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(Circulation. 1997;95:809-813.)
© 1997 American Heart Association, Inc.

Articles

Acute Profound Thrombocytopenia After c7E3 Fab (Abciximab) Therapy

Scott D. Berkowitz, MD; Robert A. Harrington, MD; Michele M. Rund, RN; James E. Tcheng, MD

the Department of Medicine, Duke University Medical Center, Durham, NC.

Correspondence to Scott D. Berkowitz, MD, Divisions of Hematology/Coagulation and Cardiology, Department of Medicine, Box 3471, Duke University Medical Center, Durham, NC 27710.

	Abstract

Top Abstract Introduction Methods and Results Discussion References

 
Background Platelets play a crucial role in the ischemic complications of percutaneous coronary procedures. The recent availability of c7E3 Fab (abciximab; ReoPro), a chimeric monoclonal antibody Fab fragment directed against the platelet glycoprotein IIb/IIIa receptor, has reduced abrupt closure and other adverse clinical events and lessened the need for revascularization procedures. As experience accrues, rare cases of acute profound thrombocytopenia have been revealed.

Methods and Results From November 1991 to July 1996, patients at Duke University Medical Center who underwent percutaneous coronary revascularization and received their first exposure to c7E3 Fab were evaluated for the development of acute profound thrombocytopenia, defined as a platelet count <20x10⁹/L occurring within 24 hours of initial treatment. Four patients (0.5%) developed acute profound thrombocytopenia within 11 to 21 hours of receiving the c7E3 Fab bolus. Nadir platelet counts ranged from 1 to 16x10⁹/L and occurred within 11 to 26 hours. No patient developed a significant hemorrhagic complication, and each patient's platelet count responded to platelet transfusion. Platelet counts remained depressed for at least 3 days but returned to baseline within 2 weeks.

Conclusions Acute profound thrombocytopenia can occur after c7E3 Fab administration. Its development was not predictable, and it requires consideration in every patient treated. A platelet count 2 to 4 hours after the bolus would likely have detected these four cases. When indicated, platelet transfusion will raise the platelet count to safer levels without adverse effects. The differential diagnosis (including heparin-induced thrombocytopenia), a plan for management, and postulates as to the mechanism are discussed.

Key Words: glycoproteins • angioplasty • abciximab • thrombocytopenia • platelets

	Introduction

Top Abstract Introduction Methods and Results Discussion References

 
Platelet- and thrombin-mediated thromboses contribute to the abrupt artery closure and acute ischemic complications that may follow percutaneous coronary intervention. c7E3 Fab (abciximab; ReoPro, Eli Lilly and Centocor), the Fab fragment of the chimeric human-murine monoclonal antibody c7E3, is a new, highly potent antiplatelet agent increasingly used to prevent ischemic complications of percutaneous coronary revascularization, but it is associated with an increased incidence of hemorrhagic complications.^{1 2} This agent binds to the platelet glycoprotein (GP) IIb/IIIa receptor and inhibits aggregation by preventing adhesive molecules with the RGD sequence from binding to this platelet integrin.^{3 4}

Thrombocytopenia and severe thrombocytopenia have been observed with the use of c7E3 Fab and may contribute to the hemorrhagic risk. We report the development of acute profound thrombocytopenia in four patients from our institution after they received a bolus and 12-hour infusion of c7E3 Fab as their first exposure.

	Methods and Results

Top Abstract Introduction Methods and Results Discussion References

 
Between November 1991 and July 1996, experience with c7E3 Fab at Duke University Medical Center included the treatment of 38 patients in the EPIC trial, 56 patients in the EPILOG trial, and 650 patients treated with open-label drug. All patients had platelet counts checked the morning after c7E3 Fab therapy. Four of these 744 patients fit our definition of acute profound thrombocytopenia.

