Revascularization of Acute Stent Thrombosis after Carotid Artery Stenting in a Clopidogrel Resistance Patient

Carotid artery stenting (CAS) is an alternative strategy to prevent ischemic stroke in patients who are at high risk of surgery compared with carotid endarterectomy (CEA). Acute carotid stent thrombosis (ACST) is an extremely rare but devastating complication after CAS. Theoretically , it occurs within 30 days after CAS . There are several reasons causing ACST, such as inadequate antiplatelet therapy, early discontinuation of antiplatelet therapy, clopidogrel resistance, hypercoagulable state, local vessel dissection, vasospasm, and intimal injury. Although successful recanalization cases have been reported, there is still a lack of experience in the choice of treatment methods and the timing of ACST treatment, especially when the patient has clopidogrel resistance. Here, we report a case with successful revascularization after ACST in a patient with evidenced clopidogrel resistance, which was further conrmed by genetic testing.In this case, both thrombus aspiration and platelet glycoprotein IIb/IIIa antagonist (GPIs) were used for recanalization. In addition, we review the literature and discuss appropriate treatment strategies for this devastating and rare event.


Abstract
Carotid artery stenting (CAS) is an alternative strategy to prevent ischemic stroke in patients who are at high risk of surgery compared with carotid endarterectomy (CEA). Acute carotid stent thrombosis (ACST) is an extremely rare but devastating complication after CAS. Theoretically , it occurs within 30 days after CAS . There are several reasons causing ACST, such as inadequate antiplatelet therapy, early discontinuation of antiplatelet therapy, clopidogrel resistance, hypercoagulable state, local vessel dissection, vasospasm, and intimal injury. Although successful recanalization cases have been reported, there is still a lack of experience in the choice of treatment methods and the timing of ACST treatment, especially when the patient has clopidogrel resistance. Here, we report a case with successful revascularization after ACST in a patient with evidenced clopidogrel resistance, which was further con rmed by genetic testing.In this case, both thrombus aspiration and platelet glycoprotein IIb/IIIa antagonist (GPIs) were used for recanalization. In addition, we review the literature and discuss appropriate treatment strategies for this devastating and rare event.
Background Carotid artery stenting (CAS) is an alternative strategy to prevent primary or secondary ischemic stroke in selected patients compared with carotid endarterectomy (CEA) 1 . It is well-known that acute carotid stent thrombosis (ACST) is an extremely rare event, but it is accompanied by devastating complications 2 . The incidence rate of ACST is 0.5%-0.8% 2 . Although successful recanalization cases have been reported 3 4 , there is still a lack of experience in the choice of treatment methods and the timing of ACST treatment, especially when the patient has clopidogrel resistance. Here, we report successful revascularization of ACST in a patient with clopidogrel resistance, and this resistance was further con rmed by genetic testing. We further review the literature and discuss appropriate treatment strategies for this rare event.

