Journal Pre-proof Carotid free-floating thrombus in a stent six months after carotid artery stenting: A case report Akira Sugie, MD, Makoto Yamada, MD, Kunio Yokoyama, MD, Masashi Yamashita, MD, Yutaka Ito, MD, Hidekazu Tanaka, MD, Yukiya Nomura, MD, Masutugu Fujita, MD, Toshio Nakatani, MD, Masahiro Kawanishi, MD PII: S1878-8750(20)31358-9 DOI: https://doi.org/10.1016/j.wneu.2020.06.100 Reference: WNEU 15319 To appear in: World Neurosurgery Received Date: 10 April 2020 Revised Date: 10 June 2020 Accepted Date: 12 June 2020 Please cite this article as: Sugie A, Yamada M, Yokoyama K, Yamashita M, Ito Y, Tanaka H, Nomura Y, Fujita M, Nakatani T, Kawanishi M, Carotid free-floating thrombus in a stent six months after carotid artery stenting: A case report, World Neurosurgery (2020), doi: https://doi.org/10.1016/ j.wneu.2020.06.100. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. Carotid free-floating thrombus in a stent six months after carotid artery stenting: A case report Akira Sugie, MD1, 2, Makoto Yamada, MD1, Kunio Yokoyama, MD1, Masashi Yamashita, MD1, Yutaka Ito, MD1, Hidekazu Tanaka, MD1, Yukiya Nomura, MD2, Masutugu Fujita, MD2, Toshio Nakatani, MD2, and Masahiro Kawanishi, MD1 1 2 Department of Neurosurgery, Ijinkai Takeda General Hospital, Kyoto, Japan Emergency Medical center, Ijinkai Takeda General Hospital, Kyoto, Japan Akira Sugie, MD, Ph.D Department of Neurosurgery, Ijinkai Takeda General Hospital Ishidamori-minamimachi 28-1, Fushimi-Ku, Kyoto City, Kyoto Prefecture, 601149, Japan. Phone: + 81-75-572-6331 Fax: +81-75-572-8166 Email: neu055@osaka-med.ac.jp Key words: Carotid free-floating thrombus, Endovascular management, Carotid artery stenting, Plaque rupture, Type 2 diabetes mellitus Short title: Carotid free-floating thrombus in a stent Carotid free-floating thrombus in a stent six months after carotid artery stenting: A case report Akira Sugie, MD1, 2, Makoto Yamada, MD1, Kunio Yokoyama, MD1, Masashi Yamashita, MD1, Yutaka Ito, MD1, Hidekazu Tanaka, MD1, Yukiya Nomura, MD2, Masutugu Fujita, MD2, Toshio Nakatani, MD2, and Masahiro Kawanishi, MD1 1 Department of Neurosurgery, Ijinkai Takeda General Hospital, Kyoto, Japan 2 Emergency Medical center, Ijinkai Takeda General Hospital, Kyoto, Japan Akira Sugie, MD, Ph.D Department of Neurosurgery, Ijinkai Takeda General Hospital Ishidamori-minamimachi 28-1, Fushimi-Ku, Kyoto City, Kyoto Prefecture, 601149, Japan. Phone: + 81-75-572-6331 Fax: +81-75-572-8166 Email: neu055@osaka-med.ac.jp Key words: Carotid free-floating thrombus, Endovascular management, Carotid artery stenting, Plaque rupture, Type 2 diabetes mellitus Short title: Carotid free-floating thrombus in a stent 1 ABSTRACT BACKGROUND: Carotid free-floating thrombus (CFFT) is defined as a blood clot attached to the arterial wall with surrounding blood flow at its distal component. Although rare, it is a clinically significant cause of embolic stroke. CFTT within a stent has not been previously reported. CASE DESCRIPTION: We report a 64-year-old man who underwent carotid artery stenting (CAS) for asymptomatic right carotid artery stenosis. Six months after CAS, he was admitted to the emergency department 1 hour after onset left hemiparesis and dysarthria. His National Institute of Health Stroke Scale score was 10. His medical history was notable for hypertension, chronic renal insufficiency, and type 2 diabetes mellitus. Carotid ultrasonography showed a dumbbell-shaped CFFT attached to the carotid stent that was moving in synchrony with his heartbeat. CFFT removal was performed via an endovascular approach with manual suction using a Luer Lock syringe. The CFFT was completely removed without residual stenosis. Histological examination suggested plaque rupture associated with a lipid-rich necrotic core. CONCLUSION: Carotid plaque formation and plaque rupture can occur within a carotid stent and