Revascularization of Acute Stent Thrombosis after Carotid Artery Stenting in 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) was extremely rare, but devastating complication after CAS. Academically, it occurred 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, intimal injury, and so on. Although successful recanalization cases were reported, however, 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. We are here to provide a case that successfully revascularization after ACST in patient with evidenced clopidogrel resistance, which was further conrmed by genetic testing. In our case, both thrombus aspiration and platelet glycoprotein IIb/IIIa antagonist (GPIs) were used for recanalization. Also, we review the literature and discuss appropriate treatment strategies for this deadly and rare event.

successfully revascularization after ACST in patient with evidenced clopidogrel resistance, which was further con rmed by genetic testing. In our case, both thrombus aspiration and platelet glycoprotein IIb/IIIa antagonist (GPIs) were used for recanalization. Also, we review the literature and discuss appropriate treatment strategies for this deadly 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, while that accompanies with devastating complication 2 , and its incidence rate was accounted for 0.5%-0.8% 2 . Although successful recanalization cases were reported 3 4 , however, 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, for the rst time, we aimed to report a successful revascularization of ACST in a patient with clopidogrel resistance, which was further con rmed by genetic testing. We attempted to review the literature and discuss appropriate treatment strategies for this rare event.

Case Presentation
The study protocol was approved by the Ethics Committees of the the Fifth People's Hospital of Chengdu, Chengdu, and all participants provided written informed consent.
A 69-year-old man was admitted to the Fifth People's Hospital of Chengdu, Chengdu, China for the weakness of right limb, right central facial paralysis, and hemianalgesia for 2 days. The weakness of his right limb aggravated and barylalia was detected for a half of day. He had a history of hypertension for four years due to the poor blood pressure control. After hospitalization, the magnetic resonance imaging (MRI) showed multiple internal border zone infarcts in a rosary-like pattern along the left centrum semiovale. Computed tomography (CT) angiography showed severe stenosis at the beginning of left internal carotid artery (LICA) (Figure 1). His platelet count was 107*10 9 /L and his coagulation function was normal as well. After discussion, we attempted to perform the left carotid stenting to prevent cerebral infarction. Before the surgery, the patient used 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 patient was 5 as well.
Carotid artery stenting (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 left carotid artery by The North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Firstly, we positioned a cerebral protection (spider FX; eV3 Inc., Plymouth, MN, USA). Then, the stenosis of the left internal carotid artery was predilated with a 5 * 30 mm balloon (Viatrac 14 Plus; Abbott Vascular, Temecula, CA, USA).
Eventually, a 7 × 40 mm self-expandable carotid stent (Wallstent; Boston Scienti c, Marlborough, MA, USA) was placed by a 0.014-inch guidewire and a 8-F guide catheter. Besides, the CAS was performed without any complication ( Figure 2).
After the surgery, the patient continued to use 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. After that, 5 days after surgery, the patient got lethargy, gaze to the left-side, motor aphasia, and right hemiplegia, and the patient's NIHSS score was 18. CT angiography showed acute stent thrombosis of the left internal carotid artery immediately ( Figure 3).
We performed the 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. showed thrombosis in the M1 segment. Considering that the patient's sudden aggravation of symptoms is closely associated with endovascular coil embolization of middle cerebral artery (MCA), preferentially opening the MCA blood vessel was conducted through a 4 × 20 mm Solitaire FR (ev3 Inc., Irvine, CA, USA) stent, with accompanying a thrombus about 2-3 cm long. Then, 6F Navien (ev3 Inc., Irvine, CA, USA) was used to enter the stent thrombus for thrombus aspiration, and a thrombus of about 4 cm in length was aspirated as well. After the angiography, the blood ow in the stent was partially restored, however, the forward blood ow was still very 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, while there were some thrombus in the stent. Tiro ban (10 ml) was given through Rebar 18 microcatheter (ev3 Inc., Irvine, CA, USA). After that, the angiography showed complete disappearance of the thrombus and complete recovery of the forward blood ow (Figure 4). After surgery, the patient's NIHSS score was 12.
Postoperative CT showed severe cerebral edema and contrast agent leakage without hemorrhage. Then, 2 days after thrombus aspiration, CT angiography showed complete recanalization of the stent, and most of contrast agents were absorbed. However, 4 days after the second surgery, CT showed a slight hemorrhage in basal ganglia and cerebral edema around the hemorrhage area. Regarding stent thrombosis, the patient continued to use aspirin, clopidogrel, and atorvastatin. Next, 2 weeks after thrombus aspiration, CT showed hemorrhage absorption. The patient discharged from hospital when he was consuming aspirin, clopidogrel, and atorvastatin. The patient's NIHSS score was 8 during discharge.
Three months after the dual-antiplatelet, the patient switched to a single-antiplatelet. After 6 months of follow-up, the patient's NIHSS score was 3 and modi ed Rankin scale (mRS) score was 1. Besides, there was no stent restenosis in CT angiography at that time-period as well ( Figure 5).

