Severe thrombocytopenia following tirofiban infusion.

A 44-year-old man presented with acute coronary syndrome. He was administered glycoprotein IIb/IIIa receptor antagonist (tirofiban) for a left anterior descending artery thrombus detected during percutaneous coronary intervention. He developed very severe thrombocytopenia 24 h after tirofiban infusion with no signs of bleeding. The thrombocytopenia spontaneously resolved after stopping tirofiban without any significant clinical sequelae. To our knowledge, this is the first case report of tirofiban-induced severe thrombocytopenia from the Middle East. Clinicians using this drug should be aware of this potentially lethal adverse drug reaction. Close monitoring of platelet count early after the initiation of tirofiban infusion is suggested and discontinuation of tirofiban infusion can reverse thrombocytopenia spontaneously.

Introduction

Glycoprotein IIb/IIIa receptor antagonists (GPRAs) have been increasingly used in the treatment of acute coronary syndrome (ACS) and after percutaneous coronary intervention (PCI).[1-3] These drugs cause thrombocytopenia in approximately 1-2% of patients.[1-3] Here, we report a case of very severe thrombocytopenia after 24 h of tirofiban treatment in a patient who underwent urgent PCI for ACS.

Case Report

A 44-year-old Egyptian man presented with chest pain of 1 h duration. His electrocardiogram showed ST depression and T inversion in anterolateral leads, and his Troponin T was positive at 0.7 ng/ml. He was a nonsmoker with a history of hyperlipidemia and hypertension. The patient was not on any medications. On hospital admission, he had a normal complete blood count (CBC) including platelet count (411 × 109/l [n = (150--450) × 109/l]). His renal function was normal. He was sent for PCI after he had received a loading dose of clopidogrel (300 mg), aspirin (325 mg), and bolus dose of enoxaparin 80 mg subcutaneously. Coronary angiography revealed 90% tight stenosis of mid-left anterior descending coronary artery with fresh large thrombus and other coronary arteries were normal. Since the clot burden was large, it was decided to administer tirofiban and enoxaparin for 48 h and then perform PCI. Tirofiban was intravenously administrated at a dose of 0.4 μg/kg/min for 30 min followed by 0.1 μg/kg/min continuous infusion. CBC at 6 h was normal. After 24 h of infusion, CBC revealed very severe thrombocytopenia (platelet count, 7 × 109/l). Immunoplatelet count CD61 was 6.4 × 109/l [n = (150-400) × 109/l]). A thorough examination of the blood film under a microscope confirmed the finding of marked thrombocytopenia without evidence of microangiopathic hemolytic anemia. Accordingly, tirofiban, clopidogrel, and aspirin were discontinued. After 6 h of stopping tirofiban, the platelet count had increased to 18 × 109/l, and at 12 h it was 38 × 109/l. There was no fall in hemoglobin. There were no symptoms or signs of bleeding. He complained of right loin pain and a computed tomographic scan was negative for retroperitoneal hematoma or any other source of internal hemorrhage. The platelet count increased gradually. Figure 1 shows the time course of platelet recovery. At 72 h, platelet count was back to normal and the patient was started again on aspirin and clopidogrel. He underwent successful PCI with drug-eluting stent implantation to left anterior descending artery. There was no significant clot in the artery. The patient's further hospital course was uneventful, and he was discharged next day of intervention with normal hematological test results (platelet count, 362 × 109/l). His repeat platelet counts at 1 and 3 months were 302 × 109/l and 335 × 109/l, respectively, while taking aspirin and clopidogrel.

