Use of Ticlopidine and Cilostazol after Intracoronary Drug-Eluting Stent Placement in a Patient with Previous Clopidogrel-Induce

Case Report. A 79-year-old female with a medical history of obesity, hypertension and coronary artery disease was admitted to an outside institution with complaints of shortness of breath and chest heaviness. Myocardial infarction was excluded through serial measurement of troponin-I and creatine phosphokinase (CPK) levels. She was diagnosed with unstable angina and mild congestive heart failure and treated with intravenous diuretics, oral nitrates, enoxaparin and aspirin. A single dose of clopidogrel 75 mg was also administered. She was subsequently transferred to our institution for further evaluation. Her past medical history was also significant for thrombotic thrombocytopenic purpura (TTP) after clopidogrel administration 2 years previously. At that time she had presented with shortness of breath and was diagnosed with a non-ST-segment elevation myocardial infarction. She was treated with unfractionated heparin, and cardiac catheterization revealed an 80% stenosis of the right coronary artery (RCA) which was treated with stenting after administration of eptifibatide and clopidogrel. Subsequently, she developed fever, ecchymoses, thrombocytopenia, hemolytic anemia and acute renal failure. No neurologic or mental status changes were noted. Heparin-induced thrombocytopenia was excluded with an antibody test. Her peripheral blood smear revealed schistocytes and a presumptive diagnosis of TTP was made. Clopidogrel was discontinued and she was treated with oral corticosteroids and plasmapheresis, with eventual resolution of her renal failure and thrombocytopenia. The patient’s medications at the time of transfer to our institution included furosemide, isosorbide mononitrate, metoprolol and aspirin. Clopidogrel had been discontinued after the first dose in light of her previous history. On physical examination, she was afebrile and hypertensive at 170/74 mmHg, but otherwise had no notable findings. Laboratory testing revealed a white blood cell count of 9,100/uL, a hematocrit of 42%, a platelet count of 221,000/uL, and a creatinine of 0.8 mg/dL. Troponin T, CPK, and CPK-MB levels were within normal limits. Coronary angiography revealed a long, tubular 80% stenosis of the mid-left anterior descending (LAD) artery involving the first diagonal branch, and 70% ostial and 80% mid-vessel stenoses of the RCA. The previously placed RCA stent was widely patent. The patient would not consent to undergo coronary artery bypass surgery (CABG). She was treated with abciximab and underwent complex multivessel percutaneous coronary intervention using Cypher™ (Cordis Corp., Miami, Florida) sirolimus-eluting stents (DES). The bifurcation lesion in the LAD was treated with “kissing stents” placed in the LAD and diagonal, overlapping a more proximal stent in the LAD. Non-overlapping stents were placed in the ostial and mid-RCA. At the end of the procedure the patient had a small amount of hemoptysis and was transferred to the intensive care unit for monitoring. She was hemodynamically stable upon arrival. Following the interventional procedure, the patient was treated with a loading dose of ticlopidine 500 mg followed by 250 mg twice daily. Aspirin and the other medications were continued as well. A daily complete blood count, peripheral blood smear, lactate dehydrogenase, haptoglobin and creatinine levels were obtained. No thrombocytopenia, schistocytes, or increase in creatinine were observed to suggest recurrence of TTP, and the patient was subsequently discharged in good condition on day 4. Her discharge medications included ticlopidine 250 mg twice daily and aspirin 325 mg daily. She continued ticlopidine for 6 weeks after which she was switched to cilostazol 200 mg daily and aspirin 81 mg daily, having never developed any signs or symptoms of TTP. Discussion. We report the case of a patient with a history of clopidogrel-induced thrombotic thrombocytopenic purpura therapy who was treated with aspirin, ticlopidine and subsequently, cilostazol, after multivessel stenting for severe coronary artery disease. To our knowledge, this is the only report of re-administration of a drug in the same class as a previously-known offending agent. TTP is an extremely rare and life-threatening condition characterized by microangiopathic hemolytic anemia, acute renal failure, fever and mental status changes. Multiorgan dysfunction results from platelet microthrombi that occlude arterioles and capillaries, resulting in organ ischemia. The exact cause of TTP is unclear. However, several precipitating factors have been identified including pregnancy, toxins, malignancy, antineoplastic agents and several other drugs in addition to the thienopyridines. The overall incidence of TTP is estimated at 3.7 cases per million persons per year.^1,2 The thienopyridines are prescribed for stroke prophylaxis and to prevent stent thrombosis after coronary or peripheral vascular intervention. Ticlopidine is a well-recognized, though rare, cause of TTP.³ The incidence in patients treated with ticlopidine after percutaneous coronary intervention has been estimated at 0.02–0.06%, much greater than that of the general population.⁴ Because of this and other toxic hematologic side effects, ticlopidine has largely been replaced by clopidogrel. Early randomized trials demonstrated no risk of TTP with clopidogrel, however, subsequent postmarketing surveillance has identified a number of cases.