ABSTRACT: Recurrent in-stent thrombosis is rarely reported, with catastrophic clinical consequences of either acute coronary syndrome or death. We present a case of recurrent in-stent thrombosis with its outcome and a concise literature review.
J INVASIVE CARDIOL 2011;23:E208–E210
Case Report. We present the case of a 63-year-old gentleman with history of anterior wall myocardial infarction in October 2002 with subsequent stenting to the left anterior descending artery with a bare-metal stent (BMS). In addition to antiplatelet therapy, he was treated with warfarin for atrial fibrillation. Recurrence of a moderately differentiated colorectal adenocarcinoma was diagnosed 3 weeks prior to admission in 2008 for elective bowel resection. Aspirin was stopped 7 days preoperatively with discontinuation of warfarin 3 days before surgery. The night before the operation, he developed anterior ST-elevation myocardial infarction (STEMI) complicated by ventricular fibrillation cardiac arrest. He was successfully resuscitated and underwent emergency coronary angiography which demonstrated in-stent thrombosis (IST) requiring balloon dilatation and subsequent placement of a 3.0 x 18 mm Driver BMS (Medtronic Corporation, Minneapolis, Minnesota) (Figures 1A and 1B). An intra-aortic balloon pump was inserted for hemodynamic support. The patient also received abciximab, aspirin, clopidogrel and enoxaparin. Eight days later, the patient experienced chest pain and anterior STEMI. He was taken for emergency angiography which showed recurrent IST. This was again predilated with a 3 x 12 mm Sprinter balloon (Medtronic Corporation) and restented with another 3.0 x 18 mm Driver BMS at 18 atm (Figures 1C and 1D). A good angiographic result was obtained with no evidence of dissection. Abciximab bolus and infusion for 24 hours was given in addition to doubling the standard aspirin and clopidogrel doses to 150 mg each. Two days later, and for the third time, the patient developed chest pain and anterior STEMI requiring a third emergency angiogram showing IST which on this occasion was balloon dilated without further stent placement (Figures 1E and 1F. The patient was kept on dual antiplatelet therapy of 150 mg each, enoxaparin and abciximab infusion for 3 days. The patient’s condition settled. One week later, clopidogrel was stopped and the patient was kept on the aspirin 150 mg/day until the day of bowel surgery. Enoxaparin was switched to intravenous heparin the night before the surgery and was stopped 6 hours before surgery. In the recovery room following surgery, the patient developed ventricular fibrillation. He was resuscitated successfully and was taken for his fourth emergency coronary angiogram. Once again, this demonstrated IST (Figures 1G and 1H), requiring multiple balloon inflations. Because of a persistent filling defect, we proceeded to deploy a 3.0 x 20 mm Driver BMS at 20 atm, and the patient was kept on 300 mg of aspirin and intravenous heparin.
The patient did well after that and he was discharged 2 weeks later on aspirin, clopidogrel and warfarin. His echocardiogram on discharge showed modest impairment of left ventricular systolic function and anteroseptal and apical akinesia. One year later, the patient continues to do well with no reported angina or symptoms of heart failure.
Discussion. The central issue raised by this case is development of IST in a BMS, remote from the implantation date at the time of surgery for recurrent bowel carcinoma. Furthermore; we have not witnessed the recurrent nature of the problem as described in this case and propose that it may be related to the prothrombotic milieu associated with malignancy. This observation may underline the need to be even more cautious when removing patients from anticoagulant and antiplatelet therapies for surgery in these circumstances. Although stent thrombosis is a recognized complication of coronary intervention, recurrent stent thrombosis is rarely reported. The clinical consequences of stent thrombosis are catastrophic, either STEMI (60–70%) or death (20–25%).1
Stent thrombosis can present early (< 24 hours), subacutely (between 1 and 30 days) and late (> 30 days). The overall rate of stent thrombosis after drug-eluting stent (DES) implantation was ≈ 0.6% (0.5–2.2% ) and did not differ between sirolimus and paclitaxel DES. This incidence is comparable to that of BMS,1,2 but late acute stent thrombosis events were uncommon with BMS except after brachytherapy.3
Several mechanisms of IST with DES have been postulated: a local drug effect resulting in delayed endothelialization or dysfunctional endothelium; a hypersensitivity or inflammatory reaction to the polymer; or the development of neointimal hyperplasia with occlusive thrombus formation as the acute event.4
In a meta-analysis study, the variables most significantly associated with the probability of stent thrombosis were persistent dissection NHLBI grade B or higher after stenting (OR: 3.7), total stent length (OR: 1.3 per 10 mm), and final minimal lumen diameter within the stent (OR: 0.4 per 1 mm).1 In a study by Kotani et al, who performed angioscopy on 37 consecutive stented coronary artery lesions, at 3–6 months after stent implantation, all 22 BMS showed complete intimal coverage.5 This supports the observation that late stent thrombosis is less likely with BMS.