Definitions
In the strict hematologic sense, thrombocytopenia is defined as a platelet count <150x10⁹/L or a >40% decline from baseline. Mild thrombocytopenia is a platelet count between 100 and 150x10⁹/L, moderate thrombocytopenia is a platelet count between 50 and 99x10⁹/L, and counts <50x10⁹/L are termed severe thrombocytopenia. We define acute profound thrombocytopenia secondary to c7E3 Fab as a platelet count <20x10⁹/L within 24 hours of receiving the bolus.

Case Histories
Patient 1 was a 49-year-old black woman with a history of insulin-dependent diabetes mellitus, hypertension, hyperlipidemia, obesity, and a hysterectomy with bilateral salpingo-oophorectomy. She first developed angina in January 1995. Cardiac catheterization documented a 95% stenosis in the left anterior descending artery, and she underwent balloon angioplasty, with placement of two Palmaz-Schatz stents (Johnson & Johnson Interventional Systems). Several months later, her chest pain recurred and a repeat cardiac catheterization documented restenosis of the left anterior descending artery. Balloon angioplasty was performed, successfully reducing the stenosis to a 25% residual lesion. During the procedure, this patient received two boluses of heparin (but none before or after) and a bolus of c7E3 Fab followed by a 12-hour infusion. Her platelet count 1.5 hours before receiving c7E3 Fab was 312x10⁹/L. The platelet count was 182x10⁹/L 1 hour after and the nadir was 10x10⁹/L. She had no outward evidence of bleeding. Except for heparin, she received no other medications associated with thrombocytopenia. Two heparin-induced platelet aggregation studies were negative. Aspirin was discontinued, and she received a pooled platelet transfusion, after which the platelet count rose to 81x10⁹/L. On discharge (66 hours after c7E3 Fab bolus), the platelet count was 133x10⁹/L; at 30 days, it was 349x10⁹/L.

Patient 2 was a 53-year-old white man with a history of hypertension and hypercholesterolemia. He sustained an inferior myocardial infarction in April 1992. Recurrent symptoms in November 1995 led to a cardiac catheterization that revealed a 75% mid–left circumflex lesion in a left-dominant circulation. Heparin was given, and balloon angioplasty was performed. Dilation resulted in an occlusive dissection; a 3.0-mm Palmaz-Schatz stent was placed, and a c7E3 Fab bolus plus infusion was administered. Intracoronary tissue plasminogen activator was delivered into the left posterior descending artery during the procedure, and an intra-aortic balloon pump was in place for the next 48 hours. Six hours before the c7E3 Fab bolus, the platelet count was 161x10⁹/L. Eight hours after the bolus, the platelet count was 23x10⁹/L. Three hours later, it was 16x10⁹/L. After two pooled platelet transfusions, the platelet count remained in the range of 60x10⁹/L. Heparin was continued until the intra-aortic balloon pump was removed. The only signs of bleeding were a small hematoma and slight oozing at the vascular sheath site. Except for heparin, ticlopidine, and c7E3 Fab, this patient received no other medications associated with thrombocytopenia. A negative heparin-induced platelet aggregation study was obtained 2 hours after heparin was stopped. By 3.5 days, the platelet count rose to 90x10⁹/L without further platelet transfusion. Twelve days after the c7E3 Fab bolus, the patient's platelet count was 246x10⁹/L.

Patient 3 was an 83-year-old white man with a history of cigarette smoking, hypertension, and a stroke in 1992 that left him with residual left lower-extremity weakness. In February 1996, he sustained an acute myocardial infarction complicated by cardiopulmonary arrest. After resuscitation, he was treated with heparin, nitrates, and metoprolol. Cardiac catheterization revealed a normal left ventricle, a diffusely diseased large obtuse marginal artery, and a nondominant right coronary artery with a 95% proximal lesion. Heparin therapy was continued, and the next day the patient underwent balloon angioplasty. No further heparin was administered subsequent to the procedure. There were no signs of bleeding. Sixteen hours before the c7E3 Fab bolus, the platelet count had been 139x10⁹/L. A platelet count 18.5 hours after the bolus was 15x10⁹/L; 2.5 hours later, it was 7x10⁹/L. After a pooled platelet transfusion (6 U), the platelet count was 43x10⁹/L. Aspirin was discontinued. This patient's platelet count 48 hours after c7E3 Fab bolus was 28x10⁹/L. Except for heparin and c7E3 Fab, he received no other medications associated with thrombocytopenia. Heparin-induced platelet aggregation studies 1 and 3 days after heparin was discontinued were negative. Four days after the procedure, the platelet count was 28x10⁹/L; 10 days after the procedure, it was 185x10⁹/L.