⁵ Clopidogrel is certainly a much rarer cause of TTP than ticlopidine, the incidence varying from 1 in 8,500 to 26,000 patients.⁶ The clinical course of clopidogrel-induced TTP also seems to differ from that induced by ticlopidine. Bennett and colleagues, in their original case series, reported that clopidogrel-induced TTP usually occurs within the first two weeks of therapy, whereas with ticlopidine, subjects often develop the condition much later. Additionally, response to plasmapheresis usually occurs much more quickly with ticlopidine, while relapses are more frequent with clopidogrel.⁵ These clinical observations suggest possible mechanistic differences in the induction of TTP between the two drugs. Though the exact cause of TTP is unclear, the underlying pathophysiologic defect relates to the accumulation of ultra-large von Willebrand factor multimers (ULvWF) released from damaged endothelial cells that bind to and cause platelet activation and aggregation (Figure 1). These ULvWFs are normally rapidly cleaved and degraded by a specific protease that only recently has been identified as the metalloproteinase ADAMTS 13. Severe deficiency of ADAMTS 13, whether congenital or antibody-induced, has been identified in most cases of TTP in the general population.^1,7 Tsai and colleagues, in a case series of 7 patients with ticlopidine-induced TTP, reported severe deficiency of ADAMTS 13 in all patients.⁸ The deficiency seemed to be auto-antibody-mediated. Patients were successfully treated with plasmapheresis and the abnormality in metalloproteinase subsequently resolved. Bennett and colleagues demonstrated similar findings in 2 patients with TTP related to clopidogrel.⁵ However, Evens and colleagues reported normal levels and lack of antibody-mediated inhibition of metalloproteinase in a transplant patient with clopidogrel-induced TTP, suggesting a possible nonimmune-related mechanism.⁹ Further evidence to support a mechanistic difference is drawn from experiments by Mauro and colleagues that demonstrated that plasma from ticlopidine-linked TTP induces apoptosis of microvascular endothelial cells in culture. This microvascular endothelial apoptosis has also been demonstrated with plasma from patients with idiopathic and HIV-induced, but not clopidogrel-induced, TTP.¹⁰ Despite possible differences in the underlying pathophysiology, the mainstays of therapy of thienopyridine-induced TTP are discontinuation of the offending agent, corticosteroids and rapid initiation of plasmapheresis. Mortality rates in untreated patients range from 50–67%, whereas early initiation of plasmapheresis reduces this to 20–25%.^3,4,11 Of considerable interest in this case is that our patient did receive one dose of clopidogrel without recurrence of TTP. This fact lends further support to a possible nonimmune-mediated mechanism. Alternatively, rapid plasmapheresis and clearance of autoantibodies may have prevented induction of immune system memory. Regardless, the successful use of ticlopidine in this setting lends support to the existence of critical pathophysiologic differences in induction of TTP between the two agents. This may result from the slight differences in their chemical structure (Figure 2), leading to the formation of different metabolites. Other possible explanations for the lack of recurrence of TTP in this case were considered. It is plausible that the original diagnosis was incorrect or that there was a different offending agent. The patient did not have neurologic changes, one of the classic clinical features in the diagnostic pentad of TTP² associated with her original diagnosis. However, in Bennett’s original case series of clopidogrel-induced TTP, neurologic changes were not present in 4 out of 11 subjects. Further, no other obvious cause of microangiopathic hemolytic anemia was identified, and heparin-induced thrombocytopenia had been ruled out. Eptifibatide can cause thrombocytopenia, however, it would not explain the other clinical findings. Finally, we are not aware of any case reports of glycoprotein IIb/IIIa inhibitor-induced TTP. That our patient continues to do well in the long term on an alternate platelet regimen of cilostazol and low-dose aspirin is also of note. There has been a great deal of concern surrounding the apparent increased long-term risk of stent thrombosis associated with DES over bare-metal stents,^12,13 particularly when used in bifurcation lesions.¹⁴ The use of cilostazol with DES has been evaluated in a nonrandomized fashion in the ASPECT trial of paclitaxel-eluting versus bare-metal stents.¹⁵ Only 37 patients in this trial were treated with cilostazol, and there was an excess of stent thromboses⁴ as compared to patients treated with ticlopidine. However, all of these events occurred within the first month. In conclusion, this case and previous studies support the theory that TTP caused by thienopyridines is mediated through different pathways. Thus, in patients with a previous history of TTP to clopidogrel, it may be safe to administer ticlopidine. Until more is known about the pathophysiology and mechanism of thienopyridine-induced TTP, this should be avoided unless absolutely necessary. Further, CABG, rather than complex PCI, is probably the optimal management strategy in this setting, though our patient would not consent to surgery. Finally, long-term therapy with the alternate antiplatelet agent cilostazol, while lacking supporting data, may be safe and efficacious in this situation.

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