SARS-CoV-2 and Acute Cerebrovascular Events: An Overview

Since the coronavirus disease 2019 (COVID-19) pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, accumulating evidence indicates that SARS-CoV-2 infection may be associated with various neurological manifestations, including acute cerebrovascular events (i.e., stroke and cerebral venous thrombosis). These events can occur prior to, during and even after the onset of COVID-19’s general symptoms. Although the mechanisms underlying the cerebrovascular complications in patients with COVID-19 are yet to be fully elucidated, the hypercoagulability state, inflammation and altered angiotensin-converting enzyme 2 (ACE-2) signaling in association with SARS-CoV-2 may play key roles. ACE-2 plays a critical role in preserving heart and brain homeostasis. In this review, we discuss the current state of knowledge of the possible mechanisms underlying the acute cerebrovascular events in patients with COVID-19, and we review the current epidemiological studies and case reports of neurovascular complications in association with SARS-CoV-2, as well as the relevant therapeutic approaches that have been considered worldwide. As the number of published COVID-19 cases with cerebrovascular events is growing, prospective studies would help gather more valuable insights into the pathophysiology of cerebrovascular events, effective therapies, and the factors predicting poor functional outcomes related to such events in COVID-19 patients.


Introduction
The coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the first one of the recorded pandemics that has caused a global burden on society and healthcare professionals. As of the date of writing this article, on 7 June 2021, over 173.41 million cases have been reported across 188 countries and territories, resulting in more than 3.73 million deaths, and over 2.13 billion people have been vaccinated [1]. The clinical manifestations of this disease are broad, ranging from asymptomatic cases to those with the severe symptomatic disease, with a case fatality rate of 2.3% [2]. The mortality is higher in elderly individuals, patients with medical comorbidities, and those with immunocompromised conditions [3]. While the primary mode of attack of the SARS-CoV-2 is through the respiratory pathways, early in the pandemic, reports from Wuhan, China, revealed that patients with COVID-19 might also develop neurologic symptoms (e.g., headache, dizziness and myalgia) [4]. Ever since, it has been found worldwide that neurological complications affecting both the central and peripheral nervous system (CNS and PNS, respectively) may occur in a considerable number of patients with COVID-19 [3][4][5][6]. The direct invasion of the nervous system by SARS-CoV-2 through the olfactory nerve, retrograde axonal transport, the gut-brain axis, or hematogenous spread has been suggested [6][7][8][9]. Critically ill COVID-19 patients admitted to the intensive care unit (ICU) may have additional risk factors for nervous system involvement, which include deep sedation and prolonged mechanical ventilation related to severe prolonged hypoxemia, immobility, and critical illness myopathy or neuropathy related to prolonged hospitalization, social isolation and delirium [10]. A correlation between SARS-CoV-2-related acute lung injury and brain hypoxia has been recently described, which may play an important role in the neurological dysfunction following SARS-CoV-2 infection [11,12].
Recent investigations have also indicated that some patients with COVID-19 may present with acute cerebrovascular events such as stroke [13,14] and cerebral venous thrombosis [15,16]. Although the mechanisms underlying such complications remain to be fully elucidated, the hypercoagulability state, hyper-inflammation, cytokine storm and cerebral endothelial dysfunction may play crucial roles [17][18][19][20]. In this review, we discuss the possible mechanisms underlying the acute cerebrovascular events related to SARS-CoV-2 infection, and also review the current epidemiological studies and case reports of neurovascular complications in patients with COVID-19 and relevant therapeutic approaches that have been considered worldwide.

Hypercoagulability Related to SARS-CoV-2
One of the important findings related to the SARS-CoV-2 infection is a widespread observation of the hypercoagulable state indicated by elevated D-dimer levels, the prolongation of the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and abnormal platelet counts [18,21]. Both thrombocytopenia and elevated D-dimers can be justified by the disproportionate activation of the coagulation cascade and the use of its substrates; however, the pathophysiology of SARS-CoV-2-related coagulopathy is still debatable.
