GPIIb/IIIa Antagonists and Other Anti-Integrins

ABSTRACT

Platelet aggregation involves the binding of adhesive proteins (fibrinogen, von Willebrand factor) to the αIIbβ3 integrin, which assumes a high-affinity state for adhesive proteins during platelet activation. The occupied integrin sends signals back into the platelet, and the bound adhesive protein forms the bridges linking platelets together. Anti-integrin therapy is designed to inhibit this process in arterial thrombosis. Abciximab, mouse-human chimeric Fab fragments, blocks platelet aggregation and provides proven clinical benefit in acute situations such as in patients with unstable angina undergoing angioplasty or stenting. Eptifibatide and tirofiban are small molecular mass inhibitors also in current use. In contrast, oral inhibitors of αIIbβ3 have proved disappointing, provoking increased mortality without assuring an adequate blockade of αIIbβ3. The problems of using anti-integrin therapy are discussed in this article as are ways of improving its efficacity. Final thoughts provide ideas for a new generation of inhibitors.

KEYWORDS

Anti-integrin therapy - αIIbβ3 - platelets - arterial thrombosis

REFERENCES

• 1 Italiano J E, Lecine P, Shivdasani R A, Hartwig J H. Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes.  J Cell Biol . 1999;  147 1299-1312
• 2 Savage B, Almus-Jacobs F, Ruggeri Z M. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow.  Cell . 1998;  94 657-666
• 3 Nurden A T, George J N. Inherited abnormalities of the platelet membrane: Glanzmann thrombasthenia, Bernard-Soulier syndrome, and other disorders. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis, Basic Principles and Clinical Practice Philadelphia, PA: Lippincott, Williams & Wilkins 2000: 921-943
• 4 Plow E F, Cierniewski C S, Xiao Z. αIIbβ3 and its antagonism in the new millenium.  Thromb Haemost . 2001;  96 34-40
• 5 Shattil S J, Kashiwagi H, Pampori N. Integrin signalling: the platelet paradigm.  Blood . 1998;  91 2645-2657
• 6 Woodside D G, Liu S, Ginsberg M H. Integrin activation.  Thromb Haemost . 2001;  86 316-323
• 7 Phillips D R, Nannizzi-Alaimo L, Prasad K SS. β3 tyrosine phosphorylation in αIIbβ3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling.  Thromb Haemost . 2001;  86 246-258
• 8 Gawaz M P, Loftus J C, Bajt M L. Ligand bridging mediates integrin α_IIbβ₃ (platelet GPIIbIIIa) dependent homotypic and heterotypic interactions.  J Clin Invest . 1991;  88 1128-1134
• 9 Coller B S. Anti-GPIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost . 2001;  86 427-443
• 10 Bhatt D L, Topol E J. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.  JAMA . 2000;  284 1549-1558
• 11 Puzon-McLaughlin W, Kamata T, Takada Y. Multiple discontinuous ligand-mimetic antibody binding sites define a ligand binding pocket in integrin αIIbβ3.  J Biol Chem . 2000;  275 7795-7802
• 12 Mascelli M A, Lance E T, Damaraju L. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GPIIb-IIIa receptor blockade.  Circulation . 1998;  97 1680-1688
• 13 Nurden P, Poujol C, Durrieu-Jais C. Labeling of the internal pool of GPIIb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to the transport.  Blood . 1999;  93 1622-1633
• 14 Kleiman N S, Raizner A E, Jordan R. Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb-IIIa receptors.  J Am Coll Cardiol . 1995;  26 1665-1671
• 15 Bihour C, Durrieu-Jais C, Macchi L. Expression of markers of platelet activation and the interpatient variation in response to abciximab.  Arterioscler Thromb Vasc Biol . 1999;  19 212-219
• 16 Phillips D R, Teng W, Arsften A. Effect of Ca²⁺ on GPIIb-IIIa interactions with integrilin. Enhanced GPIIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate.  Circulation . 1997;  96 1488-1494
• 17 The IMPACT investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II.  Lancet . 1997;  349 1422-1428
• 18 The RESTORE investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty.  Circulation . 1997;  96 1445-1453
• 19 O'Neill W W, Serruys P, Knudtson M. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization.  N Engl J Med . 2000;  342 1316-1324
• 20 Quinn M J, Cox D J, Foley J B. Glycoprotein IIb/IIIa receptor number and occupancy during chronic administration of an oral antagonist.  J Pharmacol Exp Ther . 2000;  295 670-676
• 21 Cannon C P, McCabe C H, Wilcox R G. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.  Circulation . 2000;  102 149-156
• 22 Cox D, Smith R, Quinn M. Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients with acute coronary syndromes.  J Am Coll Cardiol . 2000;  36 1514-1519
• 23 Alderley S, Fitzgerald D. Glycoprotein IIb-IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase-3 activation.  J Biol Chem . 2000;  275 5760-5766
• 24 Reverter J C, Beguin S, Kessels H. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and `clinical restenosis'.  J Clin Invest . 1996;  98 863-874
• 25 Peter K, Schwartz M, Ylänne J. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (αIIbβ3) inhibitors.  Blood . 1998;  92 3240-3249
• 26 Ndoko S, Poujol C, Combrié R. Paradoxical platelet activation was not observed after dissociation of c7E3 (abciximab) from GPIIb-IIIa complexes.  Thromb Haemost . 2002;  87 317-322
• 27 Peter K, Straub A, Kohler B. Platelet activation as a potential mechanism of GP IIb/IIIa inhibitor-induced thrombocytopenia.  Am J Cardiol . 1999;  84 519-524
• 28 Ault K A, Cannon C P, Mitchell J. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial.  J Am Coll Cardiol . 1999;  33 634-639
• 29 Steinhubl S R, Kottke-Marchant K, Molierno D J. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention.  Circulation . 1999;  100 1977-1982
• 30 Steinhubl S R, Talley J D, Braden G A. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention. Results of the Gold (AU-assessing Ultegra) Multicenter Study.  Circulation . 2001;  102 2572-2578
• 31 Hollopeter G, Jantzen H M, Vincent D. Identification of the platelet ADP receptor targeted by antithrombotic drugs.  Nature . 2001;  409 202-207
• 32 Law D A, DeGuzman F R, Heiser P. Integrin cytoplasmic tyrosine motif is required for outside-in αIIbβ3 signalling and platelet function.  Nature . 1999;  401 808-811
• 33 Rooney M M, Parise L V, Lord S T. Dissecting clot retraction and platelet aggregation. Clot retraction does not require an intact fibrinogen gamma chain C terminus.  J Biol Chem . 1996;  271 8553-8555
• 34 Ni H, Dennis C V, Subbarao S. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen.  J Clin Invest . 2000;  106 385-392
• 35 André P, Denis C V, Papalia J M, Wagner D D. Defect in arterial thrombus formation in CD40L -/- mice. Thromb Haemost. CD-ROM Suppl July 2001; abstr OC1704
• 36 Kupatt C, Habazettl H, Hanusch P. C7E3Fab re- duces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury.  Arterioscler Thromb Vasc Biol . 2000;  20 2226-2232
• 37 Curley G P, Blum H, Humphries M J. Integrin antagonists.  Cell Mol Life Sci . 1999;  56 427-441