Optimal Use of Platelet Glycoprotein IIb/IIIa Receptor Antagonists in Patients Undergoing Percutaneous Coronary Interventions
Division of Cardiology, University of North Carolina, Chapel Hill, NC 27599-7075, USA. Drugs
(Impact Factor: 4.34).
10/2011; 71(15):2009-30. DOI: 10.2165/11595010-000000000-00000
Discovery of the central role of platelets in the pathogenesis of acute coronary syndromes (ACS) and ischaemic complications of percutaneous coronary interventions (PCI) has led to the widespread use of oral and parenteral platelet inhibitors to treat these conditions. Glycoprotein (GP) IIb/IIIa (also known as αIIbβ3) receptors on the surface of platelets play an essential role in platelet aggregation and serve as a key mediator in the formation of arterial thrombus. When activated, GP IIb/IIIa receptors bind to fibrinogen, which serves as the ‘final common pathway’ in platelet aggregation. Of the numerous agents developed for modulating platelet activity, intravenous platelet GP IIb/IIIa receptor antagonists are the most potent.
There are four agents in clinical use, including abciximab, eptifibatide, tirofiban and lamifiban, although lamifiban is not approved for use in the US. While all agents block fibrinogen binding to GP IIb/IIIa, they do so by different mechanisms. Abciximab is a humanized form of a murine monoclonal antibody directed against GP IIb/IIIa, eptifibatide is a synthetic, cyclic heptapeptide that contains a lysine-glycine-aspartic acid (KGD) sequence that mimics the arginine-glycine-aspartic acid (RGD) sequence found on GP IIb/IIIa, tirofiban is a non-peptide antagonist derived by optimization of the tyrosine analogue that structurally mimicks the RGD-containing loop of the disintegrin echistatin, and lamifiban is a synthetic, non-cyclic, non-peptide, low-molecular-weight compound. In clinical trials, use of these agents reduces ischaemic adverse cardiovascular events in patients with ACS undergoing PCI, but at a cost of increased bleeding.
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ABSTRACT: From the discovery of the platelet glycoprotein (GP) IIb/IIIa and identification of its central role in haemostasis, the integrin GPIIb/IIIa (αIIbβ3, CD41/CD61) was destined to be an anti-thrombotic target. The subsequent successful development of intravenous ligand-mimetic inhibitors occurred during a time of limited understanding of integrin physiology. Although efficient inhibitors of ligand binding, they also mimic ligand function. In the case of GPIIb/IIIa inhibitors, despite strongly inhibiting platelet aggregation, paradoxical fibrinogen binding and platelet activation can occur. The quick progression to development of small-molecule orally available inhibitors meant that this approach inherited many potential flaws, which together with a short half-life resulted in an increase in mortality and a halt to the numerous pharmaceutical development programs. Limited clinical benefits, together with the success of other anti-thrombotic drugs, in particular P2Y12 ADP receptor blockers, have also led to a restrictive use of intravenous GPIIb/IIIa inhibitors. However, with a greater understanding of this key platelet-specific integrin, GPIIb/IIIa remains a potentially attractive target and future drug developments will be better informed by the lessons learnt from taking the current inhibitors back to the bench. This overview will review the physiology behind the inherent problems of a ligand-based integrin inhibitor design and discuss novel promising approaches for GPIIb/IIIa inhibition.
Available from: John C Moscona
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ABSTRACT: Glycoprotein (GP) IIb/IIIa receptor antagonists are powerful antiplatelet agents that are typically used in percutaneous coronary intervention. All three GP IIb/IIIa agents currently approved for use in the United States cause thrombocytopenia as a rare side effect. Abciximab is unique to the class in that it is a modified monoclonal antibody to the GP IIb/IIIa receptor, a property that can lead to increased platelet destruction. Presented herein is a patient who received a local infusion of abciximab for a lower-extremity thrombus and within 2 hours developed an acute profound thrombocytopenia that likely caused a large retroperitoneal hematoma. This case demonstrates the importance of checking platelet count within 2 to 4 hours after local (in addition to systemic) abciximab administration. Additionally, this report outlines how other causes of acute precipitous platelet drops, such as heparin-induced thrombocytopenia and pseudothrombocytopenia, can be rapidly excluded and allow for the prompt initiation of optimal therapy to minimize bleeding.
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ABSTRACT: To evaluate the hypothesis that platelets and fibrin differentially accrue at microvascular anastomoses in arteries versus veins and under different pharmacologic conditions.
We evaluated mouse arterial and venous anastomoses with intravital fluorescence imaging, using fluorophore-labeled platelets and anti-fibrin antibodies to measure the extent of thrombus component development in the intraluminal anastomotic site. We evaluated systemic heparin or eptifibatide (platelet aggregation inhibitor) to determine their relative influences on thrombus composition.
Platelets accumulated rapidly in both arterial and venous repairs, and then fell in number after 10 to 30 minutes of reflow. Fibrin had a relatively steady development over 60 minutes in veins, with a more variable increase in arteries. Heparin reduced platelet accumulation in arteries and fibrin development in veins. Eptifibatide reduced platelets in both arteries and veins and had an apparent effect on lowering the amount of fibrin in veins.
These findings show that platelets have a rapid, transient response, whereas fibrin has a slower, more sustained accrual in both arterial and venous anastomoses. Furthermore, inhibition of either coagulation or platelet aggregation can influence presumably non-targeted components of thrombosis in vascular repairs of both arteries and veins.
Preventing replantation failure using antithrombotic therapies requires a better understanding of the effect of each pharmacologic compound on the various aspects of thrombogenesis.
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