Late In-Stent Thrombosis in a Patient with Systemic Lupus Erythematosus and Hyperhomocysteinemia while on Clopidogrel and Aspiri

November 2004 angiogram showing occluded stent.
Late In-Stent Thrombosis in a Patient with Systemic Lupus Erythematosus and Hyperhomocysteinemia while on Clopidogrel and Aspiri
Author(s): 

Andre C. Olivier, MD and Jay L. Hollman, MD

Recent case reports of late stent thrombosis following the discontinuation of aspirin have raised the concern that drug-eluting stents might be more prone to this complication. McFadden et al reported on 4 patients, 2 who received a paclitaxel-eluting stent, and 2 who received a sirolimus-eluting stent. The time from stent implantation to stent thrombosis was 335 to 442 days. All patients had finished dual antiplatelet drugs and were being maintained on aspirin. The aspirin was discontinued for elective surgery 4 days to 2 weeks prior to stent thrombosis. Two patients received bare metal stents in addition to their drug-eluting stents; neither of the bare metal stents thrombosed. This led the authors and editorial author Eisenberg to speculate that similar to radiation-treated arteries, arteries treated with drug-eluting stents might be especially prone to late thrombosis.
Three recently published studies have analyzed the risk of stent thrombosis from clinical trials. Bavry et al., in a meta-analysis of 8 randomized trials of paclitaxel-eluting stents, found no excessive risk of stent thrombosis compared to bare metal stents except in patients receiving aspirin and cilostazol, instead of aspirin and a thienopyridine. The group at Rotterdam reviewed their clinical experience with both types of stents and found that thrombosis rates were about 1% in all groups followed for 6 months. The only risk factor identified were bifurcation stenosis and stent implantation in the setting of acute myocardial infarction. Moreno et al performed a meta-analysis of 10 studies that randomized bare metal stents and drug-eluting stents, and found no difference in stent thrombosis rate. They did document a relationship between lesion length and the potential for stent thrombosis, with longer stented regions having an increased risk of stent thrombosis. They raised concerns because stent thrombosis in drug-eluting stents seems to occur later and has been reported in randomized trials between 6 and 12 months. This has led to the suggestion that dual antiplatelet drugs should be continued for 12 months in patients who receive drug-eluting stents. We report here a patient with a drug-eluting stent presenting with stent thrombosis occurring more than 1 year after stent implantation. Moreover, thrombosis occurred despite the uninterrupted use of aspirin and clopidogrel. Hypercoaguability secondary her systemic lupus erythematosus (SLE) and hyperhomocysteinemia might well have contributed to late stent thrombosis in this patient.

Case Report. A 52-year-old female with a history of hypertension and SLE initially presented to the emergency department on October 5, 2003, with 10 out of 10 chest pain and diaphoresis. Her laboratory data revealed a CK of 823, CK-MB of 108, and troponin I of 6.02. Based on her history and laboratory findings, she was diagnosed with a non-ST-segment elevation myocardial infarction and underwent percutaneous coronary intervention on October 14, 2003. She received a 2.5 x 16 mm Taxus® Express2 paclitaxel-eluting stent (Boston Scientific Corp., Natick, Massachusetts) to her mid-left anterior descending artery (LAD). Just proximal to this, a 2.5 x 13 mm Cypher™ sirolimus-eluting stent (Cordis Corp., Miami, Florida) was deployed with some overlap. Intravascular ultrasound indicated incomplete deployment of the proximal stent, necessitating the use of a 3.0 x 12 mm noncompliant balloon for complete deployment. TIMI 3 flow was ultimately achieved. She was given integrelin for 12 hours, then discharged with clopidogrel 75 mg and aspirin 81 mg.
The patient subsequently presented to the emergency department November 14, 2004, exactly 13 months after her initial intervention, again with substernal chest pain. She had been chest pain-free until this acute event. She was diagnosed with an anterior-septal ST-segment elevation myocardial infarction and taken immediately to the catheterization laboratory. Angiography revealed complete occlusion of her LAD at the origin of the proximal stent (see Figure). After restoring patency with a 3.0 x 20 mm Maverick™ 2 balloon (Boston Scientific), ventriculography was performed, which demonstrated an estimated ejection fraction of 30% with anterior apical akinesia.
Subsequent laboratory data obtained in February 2005 revealed a serum homocysteine level of 24.4 micromoles per liter (Ref. 3.3–10.4), and negative antiphospholipid antibodies (see Table). Her lupus was considered to be stable throughout this time period.