Discussion
It has been con rmed that CAS is an alternative strategy to prevent ischemic stroke in patients who are at high-risk of surgery compared with carotid endarterectomy (CEA) 1 . It was reported that the incidence of in-stent restenosis after CAS ranged from 3%-16.6%, and the majority of patients were asymptomatic 5 . Acute carotid stent thrombosis (ACST) was extremely rare, while the complication was devastating, and it occurred within 30 days after CAS 2 . We reviewed articles related to ACST which were published in English, and their details have listed in Table 1.
There are several reasons causing ACST, such as inadequate antiplatelet therapy, early discontinuation of antiplatelet therapy, clopidogrel resistance, hypercoagulable state, soft plaque and its protrusion, local vessel dissection, vasospasm, intimal injury, and so on 6-8 . In one hand, a number of reasons, including cause of CAS (i.e., stent underexpansion, in which stent does not fully adhere to the blood vessel 6 , balloon burst 9 , etc.), plaque protrusion 4 , and vasospasm that might immediately lead to ACST. Also, they can be timely resolved without any defect in the nervous system. On the other hand, other reasons, such as inadequate antiplatelet therapy [10][11][12] , early discontinuation of antiplatelet therapy 13 , clopidogrel resistance, and hypercoagulable state 7 , could cause ACST a few days after CAS procedure. Eventually, these may cause patient's death or severe paralysis 10 .
According to the review of 32 cases, 10 cases were found without reporting the relevant reasons caused disease 10, 12-19 , 11 cases due to CAS procedure 6, 9, 19-22 , 2 cases due to antiplatelet resistance 18, 23 , 3 cases due to hypercoagulable state 4, 7, 22 , 4 cases due to discontinuation of antiplatelet 11, 13, 24, 25 , 1 case due to cardiac multiple embolism 13 , and 1 case remained unclear 26 . As we mentioned previously, the ACST caused by CAS is often timely resolved and patients may have a good prognosis, and that may be the most common reason as well. However, for antiplatelet resistance, it is a particularly rare cause for ACST, and lack of experience in the treatment and prognosis of such patients is still a main challenge. After affecting by ACST, we tested the CYP2C19 of our patient, and found CYP2C19 *1/*2, which is one of the genetic polymorphism causing clopidogrel resistance. In absence of hypercoagulable and also antiplatelet therapy is adequate in patient, we speculate that clopidogrel resistance may be an important cause of ACST. Since an effective antiplatelet therapy is very important in treatment of CAS, some scholars recommended that the antiplatelet resistance tests should routinely be performed 3 .
We carried out the thrombus aspiration immediately after affecting by ACST. However, because of slow forward blood and existence of stent thrombus in the stent, Tiro ban (10 ml) was given by Rebar 18 microcatheter. After that, we performed a successful recanalization. The solution for ACST maybe multiplex. Drugs uses, such as thrombolysis or platelet glycoprotein IIb/IIIa antagonist (GPIs), surgical therapy including thromboendarterectomy, mechanical thrombolysis and thrombus aspiration or use these two methods exibly, these purpose is to recanalization as soon as possible.
It has been reported that Abciximab was successfully used in treatment of ACST patients 4,14 . However, regarding Tiro ban, we herein presented the rst case report including its application in treatment of symptomatic ACST patient accompanying with evidenced clopidogrel resistance. After Tiro banf was given, the thrombus immediately shrank. As Tiro ban is a non-peptide tyrosin 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, it possesses an advantage when we need to rapidly reversal antiplatelet such as in combination with thrombolysis or thromboaspiration. In an ACST patient, especially after thrombus aspiration, Tiro ban plays a more signi cant role 17 .
It was revealed that 4 days after the second surgery, hemorrhage was detected without any clear cause.
Regarding stent thrombosis, dual-antiplatelet therapy was continuously performed. We did not analyze the causes in-depth and did not treat cerebral hemorrhage actively as well. In other cases, cerebral hemorrhage was not reported after recanalization. We found that our patient had an appropriate progress after 6 months of follow up.

Conclusions
ACST is an extremely rare event, however, fetal complication after CAS and clopidogrel resistance are probably the reasons leading to ACST. The treatment of ACST after CAS must be undertaken urgently and immediately in order to cause 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 can only assist to illuminate 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.