Bleeding Complications of Platelet Glycoprotein IIb/IIIa Inhibitor Abciximab (ReoPro‚Ñ¢)

Antagonists of platelet receptor glycoprotein (GP) IIb/IIIa are a novel class of antithrombotic agents that provide more comprehensive platelet blockade than the combination of aspirin and heparin. Studies of patients scheduled for percutaneous coronary intervention (PCI) with acute coronary syndrome (unstable angina or non-Q wave myocardial infarction) have shown that the addition of intravenous GP IIb/IIIa inhibitors to aspirin and heparin is associated with a reduction in death or myocardial infarction compared to therapy with aspirin and heparin alone.1,2 As with other antithrombotic agents, the principle safety issue with GP IIb/IIIa inhibitors is the risk of bleeding, as the potent antiplatelet effect of these drugs may adversely affect hemostasis. In addition, antagonists of GP IIb/IIIa may increase the risk of thrombocytopenia.3,4 We report a case of abciximab-induced severe thrombocytopenia which led to fatal intra-cranial hemorrhage. Case Report. A 68-year-old white female underwent coronary angiography because of a positive stress test that revealed critical stenosis in the ostium and proximal portion of the right coronary artery. Percutaneous transluminal coronary angioplasty and stent deployment were performed. The patient received abciximab and was discharged home after an uneventful procedure. Five months after the first procedure, she developed chest pain. A pharmacologic stress test showed severe inferior wall ischemia. Coronary angiography revealed an ejection fraction of 60%, normal left main artery, 30% stenosis in the mid left anterior descending artery, total occlusion of the mid left circumflex artery and 90% in-stent restenosis of the right coronary artery. PTCA with stent deployment was performed in the proximal right coronary artery with excellent angiographic result. Abciximab was started. Within 4 hours of starting abciximab infusion, the patient’s platelet count dropped to 4,000 cells/µl, which was checked manually (Table 1). The patient was asymptomatic and had no evidence of petechiae or bleeding from oral mucosa. Her neurological status was intact. Abciximab infusion was stopped immediately and the patient did not receive post-procedure aspirin or clopidogrel. On the second and fourth post-procedure day, the patient received platelet infusion for persistent severe thrombocytopenia with evidence of petechiae on the skin. The patient received WinRho-SD® (Rho-D, human immunoglobulin) 4,000 µg intravenously on the fourth post-procedure day and platelet count increased to 93,000 cells/µl. The patient became suddenly unresponsive on the fifth post-procedure day. A computer tomography (CT) scan of the head showed large right cerebellar, small left cerebellar and moderate left occipital hemorrhages, acute hydrocephalus and bilateral tonsillar herniation (Figure 1). EEG performed the next day showed electro cerebral silence. The patient’s subsequent hospital course in the Critical Intensive Care Unit was complicated by infection, renal failure and electrolyte imbalance; she died 2 weeks post-procedure. An autopsy revealed the cause of death to be intraparenchymal cerebral hemorrhage secondary to severe thrombocytopenia as a complication of abciximab. Discussion. Abciximab (Reopro®, Eli Lilly & Company, Indianapolis, Indiana) is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. It is indicated as an adjunct to PCI for the prevention of cardiac ischemic complications and in patients with unstable angina who fall into a high-risk category. Abciximab is intended for use with aspirin and heparin.1 Information regarding the incidence of bleeding associated with abciximab during angioplasty is available from two primary phase III clinical trials, the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) trial2 and the EPILOG (Evaluation of PTCA to Improve Long-term Outcome by C7E3A GP IIb/IIIa receptor blockade) trial.5 The EPIC trial showed a statistically significant increase in the incidence of bleeding episodes with abciximab, while the EPILOG trial showed no difference in the incidence of major bleeding with abciximab compared to placebo. These studies have shown that femoral vascular access site bleeding is the most frequent site for major bleeding. Patients with contraindications for the use of GP IIb/IIIa should not receive abciximab. These contraindications include: active internal bleeding; recent (within 6 weeks) gastrointestinal (GI) or genito-urinary bleeding of clinical significance; history of cerebrovascular accident within two years; bleeding diathesis; administration of oral anticoagulation within 7 days unless prothrombin time is 2 hours after discontinuation of heparin; activated clotting time less than 175 seconds prior to sheath removal; pressure application to the access site for at least 30 minutes; and groin check for bleeding or hematoma for 6 hours after sheath removal. If bleeding is noted, it should be managed by lowering the head of the bed to 0°, applying manual pressure or compression device until hemostasis is achieved, obtaining stat complete blood count with platelets and obtaining stat partial thromboplastin time if patient is receiving heparin. If major bleeding is detected, abciximab, heparin, aspirin and clopidogrel should be discontinued and blood product transfusions and platelet infusions should be performed as needed. If major bleeding