While pneumonia itself can cause inflammation and a hypercoagulable state, cytokine release syndrome (CRS)-and macrophage activation-like syndrome (MAL)-like phenomena are also likely to play important roles [17][18][19]21]. When endothelial cells are damaged, generally, sub-endothelial cells-which are chromogenic-are exposed. The subendothelial cells contain Von Willebrand factor (VWF) and other thrombophilic proteins. Activated endothelial cells, along with VWF, will cause platelet aggregation and platelet plug formation as the primary homeostasis response ( Figure 1). Secondarily, the coagulation cascade is activated, and it involves both extrinsic and intrinsic pathways, followed by a common pathway [22]. When the coagulopathy results from hyper inflammation and not an endothelial cell injury, the activated cascade would be an extrinsic pathway by the activation of a tissue factor or CD142 [23]. Tissue factor is expressed on mononuclear cells in response to interleukin (IL)-6 and other inflammatory cytokines, and will activate the extrinsic pathway [24]. Furthermore, inflammatory cytokines impose an inhibitory effect on anticoagulation regulators like tissue factor pathway inhibitors and ADPase [25,26]. Viral infection pro-coagulopathy seems to be both dependent on endothelial cells and innate immunity by the hyper-activation of toll-like receptors (TLRs) along the surface of monocytes, macrophages, dendritic cells and fibroblasts. Another possible contributor to this hypercoagulable phenomenon is the formation of acute reactive oxygen species and oxidized phospholipids due to acute lung injury, which seems to initiate the Toll-like receptor 4 (TLR4)−TRIF (TIR-domain-containing adapter-inducing interferon-β)−TRAF6 (TNF receptor-associated factor 6)−NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) pathway [27,28]. The downstream pathway for both the hyperactivation of TLRs in response to viral infection and acute lung injury involves NF-κB activation. As a result of the NF-κB activation, there will be more IL-6 and TNF-α, which are also bi-product of CRS and MAL reactions [19,29]. Coagulopathy was previously observed in infection with other Coronaviridae viruses, including SARS and Middle East respiratory syndrome (MERS) [27,30]. It has also been suggested that COVID-19 may induce antiphospholipid antibodies, but usually these antibodies are transient and found not to be pathogenic [31]. Schematic representation of (A) the normal coagulation cascade triggered by an injury to the endothelial cells and (B) the hypercoagulability state related to SARS-CoV-2 infection. Generally, with an injury to the endothelial cell, the first response is platelet aggregation, followed by the activation of both the extrinsic and intrinsic pathways that lead to the generation of factor Xa and common pathway initiation. The product of the secondary coagulation cascade is a fibrin clot which will enhance platelet aggregates. ADPase and tissue factor (TF) pathway inhibitors (TFPI), as well as plasminogen, act as regulatory anticoagulants. The extrinsic and common pathways are initiated due to the increased TF and von Willebrand factor (VWF) in response to inflammatory cytokines such as interleukin (IL)-6 and the expression of TF by mononuclear cells in response to IL-6, which is elevated in SARS-CoV-2 infection. TFPI and ADPase are inhibited by the cytokines as well.
Although there are some prospective studies currently looking at the incidence of thrombotic events, early studies have already confirmed the increased frequency of intravascular thrombosis leading to pulmonary embolism, myocardial infarction, ischemic strokes and even cerebral venous sinus thrombosis. A thrombotic event has sometimes been reported as the first presentation of COVID-19 infection [18,32,33]. However, whether prophylactic anticoagulation for severe SARS-CoV-2 infection is beneficial still has to be considered according to common concurrent thrombocytopenia [17,21].

SARS-CoV-2 and Angiotensin-Converting Enzyme 2
SARS-CoV-2 has spike (S) glycoproteins on its outer envelope, which have a strong affinity toward the human angiotensin-converting enzyme 2 (ACE-2) as the host cell receptor [34,35]. The binding of SARS-CoV-2 to ACE-2 is a crucial element for viral infectivity and multi-organ damage. ACE-2 is expressed in various human tissues such as CNS (glial cells and neurons), skeletal muscle, the gastrointestinal tract and endothelial cells [35]. In the cerebral vasculature, endothelial ACE-2, as part of the renin-angiotensin system (RAS), plays an important role in the modulation of cerebral blood flow. The key components of RAS are angiotensinogen, renin, angiotensin I (Ang I), angiotensin II (Ang II), ACE, ACE-2, Ang type-1 receptor (AT1R), Ang type-2 receptor (AT2R) and Mas receptor ( Figure 2). Classically, the Ang II that is produced from Ang I by ACE activity mediates vasoconstriction, neuroinflammation and oxidative stress through the activation of AT1R and AT2R. Alternatively, Ang II can be converted to Ang-(1-7) by ACE-2 activity, which in turn activates the Mas receptor, mediating vasodilation, anti-inflammatory and antioxidant responses [36]. Schematic effects of SARS-CoV-2 on the renin-angiotensin system (RAS) in the cerebral vasculature. After the binding of the SARS-CoV-2 spike (s) glycoprotein to angiotensin converting enzyme 2 (ACE-2), the virus enters the cell. The virus also downregulates ACE-2 and competes with angiotensin II (Ang II) for binding to ACE-2, which ultimately decreases the activity of the ACE-2-Ang-(1-7)-Mas receptor (alternative) axis. This also leads to the greater activation of the ACE-Ang II-AT1R (classical) axis. The outcome of such events is an aberrant renin-angiotensin system (RAS), causing vasoconstriction, inflammation, oxidative stress, and thrombogenesis, causing ischemic stroke in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-COV-2. TMPRSS2, Transmembrane protease, serine 2; AT1R: angiotensin 1 receptor; AT2R: angiotensin 2 receptor.
