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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with coagulopathy causing venous and arterial thrombosis.1 2 Recent data from the pandemic epicentre in Wuhan, China, reported neurological complications in 36% of 214 patients with COVID-19; acute cerebrovascular disease (mainly ischaemic stroke) was more common among 88 patients with severe COVID-19 than those with non-severe disease (5.7% vs 0.8%).3 However, the mechanisms, phenotype and optimal management of ischaemic stroke associated with COVID-19 remain uncertain. We describe the demographic, clinical, radiological and laboratory characteristics of six consecutive patients assessed between 1st and 16th April 2020 at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK, with acute ischaemic stroke and COVID-19 (confirmed by reverse-transcriptase PCR (RT-PCR)) (table 1). All six patients had large vessel occlusion with markedly elevated D-dimer levels (≥1000μg/L). Three patients had multiterritory infarcts, two had concurrent venous thrombosis, and, in two, ischaemic strokes occurred despite therapeutic anticoagulation.
Demographic, clinical, radiological and laboratory findings
Supplemental material
Supplemental material
Patient 1
A 64-year-old man presented 10 days after COVID-19 symptom onset (cough, breathlessness, fever, myalgia and poor appetite), with respiratory failure warranting intensive care unit admission. Mycoplasma pneumoniae infection was treated with clarithromycin. On day 15, he developed mild left arm weakness and incoordination. MRI confirmed intradural left vertebral artery occlusion and acute left posterior inferior cerebellar artery territory infarction with petechial haemorrhage (online supplementary figure S1A). D-dimer was >80 000 µg/L. He received aspirin and clopidogrel. On day 19, he developed bilateral pulmonary embolism, treated with therapeutic low molecular weight heparin (LMWH). On day 22, he developed acute bilateral incoordination and right homonymous hemianopia; MRI brain showed extensive acute posterior cerebral artery territory infarction (online supplementary figure S1B); he received high-intensity LMWH anticoagulation.
Patient 2
A 53-year-old woman, taking warfarin for valvular atrial fibrillation (AF), presented 24 days after COVID-19 symptom onset (cough, dyspnoea), with acute confusion, incoordination and drowsiness; CT brain confirmed acute large left cerebellar and right parieto-occipital infarcts (online supplementary figure S1 C, D). D-dimer was 7750 µg/L, and the International Normalised Ratio (INR) 3.6 at the time of stroke symptoms. Following external ventricular drainage for hydrocephalus she was given therapeutic LMWH anticoagulation. She died following cardiorespiratory deterioration due to COVID-19 pneumonia.
Patient 3
An 85-year-old man presented 10 days after COVID-19 symptom onset with dysarthria and right hemiparesis. He had AF, hypertension and ischaemic heart disease. CT brain showed left posterior cerebral artery occlusion and infarction (online supplementary figure S1 E, F). D-dimer was 16 100 µg/L. He was treated with apixaban for AF secondary prevention.
Patient 4
A 61-year-old man with hypertension, previous stroke and high body mass index presented with dysarthria and left hemiparesis. MRI brain showed an acute right striatal infarct (online supplementary figure S1 G, H). D-dimer was 27 190 µg/L. Two days following admission, he developed respiratory symptoms. RT-PCR confirmed SARS-CoV-2 infection and CT pulmonary angiogram an embolus. He was treated with therapeutic LMWH.
Patient 5
An 83-year-old man with a history of hypertension, diabetes, ischaemic heart disease, heavy smoking and alcohol consumption, presented with dysarthria and left hemiparesis 15 days after COVID-19 symptom onset. CT angiogram showed thrombotic occlusion of a proximal M2 branch of the right middle cerebral artery (online supplementary figure S2 A); the following day an infarct was shown in the right insula (online supplementary figure S2B). D-dimer was 19 450 µg/L. He was treated with intravenous thrombolysis.
Patient 6
A 73-year-old man presented, 8 days after COVID-19 symptom onset, with dysphasia and right hemiparesis. MRI brain showed a thrombus in the basilar artery, bilateral P2 segment stenosis and multiple acute infarcts (right thalamus, left pons, right occipital lobe and right cerebellar hemisphere) (online supplementary figure S2 C, D, E, F). He received intravenous thrombolysis, after which D-dimer was 1080 µg/L.
