Ⅵ REVIEW ARTICLE David C. Warltier, M.D., Ph.D., Editor Anesthesiology 2002; 96:1237–49 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Platelet Glycoprotein IIb/IIIa Antagonists Pharmacology and Clinical Developments Peter C. A. Kam, F.R.C.A., F.A.N.Z.C.A., F.C.A.R.C.S.I., F.H.K.C.A.(Hon.),* Mark K. Egan, F.A.N.Z.C.A.† Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/5/1237/404746/0000542-200205000-00029.pdf by guest on 01 October 2021 PLATELETS are critical for normal hemostasis and throm- with plasma coagulation factors causes a conformational bus formation.1 Thrombus formation initiated by plate- change in the glycoprotein IIb/IIIa receptor complex. lets plays a central role in the pathogenesis of acute Activated glycoprotein IIa/IIIb receptors become recep- coronary syndromes (unstable angina and myocardial tive to fibrinogen that, on binding to glycoprotein IIb/ infarction). Platelets are involved in events causing an- IIIa receptors located on two different platelets, builds gioplasty failure and stent thrombosis and may also play the cross-link for platelet-to-platelet aggregation.5 The an important role in restenosis through the release of initial thrombus contains a platelet-rich core (white potent prothrombotic, vasoactive, mitogenic, and in- thrombus) that may enlarge progressively from an in- flammatory factors.2,3 The identification of the platelet creasingly large fibrin net that entraps erythrocytes and glycoprotein IIb/IIIa receptor, a fibrinogen receptor im- leukocytes to form the “red” thrombus. Blood flow de- portant for platelet aggregation, has led to the develop- clines as the thrombus develops, and interactions be- ment of receptor antagonists. Although aspirin lowers tween additional platelet glycoprotein complexes (gly- the risk of death and myocardial infarction (MI) in pa- coprotein Ia/IIa with vessel wall collagen, glycoprotein tients with acute coronary syndromes, intravenous gly- Ic/IIa with fibronectin and laminin, and ␥␯␤3 complex coprotein IIb/IIIa antagonists further reduce the rates of with vitronectin) enhance the adhesion of platelets to ischemic events and coronary angioplasty complications the vessel wall. and improve the results of coronary stenting.2 Further- The changes in the plasma membrane of the adherent more, uses of these drugs are extending to the treatment platelets activated by collagen and thrombin produce a of cerebrovascular and peripheral vascular disease. This negatively charged surface for factors IXa–VIIIa and article provides an overview of the pharmacology of the Xa–Va complexes. This enhances the formation of the glycoprotein IIa/IIIb antagonists and a commentary on fibrin clot. Finally P-selectin and activated glycoprotein the perioperative issues in patients receiving this class of IIb/IIIa are exposed on the platelet surface, causing the drugs. platelet to bind to other platelets and leukocytes and recruit granulocytes and monocytes into the growing thrombus. Platelet Physiology Damaged endothelial surfaces associated with plaque rupture or fissure exposes highly thrombogenic compo- Structure and Function of the Glycoprotein nents that induce platelet activation and initiate the IIb/IIIa Receptor 4 coagulation cascade. The glycoprotein IIb/IIIa receptor The platelet membrane glycoproteins are integrins (␣ on the platelet surface is important for platelet aggrega- and ␤ subunits) that are found on virtually all cells.6 The tion. Platelet activation by exposure to vessel collagen glycoprotein IIb/IIIa, an integrin (␣IIb/␤3 dimer) present and to thrombin generated by interaction of tissue factor on platelet surfaces, is a receptor for fibrinogen, fi- bronectin, vitronectin, von Willebrand factor, and thrombospondin. It mediates aggregation, adhesion, and * Associate Professor, † Fellow. spreading of platelets.7,8 Platelet activation, associated Received from the Department of Anaesthesia and Pain Management, Univer- with the release of agonists (epinephrine, serotonin, sity of Sydney at the Royal North Shore Hospital, St Leonards, New South Wales, Australia. Submitted for publication January 30, 2001. Accepted for publication thromboxane A2) from the platelet-dense granules, leads November 7, 2001. Support was provided solely from institutional and/or de- to the recruitment of the internal pool of glycoprotein partmental sources. Address reprint requests to Dr. Kam: Department of Anaesthesia and Pain IIb/IIIa receptors, and this increases the number of sur- Management, University of Sydney at the Royal North Shore Hospital, St. Leo- face receptors by 50%. The binding of prothrombin to nards, NSW 2065, Australia. