Delayed immunologic thrombocytopenia induced by abciximab

Paquita Nurden; Gisèle Clofent-Sanchez; Catherine Jais; Emilse Bermejo; Lionel Leroux; Pierre Coste; Alan T. Nurden

doi:10.1160/TH04-04-0237

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(04): 820-828
DOI: 10.1160/TH04-04-0237

Platelets and Blood Cells

Schattauer GmbH

Delayed immunologic thrombocytopenia induced by abciximab

Paquita Nurden

¹IFR4/FR21, Laboratoire d’Hématologie et

,

Gisèle Clofent-Sanchez

¹IFR4/FR21, Laboratoire d’Hématologie et

³UMR 5536, RMSB, Université Victor Ségalen Bordeaux, Bordeaux, France

,

Catherine Jais

¹IFR4/FR21, Laboratoire d’Hématologie et

²Service des Soins Intensifs, Hôpital Cardiologique, Pessac, France

,

Emilse Bermejo

¹IFR4/FR21, Laboratoire d’Hématologie et

,

Lionel Leroux

¹IFR4/FR21, Laboratoire d’Hématologie et

²Service des Soins Intensifs, Hôpital Cardiologique, Pessac, France

,

Pierre Coste

¹IFR4/FR21, Laboratoire d’Hématologie et

²Service des Soins Intensifs, Hôpital Cardiologique, Pessac, France

,

Alan T. Nurden

¹IFR4/FR21, Laboratoire d’Hématologie et

› Author Affiliations

Abstract

Summary

Abciximab is an anti-GPIIb-IIIa drug widely used to prevent thrombotic complications during percutaneous coronary intervention. We now report on the immunologic origin of thrombocytopenia developing between 7 and 12 days after the onset of abciximab infusion. Antibodies directed against abciximabcoated platelets were located in 5 patients with delayed thrombocytopenia, just as they were present in a patient whose platelet count fell within a few hours after receiving the drug. Abciximab-dependent IgG antibody was revealed in serum using control platelets in the monoclonal antibody immobilization of platelet antigens assay (MAIPA) performed with SZ22, a MoAb to GPIIb. The presence of IgG antibodies specific for platelets sensitized with abciximab was confirmed by flow cytometry. They were not located in 13 patients receiving abciximab but whose platelet counts remained stable. For three patients, antibodies were transient and their presence related to the extent of the thrombocytopenia. Surprisingly, antibodycontaining plasma from three patients induced abciximabdependent activation and aggregation of normal platelets, a finding confirmed by electron microscopy. Immunogold labeling revealed that abciximab was associated with platelets in the aggregate, suggesting that its inhibitory effect was overcome by the platelet stimulation. In summary, these results show that abciximab-dependent thrombocytopenia can be delayed and potentially prothrombotic.

Keywords

Abciximab - percutaneous coronary intervention - delayed thrombocytopenia - thrombotic risk