Discussion
SARS-CoV-2infection is linked to a prothrombotic state causing venous and arterial thromboembolism and elevated D-dimer levels.2 Severe COVID-19 is associated with proinflammatory cytokines which induce endothelial and mononuclear cell activation with expression of tissue factor leading to coagulation activation and thrombin generation. Circulation of free thrombin, uncontrolled by natural anticoagulants, can activate platelets and lead to thrombosis.2 Although ischaemic stroke has been recognised as a complication of COVID-19 (usually with severe disease),3 the mechanisms and phenotype are not yet understood. Our observations suggest that acute ischaemic stroke accompanying COVID-19 infection may have distinct characteristics, with implications for diagnosis and treatment. All patients had large-vessel occlusion; in three these were in multiple territories. In two patients (1 and 2) one recurrent stroke and one initial ischaemic stroke, respectively, occurred despite therapeutic anticoagulation. Two patients had concurrent venous thromboembolism. Five patients had very high D-dimer levels (>7000 µg/L), substantially higher than the median level reported in COVID-19 (900 µg/L);3 the D-dimer for patient 6 was 1080 µg/L after intravenous thrombolysis. In five of six patients, ischaemic stroke occurred 8–24 days after COVID-19 symptom onset, and in one patient during the presymptomatic phase, suggesting that COVID-19 associated ischaemic stroke is usually delayed, but can occur both early and later in the course of the disease.
It has been suggested that COVID-19 might stimulate the production of antiphospholipid antibodies (aPL)4 as a mechanism of ischaemic stroke, although postinfection aPL are usually transient and unassociated with thrombosis. Five of six patients had a positive lupus anticoagulant, one with medium-titre IgM anticardiolipin and low-titre IgG and IgM anti–β2-glycoprotein-1 antibodies. Screening for aPL might be reasonable in patients with COVID-19 associated ischaemic stroke, although their pathogenic relevance remains uncertain. All patients had elevated ferritin and lactate dehydrogenase levels, both of which have been reported in severe COVID-19.1
Our data cannot confirm a causal relationship between SARS-CoV-2 and ischaemic stroke, since competing vascular risk factors and mechanisms were present in most patients (table 1); four of six had hypertension, and two had AF. It is also possible that the effects of social distancing measures and anxiety about attending hospital might have influenced the spectrum of ischaemic stroke mechanisms in patients seen at our hospital.
Nevertheless, our findings suggest that ischaemic stroke linked to COVID-19 infection can occur in the context of a systemic highly prothrombotic state, supporting recommendations for immediate prophylactic anticoagulation with LMWH.5 Early therapeutic anticoagulation with LMWH could also be beneficial to reduce thromboembolism in patients with COVID-19-associated ischaemic stroke but must be balanced against the risk of intracranial haemorrhage, including haemorrhagic transformation of the acute infarct; clinical trials are warranted to determine the safety and efficacy of this approach.
Footnotes
AC and DJW contributed equally.
Correction notice This paper has been corrected since it was published Online First. The following standard funding statement has been added, along with minor formatting changes. "This work was undertaken at UCLH/UCL which receives a proportion of funding from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme."
Contributors DJW and AC had the idea for the paper. RB prepared the first draft with DJW and AC. DJW prepared the draft figures. MEA and SS assisted with imaging interpretation and critically reviewed the manuscript for intellectual content. AC, DJW, RB, HC, SFF, YYG, FH, RJS, DT, NAL and RJP were involved in the clinical care of the patients and critically reviewed the manuscript for intellectual content. HRJ assisted with imaging interpretation and preparation of the figures, and critically reviewed the manuscript for intellectual content.
Funding This work was undertaken at UCLH/UCL which receives a proportion of funding from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme.
Competing interests DJW has received personal fees from Bayer, Alnylam and Portola, outside the submitted work
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; internally peer reviewed.