(Circulation. 1998;98:2629-2635.)
© 1998 American Heart Association, Inc.
Cardiovascular Drugs |
Glycoprotein IIb/IIIa Integrin Blockade
From Duke Clinical Research Institute, Durham, NC.
Correspondence to James E. Tcheng, MD, Box 3275, Duke University Medical Center, Durham, NC 27710. E-mail tchen001@mc.duke.edu
Key Words: glycoproteins • platelet aggregation inhibitors • coronary disease • trials {texf}The importance of thrombosis in the pathogenesis of acute coronary syndromes is now unequivocally established.1 2 These syndromes (unstable angina, non-Q-wave myocardial infarction [MI], acute [ST-elevation] MI, and abrupt closure after coronary intervention) share a common pathophysiology of atherosclerotic plaque rupture, activation of the coagulation cascade, and adhesion, activation, and aggregation of platelets. Numerous investigators have shown that the glycoprotein IIb/IIIa (GP IIb/IIIa) integrin mediates the "final common pathway" in platelet aggregation, spawning the development of GP IIb/IIIa receptor antagonists.3 4 5 This article reviews the current status of GP IIb/IIIa blockade in the management of coronary artery disease, examining the results of pivotal clinical trials and reviewing current challenges and directions for future investigation.
Platelets and GP IIb/IIIa
In atherosclerotic disease, plaque rupture exposes the
subendothelium and initiates hemostasis. Platelets
adhere to the subendothelium principally via class I
glycoproteins, an effect greatly enhanced by von
Willebrand factor under conditions of flow and high shear
rates.6 7 Platelet activation follows
adhesion and can be initiated by numerous agonists (Figure 1
). With activation, the platelet
degranulates, releasing serotonin, ADP, and other
vasoactive substances into the local environment to further recruit and
stimulate platelets. GP IIb/IIIa undergoes a conformational change
that results in a ligand-receptive state that permits fibrinogen
binding. Cross-linking of fibrinogen bound to activated
platelets culminates in aggregation and thrombus formation.
Regardless of the stimulus for platelet activation, the final
common pathway to coronary thrombosis is mediated by the GP
IIb/IIIa receptor.
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The GP IIb/IIIa receptor belongs to the integrin family of cell
membrane glycoproteins. Integrins have been isolated from
cells throughout the body and are mediators of cell-cell and
cell-substrate adhesion and signaling.8 The GP
IIb/IIIa integrin consists of 2 noncovalently linked 
(IIb) and ß (ß3)
subunits (Figure 2). The importance of
this integrin in platelet aggregation was first noticed in patients
with Glanzmann's thrombasthenia, an inherited disorder
characterized by recurrent mucocutaneous bleeding due to either absent
or dysfunctional GP IIb/IIIa.10 11 There
are 2 binding sites on GP IIb/IIIa, one that recognizes the amino
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