Patient 4 was a 62-year-old white man with a history of hypercholesterolemia and hypertension. During an annual physical exam, his ECG revealed new anterolateral T-wave inversions. Cardiac catheterization documented a diffusely diseased right coronary artery with 70%/70% stenoses and a filling defect. A heparin infusion was begun, and balloon angioplasty was performed with placement of a Palmaz-Schatz intracoronary stent. Heparin was discontinued after 22 hours. Four hours before intervention, the platelet count was 135x10⁹/L; 21 hours after the initiation of c7E3 Fab, it was 1x10⁹/L. A platelet count performed on citrated blood at 29 hours was 2x10⁹/L. Heparin-induced platelet aggregation testing was negative. He received a plateletpheresis transfusion and at 35 hours after the c7E3 Fab bolus, the platelet count was 35x10⁹/L. After another plateletpheresis transfusion, the platelet count rose to 81x10⁹/L. Six days after the c7E3 Fab therapy, the platelet count was 157x10⁹/L.

	Discussion

Top Abstract Introduction Methods and Results Discussion References

 
Despite the development of profound thrombocytopenia within 11 to 21 hours of administration of c7E3 Fab in these four patients, no hemorrhagic complications were observed. The nadir platelet counts ranged from 1 to 16x10⁹/L within 11 to 26 hours of the start of the c7E3 Fab infusion (Fig 1). Each patient's platelet count responded to platelet transfusion without an adverse event.

View larger version (28K): [in this window] [in a new window]   Figure 1. Platelet counts before and during therapy and after recovery in four patients who developed acute profound thrombocytopenia after receiving c7E3 Fab bolus plus infusion. The inset focuses on the platelet counts during the first 48 hours and notes the first platelet transfusion (Plt Txn) given.

All four patients had normal baseline platelet counts before c7E3 Fab treatment, which made immune thrombocytopenia, rheumatologic/immunologic conditions, or a bone marrow disorder unlikely causes. Splenomegaly was not detected in any patient. We eliminated other potential causes of thrombocytopenia after we found in each patient normal prothrombin times, fibrinogen levels, D-dimer titers, and red and white cell components of the complete blood count and an absence of abnormalities in the peripheral blood smears. Temporally, the acute profound thrombocytopenia was related to c7E3 Fab administration. It could not be determined whether these events were related to the pharmacology of c7E3 Fab or if this was a lot-specific effect. Other than heparin, none of the patients received a medication likely to induce such severe thrombocytopenia (ie, sulfonamides, quinidine or quinine, thiazides, or phenytoin). Patients 3 and 4 received heparin while awaiting their revascularization procedure, but neither developed clinical evidence for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS), and like the first two patients, the heparin-induced platelet aggregation testing was negative.