Figure 1

Time course of platelet count changes after tirofiban infusion

Discussion

GPRAs are widely used in the management of patients with ACS and during PCI. GPRAs react with the platelet glycoprotein IIb/IIIa receptor to block fibrinogen binding and platelet--platelet aggregation and thrombus formation. They decrease ischemic complications and mortality associated with ACS and PCI.[1-3] Major adverse drug reactions to these agents include bleeding and thrombocytopenia. Five patterns of GPRA-induced thrombocytopenia have been identified: acute severe thrombocytopenia (platelet count <10 × 109/l) within 12 h of first exposure, acute thrombocytopenia within 12 h of second exposure, delayed thrombocytopenia (5–7 days after treatment), anaphylaxis after first or second exposure, and pseudo-thrombocytopenia due to platelet clumping.[4]

GPRAs cause drug-induced immune thrombocytopenia secondary to the development of circulating antibodies against IIb/IIIa antagonists, which occurs in patients who have previously been exposed to the drug or due to naturally occurring antibodies.[45] Delayed onset of thrombocytopenia is explained by the persistence of platelet-bound drug for several weeks after treatment, rendering platelets susceptible to destruction by newly formed antibody. The naturally occurring antibodies are thought to be responsible for GPRA-induced thrombocytopenia within hours of administration.[45] These antibodies react with IIb/IIIa antagonist-coated platelets and cause their destruction. It is proposed that IIb/IIIa antagonist molecule acts as an antigen itself or induces a conformational change to the platelet receptor, resulting in the exposure of a ligand-induced binding site (epitopes) that binds directly either to the antibody or to the glycoprotein receptor antagonist–antibody complex.[45]

The incidence of thrombocytopenia, defined as an absolute platelet count of <90 × 109/l, was 1.1% in the PRISM study,[1] 1.9% in PRISM-PLUS study,[2] and 1.1% in RESTORE trial.[3] Severe thrombocytopenia (platelet count, <50 × 109/l) has occurred in 0.5% of patients in clinical trials.[2] Among the GPRAs, abciximab has been associated with a higher incidence of thrombocytopenia (2.4%) than does eptifibatide or tirofiban (0.5%).[6] Patients with thrombocytopenia had more frequent severe bleeding, received blood transfusions more frequently, and had a higher incidence of death, myocardial infarction, or the need for target vessel revascularization at 30 days.[6] However, this patient did not have any signs of bleeding or other events.

It is important to monitor platelet counts closely after initiation of GPRAs. Monitoring of platelet counts at 6, 12, and 24 h will detect most cases of acute thrombocytopenia. Our patient developed thrombocytopenia after 24 h of administration of tirofiban, which is similar to a study by Merlini et al.[6] In their study the mean time to onset of thrombocytopenia was 24 h. The possibility of heparin-induced thrombocytopenia (HIT) was low, as he did not receive any unfractionated heparin and had only received 2--3 doses of enoxaparin. HIT usually results from the formation of antiplatelet antibodies and thrombocytopenia typically develops after 5 days in naive patients and within minutes to hours of post-exposure in those who have received heparin therapy within the past 6 months. This patient was not exposed to any heparins previously. Isolated profound thrombocytopenia is rarely known to occur with aspirin and clopidogrel.[7] The mechanism in these cases is usually due to induction of some sensitizing antibodies at the time of previous treatment with these drugs.[7] This patient had received only one dose of aspirin and clopidogrel and chance of developing sensitizing antibodies is very low. Furthermore, he was again given aspirin and clopidogrel before his final PCI and continued these after PCI without any thrombocytopenia.

Clopidogrel commonly causes thrombotic thrombocytopenic purpura (which was not seen in this patient) and only 6 cases of isolated thrombocytopenia without thrombotic thrombocytopenic purpura are reported,[7] even though aspirin, clopidogrel, and heparins can cause isolated thrombocytopenia; in this patient it seemed more likely due to tirofiban infusion. The fact that the platelet count in our patient rapidly increased after stopping tirofiban infusion supports the hypothesis of immune-mediated thrombocytopenia. Once thrombocytopenia is detected, it is mandatory to stop tirofiban infusion. Upon discontinuation of treatment, platelet levels return to normal in 2–5 days.[4] Other treatment options are use of steroids, immunoglobulins, and platelet transfusion.[8] Naranjo's algorithm for demonstrating causality assessment of adverse drug reaction (ADR) revealed a score of 5, indicating probable ADR.

Conclusion

The use of tirofiban may induce very severe thrombocytopenia. Clinicians using this drug must be aware of this potentially lethal complication. Close monitoring of platelet count early after the initiation of tirofiban infusion is necessary and discontinuation of tirofiban infusion can reverse thrombocytopenia spontaneously.