Case Report
The study protocol was approved by the Ethics Committees of the Fifth People's Hospital of Chengdu, Chengdu, and the patient provided written informed consent.
The 69-year-old man was admitted to the Fifth People's Hospital of Chengdu, Chengdu, China for weakness of right limb, right central facial paralysis, and hemianalgesia for 2 days. The weakness of his right limb was aggravated, and barylalia was detected for a half of day. He had a history of hypertension for four years due to poor blood pressure control. After hospitalization, magnetic resonance imaging (MRI) showed multiple internal border zone infarcts in a rosary-like pattern along the left centrum semiovale. A computed tomography (CT) angiography showed severe stenosis at the beginning of the left internal carotid artery (LICA) (Figure 1). His platelet count was 107x10 9 /L, and his coagulation function was normal. After multidisciplinary consultation, including Cardiology, Respiratory Medicine, Neurosurgery, and Anesthesiology, anesthesiologists believed that the risk of general anesthesia was greater due to poor lung function in the patient, resulting in left carotid stenting rather than endarterectomy for secondary prevention. Before the surgery, the patient took aspirin (100 mg) and clopidogrel (75 mg) for 5 days, and atorvastatin (20 mg) was routinely administered for 5 days. The National Institute of Health Stroke Scale (NIHSS) score of the patient was 5.
CAS was performed under local anesthesia. Heparin was administered intravenously at a dose of 5,000 U (100 U/kg) bolus immediately after femoral artery puncture and at a dose of 1,000 U/h during the procedure. Angiography revealed 90% stenosis in the left carotid artery according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. First, we positioned a distal protection device (spider FX; eV3 Inc., Plymouth, MN, USA), and the stenosis of the left internal carotid artery was then predilated with a 5 x 30 mm balloon (Viatrac 14 Plus; Abbott Vascular, Temecula, CA, USA). A 7 × 40 mm self-expandable carotid stent (Wallstent; Boston Scienti c, Marlborough, MA, USA) was then placed by a 0.014-inch guidewire and an 8-F guide catheter. In addition, the CAS was performed without any complications (Figure 2), and the patient did not show any symptoms during the CAS procedure.
After the surgery, the patient continued to take aspirin 100 (mg), clopidogrel (75 mg), and atorvastatin (20 mg). One day after surgery, we assayed his platelet count and coagulation function as a routine procedure. His platelet count and coagulation function were both in the normal range. Additionally, the patient did not complain about any discomfort. Five days after surgery, the patient showed lethargy, gaze to the left-side, motor aphasia, and right hemiplegia, and the patient's NIHSS score was 18. After 30 minutes, CT angiography showed acute stent thrombosis of the left internal carotid artery ( Figure 3).
We performed thrombus aspiration via right percutaneous transfemoral access under local anesthesia. After the 8F guiding catheter (Boston Scienti c, Marlborough, MA, USA) was placed, the angiography showed acute thrombosis at the proximal end of the stent without forward blood ow. The Synchro2 Microwire (Stryker, Kalamazoo, MI, USA) with a Rebar 18 microcatheter (ev3 Inc., Irvine, CA, USA) showed thrombosis in the M1 segment. We preferential opening of the MCA blood vessel was conducted through a 4 × 20 mm Solitaire FR (ev3 Inc., Irvine, CA, USA) stent with a thrombus approximately 2-3 cm long Figure 5 . A 6F Navien (ev3 Inc., Irvine, CA, USA) was used to enter the stent thrombus for thrombus aspiration, and a thrombus of approximately 4 cm in length was aspirated as well ( Figure 5). After the angiography, the blood ow in the stent was partially restored, but the forward blood ow was still slow. A Spider distal protection device was positioned (ev3 Inc., Irvine, CA, USA), and a 5 × 30 mm balloon (Boston Scienti c, Marlborough, MA, USA) was expanded twice by 12 atm. The angiography showed a signi cant improvement in the anterior blood ow, but there was some thrombus in the stent. Tiro ban (10 ml) was given through a Rebar 18 microcatheter (ev3 Inc., Irvine, CA, USA). The angiography then showed complete disappearance of the thrombus and complete recovery of forward blood ow ( Figure 5). After surgery, the patient's NIHSS score was 12.
The postoperative CT showed severe cerebral edema and contrast agent leakage without hemorrhage. Two days after thrombus aspiration, the CT angiography showed complete recanalization of the stent, and most of the contrast agents were absorbed. Four days after the second surgery, however, the CT showed a slight hemorrhage in the basal ganglia and cerebral edema around the hemorrhage area. Regarding stent thrombosis, the patient continued to take aspirin, clopidogrel, and atorvastatin. Ten days after the second surgery, we found out that the patient is a CYP2C19*2 heterozygote. Thus, we gave the patient a triple dose of clopidogrel compared to the preoperative dose 5 . Two weeks after thrombus aspiration, the CT showed hemorrhage absorption. The patient was discharged from the hospital, but he was still taking aspirin, clopidogrel, and atorvastatin. The patient's NIHSS score was 8 during discharge. Three months after the dual-antiplatelet treatment triple dose of clopidogrel , the patient was switched to a single-antiplatelet treatment. After 6 months of follow-up, the patient's NIHSS score was 3, and the patient's modi ed Rankin scale (mRS) score was 1. In addition, there was no stent restenosis in the CT angiography at the 6-month follow-up ( Figure 6).