Full Text

References

References
1 Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC investigation. N Engl J Med 1994; 330: 956-61.
2 Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997 349. 1429-35.
3 Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization: the EPILOG investigators. N Engl J Med. 1997 336. 1689-96.
4 Randomised placebo-controlled and balloon angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT investigators. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet. 1998 352. 87-92.
5 Berkowitz SD, Sane DC, Sigmon KN. et al. Occurrence and clinical significance of thrombocytopenia in a population undergoing highrisk percutaneous coronary revascularization. Evaluation of c7E3 for the prevention of ischemic complications (EPIC) study group. J Am Coll Cardiol 1998; 32: 311-9.
6 Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword?. Circulation 2002; 106: 379-85.
7 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. The RESTORE investigators. Randomized efficacy study of tirofiban for outcomes and restenosis. Circulation. 1997 96. 1445-53.
8 Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT trial investigators. Platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy. N Engl J Med. 1998 339. 436-43.
9 Tardiff BE, Califf RM, Tcheng JE. et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. IMPACT-II investigators. Integrilin (eptifibatide) to minimize platelet aggregation and coronary thrombosis-II. J Am Coll Cardiol 1999; 33: 88-96.
10 Dasgupta H, Blankenship JC, Wood GC. et al. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: A pooled analysis. Am Heart J 2000; 140: 206-11.
11 Hongo RH, Brent BN. Association of eptifibatide and acute profound thrombocytopenia. Am J Cardiol 2001; 88: 428-31.
12 Nagge J, Jackevicius C, Dzavik V. et al. Acute profound thrombocytopenia associated with eptifibatide therapy. Pharmacotherapy 2003; 23: 374-9.
13 Suleiman M, Gruberg L, Hammerman H. et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, eptifibatide and abciximab: outcomes, complications and thrombocytopenia during percutaneous coronary intervention. J Invasive Cardiol 2003; 15: 319-23.
14 Khaykin Y, Paradiso-Hardy FL, Madan M. Acute thrombocytopenia associated with eptifibatide therapy. Can J Cardiol 2003; 19: 797-801.
15 Pereira J, Aster RH. S, Maurath C. et al. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood 2002; 100: 2071-6.
16 Curtis BR, Swyers J, Divgi A. et al. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets. Blood 2002; 99: 2054-9.
17 Keriakes DJ, Essell JH, Abbottsmith CW. et al. Abciximab-associated profound thrombocytopenia: Therapy with immunoglobulin and platelet transfusion. Am J Cardiol 1996; 78: 1161-3.
18 Bougie DW, Wilker PR, Wuitschick ED. et al. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood 2002; 100: 2071-6.
19 Jenkins LA, Lau S, Crawford M. et al. Delayed profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1998; 97: 1214-5.
20 Kaluski E, Leitman M, Khiger I. et al. Delayed thrombocytopenia following abciximab therapy. Int J Cardiovasc Intervent 2001; 04: 151-5.
21 Reddy MS, Carmody TJ, Kereiakes DJ. Severe delayed thrombocytopenia associated with abciximab (ReoPro) therapy. Catheter Cardiovasc Interv 2001; 52: 486-8.
22 Sharma S, Bhambi B, Nyitray W. et al. Delayed profound thrombocytopenia presenting 7 days after use of abciximab (ReoPro). J Cardiovasc Pharmacol Ther 2002; 07: 21-4.
23 Macchi L, Clofent-Sanchez G, Marit G. et al. PAICA: a method for characterizing plateletassociated antibodies–its application to the study of idiopathic thrombocytopenic purpura and to the detection of platelet-bound c7E3. Thromb Haemost 1996; 76: 1020-9.
24 Bihour C, Durrieu-Jais C, Macchi L. et al. Expression of markers of platelet activation and the interpatient variation in response to abciximab. Arterioscler Thromb Vasc Biol 1999; 19: 212-9.
25 Clofent-Sanchez G, Lucas S, Laroche-Traineau J. et al. Autoantibodies and antimouse antibodies in thrombocytopenic patients as assessed by different MAIPA assays. Br J Haematol 1996; 95: 153-60.
26 Chong BH, Du XP, Berndt MC. et al. Characterization of the binding domains on platelet glycoproteins Ib-IX and IIb-IIIa complexes for the quinine/quinidine-dependent antibodies. Blood 1991; 77: 2190-9.
27 Nurden P, Poujol C, Durrieu-Jais C. et al. Labeling of the internal pool of GP IIb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to the transport. Blood 1999; 93: 1622-33.
28 Pidard D, Montgomery RR, Bennett JS. et al. Interaction of AP-2, a monoclonal antibody specific for the human platelet glycoprotein IIb-IIIa complex, with intact platelets. J Biol Chem 1983; 258: 12582-6.
29 Puzon-McLaughlin W, Kamata T, Takada Y. Multiple discontinuous ligand-mimetic antibody binding sites define a ligand binding pocket in integrin αIIb β3. J Biol Chem 2000; 275: 7795-802.
30 Seiffert D, Stern AM, Ebling W. et al. Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia. Blood 2003; 101: 58-63.
31 Brassard JA, Curtis BR, Cooper RA. et al. Acute thrombocytopenia in patients treated with the oral glycoprotein IIb/IIIa inhibitors xemilofiban and orbofiban: evidence for an immune etiology. Thromb Haemost 2002; 88: 892-7.
32 Tcheng JE, Keriakes DJ, Lincoff AM. et al. Abciximab readministration: result of the ReoPro readministration registry. Circulation 2001; 104: 870-5.
33 Billheimer JT, Dicker IB, Wynn R. et al. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated. Blood 2002; 99: 3540-6.
34 Du X, Plow EF, Frelinger III AL. et al. Ligands »activate« integrin αIIβ 3 (GPIIb- IIIa). Cell 1991; 65: 409-16.
35 Frelinger III AL, Lam SC, Plow EF. et al. Occupancy of an adhesive glycoprotein receptor modulates expression of an antigenic site involved in cell adhesion. J Biol Chem 1988; 263: 12397-402.
36 Jennings LK, Haga JH, Slack SM. Differential expression of a ligand induced binding site (LIBS) by GPIIb-IIIa ligand recognition peptides and parenteral antagonists. Thromb Haemost 2000; 84: 1095-102.
37 Asvadi P, Ahmadi Z, Chong BH. Druginduced thrombocytopenia: localization of the binding site of GPIX-specific quinine-dependent antibodies. Blood 2003; 102: 1670-7.
38 Peter K, Schwarz M, Ylanne J. et al. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors. Blood 1998; 92: 3240-9.
39 Ndoko S, Poujol C, Combrie R. et al. Paradoxical platelet activation was not observed on dissociation of abciximab from GPIIb-IIIa complexes. Thromb Haemost 2002; 87: 317-22.
40 Frelinger AL, Furman MI, Krueger LA. et al. Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fibrinogen binding or platelet aggregation. Circulation 2001; 104: 1374-9.
41 Greinacher A. Heparin-induced thrombocytopenia: pathophysiology and clinical concerns. Baillieres Clin Haematol 1998; 11: 461-74.
42 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003; 76: 2121-31.
43 Curtis BR, Divgi A, Garritty M. et al. Delayed thrombocytopenia after treatment with abciximab: a distinct clinical entity assciated with the immune response to the drug. J Thromb Haemost 2004; 02: 985-92.