The overactivation of ACE/Ang II/AT1R/AT2R or the dysfunction of the ACE-2/Ang (1-7)-Mas receptor axis may contribute to the pathogenesis of acute ischemic stroke via increased vasoconstriction, oxidative stress and vascular inflammation (i.e., vasculitis) [36]. In SARS-CoV-2 infection, binding to ACE-2 may downregulate ACE-2 [37], leading to excess ACE-mediated Ang II production and lower ACE-2-mediated Ang-(1-7) production [20]. This SARS-CoV-2-induced imbalance between the classical and alternative RAS axes ultimately promotes ischemia via increased cerebral vasoconstriction, hyperinflammation and oxidative stress [20]. Ang II promotes thrombosis by increasing the release and secretion of plasminogen activator inhibitor type 1 (PAI-1), and enhances tissue factor (TF) expression [38]. In contrast, the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor would cause antithrombotic activity [39]. SARS-CoV-2 decreases the activation of ACE2; the result is an imbalance between the classical and alternative RAS axes, ultimately promoting ischemia via increased cerebral vasoconstriction, hyper-inflammation, oxidative stress and thrombogenesis [20]. These data raise the possibility that recombinant human ACE-2 might be beneficial in preventing ischemic stroke in COVID-19 patients with known stroke risk factors.

Acute Cerebrovascular Events in COVID-19
Prior articles indicate that viral respiratory infections are independent risk factors for both ischemic and hemorrhagic strokes [40]. Acute cerebrovascular events have been reported as one of the neurological complications that can occur in COVID-19 patients [41,42]; there is, overall, a propensity towards the occlusion of (i) large vessels (e.g., internal carotid, middle cerebral (M1 and M2 segments), or basilar arteries), (ii) multi-territory vessels, or (iii) uncommon vessels (e.g., pericallosal artery [43]) [44]. On the other hand, intracerebral hemorrhage, cerebral venous thrombosis and small-vessel brain disease develop less frequently in COVID-19 patients [44]. Several cases with atypical neurovascular presentations have also been reported, including bilateral carotid artery dissection [45], posterior reversible encephalopathy syndrome (PRES) [46], and vasculitis [47,48]. The pathophysiology, still unclear, is possibly related to the direct damage of the vessel mediated by the virus once it invades the CNS [49], or it could be related to the development of underlying coagulopathy and thromboembolisms, as we discussed earlier [33,50,51]. Another suggested mechanism is cardioembolic stroke from the direct damage of the myocardial cells, as evidenced by the cardiac dysfunction and arrhythmias in these patients [52]. Accordingly, myocardial cells express ACE-2 receptors abundantly, and are then vulnerable to SARS-CoV-2 infection [35].
In a retrospective study that included 214 patients with confirmed COVID-19 infection, about 6% presented with acute cerebrovascular events, mainly ischemic strokes. Stroke symptoms tend to appear later during the hospitalization, a median of 10 days after the onset of symptoms, and this was also confirmed by a larger retrospective study [53]. These patients seem to have a more severe infection with higher levels of inflammatory markers and higher D-dimer levels, older age, more comorbidities (hypertension in particular) and fewer typical symptoms associated with COVID-19 [54]. Indeed, for many COVID-19 patients presenting with acute strokes or other neurological manifestations, the diagnosis of infection is made after the hospital admission. The current recommendations from the American Heart Association (AHA) and American Stroke Association (ASA) include the use of personal protective equipment (PPE) for all of the stroke teams at the time of stroke code activation, as many stroke patients are unable to provide the history and information for appropriate COVID-19 screening. It is indeed suggested to treat every code stroke patient as being potentially affected by the infection in order to avoid any delay in trying to understand the infection status, following the same treating guidelines available for non-COVID-19 patients [55,56]. A dedicated track for the triage and management of suspected or proven COVID-19 patients with stroke-like symptoms was also suggested and implemented in Italy with a mobile CT scan unit [57]. The patients eligible for neurointerventional procedures should be treated accordingly, with the minimum number of staff in the angio suite and restricted access for essential staff, only ensuring the quality control of the negative pressure environment and following appropriate precaution protocols [58,59]. After the appropriate treatment, stroke patients should be admitted to a dedicated ward or ICU units where possible, and stroke teams should guide staff familiar with managing acute ischemic or hemorrhaging stroke patients [56].

