Acute ischemic stroke and COVID-19

Coagulopathy

Severely infected COVID-19 patients might be at risk of thromboembolic events from COVID-associated coagulopathy.^2,3,8,9 Hospitalized COVID-19 patients have been reported to have increased coagulation activity, marked by increased D-dimer concentrations.^3,8,10 In one study, a D-dimer value greater than 1 μg/mL was associated with fatal outcome of COVID-19.⁹ In another study, patients with both cerebrovascular disease and SARS-CoV-2 had higher D-dimer levels than SARS-CoV-2 patients without cerebrovascular disease (6.9 mg/L vs 0.5 mg/L, P < .001).⁴

At this time, it is unclear if elevated D-dimer values in COVID-19 are directly associated with either arterial or venous ischemic stroke, or both. There is only 1 recent report of cerebral venous sinus thrombosis in a 32-year-old with severe COVID-19, who was successfully managed with therapeutic anticoagulation.⁴

Antiphospholipid antibodies

Lupus anticoagulants and prolonged activated partial thromboplastin time are also frequently found in hospitalized COVID-19 patients, in whom the prevalence of lupus anticoagulant is 45% to 91%.^9–12 There is no clear association between lupus anticoagulant and thrombosis in these studies, but a case series reported the finding of antiphospholipid antibodies in 3 critically ill COVID-19 patients with bilateral cerebral infarcts in multiple vascular territories.¹² Laboratory investigations showed increased antiphospholipid antibodies, including anticardiolipin immunoglobulin A (IgA) IgA and beta-2 glycoprotein IgM and IgG, but without lupus anticoagulant.

This case series¹² suggested an acquired antiphospholipid syndrome was the underlying etiology, but unlike in the reported series of large-artery strokes in 5 young patients, these patients with antiphospholipid antibodies were over 60 years of age. The study did not provide information on other arterial or venous thromboembolism nor did it report the laboratory values or whether the patients had IgM or IgG antiphospholipid antibodies. In addition, 2 patients had prior strokes, and the underlying etiology for these prior events was not discussed. Finally, the questionable association of thrombosis with IgA antiphospholipid makes it difficult to determine a causal relationship.

These reports indicate the presence of antiphospholipid antibodies at variable frequencies, but likely higher than expected in the general population. Since their clinical significance is not yet known, these laboratory tests should not be routinely checked in COVID-19 patients without thrombosis.

Vasculitis

Other etiologies of ischemic stroke, such as virus-induced central nervous system vasculitis, were proposed when MERS and SARS patients had brain lesions in vascular patterns without a clear cerebrovascular etiology.^13,14 Postmortem histologic analysis of 3 COVID-19 patients revealed lymphocytic endotheliitis within the endothelial cells of multiple organs, including the lungs, heart, kidneys, small intestine, and liver.¹⁵

Endotheliitis can cause microcirculatory vasoconstriction and endothelial dysfunction with consequent ischemia and apoptosis.¹⁵ Direct viral infection of endothelial cells via angiotensin-converting enzyme 2 receptors, along with the host inflammatory response, may contribute to the wide spectrum of clinical sequalae of COVID-19.¹⁵ Histopathologic analysis of the central nervous system is needed to determine if SARS-CoV-2-related central nervous system vasculitis can occur due to lymphocytic endotheliitis.