Due to the concomitant use of heparin and c7E3, it is useful to distinguish between heparin-induced and c7E3 Fab–induced thrombocytopenia. There are at least two discrete forms of heparin-induced thrombocytopenia.^{5 6 7} The most clinically important is type II (HIT/HITTS), a disorder of delayed-onset but persistent thrombocytopenia (<100x10⁹/L), which begins 4 to 10 days after exposure to heparin⁸ and is associated with venous and arterial thromboses. Rarely, precipitous drops in platelet counts can be observed within 24 hours if the patient has received heparin within the last 2 months. The mechanism of this syndrome involves the presence of IgG or IgM antibodies specific for complexes of heparin attached to platelet factor 4.⁹ Binding of these antibodies to circulating platelets leads to platelet clustering, activation, and aggregation and ultimately to thrombocytopenia. The antibodies can also bind to conjugates of platelet factor 4 and heparin-like molecules (glycosaminoglycans) on the surface of endothelial cells, producing vessel wall injury and thrombosis.⁹

Testing for the presence of heparin-dependent antibodies to diagnose HIT/HITTS is not completely reliable. The heparin-induced platelet aggregation test we used is reported to be up to 90% specific,¹⁰ but its sensitivity is at best 80% in patients tested while not receiving heparin.^{10 11} When both heparin and c7E3 Fab are given, no test can definitively distinguish heparin-induced from c7E3 Fab–induced thrombocytopenia. Helpful in this discrimination, however, are knowledge of a patient's exposure to heparin within the last 2 months, the results of a test for the presence of a heparin-dependent antibody, the absence of thrombosis or hemorrhage, and the evolution of thrombocytopenia within 24 hours of exposure to c7E3 Fab. There is no evidence that platelet factor 4 is involved in the thrombocytopenia seen with c7E3 Fab infusion. Interestingly, inhibition of the heparin-induced platelet aggregation test by c7E3 has been reported in vitro, and the agent has been postulated as a potential treatment for HIT/HITTS.^{12 13} In an ex vivo angioplasty model, c7E3 Fab has been shown to effectively inhibit platelet deposition at the site of balloon injury.¹⁴ However, c7E3 Fab has not been proved to suspend the development of thrombocytopenia in the circulation or interrupt the process of thrombosis caused by damaged endothelium of the type associated with HITTS, and its presence could conceivably increase the risk of hemorrhage.

Analysis of these four cases supports the following plan for evaluation and management (Fig 2). It appears prudent to obtain a platelet count 2 to 4 hours after initiating the infusion, as the package insert suggests. If thrombocytopenia is detected, a thoughtful search should be undertaken for evidence supporting other possible diagnoses. A repeat platelet count should be evaluated on blood collected into citrate anticoagulant via peripheral vein puncture, and a peripheral blood film should be reviewed. A prothrombin time, activated partial thromboplastin time, plasma fibrinogen level, and D-dimer titer should also be performed. Serum or plasma should be tested for a heparin-dependent antibody.

View larger version (43K): [in this window] [in a new window]   Figure 2. Evaluation and management of thrombocytopenia with c7E3 Fab therapy. ANA indicates antinuclear antibody; EDTA, ethylene diamine tetraacetic acid.

The first consideration in the management of acute profound thrombocytopenia (Fig 2) should be the immediate discontinuation of c7E3 Fab and other potentially offending medications. This decision will best be made in light of the risk of acute coronary artery or stent thrombosis in each patient. It may not be necessary to discontinue aspirin and ticlopidine; however, interruption of the hemostatic mechanism beyond the quantitative decrease of platelets is likely to lead to more hemorrhagic complications. Should the platelet count fall below 20x10⁹/L, we recommend transfusion with a pooled pack of random donor platelets (or one single-donor plateletpheresis if available). Other supportive measures should include bed rest to decrease the risk of a fall, avoidance of intramuscular injections, and the use of a stool softener. The platelet count should be evaluated periodically until recovery.

