplatelet therapy.

  • Greater understanding of platelet biology is revealing novel, and potentially more precise, targets for the therapeutic modulation of platelet function. Several potential future targets for antiplatelet drugs are discussed, including: P2Y1 receptor, P2Y12 receptor, P2Y1 and P2Y12 receptors simultaneously, CD40–CD40 ligand system, RANTES, P-selectin, CD39/ATPDase, GP Ib-V-IX complex - von Willebrand factor, protease-activated receptors (PARs), pepducins, platelet leptin receptor, Arp2/3 complex, and Growth-arrest specific gene 6 (Gas6).

Abstract

Over the past decade, the platelet has emerged as a pivotal entity in cardiovascular diseases. Indeed, the 'preeminence of the platelet' has spawned a variety of drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and percutaneous revascularization procedures. Although the platelet was initially viewed only as a bystander in haemostasis, it is now evident that the platelet is in fact a key mediator of thrombosis as well as of inflammation. New insights at the cellular and genomic levels will probably generate novel drugs to inhibit platelet function more effectively and safely than previously possible.

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Figure 1: The role of platelets in thrombus formation.
Figure 2: The role of CD40 and CD40 ligand at the crossroads of platelet interaction with other inflammatory cells.
Figure 3: Different subtypes of ADP receptors.
Figure 4: The connection between G-protein-coupled protease-activated receptors and ADP.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine/Desk F25, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Deepak L. Bhatt & Eric J. Topol

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Correspondence to Deepak L. Bhatt.

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DATABASES

LocusLink

ADAMTS13

CD39

CD40 ligand

C-reactive protein

COX2

glycoprotein IIb (ITGA2B)

glycoprotein IIIa (ITGB3)

leptin

P2Y1

P2Y12

P2X1

PLA2G1B

P-selectin

thrombin

von Willebrand factor

FURTHER INFORMATION

Encyclcopedia of Life Sciences

Cardiovascular disease: epidemiology

ischaemic heart disease

John Robert Vane

Glossary

MYOCARDIAL INFARCTION

Popularly known as a heart attack, this is the death of part of the heart muscle due to sudden loss of blood supply. Typically, the loss of this supply is caused by a complete blockage of a coronary artery by a blood clot.

CAROTID STENOSIS

Plaque build-up within the major arteries to the brain, which can predispose to stroke.

GLANZMANN'S THROMBASTHENIA

An autosomal recessive bleeding disorder due to defects in the glycoprotein IIb/IIIa receptor.

APOPTOSIS

Programmed cell death, which is mediated in large part by a family of intracellular cysteine proteases known as caspases.

CLAUDICATION

Pain that occurs with walking, due to atherosclerosis of the arteries in the legs.

NEUTROPENIA

An abnormally low white blood cell count, predisposing to the development of serious infections.

THROMBOTIC THROMBOCYTOPENIC PURPURA

A rare disorder characterized by low platelet counts associated with thrombosis.

CORONARY STENTING

A common minimally invasive procedure in which a metallic stent is placed in the coronary circulation to relieve an obstruction due to atherosclerosis.

CAROTID STENTING

A newer technique to treat carotid stenosis in a minimally invasive manner.

SURGICAL CAROTID ENDARTERECTOMY

The historical way in which to treat carotid stenosis using a conventional surgical incision in the neck.

ADIPOCYTES

The type of cells that make up fat.

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Bhatt, D., Topol, E. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2, 15–28 (2003). https://doi.org/10.1038/nrd985

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