present as a CFTT. Key word: Carotid free-floating thrombus, Endovascular management, Carotid artery stenting, Plaque rupture, Type 2 diabetes mellitus 2 INTRODUCTION Carotid free-floating thrombus (CFFT) is a blood clot attached to the arterial wall with surrounding blood flow at its distal component 12. The CFFT is rare but has a significant clinical role in embolic stroke 134. We present a case of CFFT that formed in a carotid stent. To our knowledge, this is the first report of CFTT in a carotid stent. CASE REPORT A 64-year-old man with a history of minor ischemic stroke, hypertension, chronic renal insufficiency, and type 2 diabetes mellitus was admitted for asymptomatic carotid artery stenosis. Carotid ultrasonography showed a hypoechoic plaque with ulceration and stenosis (Figure. 1A). Carotid artery stenting (CAS) was performed using our standard technique with an embolic protection device (FilterWire EZ, Boston Scientific, Natick, MA, USA), 10mm / 24mm carotid stent (Carotid WALLSTENT, Stryker, Kalamazoo, MN, USA), and pre-dilatation balloon (Sterling 4mm / 40mm, Boston Scientific, Natick, MA, USA, dilated as 8 atom / 30 second) and post-dilatation balloon (Sterling 6mm / 20mm, Boston Scientific, Natick, MA, USA, dilated as 6 atom / 5 second) (Figure 2A, B). Blood aspiration and FilterWire after CAS did not capture any debris. Post-procedural diffusion-weighted magnetic resonance imaging (DWI-MRI) showed an asymptomatic small ischemic lesion in the right caudate head; carotid ultrasonography did not show plaque protrusion or stenosis (Figure 1B). He was prescribed an antiplatelet agent, statin, and antidiabetic agent, and discharged without neurologic deficit. Three months after the procedure, no abnormality was detected on carotid ultrasonography (Figure 1C). Six months after CAS, he was admitted to the emergency department 1 hour after sudden onset left hemiparesis and dysarthria. His National Institute Health of Stroke Scale score was 10. DWI- MRI showed multiple small areas of ischemia in the right cerebral hemisphere. Carotid ultrasonography showed a dumbbell-shaped CFFT attached to the carotid stent that was moving in synchrony with his heartbeat (Figure 1D and Video 1, online only). Since the presence of the carotid stent made surgery difficult, we elected to proceed with endovascular remove of the CFFT. A 9 Fr OPTIMO balloon guide catheter (Tokai Medical Products, Aichi, Japan) was navigated into the right common carotid artery. Contrast Medium was injected slowly and carefully to avoid breaking the CFTT during angiography, which showed the CFTT within the Stent 3 (Figure 2C). Subsequently, the balloon of the OPTIMO catheter was inflated, followed by a manual forced suction through the catheter with a 50 mL Luer Lock syringe (VacLoc pressure syringe, Merit Medical, UT, USA), which removed the CFFT completely without residual stenosis (Figure 2D). The removed CFFT was grossly appeared as red and white thrombus broken down into small pieces by suction (Figure 3A). Histologically, the CFFT showed structural features of plaque rupture with cholesterol clefts and a lipid-rich necrotic core (Figure 3B). On the following day, DWI-MRI showed persistence of the small multiple areas of ischemia in the right hemisphere. He was then transferred to a rehabilitation hospital. When he returned to our outpatient clinic, his modified Rankin scale score was 2. We added changed a direct oral anticoagulant (DOAC) and second antiplatelet agent to his prophylaxis since the follow-up DWI-MRI study showed an asymptomatic ischemic lesion in the left hemisphere. Due to poor compliance with the drugs, his HbA1c was 10.3% at the second admission. It seemed that he had not taken regularly and exactly neither the antidiabetic drug nor the antiplatelet and the statin. After referral to a diabetologist, his HbA1c was subsequently better