It is dangerous to assume that the development of thrombocytopenia is tolerable and provides an additional desirable therapeutic antiplatelet action. There is a difference between markedly abrogating the GP IIb/IIIa function of circulating platelets with c7E3 Fab and interrupting hemostasis to the extent caused by profound thrombocytopenia. Even in the presence of c7E3 Fab, the platelets continue to perform less visible but no less important functions to maintain hemostasis: platelet adhesion and adherence to collagen and von Willebrand factor under high shear stress remain unaffected,¹⁵ permitting platelet attachment to the damaged endothelial lining, formation of a protective monolayer of platelets, and plugging of rents in the blood vessel wall. Clinically, the development of hemorrhage in the presence of thrombocytopenia is related to the level of thrombocytopenia, whether it is a declining platelet count, the age of the circulating platelets, the rate of platelet turnover in the bone marrow, and the presence of fever, infection, coagulation defects, and anatomic lesions.¹⁶

Although the concept of a threshold for prophylactic platelet transfusion is not well supported by clinical research, pertinent points can be distilled from the literature.^{16 17} For patients with coagulation disorders or anatomic lesions and those receiving heparin, a threshold of 20x10⁹/L is suggested.¹⁸ For patients who will undergo invasive procedures or who are actively bleeding, the platelet count should be maintained at >50x10⁹/L.^{19 20}

The mechanism of the acute profound thrombocytopenia caused by c7E3 Fab is speculative. By design, c7E3 Fab has no Fc portion,²¹ making untenable the hypothesis that acute platelet removal occurs by the binding of the antibody to the Fc receptors of macrophages in the reticuloendothelial system. There are several other possibilities. Although the binding of c7E3 to the GP IIb/IIIa receptor is not known to induce platelet activation, binding of molecules to this receptor produces a conformational change resulting in the expression of new epitopes, termed ligand-induced binding sites, or LIBS. In fact, a preexisting IgG-type antibody has been found to bind to this receptor in the presence of an experimental GP IIb/IIIa receptor antagonist and to cause thrombocytopenia in chimpanzees, and it is present in humans as well.²² Platelet alterations could also be stimulated either by the presence of c7E3 Fab on the platelet surface in relation to other platelet antigens or via the ability of c7E3 Fab to bind to the vitronectin (_vß₃) receptor or the Mac-1(CD11b/CD18) integrin receptor of activated monocytes.²³ Any of these events could culminate in platelet activation and platelet-platelet interactions with consumption or removal of the platelets from the circulation. Because the production of the c7E3 Fab fragment requires cleavage of the chimeric antibody across the hinge region of the molecule, a human chimeric antibody reaction to this damaged human antibody structure may occur after infusion. None of our four patients was tested for the presence of human anti-chimeric antibodies. When tested in prior studies, rare cases of elevated reactivity in the human anti-chimeric antibody assay were reported before the first c7E3 Fab infusion, but these were not associated with the development of thrombocytopenia or allergic reactions after treatment.²⁴ Current understanding of the pharmacokinetics of c7E3 Fab bolus plus infusion (plasma half-life <30 minutes but an extended biological half-life)^{4 24 25} does not provide insight into the mechanism of the acute profound thrombocytopenia. The determination of whether acute profound thrombocytopenia is a side effect associated with other competitive GP IIb/IIIa receptor antagonists must await the analysis of ongoing and planned clinical trials.

Note Added in Proof
Since submission of this manuscript, three more cases of acute, profound thrombocytopenia after first exposure to c7E3 Fab (abciximab) have developed. One patient had a nadir platelet count of 6x10⁹/L, whereas the other two each had a nadir of 20x10⁹/L.

	Acknowledgments

 
The authors would like to express their gratitude for the critical thoughts and insights provided by Dr Barry S. Coller.

Received May 13, 1996; revision received December 5, 1996; accepted December 13, 1996.