is detected along with GP IIb/IIIa antagonist-induced thrombocytopenia, it is important to avoid unnecessary arterial/venous punctures and intramuscular injections, and to check stools and urine for occult blood and look for any other source of bleeding. The incidence occurrence rate of thrombocytopenia in various clinical trials shows an increased incidence with abciximab in comparison with placebo (Table 2). The precise mechanism of severe thrombocytopenia associated with abciximab is not clear. It is suggested in the literature that cross-reactive or endogenous antibodies targeted to ligand-induced binding sites (LIBS) expressed on abciximab-bound platelets may be involved.1,2 Administration of abciximab may result in human anti-chimeric antibody (HACA) formation, which could potentially cause allergic or hypersensitivity reactions, thrombocytopenia or diminished benefit upon readministration of abciximab. Readministration to patients who have developed a positive HACA response after initial administration has not been evaluated in clinical trials.1 Immune-mediated heparin-induced thrombocytopenia and other causes of thrombocytopenia, as well as pseudo-thrombocytopenia,10 should also be considered when a patient develops thrombocytopenia and is being treated with both drugs. Patients receiving abciximab should have platelet count checked 2–4 hours after the bolus of abciximab and at 24 hours or prior to discharge, whichever is first. Platelet count should be manually checked; if true severe thrombocytopenia is confirmed, then abciximab, heparin and aspirin should be immediately discontinued. The patient should be closely monitored for any other source of bleeding and should be treated appropriately with platelet transfusion and immunoglobulin.8 Although the incidence of intra-cranial hemorrhage in four phase III clinical trials was not significantly different in patients receiving abciximab compared to placebo (Table 3), the role of the readministration of abciximab has not been clearly addressed in these studies. In the ReoPro Readministration Registry (RRR),11 a total of 500 patients were included who received abciximab for the second or third time. This registry indicated that there was no case suggesting hypersensitivity and that the incidence of profound thrombocytopenia was higher with readministration (0.5–1.0% for patients receiving abciximab for the first time and 2.4% for patients receiving readministration). In the RRR, the presence or absence of HACA was not predictive of adverse clinical events, bleeding or thrombocytopenia. In summary, severe thrombocytopenia can occur with abciximab administration; it typically develops within several hours of abciximab administration. The thrombocytopenia appears to be self-limiting, with a spontaneous increase in platelet count averaging 20,000–25,000 cells/µl per day following the nadir count. Platelet count should be measured at baseline, 2–4 hours after the bolus dose and again at 24 hours or prior to discharge, whichever is earlier. The transfusion of platelets and immunoglobulin may be helpful in the management of severe thrombocytopenia associated with abciximab. The risk of life-threatening thrombocytopenia must be seriously considered when readministration of abciximab is contemplated, as 30–35% of the 500,000 patients who annually undergo PCI in the United States receive abciximab and there is no identifiable predictor of abciximab-induced thrombocytopenia. The use of abciximab as an adjunct to fibrinolytic therapy for acute myocardial infarction may well become widespread as the results of SPEED, TIMI-14, and GUSTO-IV9 trials are now available and as new indications undergo investigation (such as abciximab use during facilitated angioplasty and as adjunctive therapy in cerebrovascular disease and peripheral vascular interventions). Whether an alternative agent should be substituted in the retreatment indication after prior abciximab administration and whether an alternative agent would provide improved safety with at least similar efficacy have not been determined.11

References 1. Prescribing information for ReoPro® (Abciximab), Centocor/Eli Lilly & Co., Indianapolis, Indiana. 2. The EPIC Investigators. Use of monoclonal antibody directed against the platelet IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med 1994;330:956–961. 3. Blankenship JC, et al. Bleeding complications of GP IIb/IIIa receptor inhibitors. Am Heart J 1999;138:287–296. 4. Berkowitz SD, Harrington RA, Rund MM, et al. Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1997;95:809. 5. The EPILOG Investigators. Platelet GP IIb/IIIa blockade and low dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689. 6. The CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina. Lancet 1997;349:1429. 7. The EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) Investigators. Lancet 1998;352:87. 8. Kereiakes DJ, Essel JH, Abbottsmith CW, et al. Abciximab associated profound thrombocytopenia: Therapy with immunoglobulin and platelet transfusion. Am J Cardiol 1996;78:1161–1163. 9. Fry ET, et al. Readministration of abciximab in percutaneous coronary intervention. J Invas Cardiol 1999;11:251–258. 10. Moll S, Poepping I, Hauck S, et al. Pseudo-thrombocytopenia after abciximab treatment. Circulation 1999;100:1460. 11. Tcheng JE, Kereiakes DL, Lincoff AM, et al. Abciximab readministration: Result of ReoPro readministration registry. Circulation 2001;104:870–875.