(Radiology. 2001;220:142-144.)
© RSNA, 2001
Fatal Late Coronary Thrombosis after Implantation of a Radioactive Stent: Postmortem Angiographic and Histologic Findings—Case Report1
Paul Wexberg, MD, BM,
Michael Gottsauner-Wolf, MD,
Irene Sulzbacher, MD,
Peter Birner, MD,
Anton Laggner, MD and
Dietmar Glogar, MD
1 From the Department of Cardiology, Clinic for Internal Medicine II (P.W., M.G.W., D.G.), Clinical Department of Pathology (I.S., P.B.), and Department of Emergency Medicine (A.L.), University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Received September 5, 2000; revision requested October 18; revision received December 4; accepted December 19. Address correspondence to P.W. (e-mail: paul.wexberg@akh-wien.ac.at).
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ABSTRACT
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Postmortem angiography and histologic analysis of a fatal coronary thrombosis 4 months after implantation of a radioactive stent are described. Histologic findings suggested incomplete re-endothelialization in the segment with the stent. Ionizing radiation may delay re-endothelialization after revascularization, thus maintaining the thrombogenicity of the irradiated vessel segment. Thus, prolonged antiplatelet therapy should be considered after intravascular radiation therapy.
Index terms: Angiography, 54.124 • Coronary vessels, stents and prostheses, 54.126 • Coronary vessels, thrombosis, 54.442, 54.47 • Heart, US, 54.1298 • Stents and prostheses, 54.126 • Stents and prostheses, radiation, 54.47 • Thrombosis, arterial, 54.442, 54.47
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INTRODUCTION
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The potency of intravascular radiation therapy to prevent restenosis in the long run has been shown in a number of clinical studies (1). Recently, Costa et al (2) reported the occurrence of thrombosis 1–4 months after radiation therapy. These findings have been attributed to delayed re-endothelialization and enhanced recruitment of platelets after irradiation (3).
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Case Report
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Clinical Course
A 79-year-old man with a history of anterior wall myocardial infarction presented with angina and dyspnea at exertion (Canadian Cardiovascular Society, or CCS, grade III; New York Heart Association, or NYHA, grade III). Resting electrocardiographic results showed sinus rhythm, sluggish R progression, and unspecific repolarization disturbances in the anterior leads. Echocardiography revealed preserved global left ventricular function with hypokinesia of the anterior wall, which suggests rest viability. Coronary angiography showed a long, diffuse, eccentric, and calcified stenosis in the left anterior descending coronary artery.
After giving written informed consent, the patient was enrolled in the Phosphorus 32 Dose-response Study, which was approved by our institutional ethics committee (University of Vienna, Austria). The lesion was treated with two radioactive stents (distal: 3.0-mm diameter and 15-mm length, 19.77 µCi [0.73 MBq]; proximal: 3.5-mm diameter and 15-mm length, 13.80 µCi [0.51 MBq]; Isostent, Belmont, Calif) separated by a gap of approximately 5 mm. Postinterventional intravascular ultrasonography showed full deployment and good apposition of the stent without any signs of dissection. Despite intravenous administration of tirofiban hydrochloride, the patient had a non–Q wave infarction (creatine kinase maximum, 247 U/L; creatine kinase-MB fraction, 32 U/L); he was discharged free of symptoms 4 days after the intervention and was given ticlopidine hydrochloride (500 mg/d) and acetylsalicylic acid (100 mg/d). At a bicycle stress test after 10 weeks, the patient performed at 65% of the age- and body weight–adjusted exercise capacity without any signs of ischemia. Ticlopidine was discontinued 3 months after the intervention, according to the study protocol, and the patient received acetylsalicylic acid only.
Four months after stent implantation, the patient was admitted to a different hospital and had signs of an acute anterior wall infarction (creatine kinase maximum, 1,650 U/L; creatine kinase-MB fraction, 169 U/L). The patient underwent systemic thrombolysis with alteplase (recombinant tissue-type plasminogen activator), or rt-PA (Neuhaus scheme), and was transferred to our clinic, where he died of cardiogenic shock before angiography could be performed.
Postmortem Angiography and Histology
Autopsy revealed dilatation of all heart chambers and a large transmural infarction, with rupture of the left anterior wall, causing pericardial tamponade. The heart was removed in toto, and postmortem coronary angiography was performed with a 6-F guiding catheter. Injection of contrast material revealed total occlusion, which was suggestive of thrombosis, of the left anterior descending coronary artery at the proximal stent entrance (Fig 1).
The left anterior descending coronary artery and the adjacent myocardium were excised, fixed in Schaffer fluid, dehydrated, and embedded in methyl methacrylate (4). To present cross sections of the vessel with an intact interface between vascular tissue and the incorporated stent, the stent struts were not removed, and ground sections (5) 8 µm thick were prepared and stained with toluidine blue stain. Cross sections were obtained from 5 mm proximal to the stent and from the middle of the stent. The sections were evaluated with light microscopy. Figure 2 (left panel) shows a segment of the artery without stent, manifesting eccentric fibrous atherosclerotic plaque with a small area of calcification. The plaque was hypocellular and consisted mainly of collagen and elastin. The neointima contained fibroblasts, smooth muscle cells, and some monocytes, and the media showed severe atrophy. The luminal side was covered by a monolayer of endothelium-like cells, without any signs of cell activation. Plastic embedding did not allow reliable immunohistochemical staining because methyl methacrylate disguised the epitopes for the respective antibodies.