Ischemic Stroke
Acute ischemic stroke appears to be the most common form of stroke seen in patients with COVID-19. The initial retrospective case reports from Wuhan in China reported six cases (2.34%) of stroke among the 214 patients analyzed, five of which were ischemic in nature [54]. Another study from Italy reported nine ischemic strokes (2.5%) among a cohort of 388 patients [51]. Different incidence rates were reported in two large studies. The first is a recent case series of 1419 patients with the diagnosis of COVID-19 admitted in a hospital in Madrid, Spain; it reported a total of 14 patients with systemic arterial thrombotic events (1% incident), of which eight presented with a cerebrovascular event (six with acute ischemic stroke and two with transient ischemic attack) [53]. A similar incidence (0.9%) was reported in the second large retrospective study of 3556 COVID-19 positive patients, of which 32 were diagnosed with ischemic stroke, 65.6% were defined as the cryptogenic subtype, and 34.4% were defined as an embolic stroke of undetermined source [60]. There is a possibility that the total numbers were underestimated because patients with small acute strokes may present without apparent focal neurological symptoms, and may go undiagnosed. Indeed, a case series from France documented three encephalopathic patients, with no signs suggestive of ischemic stroke, of whom the diagnosis was made after undergoing MRI to better address the cause of their encephalopathy [61]. Furthermore, the difference in the incidence rates could be explained by the different patient populations and larger cohorts. Another case series in Houston (TX, USA) reported a total of 12 patients with COVID-19 who developed stroke, among which 10 cases had an ischemic stroke (including one patient with hemorrhagic transformation), and two had intracerebral hemorrhage [62]. The inflammatory markers (e.g., D-dimer and IL-6) were elevated in a majority of these cases [62]. The etiology was an embolic stroke of undetermined source (ESUS, 6 cases), cardioembolic (2), carotid dissection (1), hypertension-related hemorrhage (1), the rupture of mycotic aneurysm related to infectious endocarditis (1), and unknown (one case due to limited workup) [62].
Stroke patients with COVID-19 infection usually present with a higher National Institutes of Health Stroke Scale (NIHSS) score at admission [60,63], a more severe disease course, immunocompromisation, and with different comorbidities and cardiovascular risk factors [53,54]. The age range is reported to be usually over 50 years old. However, more recently, a case series from New York City showed five COVID-19 patients younger than 50 affected by a large vessel ischemic stroke presented in the emergency department within a two-week period higher than usual ( Table 1). Two of the five patients were previously healthy; one had hypertension and hyperlipidemia, another had undiagnosed diabetes, and the last reported patient had a history of prior mild stroke and diabetes [64]. The data from a larger patient cohort from New York City reported stroke in COVID-19 positive patients, mainly in men (71.9%) and white people (70%), with an average age of 62.5 versus 70 in the COVID-19−negative stroke patients. Moreover, patients with COVID-19 and ischemic stroke appeared to have higher mortality than the controls [60].       A large multicenter study reported stroke characteristics in 432 COVID-19 patients admitted to 71 centers from 17 countries. They observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young strokes when compared with the population studies before the pandemic [63]. More data and studies on the incidence of stroke in young COVID-19 patients are needed.
A large international multicenter study on 17,799 COVID-19 hospitalized patients reported 156 stroke episodes, 123 (79%) of whom presented with acute ischemic stroke, 27 (17%) of whom had intracranial hemorrhage, and 6 (4%) of whom presented with cerebral venous sinus thrombosis. The mean age for ischemic stroke among hospitalized COVID-19 patients was 68.6 years [79]. Another multicenter prospective cohort study which included 150 patients with COVID-19 related ARDS showed 64 thrombotic complications, two of which were acute ischemic stroke despite anticoagulation [80].
