Supplementary Material for: Ischemic Stroke and Vaccine-Induced Immune Thrombotic Thrombocytopenia following COVID-19 Vaccine: A Case Report with Systematic Review of the Literature

<b><i>Introduction:</i></b> Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a prothrombotic syndrome observed after adenoviral vector-based vaccines for severe acute respiratory syndrome coronavirus 2. It is characterized by thrombocytopenia, systemic activation of coagulation, extensive venous thrombosis, and anti-platelet factor 4 antibodies. Arterial thrombosis is less common and mainly affects the aorta, peripheral arteries, heart, and brain. Several cases of ischemic stroke have been reported in VITT, often associated with large vessel occlusion (LVO). Here, we describe a case of ischemic stroke with LVO after Ad26.COV2.S vaccine, then we systematically reviewed the published cases of ischemic stroke and VITT following COVID-19 vaccination. <b><i>Methods:</i></b> We describe a 58-year-old woman who developed a thrombotic thrombocytopenia syndrome with extensive splanchnic vein thrombosis and ischemic stroke due to right middle cerebral artery (MCA) occlusion, 13 days after receiving Ad26.COV2.S vaccination. Then, we performed a systematic review of the literature until December 3, 2021 using PubMed and EMBASE databases. The following keywords were used: (“COVID-19 vaccine”) AND (“stroke”), (“COVID-19 vaccine”) AND (“thrombotic thrombocytopenia”). We have selected all cases of ischemic stroke in VITT. <b><i>Results:</i></b> Our study included 24 patients. The majority of the patients were females (79.2%) and younger than 60 years of age (median age 45.5 years). Almost all patients (96%) received the first dose of an adenoviral vector-based vaccine. Ischemic stroke was the presenting symptom in 18 patients (75%). Splanchnic venous thrombosis was found in 10 patients, and cerebral venous thrombosis in 5 patients (21%). Most patients (87.5%) had an anterior circulation stroke, mainly involving MCA. Seventeen patients (71%) had an intracranial LVO. We found a high prevalence of large intraluminal thrombi (7 patients) and free-floating thrombus (3 patients) in extracranial vessels, such as the carotid artery, in the absence of underlying atherosclerotic disease. Acute reperfusion therapy was performed in 7 of the 17 patients with LVO (41%). One patient with a normal platelet count underwent intravenous thrombolysis with alteplase, while 6 patients underwent mechanical thrombectomy. A malignant infarct occurred in 9 patients and decompressive hemicraniectomy was performed in 7 patients. Five patients died (21%). <b><i>Conclusion:</i></b> Our study points out that, in addition to cerebral venous thrombosis, adenoviral vector-based vaccines also appear to have a cerebral arterial thrombotic risk, and clinicians should be aware that ischemic stroke with LVO, although rare, could represent a clinical presentation of VITT.

<b><i>引言：</i></b> 疫苗诱导的免疫性血栓性血小板减少症（VITT）是接种腺病毒载体疫苗后出现的一种促血栓综合征，多见于严重急性呼吸综合征冠状病毒2（SARS-CoV-2，即新型冠状病毒）感染相关疫苗接种后。该病以血小板减少、凝血系统全身性激活、广泛静脉血栓形成以及抗血小板因子4抗体阳性为特征。动脉血栓形成相对少见，主要累及主动脉、外周动脉、心脏与脑部。已有多例VITT合并缺血性脑卒中的报道，此类病例常伴随大血管闭塞（LVO）。本文首先报告1例接种Ad26.COV2.S疫苗后出现伴大血管闭塞的缺血性脑卒中病例，随后系统回顾了新冠疫苗接种后并发VITT与缺血性脑卒中的已发表病例。<b><i>方法：</i></b> 本次研究报告1例58岁女性患者，在接种Ad26.COV2.S疫苗13天后出现血栓性血小板减少综合征，表现为广泛内脏静脉血栓形成以及右侧大脑中动脉（MCA）闭塞所致缺血性脑卒中。随后，我们检索PubMed与EMBASE数据库，对截至2021年12月3日的相关文献进行系统回顾。检索关键词组合为：（“COVID-19疫苗”） AND （“脑卒中”）、（“COVID-19疫苗”） AND （“血栓性血小板减少症”）。最终筛选出所有VITT合并缺血性脑卒中的病例。<b><i>结果：</i></b> 本研究共纳入24例患者。其中绝大多数为女性（79.2%），年龄均低于60岁（中位年龄45.5岁）。几乎全部患者（96%）仅接种了1剂腺病毒载体疫苗。18例患者（75%）以缺血性脑卒中为首发临床表现。10例患者合并内脏静脉血栓形成，5例患者（21%）合并脑静脉血栓形成。多数患者（87.5%）为前循环卒中，主要累及大脑中动脉。17例患者（71%）存在颅内大血管闭塞。研究还发现，在无基础动脉粥样硬化性疾病的前提下，颅外血管（如颈动脉）内存在大型管腔内血栓（7例）及游离漂浮血栓（3例）的比例较高。17例合并大血管闭塞的患者中，7例（41%）接受了急性再灌注治疗：1例血小板计数正常的患者接受了阿替普酶静脉溶栓，6例患者接受了机械取栓术。9例患者出现恶性脑梗死，其中7例接受了去骨瓣减压术。5例患者死亡，病死率为21%。<b><i>结论：</i></b> 本研究表明，除脑静脉血栓形成外，腺病毒载体疫苗还可能存在脑动脉血栓形成风险；临床医师需警惕，尽管罕见，但伴大血管闭塞的缺血性脑卒中可能是VITT的临床表现之一。