Discussion. Current recommendations for dual antiplatelet therapy are 2 to 3 months for sirolimus-eluting stents, and 6 months after the implantation of a paclitaxel-eluting stent. Aspirin therapy is a life-long recommendation, not just for prevention of late stent thrombosis, but also for the prevention of vascular disease in general.
There are other reports of late in-stent thrombosis (greater than 6 months post-stent deployment), most of which were associated with withdrawal of antiplatelet agents, either the discontinuation of a thienopyridine with maintenance of aspirin, or with withdrawal of aspirin therapy. A recent study by Ong et al reports 8 cases of late stent thrombosis in 2,006 patients receiving drug-eluting stents (0.35%), 5 occurring as early as 2 months after implantation and as late as 26 months. Of note, none occurred in patients remaining on dual antiplatelet therapy with aspirin and clopidogrel. All of these events occurred at various timeframes after stopping clopidogrel, with or without aspirin. Our patient had remained on clopidogrel and aspirin and was chest pain-free for 13 months until she presented with an anterior ST-segment elevation myocardial infarction with angiographic and clinical characteristics of stent thrombosis. The patient’s angiographic risk factors for stent thrombosis — lesion length, small vessel diameter and the use of multiple stents — might have predisposed her to this late thrombotic events, although studies on angiographic risk factors for late stent thrombosis have focused on stent thrombosis occurring early (< 6 months) after stent implantation. Incomplete stent deployment is a risk factor for late thrombosis, however this is excluded by the intravascular ultrasound performed at stent deployment. The stent overlap of 5 mm is not considered a risk factor for late stent thrombosis. Overlapping stents, in theory, prevent the “edge effect”, and usually do not present with catastrophic thrombosis. In-stent stenosis of a bare metal stent usually results from endothelial hyperplasia and occurs within the first 6 months. After this timeframe, lack of morbidity implies endothelialization without overproliferation. Complete strut endothelialization is believed to be protective. Although thrombosis of the bare metal stent might have been the source of our patient’s occlusion, the proximal location of this obstruction in the drug-eluting stent and recent reports make it more likely that the sirolimus-eluting stent was responsible.
Recent registry analyses of stent thrombosis3–5 have been reassuring in that they demonstrate that patients with drug-eluting stents were no more likely to have stent thrombosis than patients receiving bare metal stents. Registry studies have documented that stent thrombosis occurs later on average in drug-eluting stents compared to bare metal stents, reflecting perhaps the delayed healing associated with these newer stents.
Our patient is the second reported case of late thrombosis that occurred despite continued dual antiplatelet therapy, and is the first to postulate a definite treatable mechanism. Wenaweser and colleagues have documented that aspirin resistance likely predisposes to early stent thrombosis following implantation of bare metal stents. One proposed mechanism for aspirin resistance involves an alternate pathway of platelet aggregation, bypassing aspirin’s inhibitory activities. A case of late coronary stent thrombosis 19 months post-stent implantation leading to an acute MI despite continued ticlopidine and aspirin use, has been documented.8 The author postulated that abnormal platelet aggregation may be to blame for the late stent thrombosis, but did not supply any data to support this hypothesis. Ebbesen et al. contend that homocysteine enhances platelet activation and aggregation by increasing thromboxane production.11 This suggests that hyperhomocysteinemia may play a role in aspirin resistance.
In our patient, a high homocysteine level of 24.4 micromoles per liter, nearly 2.5 times the upper limit of normal, was documented. Hyperhomocysteinemia in a patient with SLE greatly increases the likelihood of an arterial thrombus. Martinez-Berriotoxa et al. in 2004 reported a link between elevated serum homocysteine levels and arterial thrombosis in lupus patients without the antiphospholipid antibody. Fijnheer et al. studied 175 patients with SLE and found that those with serum homocysteine levels greater than 19.3 micromoles per liter had an odds ratio of 3.7 of having an arterial thrombosis. Proposed mechanisms include homocysteine’s direct toxicity to the endothelium, impairment of thrombolysis, and enhanced antioxidant effects.9 Several studies suggest hyperhomocysteinemia inhibits both expression of thrombomodulin and activation of protein C, and may impair endothelium-derived relaxation factors, including nitric oxide.
More importantly, studies have shown homocysteine to enhance platelet activation and aggregation by increasing thromboxane production,10 thus mimicking aspirin resistance and predisposing our patient to late stent thrombosis. This case is unique in that it involves very late in-stent thrombosis in a patient with lupus and hyperhomocysteinemia, despite the continued use of clopidogrel and aspirin. Increased homocysteine levels, especially in a patient with systemic lupus without the antiphospholipid antibody, are a risk factor for arterial thrombosis. This patient has been started on folic acid therapy.
This case raises several issues that are relevant to the routine use of drug-eluting stents. Stent thrombosis can occur after 1 year with drug-eluting stents, even if dual antiplatelet drugs are continued. Lesion and patient risk factors should be considered in advising patients regarding the length of dual antiplatelet therapy. Finally, when unexplained late thrombosis occurs, one should search for a coagulation disorder or consider aspirin resistance. The association with high homocysteine and arterial thrombosis in lupus patients without the antiphospholipid antibody offers an additional explanation for this patient’s myocardial infarction. High homocysteine is treatable and might prevent future events in this patient.


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