controlled around 7.0%. Over next two years, He has not experienced cerebrovascular event. DISCUSSION Carotid artery plaques that exhibit with mobility on ultrasonography have been referred as “mobile plaques,” “floating plaques”, “mobile thrombi”, or “floating thrombi” in numerous case reports 3. Fridman et al. defined such a plaque as a CFTT which is a blood clot attached to the arterial wall with surrounding blood flow at its distal component, and reviewed systemic the literature1. CFFT is rarely diagnosed in ischemic stroke patients with frequency ranging from 0.4% to 1.6%12. Approximately 500 CFTT have been reported in 58 case series and 83 case reports1. Most cases of CFFT are associated with atherosclerosis in the carotid artery13. Mobile plaques are histologically different from non-mobile plaques: they have a large, soft, and lipid-rich necrotic core which can explain their mobility3. The plaque characteristics in our case, even though broken into small pieces by the suction technique, were similar to those of mobile plaque. Although most chronic intra-stent stenoses are caused by non-mobile plaques, our experience shows that mobile plaques may occur within carotid stents. Ogata et al. classified mobile plaques into four types according to morphology among 12 patients in 4 a carotid ultrasonography study: jellyfish-type, streaming-band-type, 4 mobile-thrombus-type, and fluctuating-ulcer-type . We classified the CFTT in our case as mobile-thrombus type; only one such patient was reported by Ogata et al4. We consider the carotid ultrasonography is the most useful tool for the routine follow-up to decrease the risk of CFTT, because it can image not only morphological change but also kinetic change. However, 3 months study interval in early stage of our patient might have been too long. Additionally, as the CFTT in our case seemed to develop near the previous ulceration, more frequent ultrasonographic study might have advised, although it is not clear relation between the ulceration and CFTT formation. Plaque protrusion is defined as the projection of plaque into the stent lumen during CAS; its frequency has been reported to range from 2.6% to 7.8% in intravascular ultrasound studies567. Soft unstable plaques have been reported to result in plaque protrusions within several days after CAS. Our case had an unstable plaque but did not show any plaque protrusion on angiography immediately after CAS nor on carotid ultrasonography the following day. Management of CFFT is selected on an individual basis: with medical8, surgical910, and endovascular options111213 are available. Setacci et al. reported surgical management of acute carotid thrombosis after CAS, which consisted of removal of the stent and carotid thromboendoarterectomy14. However, in our case, we considered stent removal difficult because of the likelihood of chronic adhesion between the stent and the arterial wall. We considered using an aspiration microcatheter or a stent retriever as another option, but only the manual forced suction technique15 could completely remove the CFTT. Fridman et al. reported that patients who received intravenous recombinant tissue plasminogen activator had an increased risk of ischemic stroke recurrence within the first 24 hours1. They proposed that unproven approaches such as acute thrombectomy with carotid angioplasty with stenting or triple therapy should be applied with caution and reserved for select cases1. Primary, we selected aspirin as an antiplatelet. In addition, second or third antiplatelet should have taken into consideration in early stage for such high-risk patients after CAS. In some patients, antiplatelet function monitor such as VertifyNow16 may be effective, but it can only in use for research in Japan. We added second antiplatelet as clopidogrel just after second admission, and in the follow up period, we added