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the Journal Web site, glycoprotein IIb/IIIa enhances the conversion of pro- 9 www.anesthesiology.org. thrombin to thrombin. Platelet activation increases the Anesthesiology, V 96, No 5, May 2002 1237 1238 P. C. A. KAM AND M. K. EGAN affinity for fibrinogen at the glycoprotein IIb/IIIa ligand- binding site by conformational changes and clustering of glycoprotein IIb/IIIa receptors on the platelet surface (known as “inside-out signaling”). This conformational change is mediated by chemical changes of the cytoplas- mic domains of the ␣ and ␤ chains of the glycoprotein IIb/IIIa receptor.7 The head domain of an intracellular protein, called talin, binds the intracellular part of inte- grin and regulates integrin function.10 Agonist-stimulated increases in platelet cytosolic calcium concentration ini- tiate actin filament turnover that removes cytoskeletal constraints on the glycoprotein IIb/IIIa receptor, leading Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/5/1237/404746/0000542-200205000-00029.pdf by guest on 01 October 2021 to the binding for soluble fibrinogen and von Willebrand factor that mediate aggregation.11,12 The bound ligand induces conformational changes in the receptor, expos- ing new binding sites, called ligand-induced binding sites. Although the exact role of the ligand-induced bind- ing site has not been clearly defined, it is suggested the ligand-induced binding sites attract other glycoprotein Fig. 1. Schematic overview of action of glycoprotein IIb/IIIa .glycoprotein ؍ antagonists. GP IIb/IIIa receptors that merge on the platelet surface (“outside-in signaling”), resulting in clot retraction and of a chimeric monoclonal antibody that binds nonspe- the spread of platelets on an adhesive surface.13 cifically to the glycoprotein IIb/IIIa receptor. Epifibatide Another integrin, the vitronectin receptor (␣V/␤3), (Integrilin®; COR Therapeutics, South San Francisco, shares the same ␤ subunit with glycoprotein IIb/IIIa and CA), a cyclic heptapeptide, and tirofiban (Aggrastat®; cross-reacts with some glycoprotein IIb/IIIa antagonists Merck & Co., Whitehouse Station, NJ), a nonpeptide, and binds thrombospondin.14 The vitronectin receptor selectively bind to the glycoprotein IIb/IIIa receptor is expressed in platelets as well as endothelial and (table 1). smooth muscle cells.15 Fibrinogen binds to the glycop- rotein IIb/IIIa receptor, primarily through the terminal Intravenous Antagonists hexapeptide sequence chain [Lys-Gln-Ala-Gly-Asp-Val, The first glycoprotein IIb/IIIa antagonists developed (KQAGDV)] located at the carboxy terminus of the ␥-of were murine monoclonal antibodies to the glycoprotein fibrinogen.12 von Willebrand factor binds to platelets at IIb/IIIa complex.18 The structure of the antibody was the glycoprotein IIb/IIIa receptor via an arginine-gly- modified by replacing the constant domain of the mu- cine-aspartic acid sequence3,16 and also at a glycoprotein rine antibody with the corresponding human sequence, Ib/V/IX receptor complex, enhancing platelet producing a chimeric compound that was less immuno- adhesion.12 genic. Abciximab is a Fab fragment of the chimeric Glycoprotein IIb/IIIa antagonists vary in their specific- human–murine monoclonal antibody, chimeric 7E3 im- ity for the glycoprotein IIb/IIIa ligand binding sites and munoglobulin G, that contains murine variable regions their ability to block other receptors (e.g., vitronectin receptor and Mac 1). Near total inhibition of aggregation Table 1. Classification of Glycoprotein IIb/IIIa Antagonists (induced by 20 ␮M adenosine diphosphate [ADP]) is achieved when 80% or more of the receptors are Type Name Route Status 17 blocked. Monoclonal Abciximab Parenteral ACS, PCI antibodies Peptides Eptifibatide Parenteral ACS, PCI Small Tirofiban Parenteral ACS Classification of Glycoprotein IIb/IIIa molecules Antagonists Lamifiban Parenteral ACS (phase III) Fradafiban Parenteral ACS (phase III) The development of a new class of drugs that block Xemilofiban Oral PCI (phase III) fibrinogen binding to the platelet glycoprotein IIb/IIIa Orbofiban Oral ACS (phase III) Sibrafiban Oral ACS (phase III) receptors (the “final common pathway” of platelet acti- Roxifiban Oral ACS (phase III) vation) has raised the possibility that these potent agents Lotrafiban Oral ACS, CBVD (phase II) may reduce thrombotic complications in acute coronary Lefradifiban Oral ACS (phase II) syndromes or after percutaneous coronary interventions SR121787 Oral ACS (phase II) ® (fig. 1). Abciximab (ReoPro ; Centocor Inc., Malvern, ACS ϭ acute coronary syndromes; PCI ϭ percutaneous coronary interven- PA, and Eli Lilly Co., Indianapolis, IN) is a Fab fragment tions; CBVD ϭ cerebrovascular disease. Anesthesiology, V 96, No 5, May 2002 GLYCOPROTEIN IIb/IIIa ANTAGONISTS 1239