Malignancy: An Unrecognized Risk Factor for Coronary Stent Thrombosis?

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J INVASIVE CARDIOL 2008;20:E120-E123

Stent thrombosis (ST) is an important, life-threatening complication of percutaneous coronary intervention (PCI) and coronary stent placement that has been associated with mortality rates of up to 45%.¹ There is currently particular concern regarding the frequency of late ST in PCI patients receiving drug-eluting stents (DES) in whom, despite optimal therapy, the incidence in large “realworld” series remains 0.5–1%.^2,3 The etiology of ST is likely to be multifactorial.⁴ It is well established that there are: (a) procedural risk factors including stent underdeployment,⁵ length of stented segment,⁶ and the presence of residual dissection;⁷ (b) hematological variables such as increased platelet reactivity,⁸ premature discontinuation of or resistance to antiplatelet medication;^9–15 and (c) idiosyncratic factors including a form of hypersensitivity.¹⁶ In addition, there are reports of associations between ST and other hematological conditions including lupus anticoagulant,¹⁷ primary antiphospholipid syndrome,¹⁸ heparininduced thrombocytopenia,¹⁹ protein C and S deficiencies,²⁰ systemic lupus erythematosus, and hyperhomocysteinemia,²¹ polycythemia vera,²² and essential thrombocythemia.²³ Recognition of potential risk factors for ST is important, as it may influence pre-PCI management and thereby help in its prevention.
We have previously described 1 case of recurrent ST in association with malignancy.¹⁷ In our institution we identified 25 additional cases of ST in 22 patients over a 2-year period.² Here we describe 3 further cases we identified in which ST (including 2 cases of recurrent ST) occurred in association with malignancy. In addition, we discuss the potential mechanisms behind an association and review other previously-reported cases of ST occurring in association with malignancy.^24–31