Discussion
CAS has been con rmed as an alternative strategy to prevent ischemic stroke in patients who are at high-risk of surgery compared with carotid endarterectomy (CEA) 1 . The incidence of in-stent restenosis after CAS was reported to range from 3%-16.6%, with the majority of patients being asymptomatic 6 . Acute carotid stent thrombosis (ACST), a major potential complication of CAS, was extremely rare and only occurred within 30 days after the procedure 2 . We reviewed articles related to ACST that were published in English; their details have been listed in Table 1.
Many factors cause ACST, such as inadequate or early discontinuation of antiplatelet therapy, clopidogrel resistance, hypercoagulable state, soft plaque protrusion, local vessel dissection, vasospasm, and intimal injury [7][8][9] . Also, the stent morphology plays an important role in ACST 10 . Several of these factors (e.g., stent under-expansion, in which the stent does not fully adhere to the blood vessel 7 or balloon bursts 11 ), plaque protrusion 4 , and vasospasm can immediately cause ACST, but if promptly treated, can be resolved without any long-term defect to the nervous system. Other factors, such as inadequate or early discontinuation of antiplatelet therapy [12][13][14] , clopidogrel resistance, and hypercoagulable state 8 , may cause ACST a few days after the CAS procedure. These factors are much more critical and may eventually cause death or severe paralysis 12 .
In our patient, ACST was likely caused by more than one factor. After detection of ACST, we tested for CYP2C19 in our patient and found the presence of CYP2C19 *1/*2, a genetic polymorphism conferring clopidogrel resistance. Since we did not detect a hypercoagulable state and antiplatelet therapy was adequate in our patient, we speculate that clopidogrel resistance may be an important contributor to ACST. Furthermore, we did not perform post-stenting balloon dilation, so it is possible that stent under-expansion also contributed to ACST in this patient 6 .
We performed thrombus aspiration immediately after detection of ACST; however, because of slow forward blood ow and the existence of a thrombus in the stent, tiro ban (10 ml) was administered using a Rebar 18 microcatheter. After tiro ban treatment, we performed successful recanalization. As ACST is a rare complication, its treatment is still largely untested. ACST should be treated considering a combination factors such as thrombogenesis, timely action (intraoperative, ideally either just before or after surgery), severity of neurological de cits, and area of infarction. For cases involving severe clinical deterioration, ACST treatment should have relatively positive effects, with the goal of rapid revascularization to avoid serious long-term consequences 14 . Possible solutions for ACST may be multiplex, including the administration of drug 4, 15, 16 , thrombolysis 11-13, 17, 18 , thrombolytic therapy combined with anticoagulation or antiplatelet therapy 4 , and surgical therapy including thromboendarterectomy 19 , mechanical thrombolysis and thrombus aspiration 14,20 , either individually or in combination 21 .
GPIs such as abciximab and tiro ban have successfully been used in the treatment of ACST patients 4,15,16 . In our clopidogrel resistance patient with ACST, the thrombus immediately shrank after tiro ban administration. As tiro ban is a non-peptide tyrosine derivative that mimics the Arg-Gly-Asp (RGD) integrin recognition sequence, it has a very short platelet-bound half-life and relatively long plasma half-life. Therefore, its use is advantageous when rapid antiplatelet reversal is required, such as in combination with thrombolysis or thrombus aspiration.
Four days after the second surgery, hemorrhage was detected without any clear cause. Regarding stent thrombosis, dual-antiplatelet therapy was continuously performed triple dose of clopidogrel . We did not analyze the causes in-depth and did not actively treat cerebral hemorrhage. In other cases, cerebral hemorrhage has not been reported after recanalization. Our patient showed appropriate progress after 6 months of follow-up.

Conclusions
ACST is an extremely rare event, but fatal complications after CAS and clopidogrel resistance may lead to ACST. The treatment of ACST after CAS must be undertaken urgently and immediately to allow restoration of blood ow and avoid major neurological adverse events. Thrombus aspiration with GPIs would be effective in treatment of ACST. The presented case report only illuminates the available treatment strategies rather than providing general therapeutic recommendations.

Consent to publish
All writers agreed to publish this manuscript. The patient has signed an informed consent form.

Authors Contributions
Wei Wei and Pian Wang drafted the manuscript for intellectual content, Yan Wang design and conceptualized study, Zheng Li and Qingbin Zhang analyzed the data.

Funding
No funding was obtained for this study.

Competing Interests
Non-nancial competing interests.

Availability of data and materials
Access to study data is regulated by Chinese law. Data are available from the Fifth People's Hospital of Chengdu Institutional Data Access/Ethics Committee for researchers who meet the criteria.   The thrombus aspiration was carried out for the patient with acute carotid stent thrombosis. (A) Angiography con rmed acute stent thrombosis of the left internal carotid artery, however, there was no blood ue at the distal end of the stent; (B) After thrombus aspiration, the blood ow in the stent was partially restored, while the forward blood ow was still very slow and there were some thrombus in the stent; (C) The acute carotid thrombosis was fully solved after balloon expansion, and Tiro ban (10 ml) was given through Rebar18 microcatheter.

Figure 5
Extracted thrombus in this ACST patient.

Figure 6
A-F shows the radiographic changes in the patient after thrombus aspiration. (A) The postoperative CT showed contrast agent leakage; (B,C) Two days after thrombus aspiration, the CT angiography showed complete recanalization of the stent, and most of the contrast agents were absorbed; (D) Four days after the second surgery, the CT showed a slight hemorrhage in basal ganglia and cerebral edema around the hemorrhage area; (E) Two weeks after thrombus aspiration, the CT showed hemorrhage absorption; (F) There was no stent restenosis in the CT angiography after 6 months of follow-up.