It is likely that in this case, the precipitants of late stent thrombosis in a BMS were removal of antiplatelet and anticoagulant therapy in a prothrombotic milieu secondary to metastatic spread of bowel carcinoma. Malignancy has been shown to interact with the hemostatic system in multiple ways, but the two principal mechanisms are: 1) the capacity to produce and release procoagulant substances, as well as inflammatory cytokines; and 2) direct interaction with other blood cells, i.e., endothelial cells, platelets, and monocytes.6
Cancer procoagulant (CP) is a cysteine protease of 68 kDa; it can activate factor X independently of factor VII and cleaves the factor X heavy chain at a different site compared with other known factor X activators. CP can be measured by enzyme-linked immune sorbent assay (ELISA) and has been shown to be elevated in 85% of cancer patients.6
Tumor cells produce and secrete a number of different proinflammatory cytokines, some of which can adversely affect the normal anticoagulant system in the vascular endothelium. For example, TNF-a and IL-1b can induce the expression of tissue factor (TF) by vascular endothelial cells. TF forms a complex with factor VII. This TF/FVII complex initiates blood coagulation by proteolytically activating factor IX and X.6,7
High doses of dual antiplatelet therapy and anticoagulation were used in this case, but failed to abort recurrent thrombosis. Mechanical revascularization was also unsuccessful until the malignancy was surgically removed.
Re-PCI is the commonly adopted approach to restore blood flow in the obstructed stent. It is unclear whether balloon inflation alone, if associated with a good result, is preferable to redeploying a further stent. However, there are few to support stenting within a stent, and in our case within a third stent.
Perioperative management of anticoagulants and antiplatelet should be balanced between risks of bleeding and the risk of stent thrombosis. Bridging therapy, which may be used in this scenario, refers to the substitution of an irreversible antiplatelet agent with a reversible and short-acting anticoagulant and/or antiplatelet drug to offer thrombosis prophylaxis during the perioperative period. DeVile and colleagues suggested that patients with low-to-moderate bleeding risk maintain dual antiplatelet therapy whenever possible. Patients with high risk of bleeding or IST, e.g., patients with previous history of IST, multivessel stenting, or cancer should be considered for bridging therapy if clopidogril should be stopped. In this case, a reversible and short-acting antiplatelet like intravenous infusion of tirofiban given intravenously for 3–4 days before the surgery starting 24 hours after stopping clopidogrel. Bridging therapy should be stopped 4 hours before surgery and clopidogrel restarted postoperatively.8,9 A multidisciplinary approach involving the cardiologist, surgeons, and anesthetist is advisable for high-risk patients.
In summary, repeated IST is rare, but it is associated with a high rate of adverse clinical outcomes. Few data are available to favor in-stent stenting over in-stent ballooning.
- Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–1971.
- Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis: Results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954–959.
- Costa MA, Sabate M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789–792.
- Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088–2092.
- Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol 2006;47:2108–2111.
- Caine GJ, Stonelake PS, Lip GY, Kehoe ST. The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 2002;4:465–473.
- Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989;73:159–165.
- Savonitto S, D'Urbano M, Caracciolo M, et al. Urgent surgery in patients with a recently implanted coronary drug-eluting stent: A phase II study of 'bridging' antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth 2010;104:285–291.
- DeVile M, Foëx P. Antiplatelet drugs, coronary stents, and non-cardiac surgery. Contin Educ Anaesth Crit Care Pain 2010;10:187–191.
Editor’s Comments: Very late stent thrombosis (ST) is not uncommon after DES but has been rarely reported after BMS also. It is likely due to neo-plaque (atherosclerosis) rather than delayed endothelization and may be caused by other extrinsic factors like hyper-coagulable state of cancer, post-op. These patients should be treated aggressively by aspiration/mechanical thrombectomy and high-pressure balloon dilatation and re-stenting should be avoided to prevent another episode of ST. – Samin K. Sharma, MD, Mount Sinai Medical Center, New York, New York.
From the Department of Cardiology, St Vincent’s University Hospital, Dublin, Ireland.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted November 29, 2010, provisional acceptance given December 8, 2010, final version accepted February 16, 2011.
Address for correspondence: Mohammed Ali, MD, Department of Cardiology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Email: firstname.lastname@example.org