Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2

Abstract

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

“…hypoxia, hypotension, dysautonomia), coagulation dysfunction, large vessel occlusion, arterial stiffness, impaired vasoreactivity, neurotropic infection, parenchymal haemorrhage, or autoimmune responses against diverse antigens (Chen et al, 2020; Marcic et al, 2021; Mohkhedkar et al, 2021; Schnaubelt et al, 2021). Acute COVID-19 has also been associated with microvascular injury from vasculitis or endothelialitis (Becker, 2020; McGonagle et al, 2021), with endotheliopathy (Kakarla et al, 2021), vasogenic oedema and microthrombosis in the acute phase (Iba et al, 2020; Levi et al, 2020) and hypoperfusion in subacute phase (Hosp et al, 2021). While this acute pathophysiology is detectable using neuroimaging (Hanafi et al, 2020; Lersy et al, 2021; Newcombe et al, 2020), the persistence and effects of cerebrovascular dysfunction over the medium- and long-term remain unknown.…”

Characteristics and comparisons of acute stroke in “recovered" to “active COVID-19 and “pre-pandemic” in Qatar database

“…Our study suggests that COVID-19 did not contribute to the etiology of stroke once the patient recovers. There are however several factors related to COVID-19 that may increase the risk of stroke in patients who have recovered and these needs attention [13,14]. Potential mechanisms include continued endothelial injury [13], cardioembolism and potential paradoxical embolism via a PFO [15] or arterial dissection [16].…”

“…There are however several factors related to COVID-19 that may increase the risk of stroke in patients who have recovered and these needs attention [13,14]. Potential mechanisms include continued endothelial injury [13], cardioembolism and potential paradoxical embolism via a PFO [15] or arterial dissection [16]. While the recovery is complete following COVID-19 in most patients, the "long-haulers" may have prolonged illness and therefore are at risk for complications [17].…”

“…While the recovery is complete following COVID-19 in most patients, the "long-haulers" may have prolonged illness and therefore are at risk for complications [17]. COVID-19 infection results in injury to the arterial endothelium, resulting in a prothrombotic state [13]. The prothrombotic state may persist and increase the risk of stroke.…”

Case Report: Cerebrovascular Events Associated With Bacterial and SARS-CoV-2 Infections in an Adolescent

“…Beyond F. necrophorum's reported affinity to endothelial cells and effects on coagulation (19,20), well-described SARS-Cov-2 direct proinflammatory and pro-coagulant effects may represent additional risk factors for cerebrovascular events in the setting of LS. In patients with Covid-19, marked inflammatory status has been associated with stroke (3), and vasculitis related to endothelial cell infection via ACE2 receptors has been observed, with endothelial damage and increased subintimal inflammation, followed by hemorrhage or thrombosis (4,21). Diffuse endothelial inflammation leading to ischemia was demonstrated in several organs including kidney, small bowel, and lung (22).…”