Ischemic Stroke, Inflammation, and Endotheliopathy in COVID-19 Patients

Abstract

Background and Purpose: Reports indicate an increased risk of ischemic stroke during coronavirus disease 2019 (COVID-19) infection. We aimed to identify patients with COVID-19 and ischemic stroke and explore markers of inflammation, hypercoagulability, and endotheliopathy, a structural and functional disturbance of the vascular endothelium due to a stressor. Methods: This was a retrospective, observational cohort study comparing acute ischemic stroke patients with and without COVID-19 across 3 hospitals. Timing of stroke onset during COVID-19 course and markers of inflammation, hypercoagulability, and endothelial activation were evaluated by COVID-19 status and stroke cause. Results: Twenty-one patients with ischemic stroke were diagnosed with COVID-19 during the study period. Patients with COVID-19 had a similar age and burden of vascular risk factors compared with the control cohort (n=168). We identified a temporal correlation between stroke onset and the peak of acute phase reactants, including CRP (C-reactive protein), ferritin, and d-dimer. In subsets of patients with labs available, embolic stroke of undetermined source was associated with elevated IL (interleukin)-6 (median, 171 [interquartile range, 13–375] versus 8 [4–11], P <0.01) and sIL (soluble IL)-2 receptor (1972 [1525–4720] versus 767 [563–1408.5], P =0.05) levels. Stroke patients with COVID-19 demonstrated elevated levels of endothelial activation markers compared with non-COVID-19 stroke controls (median von Willebrand activity 285.0% [interquartile range, 234%–382%] versus 150% [128%–183%], P =0.034; von Willebrand antigen 330.0% [265%–650%] versus 152% [130%–277%], P =0.007, and factor VIII 301% [289%–402%] versus 49% [26%–94%], P <0.001). Conclusions: Ischemic stroke in patients with COVID-19 is associated with endotheliopathy and a systemic inflammatory response in patients with vascular risk factors. Further research evaluating endothelial and inflammatory markers in the setting of ischemic stroke and COVID-19 in larger, prospective cohorts is needed to validate the findings.

Update Advances on C-Reactive Protein in COVID-19 and Other Viral Infections

“…From clinical observations, it was noted elevated concentration of D-D dimer, fibrinogen, and CRP in COVID-19 patients with acute ischemic stroke, suggesting systemic hyperinflammatory and hypercoagulable state (34). In a retrospective, observational cohort study, CRP was found to be correlated between stroke onset and the peak of acute phase reactants in COVID-19 (35). Furthermore, CRP was the mortality predictor, and its expression might be correlated with the formation of ischemia in COVID-19 associated strokes (36).…”

Prior Stroke and Age Predict Acute Ischemic Stroke Among Hospitalized COVID-19 Patients: A Derivation and Validation Study

“…The average age of non-COVID-19 patients with ischemic stroke is around 74 years old; however, multiple cohorts worldwide have found that the average age of patients with COVID-19 and concurrent ischemic stroke is substantially younger, ranging between 54.9 and 64 years old (7,(36)(37)(38)(39). It is unclear why COVID-19 increases stroke risk in younger individuals out of proportion to what would be expected in non-COVID-19 cohorts, but we hypothesize that younger patients may be more susceptible to endothelial injury as we note in our previously published study from either the direct infection or an post-infectious immunologic pathway that needs to be further elucidated (5). There may also be selection bias at play, as older patients with COVID-19 may be more likely to withdraw care and less likely to undergo further stroke testing.…”

“…As of March 2021, the global pandemic caused by coronavirus disease 2019 (COVID- 19) has infected more than 120 million individuals worldwide and has resulted in more than 2.6 million deaths (1). Although COVID-19 commonly manifests as a respiratory illness, it is also linked with an increased risk of cerebrovascular disease by multiple potential pathophysiologic mechanisms, including inflammation, hypercoagulability, and endotheliopathy (2)(3)(4)(5). Among patients with COVID-19 in a cohort in Wuhan, China, those with a history of ischemic stroke had more co-morbidities, lower platelet and leukocyte counts, and higher D-dimer, pro-brain natriuretic peptide, and interleukin-6 levels compared to their counterparts without a prior history of stroke (6).…”

SARS-COV-2 – the pandemic of the XXI century, clinical manifestations – neurological implications

“…In addition, higher levels of IL-6 and sIL-2R were noted in COVID-19 patients. This evidence suggests endotheliopathy and systemic inflammation are more frequent in COVID-19 patients leading to ischemic stroke in patients with vascular risk factors compared to control groups [ 74 ].…”