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Figure 2. Left: Cross section proximal to the left anterior descending coronary arterial segment with the stent shows eccentric fibrous atherosclerotic plaque (P) with a small area of calcification (C). The lumen (L) is basically maintained. No cells are evident in the plaque, which consists mainly of collagen and elastin. The media (M) shows severe atrophy. (Toluidine blue stain; original magnification, x20.) Left insert: The neointima (NI) contains fibroblasts, smooth muscle cells, and some monocytes. The endothelial lining is mostly maintained without any signs of cell activation. (Toluidine blue stain; original magnification, x400.) Right: Cross section of the left anterior descending coronary arterial segment with the stent shows eccentric fibrous atherosclerotic plaque with severe calcification (C). The lumen is occluded by fresh thrombus (T) consisting of fibrin with erythrocytes. The plaque and the overlying neointima are acellular. The struts (arrows) of the stent are covered by a thin neointimal lamella with a thickness of 40-200 µm. (Toluidine blue stain; original magnification, x20.) Right insert: No cells are evident in the neointima (NI) covering the struts, and no endothelial lining cells can be detected beneath the thrombus (T). No foreign body reaction or inflammation is evident around the struts. The black dots are precipitates from the ground stent. (Toluidine blue stain; original magnification, x400.)
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In contrast, the lumen of the vessel segment with the stent was occluded by fresh thrombus consisting of fibrin with erythrocytes (Fig 2, right panel). The struts of the stent were covered by a thin acellular neointimal lamella consisting mainly of fibrotic matrix with a thickness of 40–200 µm. No lining cells could be detected in the luminal side. The adjacent myocardium was focally fibrotic with vital myocytes.
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Discussion
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Subacute coronary stent thrombosis has been markedly reduced by the use of ticlopidine to an incidence of 0.8% within 30 days after stent placement (6). The replacement of thrombus by neointima and finally reendothelialization of the stent is of crucial importance in the vascular healing process after injury to provide an antithrombotic surface. As long as re-endothelialization is incomplete, the exposure of the thrombogenic subendothelium to blood enhances the risk for platelet adhesion and subsequent thrombosis.
Results of animal studies have shown that reendothelialization after stent placement takes more than 4 weeks to be completed, whereas re-endothelialization seems to be delayed up to 3 months after experimental irradiation (7). In addition, ionizing radiation is known to impair endothelial function by decreasing the production of the antithrombotic prostacyclin and increasing the chemotactic and mitogenic activity of endothelial cells (8). Furthermore, the recruitment of platelets and leukocytes is increased 30 days after intravascular irradiation in an animal model (3). In contrast to wire sources, radioactive stents expose the vessel wall to low-dose-rate radiation until the total decay of the radioisotope (ie, over several weeks). Thus, platelets may easily adhere to the subendothelium exposed in the area with the stent, as well as to the dysfunctional endothelium of the directly adjacent segments. Antiplatelet medication can prevent thrombus formation, which may easily begin once this medication is stopped.
The histopathologic data on thrombosis after intravascular irradiation are still conflicting: Results of early animal studies did not show any thrombosis, whereas the working group of Vodovotz et al (9) observed a thrombus prevalence of up to 83% in a recent retrospective evaluation of vessels irradiated after injury. Unfortunately, there is no information on endothelialization in this publication (9). In a clinical setting, Costa et al (2) reported a high rate (6.6%) of late thrombosis in 108 patients who had previously undergone intravascular radiation therapy, predominantly in lesions with stents. This means a more than tenfold increase in thrombosis rate, as compared with 0.6% after use of nonradioactive stents (10). However, in a study (11) in which the implantation of 122 radioactive stents was assessed, only one case of stent thrombosis (0.008%) was observed. All of the reported vessel occlusions occurred after cessation of antiplatelet therapy, in the range of 1–15 months after irradiation. This medication should therefore be administered for a longer period after vascular brachytherapy than after conventional stent placement.
To our knowledge, the case we report is the first histologic analysis of a human coronary artery after intravascular irradiation that suggests that the healing response may be delayed by radioactive stent placement. Unfortunately, it is not possible to perform immunohistochemical staining on the methyl methacrylate used at our center. We therefore do not know whether the lining cells in the segments adjacent to the stent represent actual endothelium. However, the neointima in the segments with the stents is not covered by any cells at all, so a disturbed reendothelialization is evident. Until the relationship between irradiation and vessel thrombosis has been clarified, the prolonged use of antiplatelet medication as an adjunct therapy should be strongly advocated. Prospective trials will be required to determine the treatment duration necessary to prevent potential lethal complications after vascular brachytherapy.
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ACKNOWLEDGMENTS
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The authors are indebted to Birgit Türk, BS, for the expert preparation and staining of the vessel ground sections. Furthermore, we thank Erna Manhardt, RT, for her valuable assistance in performing postmortem angiography and Bonni Syeda, MD, MSc, for proofreading.
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FOOTNOTES
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Author contributions: Guarantor of integrity of entire study, D.G.; study concepts, P.W., M.G.W.; study design, P.W., M.G.W., I.S., D.G.; literature research, P.W.; clinical studies, D.G., A.L.; data acquisition, P.W., P.B., I.S.; data analysis/interpretation, all authors; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, all authors.
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ABSTRACT
INTRODUCTION