DOAC because of suspected embolic stroke of undetermined source (ESUS) in the contralateral side of the 5 stent insertion. We selected closed-cell stent as WALLSTENT, plaque protrusion during CAS in acute setting occurred more frequency in patients with open-cell stents compared with those treated with closed-cell stents6. However, moderate or higher restenosis in a chronic setting occurred significantly less frequent in patients treated with open-cell stents compared with those treated with closed-cell stents17. Those problem may be resolved an emergent of a pharmacological stent in the future. Type 2 diabetes mellitus and hypertension are well-established risk factors for cerebrovascular disease as well as carotid plaque formation1819. Due to our patient’s poor compliance with the drugs, his HbA1c elevated around 10% at his second admission. Judging from the data of our patient’s HbA1c, it seemed he had not taken regularly and exactly neither the antidiabetic drug nor the antiplatelet and the statin. Education of atherosclerotic disease especially for asymptomatic patients is one of the essential problems. We should have followed-up more carefully and cautiously in a multidisciplinary approach. CONCLUSIONS Carotid plaque formation and plaque rupture can occur within a carotid stent and present as a CFTT. Endovascular thrombus removal can be effective. ACKNOWLEDMWNTS We thank Kazuho Saiga M.D., Ph.D. from the Department of Pathology, Takeda General Hospital, for the preparation of photomicrographs from the histological examination. 6 REFERENCES 1. Fridman S, Lownie SP, Mandzia J. Diagnosis and management of carotid free-floating thrombus: A systematic literature review. Int J Stroke. 2019;14(3):247-256. doi:10.1177/1747493019828554 2. Biller J, Adams HP, Boarini D, Godersky JC, Smoker WRK, Kongable G. Intraluminal clot of the carotid artery. A clinical-angiographic correlation of nine patients and literature review. Surg Neurol. 1986;25(5):467-477. doi:10.1016/0090-3019(86)90086-8 3. Funaki T, Iihara K, Miyamoto S, Nagatsuka K, Hishikawa T, Ishibashi-Ueda H. Histologic characterization of mobile and nonmobile carotid plaques detected with ultrasound imaging. J Vasc Surg. 2011;53(4):977-983. doi:10.1016/j.jvs.2010.10.105 4. Ogata T, Yasaka M, Wakugawa Y, Kitazono T, Okada Y. Morphological classification of mobile plaques and their association with early recurrence of stroke. Cerebrovasc Dis. 2010;30(6):606-611. doi:10.1159/000319889 5. Kondo H, Kiura Y, Sakamoto S, et al. Comparative Evaluation of Angioscopy and Intravascular Ultrasound for Assessing Plaque Protrusion During Carotid Artery Stenting Procedures. World Neurosurg. 2019;125:e448-e455. doi:10.1016/j.wneu.2019.01.102 6. Kotsugi M, Takayama K, Myouchin K, et al. Carotid Artery Stenting: Investigation of Plaque Protrusion Incidence and Prognosis. JACC Cardiovasc Interv. 2017;10(8):824-831. doi:10.1016/j.jcin.2017.01.029 7. Shinozaki N, Ogata N, Ikari Y. Plaque protrusion detected by intravascular ultrasound during carotid artery stenting. J Stroke Cerebrovasc Dis. 2014;23(10):2622-2625. doi:10.1016/j.jstrokecerebrovasdis.2014.06.007 8. Sallustio F, Di Legge S, Marziali S, Ippoliti A, Stanzione P. Floating carotid thrombus treated by intravenous heparin and endarterectomy. J Vasc Surg. 2011;53(2):489-491. doi:10.1016/j.jvs.2010.08.014 9. Tolaymat B, Irizarry K, Reif M, et al. Considerations beyond Stenosis for Carotid Endarterectomy in Treating Free-Floating Thrombus of the Carotid Artery. Ann Vasc Surg. 2019;60:221-228. doi:10.1016/j.avsg.2019.02.024 10. Yamaguchi S, Hamabe J, Yamashita A, Irie J, Yagi N, Suyama K. Rare Case of Floating Intimal Flap Associated with Atheromatous Carotid Plaque. World 7 Neurosurg. 