Case 1. A 53-year-old male, a smoker with chronic lung disease, was admitted with an inferior ST-segment elevation myocardial infarction (MI). He was treated with aspirin 300 mg and clopidogrel 600 mg and underwent primary PCI. He was found to have an occluded dominant right coronary artery (RCA), which was successfully reopened and directly stented with a Taxus^® DES (Boston Scientific Corp., Natick, Massachusetts). He made a good recovery and was discharged home asymptomatic and on optimal secondary preventive therapy, having been advised to stop smoking. He was prescribed aspirin 150 mg and clopidogrel 75 mg daily for 12 months, after which aspirin 75 mg daily was recommended lifelong.
He was diagnosed with small-cell lung cancer 11 months after PCI and received treatment with chemotherapy and palliative radiotherapy with a good initial response. Shortly after a recurrence with widespread pulmonary metastases, he represented (25 months after the original PCI) with a second inferior STsegment elevation MI. He again received aspirin 300 mg, was reloaded with clopidogrel 600 mg, and underwent primary PCI. The RCA had reoccluded within the stent, with intraluminal thrombus and thrombolysis in myocardial infarction (TIMI) grade 0 flow. The RCA was aspirated with a thrombus aspiration device (QuickCat, Kensey Nash Corp., Exton, Pennsylvania), with retrieval of a significant amount of thrombus. Angiographically, there was no significant in-stent restenosis. Two Driver^® bare-metal stents (BMS) (Medtronic, Inc., Minneapolis, Minnesota) were deployed in the proximal and mid RCA within the existing DES, achieving an excellent postimplantation angiographic result and restoring TIMI grade 3 flow. His peak troponin I increased to 8.38 μg/l. He was discharged home 2 days later on dual antiplatelet therapy (aspirin 150 mg and clopidogrel 75 mg daily). He died of complications related to his lung cancer 4 months later.
Case 2. An 81-year-old male admitted with ischemic chest pain and transient inferior ST-segment elevation on electrocar- diography (ECG). His troponin T was elevated at 0.22 μg/l. He was known to have localized prostatic carcinoma, initially treated with goserelin, but more recently treated with stilbestrol and then ethinylestradiol because of evidence of hormonal escape. Angiography demonstrated normal left ventricular function, sequential severe lesions in the left anterior descending artery (LAD), sequential stenoses within the mid and distal RCA, and minor irregularities within the circumflex artery. He received heparin and abciximab and underwent multivessel PCI. A 2.5 x 12 mm Taxus stent was inserted into the diagonal vessel, a 2.75 x 24 mm Taxus stent in the mid LAD, and a 2.5 x 16 mm Taxus stent in the distal LAD. In the RCA, a 3.0 x 20 mm Taxus^® stent was deployed distally, and a 3.0 x 12 mm Taxus stent in the proximal vessel with excellent angiographic results. He was maintained on aspirin 150 mg and clopidogrel 75 mg daily following this procedure.
Three days after the procedure, the patient developed a hematoma at the right groin access site, and ultrasound demonstrated a false femoral aneurysm. This was treated with ultrasoundguided compression. Following this procedure, the patient developed chest pain and dynamic ECG changes. Emergency coronary angiography demonstrated occlusion of the diagonal stent. The stents in the RCA and LAD were patent and the patient was managed conservatively. The next day, the patient received 2 units of packed red blood cells, and a residual false femoral aneurysm was treated with a thrombin injection. Six hours later, the patient became acutely unwell with chest pain, cardiogenic shock, and bradycardia. His 12-lead ECG demonstrated complete heart block and ST-segment elevation in both the anterior and inferior leads. He was immediately transferred back to the cardiac catheterization laboratory where a temporary pacemaker wire and intra-aortic balloon pump were inserted. Coronary angiography confirmed occlusion of both the LAD and RCA stents with an extensive clot burden and TIMI grade 0 flow; abciximab was administered. The LAD occlusion was crossed and extensive redilatation was performed throughout the vessel with a 2.0 mm Monorail^™ balloon (Boston Scientific), resulting in only TIMI grade 1 to 2 flow. The RCA occlusion was disobliterated and ballooned with a 3.0 mm Monorail balloon, achieving TIMI grade 2 flow. He made a slow recovery complicated by heart failure, a chest infection, and urinary retention. Echocardiography demonstrated moderate-to-severe left ventricular systolic dysfunction. A subsequent abdominal ultrasound demonstrated a large mixed echogenecity mass in the liver with features characteristic of a metastatic deposit. Significantly elevated prostate-specific antigen (59 ng/ml) and alpha-fetoprotein (17,100 KU/l) were also detected, and he was subsequently diagnosed with metastatic prostatic carcinoma from which he died 6 months later.
Case 3. A 64-year-old male was admitted with an anterior ST-segment elevation MI. He was treated with aspirin and tenecteplase, but failed to reperfuse clinically, and underwent rescue percutaneous intervention. The patient’s LAD was found to be occluded. It was successfully reopened, predilated, and then stented with 4 sequential Endeavor (Medtronic) DESs (2.75 mm x 24, 24, 14, and 12 mm), producing a good angiographic result. An intracoronary abciximab bolus was administered. After the procedure, he developed left ventricular failure, which responded to diuretic therapy. Echocardiography showed severe left ventricular impairment and an apical left ventricular thrombus. He was anticoagulated and discharged home on aspirin, clopidogrel, and warfarin 7 days after presentation. Ten days later (17 days post PCI), he re-presented with another anterior ST-segment elevation MI. Stent thrombosis was confirmed with TIMI 0 flow and was successfully treated with balloon angioplasty. Tirofiban was started and continued for 36 hours. He was discharged home on aspirin, clopidogrel, and warfarin after 5 days. Eight days later (day 30), he re-presented with yet another anterior ST-segment elevation MI. ST was again confirmed and treated with balloon angioplasty. In view of the recurrent episodes of ST and coexistent disease in other vessels, he was referred for bypass surgery, which was performed 2 weeks later. Postoperatively, he developed a hypertensive crisis. Urgent investigations revealed a 4 cm adrenal tumor and elevated plasma and urinary catecholamines (24-hour urinary noradrenaline 15,053 (normal range: 90–600 mmol/l); adrenaline 13,862 (normal range: 20–190 mmol/l). A malignant pheochromocytoma was subsequently confirmed.

