key: cord-0788266-1fqp3sl7 authors: Fara, Michael G.; Stein, Laura K.; Skliut, Maryna; Morgello, Susan; Fifi, Johanna T.; Dhamoon, Mandip S. title: Macrothrombosis and stroke in patients with mild Covid‐19 infection date: 2020-05-28 journal: J Thromb Haemost DOI: 10.1111/jth.14938 sha: 4e0385374b925fedb26a2cb19595549d04827718 doc_id: 788266 cord_uid: 1fqp3sl7 Coronavirus disease 2019 (COVID‐19) is a pandemic disease currently affecting millions of people worldwide. Its neurological implications are poorly understood, and further study is urgently required. A hypercoagulable state has been reported in patients with severe COVID‐19, but nothing is known about coagulopathy in patients with milder disease. We describe cases of patients in New York City presenting with stroke secondary to large vessel thrombosis without occlusion, incidentally found to have COVID‐19 with only mild respiratory symptoms. This is in contrast to the venous thrombosis and microangiopathy that has been reported in patients with severe COVID‐19. Our cases suggest that even in the absence of severe disease, patients with COVID‐19 may be at increased risk of thrombus formation leading to stroke, perhaps due to viral involvement of the endothelium. Further systematic study is needed, since this may have implications for primary and secondary stroke prevention in patients with COVID‐19. This article is protected by copyright. All rights reserved Coagulopathy in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection has been reported, 1 and there is evidence that the extent of coagulopathy correlates with severity of respiratory illness. 2 The predominant clinical sequelae of this coagulopathy have been venous thromboembolic events, 3 as well as end-organ failure secondary to a microangiopathy believed to be similar to disseminated intravascular coagulation. 4 Stroke is also recognized, and in the largest series to date, was seen in 5.7% of those with critical illness in comparison to 0.8% of those with milder COVID-19 disease. 5 As severity of COVID-19 illness correlates with both large artery ischemia and coagulopathy, it would seem plausible to associate the two phenomena. Herein, we describe three SARS-CoV-2 infected individuals with large artery stroke as their presenting illness in the absence of advanced COVID-19, and describe the details of their work up for coagulopathy. One of these patients has been summarized in a recent report of COVID-related stroke in patients under the age of 50. 6 The three patients presented to the emergency department with stroke-like symptoms, and were found to have sub-occlusive severe stenosis of the common carotid artery and stroke within that Accepted Article distribution. All three presented within two weeks in New York City during the SARS-CoV-2 outbreak in April 2020. None had severe respiratory symptoms, but all three tested positive for SARS-CoV-2 by reverse-transcriptase-polymerase-chain-reaction assay. One patient is a previously healthy 33-year-old woman who developed numbness of her left hand which quickly progressed to hemiplegia and hemisensory loss of the left face, arm, and leg. Computed tomography (CT) angiography revealed non-occlusive thrombus in the right common carotid artery, extending into the internal carotid artery, as well as lung findings suggestive of viral pneumonia ( Figure A) . Subsequent magnetic resonance (MR) imaging showed acute stroke within the territory of the right middle cerebral artery, with MR angiography showing no evidence of underlying arterial dissection. She complained of a recent cough, but did not develop fever or require supplemental oxygenation. She was treated initially with aspirin and clopidogrel, but later switched to apixaban 5 mg twice daily in accordance with our institution's emerging guidelines about venous thromboembolism prevention in the setting of SARS-CoV-2 infection. Repeat CT angiography ten days after presentation showed near-complete resolution of the thrombosis, and no sign of an underlying vascular abnormality ( Figure B ). The second patient is a 77-year-old woman with hypertension, hyperlipidemia, and bilateral thromboses of the deep leg veins discovered two months prior, prescribed aspirin, clopidogrel, and warfarin (although subtherapeutic on presentation), who developed the sudden onset of aphasia and left hemiparesis, and found to have non-occlusive thrombosis of the distal right common carotid artery ( Figure C) . She was coughing on presentation, and was found to be infected with SARS-CoV-2, but she did not develop a fever or require supplemental oxygenation. She was treated with enoxaparin 1 mg/kg every 12 hours, and on conventional angiography one week later the thrombosis had completely resolved, and the vessel appeared normal ( Figure D) . The third patient is a 55-year-old man with diabetes but no other prior medical history who presented with isolated left hand weakness which progressed to weakness of the left face, arm, and This article is protected by copyright. All rights reserved leg. CT angiography showed thrombosis within the right common carotid artery extending into the internal carotid artery, which appeared occlusive or near-occlusive, in addition to lung parenchymal changes suggestive of viral pneumonia ( Figure E) . He was taken for emergent conventional angiography, where the thrombosis was found to be non-occlusive. Eptifibatide was given intraarterially, and the degree of stenosis was noted to lessen ( Figure F) . No mechanical endovascular treatment was given, and he was subsequently treated with a heparin infusion. He had low-grade fever at presentation and required supplemental oxygenation but did not develop significant respiratory distress. testing positive for SARS-CoV-2, were sent on all three patients. Notably, only one (patient 2) had significantly elevated D-dimer levels, whereas all three had elevated C-reactive protein levels. Two of the three patients are young and without any evident source of thromboembolism; echocardiography was unremarkable and without evidence of patent foramen ovale. One patient had mildly elevated anti-cardiolipin antibodies, but otherwise none had serological evidence of the antiphospholipid syndrome or of hyperhomocysteinemia, conditions known to be associated with arterial thrombosis. 7 The third patient, although older and with vascular risk factors, also did not have radiographic or echocardiographic signs of a proximal source of thromboembolism. Taken together, these cases raise the possibility that in addition to the previously characterized venous thrombosis and microangiopathy potentially associated with SARS-CoV-2 infection, there may also be a tendency towards large-vessel arterial thrombosis, which has been reported in patients with SARS from a previous strain of the coronavirus. 8 There is an emerging hypothesis that virally mediated disruption of the endothelium may be playing a key role in thrombus formation in This article is protected by copyright. All rights reserved Accepted Article artery (C), and conventional angiography one week later shows resolution of the thrombus and no evidence of arterial dissection (D). For the third patient, digital subtraction angiography shows severe non-occlusive thrombus within the distal common carotid artery (E), with subsequent mild improvement in thrombus burden after local infusion of eptifibatide (F). This article is protected by copyright. All rights reserved Accepted Article Responsible for study design, literature review, drafting the initial manuscript, critical revising for intellectual content Responsible for study design, literature review, critical revising for intellectual content Responsible for patient selection, collection of clinical data Responsible for study design, literature review, critical revising for intellectual content Responsible for study design, patient selection, collection of clinical data Responsible for critical revising for intellectual content Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy COVID-19 complicated by acute pulmonary embolism Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China Large-vessel stroke as a presenting feature of Covid-19 in the young Prothrombotic states that predispose to stroke Large artery ischaemic stroke in severe acute respiratory syndrome (SARS) Is COVID-19 an endothelial disease? Clinical and basic evidence Endothelial cell infection and endotheliitis in COVID-19 Accepted ArticleR eferences None of the authors has any real or potential conflicts of interest to disclose.