Given the hypercoagulable state related to the infection, as a possible cause of ischemic stroke, prophylactic anticoagulation with low molecular weight heparin (LMWH) may be recommended for patients with severe COVID-19, according to the International Society of Thrombosis and Hemostasis (ISTH) [81]. The American Society of Hematology (ASH) guideline panel recently suggested: using prophylactic-intensity over intermediateintensity or therapeutic-intensity anticoagulation for patients with coronavirus disease 2019 (COVID-19)-related critical illness who do not have suspected or confirmed venous thromboembolism (VTE) (conditional recommendation based on very low certainty in the evidence about effects). [82] Higher mortality rates were observed in association with elevated PT and D-dimer levels, and decreased platelet counts and fibrinogen at days 10 and 14 from the onset of symptoms [81]. The monitoring of these parameters can help determine the prognosis and the selection of patients that require admission and aggressive treatments. Interestingly, in a retrospective study that included 449 patients with severe COVID-19 infection and elevated D-dimers, the use of LMWH was associated with lower mortality [83]. However, the data on the efficacy of LMWH in preventing venous and arterial thromboembolic complications are conflicting [51,80]. In a case report of six patients who presented with acute ischemic stroke and confirmed COVID-19 infection with associated elevated D-dimer levels (≥1000 µg/L), two patients had ischemic stroke despite therapeutic anticoagulation [13]. Data from the same study showed that the primary mechanism underlying the ischemic stroke was large-vessel occlusion, and the stroke usually occurred later in the course of the disease, between days 8 and 24 from the onset of symptoms. Further investigations are warranted to establish the actual need for therapeutic anticoagulation in patients with COVID-19 to reduce the risk of ischemic stroke.
PROTECT COVID (a randomized clinical trial of anticoagulation strategies in COVID-19) is ongoing, comparing the effectiveness of therapeutic versus prophylactic anticoagulation in patients with COVID-19 infection and mild-to-moderate elevations in D-dimer levels greater than 500 ng/mL (clinical trial identifier: NCT04359277) [60]. Other randomized trials are also ongoing to investigate the anticoagulation benefits in patients with COVID-19 (NCT04362085, NCT04345848, NCT04406389, NCT04528888).
Despite the lack of defined data on the prognosis of strokes related to COVID-19 infection, the overall outcome appears to be poor, as the majority of stroke patients are older and present with severe infection and more comorbidities [53,56,[84][85][86]. Nonetheless, mechanical thrombectomy for emergent large vessel occlusion could be justified, as it can improve the outcome and should be offered to all the potential candidates notwithstanding the infectious status [59].

Hemorrhagic Stroke
A small number of stroke patients with COVID-19 infection present with cerebral hemorrhage ( Table 1). The initial retrospective case series of 214 patients from Wuhan in China [54] reported only one case of hemorrhagic stroke. Similarly, another retrospective case series, again from Wuhan, reported one hemorrhagic stroke within 13 patients who presented with acute cerebrovascular events [86]. An additional five case reports of hemorrhagic stroke have been published [8,[54][55][56]. A ruptured aneurysm in the pericallosal region [74] or posterior-inferior cerebellar artery (PICA) [14] was found in two cases. A hypothesis about the underlying pathophysiologic mechanism of cerebral hemorrhage is the reduced expression and function of ACE-2 in SARS-CoV-2 infected cells. ACE-2 is expressed in vascular endothelial cells, and its signaling is involved in the regulation of cerebral blood flow and the reduction of the body's blood pressure. In the case of COVID-19 infection, the signaling is altered with subsequent hypertension and predisposition to the development of hemorrhagic stroke from arterial wall rupture [43]. Another possible mechanism is the underlying coagulopathy induced by the infection with thrombocytopenia [85]. Future observations may better clarify the incidence and clinical and laboratory characteristics of COVID-19 patients presenting with hemorrhagic strokes.

Cerebral Venous Thrombosis
Cerebral venous thrombosis has been reported in several studies. In a multinational retrospective study, all of the cases of cerebral venous sinus thrombosis (CVST) with COVID-19 infection were collected from the start of the pandemic to the end of June 2020. They reported on 13 post-COVID-19 CVST patients and compared their characteristics with the CVST data obtained before the COVID-19 pandemic from the same centers. They concluded that compared to non-COVID-19-infected CVST patients, patients with the infection tended to be older, and had fewer CVST risk factors and worse outcomes [87].