2019;122:98-101. doi:10.1016/j.wneu.2018.10.139 11. Fitzpatrick N, Motyer R, Gibney B, et al. Expanding the role of stent-retriever endovascular thrombectomy: A case series of freefloating thrombus. J Neurointerv Surg. 2018;10(12):1164-1167. doi:10.1136/neurintsurg-2018-013946 12. Psychogios MN, Maus V. Retrieval of floating clot in the internal carotid artery: Extracranial SAVE technique (eSAVE). Diagnostic Interv Radiol. 2019;25(5):413-415. doi:10.5152/dir.2019.19093 13. Yamaoka A, Miyata K, Iihoshi S, Mikuni N. Endovascular treatment of asymptomatic free-floating thrombus in the carotid artery bifurcation: A direct aspiration first-pass technique under double balloon protection. BMJ Case Rep. 2019;12(8):10-12. doi:10.1136/bcr-2019-230295 14. Setacci C, De Donato G, Setacci F, et al. Surgical management of acute carotid thrombosis after carotid stenting: A report of three cases. J Vasc Surg. 2005;42(5):993-996. doi:10.1016/j.jvs.2005.06.031 15. Yamazaki H, Imai K, Hamanaka M, et al. Angiographical Features of Acute Stroke Patients with Carotid Artery Embolic Occlusion Recanalized by Suction with Syringe via Balloon Guiding Catheter. J Neuroendovascular Ther. 2019;13(2):49-57. doi:10.5797/jnet.oa.2018-0053 16. Paniccia R, Priora R, Liotta AA, Abbate R. Platelet Function tests: A Comparative Review. Vasc Health Risk Manag. 2015;11:133-148. doi:10.2147/VHRM.S44469 17. Müller MD, Gregson J, McCabe DJH, et al. Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study. Stroke. 2019;50(11):3013-3020. doi:10.1161/STROKEAHA.118.024076 18. Katakami N, Matsuoka T aki, Shimomura I. Clinical utility of carotid ultrasonography: Application for the management of patients with diabetes. J Diabetes Investig. 2019;10(4):883-898. doi:10.1111/jdi.13042 19. Turner R, Holman R, Stratton I, et al. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J. 1998;317(7160):703-713. doi:10.1136/bmj.317.7160.703 8 Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abbreviation List CFTT: Carotid Free-floating thrombus CAS: Carotid artery stenting DWI-MRI: Diffusion-weighted magnetic resonance imaging DOAC: Direct oral anticoagulant 9 FIGURE LEGENDS Figure 1. (A) Preoperative right carotid ultrasonography (longitudinal view) showed a hypoechoic plaque with ulceration and stenosis. (B) Postoperative right carotid ultrasonography image showed sufficient dilatation of the stent in the right carotid artery without plaque protrusion or stenosis. (C) Three months after carotid artery stenting (CAS), there was no abnormality within the stent. (D) Six months after CAS, a dumbbell-shaped carotid free-floating thrombus that was attached to stent and was moving with his heartbeat was visualized. The CFFT size was approximately 10mm x 3mm. See also Video 1, online only. Figure 2. (A) Right common carotid artery angiogram (lateral view) showed high-grade stenosis with ulceration (arrow). (B) Post carotid artery stenting (CAS) right common carotid artery angiogram (lateral view) showed sufficient dilatation of the stent in the right carotid artery without plaque protrusion or stenosis. (C) Six months after the CAS, the right common carotid artery angiogram (lateral view) showed carotid free-floating thrombus (arrow). (D) After manual suction with a Luer Lock syringe, the right carotid artery angiogram (lateral view) showed that the carotid free-floating thrombus was completely removed without residual stenosis. Figure 3. (A) The removed thrombus grossly appeared as red and white thrombus broken down into small pieces by suction. (B) Photomicrograph of the removed thrombus (hematoxylin and eosin stain, 100 x magnification) showed lipid and cholesterol clefts, lipid-rich necrosis (arrow), red thrombus consisting of erythrocytes (asterisk), and white thrombus consisting of fibrin (arrowhead). 10 Abbreviation List CFTT: Carotid Free-floating thrombus CAS: Carotid artery stenting DWI-MRI: Diffusion-weighted magnetic resonance imaging DOAC: Direct oral anticoagulant Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.