	References

Top Abstract Introduction Methods and Results Discussion References

 
1. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956-961.[Abstract/Free Full Text]

2. Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT. Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet. 1994;343:881-886.[Medline] [Order article via Infotrieve]

3. Coller BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation. 1995;92:2373-2380.[Free Full Text]

4. Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kleiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation. 1994;90:1757-1764.[Abstract/Free Full Text]

5. Cola C, Ansell J. Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J. 1990;119:368-374.[Medline] [Order article via Infotrieve]

6. Schmitt BP, Adelman B. Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci. 1993;305:208-215.[Medline] [Order article via Infotrieve]

7. Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost. 1995;21:106-116.[Medline] [Order article via Infotrieve]

8. Chong BH. Heparin-induced thrombocytopenia. Aust N Z J Med. 1992;22:145-152.[Medline] [Order article via Infotrieve]

9. Aster RH. Heparin-induced thrombocytopenia. N Engl J Med. 1995;332:1374-1376.[Free Full Text]

10. Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AG, Carter CJ. Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia. J Lab Clin Med. 1984;103:606-612.[Medline] [Order article via Infotrieve]

11. Stricker H, Lammle B, Furlan M, Sulzer I. Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis: specific diagnostic test for a rare side effect. Am J Med. 1988;85:721-724.[Medline] [Order article via Infotrieve]

12. Mak K-H, Kottke-Marchant K, Brooks LM, Apheart KL, Topol EJ. Potential value of platelet GPIIb/IIIa antagonist for treating heparin-induced thrombocytopenia. J Am Coll Cardiol. 1996;27:316A.

13. Fareed J, Yang L, Hoppensteadt D, Koza M, Walenga JM, Welzel D. Glycoprotein IIb/IIIa inhibitors can prevent heparin mediated platelet activation in heparin-induced thrombocytopenia. Circulation. 1996;94(Suppl I):I-228. Abstract.

14. Kaplan AV, Leung LL-K, Leung W-H, Grant GW, McDougall IR, Fischell TA. Roles of thrombin and platelet membrane glycoprotein IIb/IIIa in platelet-subendothelial deposition after angioplasty in an ex vivo whole artery model. Circulation. 1991;84:1279-1288.[Abstract/Free Full Text]

15. Turner NA, Moake JL, Kamat SG, Schafer AI, Kleiman NS, Jordan R, McIntire LV. Comparative real-time effects on platelet adhesion and aggregation under flowing conditions of in vivo aspirin, heparin, and monoclonal antibody fragment against glycoprotein IIb-IIIa. Circulation. 1995;91:1354-1362.[Abstract/Free Full Text]

16. Beutler E. Platelet transfusions: the 20,000/µL trigger. Blood. 1993;81:1411-1413.[Free Full Text]

17. Patten E. Controversies in transfusion medicine: prophylactic platelet transfusion revisited after 25 years—con. Transfusion. 1992;32:381-385.[Medline] [Order article via Infotrieve]

18. Gmur J, Burger J, Schanz U, Fehr J, Schaffner A. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet. 1991;338:1223-1226.[Medline] [Order article via Infotrieve]

19. Lee EJ. Indications for platelet transfusion therapy. In: Kurtz SR, Brubaker DB, eds. Clinical Decisions in Platelet Therapy. Bethesda, Md: American Association of Blood Banks; 1992:31-43.

20. Murphy S. A critical view of prophylactic platelet transfusion. In: Kurtz SR, Brubaker DB, eds. Clinical Decisions in Platelet Therapy. Bethesda, Md: American Association of Blood Banks; 1992:45-54.

21. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med. 1962;266:905-909.

22. Bednar B, Bednar RA, Cook JJ, Bollag DM, Chang CT, Gaul SL, McQueney PA, Egbertson MS, Hartman GD, Holahan MA, Lynch JJ, Gould RJ. Drug-dependent antibodies against GPIIb/IIIa induce thrombocytopenia. Circulation. 1996;94(suppl I):I-98. Abstract.