Several smaller studies reported CVST in seven adults (age range between 32 and 62 years, 62.5% female; Table 1) and one pediatric (a 13-year-old male) patient with COVID-19 [16,32,[76][77][78]. Headaches were a presenting symptom in six (85.7%) cases, variably accompanied by different focal neurological deficits, confusion and impaired consciousness [16,32,76,77]. Although in three patients the treatment and outcome were not reported [16,77], the condition was fatal in three out of five cases (60%) within a few days of onset despite anticoagulation and supportive therapy. Notably, in some cases, neurological symptoms occurred about two weeks after the onset of the general symptoms (i.e., fever, cough or dyspnea) of COVID-19 [16,77]. Therefore, the possibility of this potentially life-threatening condition should not be overlooked even when patients present several days to weeks after the onset of COVID-19. A more recent multicenter 3-month cohort study of 13,500 consecutive patients with COVID-19 in New York City found an imaging-proved cerebral venous thrombosis incidence of 8.8 per 10,000 cases, which is higher than expected (i.e., 5 per million annually) [88]. In this study, despite the standard management [89] consisting of anticoagulation, endovascular thrombectomy and surgical hematoma evacuation, the mortality rate was 25% [88].
Overall, various degrees of elevated acute phase reactants (e.g., CRP and ferritin), hypercoagulability factors (e.g., D-dimer and aPTT) and abnormal platelet counts were found in these cases [16,32,76,77], suggesting a possible association with the hypercoagulability state in the setting of SARS-CoV-2 infection. It is unclear whether the monitoring of these markers has any value for the prediction of the onset or severity of cerebral venous thrombosis in these cases. This needs further detailed information on COVID-19 patients with such complications.

Therapeutic Approaches
Administering tissue plasminogen activator (tPA) in patients with COVID-19 and stroke is one of the therapeutic options. The role of other anticoagulants, such as low molecular weight heparin (LMWH) or full-dose heparin, is uncertain. There is some data to show that LMWH may be useful in sepsis-induced coagulopathy [83]. Although aspirin therapy in COVID-19 patients with ischemic stroke (especially in those who cannot take anticoagulants due to the risk of hemorrhagic transformation [67] or other medical limitations) can be considered as a secondary preventive approach, this medication is not indicated in patients with disseminated intravascular coagulation, a high risk of bleeding, or thrombocytopenia [90,91].
One reasonable treatment for COVID-19 patients is human recombinant soluble ACE-2 (hrsACE-2). There are two mechanisms of action for it: (1) preventing the SARS S protein from binding to lung and endothelial endogenous ACE-2, thereby reducing the infection of host cells; and (2) inhibiting the ACE-2 depletion by the SARS-CoV-2 virus. Considering ACE-2 is exhibited by brain endothelium and neurons, it is probable that the depletion of ACE-2 by the virus damages the endothelial function and leads to acute stroke. Along with the other known treatments, medications that affect the RAS system, such as angiotensin (1-7), may be appropriate therapies for COVID-19. Angiotensin's role is currently under evaluation in clinical trials (NCT04332666). In addition, AT1 receptor blockers (ARBs), such as losartan, could be preclusive in stroke [92]. On the other hand, another study has shown that early intravenous thrombolysis and immediate mechanical thrombectomy had poor outcomes in patients with acute ischemic stroke due to large vessel occlusion with COVID-19 [93]. Overall, more well-designed, randomized, controlled trials are needed to provide an evidence-based approach for the prevention or treatment of acute cerebrovascular events in patients with COVID-19 [94].

Conclusions
A growing body of evidence indicates that acute cerebrovascular events, including both ischemic and hemorrhagic strokes and cerebral venous thrombosis, may occur in patients with COVID-19. The underlying mechanisms of such events are still not completely understood. Still, they may include a hypercoagulability state, inflammation and cytokine storm, endothelial dysfunction, and an aberrant RAS axis due to the binding of SARA-CoV-2 to endothelial ACE-2. These abnormalities ultimately cause vasoconstriction, oxidative stress, inflammation and thrombogenesis. As these complications, especially cerebral venous thrombosis, are potentially life-threatening, physicians need to be vigilant when encountering patients with COVID-19 who have neurological symptoms such as headache, confusion, altered mental status, seizure and focal neurological deficits. Due to the small number of published cases or the mainly retrospective design of the previous clinical studies, (i) the functional outcome with the available therapies (e.g., LMWH) for thrombotic events and (ii) inflammatory or coagulable markers that can be efficiently used for the monitoring or prediction of such events in COVID-19 are still elusive, requiring a large cohort of patients with such complications.