Discussion
We have described a total of 4 patients with ST, including 3 cases of recurrent ST, occurring in the presence of concomitant malignancy, highlighting a possible association. In 3 of the 4 cases, the presence and/or extent of malignancy was previously unsuspected.
There are several potential mechanisms to explain why ST may be associated with malignancy:
1) Malignancy is sometimes associated with a prothrombotic state (Trousseau’s syndrome)^32,33 and has been previously described in association with an increased risk of both venous and arterial thrombosis, including coronary thrombosis and MI.^34,35 The underlying mechanisms are complex and multifactorial, but include the production of prothrombotic factors such as tissue factor by the tumor, the interaction of tumor cells with platelets and other inflammatory cells, decreased levels of inhibitors of coagulation, and the effects of hormonal therapy, radiotherapy, chemotherapy, and surgery. In addition, there is an association between malignancy and the antiphospholipid syndrome,^36,37 as in the case described previously of a 53-year-old male with recurrent acute ST while on dual antiplatelet therapy in the context of renal cell carcinoma and antiphospholipid syndrome.¹⁷ Catecholamines in supraphysiological concentrations (as in Case 3) can also stimulate platelet aggregation.³⁸ It is also possible that in this case, catecholamine-induced coronary vasoconstriction further increased the risk of thrombosis.
2) DES utilize chemotherapeutic agents to reduce restenosis through reducing smooth muscle proliferation. These agents are, however, associated with delayed endothelialization of the stent, which may contribute to the increase in late ST associated with DES. Systemic chemotherapy may have similar effects and has been previously proposed as a causative factor in ST.²⁴ It is possible that this mechanism may have contributed to the very late ST seen in Case 1. In addition, animal data suggest that antiproliferative agents increase the expression of prothrombotic genes such as plasminogen activator inhibitor-1.³⁹ Lastly, hematological changes due to chemotherapy may lead to rapid production of platelets unaffected by previouslyadministered antiplatelet agents.²⁹

3) Premature discontinuation of antiplatelet drugs is more likely in patients with malignancy because of bleeding or the perceived risk of bleeding (e.g., hemoptysis due to lung cancer, hematuria in renal cell and prostatic carcinoma). Interestingly, while previous reports of ST in association with malignancy have mostly occurred following cessation of antiplatelet therapy (Table 1), all the cases we report have occurred while the patients were on antiplatelet therapy.
4) The treatment of malignancy often requires urgent surgery. Surgery performed soon after coronary stent insertion, particularly in the context of premature discontinuation of antiplatelet drugs, is associated with a high risk of ST.⁴⁰
Previous case reports and series of coronary ST have included patients with malignancy and are summarized in Table 1. However, in none of the cases was the cause of ST directly attributed to malignancy, but to diverse factors such as discontinuation of antiplatelet therapy, the effects of chemotherapy, surgery, antiphospholipid syndrome, and rapid hematological changes. These reports include a broad range of cases treated with both bare-metal and DES, including acute, subacute, late, and very late ST in the context of dual antiplatelet therapy or when aspirin, clopidogrel or both have been discontinued, and in the context of a known diagnosis of malignancy prior to PCI, and when this is discovered later. Interestingly, reports of carotid ST also frequently include patients with malignancy.⁴¹
We believe that due to the combination of factors outlined above, malignancy may be a risk factor for coronary ST. These case histories highlight an apparent association between ST and malignancy. While these are isolated cases and do not represent a formal study of association, there is a sound pathophysiological basis to explain an association.
Such an association would be particularly relevant in two clinical scenarios: first, in patients with known malignancy, careful consideration should be given to revascularization strategy, and secondly, a search for occult malignancy may well be appropriate in patients presenting with unexplained ST, particularly when recurrent. Further data are required from a multinational registry and from a review of existing ST databases.

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