23. Coller BS, Scudder LE, Beer J, Gold HK, Folts JD, Cavagnaro J, Jordan R, Wagner C, Iuliucci J, Knight D, Ghrayeb J, Smith C, Weisman H, Berger H. Monoclonal antibodies to platelet glycoprotein IIb/IIIa as antithrombotic agents. Ann N Y Acad Sci. 1991;614:193-213.[Medline] [Order article via Infotrieve]

24. Simoons ML, de Boer MJ, van den Brand MJ, van Miltenburg AJ, Hoorntje JC, Heyndrickx GR, van der Wieken LR, de Bono D, Rutsch W, Schaible TF, Weisman HF, Klootwijk P, Nijssen KM, Stibbe J, de Feyter PJ, and the European Cooperative Study Group. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation. 1994;89:596-603.[Abstract/Free Full Text]

25. Faulds D, Sorkin EM. Abciximab (c7E3 Fab): a review of its pharmacology and therapeutic potential in ischemic heart disease. Drugs. 1994;48:583-598.[Medline] [Order article via Infotrieve]

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				B. Moy, J. C. Wang, G. D. Raffel, and J. P. Marcoux II Hemolytic Uremic Syndrome Associated With Clopidogrel: A Case Report Arch Intern Med, May 8, 2000; 160(9): 1370 - 1372. [Abstract] [Full Text] [PDF]

				T. A. Waldmann, R. Levy, and B. S. Coller Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy Hematology, January 1, 2000; 2000(1): 394 - 408. [Abstract] [Full Text] [PDF]

				S. Harder, C. M. Kirchmaier, H. J. Krzywanek, D. Westrup, J.-W. Bae, and H. K. Breddin Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects Circulation, September 14, 1999; 100(11): 1175 - 1181. [Abstract] [Full Text] [PDF]

				B. Bednar, J. J. Cook, M. A. Holahan, M. E. Cunningham, P. A. Jumes, R. A. Bednar, G. D. Hartman, and R. J. Gould Fibrinogen Receptor Antagonist-Induced Thrombocytopenia in Chimpanzee and Rhesus Monkey Associated With Preexisting Drug-Dependent Antibodies to Platelet Glycoprotein IIb/IIIa Blood, July 15, 1999; 94(2): 587 - 599. [Abstract] [Full Text] [PDF]

				M. J. Beddall Acute thrombocytopenia after abciximab (ReoPro [trade mark sign]) therapy Can. Med. Assoc. J., July 1, 1999; 161(1): 74 - 74. [Full Text]

				D. A. Vorchheimer, J. J. Badimon, and V. Fuster Platelet Glycoprotein IIb/IIIa Receptor Antagonists in Cardiovascular Disease JAMA, April 21, 1999; 281(15): 1407 - 1414. [Abstract] [Full Text] [PDF]

				M. Gawaz, F.-J. Neumann, and A. Schomig Evaluation of Platelet Membrane Glycoproteins in Coronary Artery Disease : Consequences for Diagnosis and Therapy Circulation, January 12, 1999; 99 (1): e1 - e11. [Full Text] [PDF]

				M. Madan, S. D. Berkowitz, and J. E. Tcheng Glycoprotein IIb/IIIa Integrin Blockade Circulation, December 8, 1998; 98(23): 2629 - 2635. [Full Text] [PDF]

				The PURSUIT Trial Investigators Inhibition of Platelet Glycoprotein IIb/IIIa with Eptifibatide in Patients with Acute Coronary Syndromes N. Engl. J. Med., August 13, 1998; 339(7): 436 - 443. [Abstract] [Full Text] [PDF]

				S. D. Berkowitz, D. C. Sane, K. N. Sigmon, J. H. Shavender, R. A. Harrington, J. E. Tcheng, E. J. Topol, R. M. Califf, and for the Evaluation of c7E3 for the Prevention of I Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization J. Am. Coll. Cardiol., August 1, 1998; 32(2): 311 - 319. [Abstract] [Full Text] [PDF]

				L. A. Jenkins, S. Lau, M. Crawford, and Y.-K. Keung Delayed Profound Thrombocytopenia After c7E3 Fab (Abciximab) Therapy Circulation, March 31, 1998; 97(12): 1214 - 1215. [Full Text] [PDF]

				D. A. Vorchheimer and V. Fuster Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety Circulation, February 3, 1998; 97(4): 312 - 314. [Full Text] [PDF]

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