Advertisement

Clinical Characteristics of Stroke with COVID-19: A Systematic Review and Meta-Analysis

      Abstract

      Background

      The coronavirus disease 2019 (COVID-19) potentially increases the risk of thromboembolism and stroke. Numerous case reports and retrospective cohort studies have been published with mixed characteristics of COVID-19 patients with stroke regarding age, comorbidities, treatment, and outcome. We aimed to depict the frequency and clinical characteristics of COVID-19 patients with stroke.

      Methods

      PubMed and EMBASE were searched on June 10, 2020, to investigate COVID-19 and stroke through retrospective cross-sectional studies, case series/reports according to PRISMA guidelines. Study-specific estimates were combined using one-group meta-analysis in a random-effects model.

      Results

      10 retrospective cohort studies and 16 case series/reports were identified including 183 patients with COVID-19 and stroke. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% ([95% confidential interval (CI)]: [0.6-1.6], I2 = 62.9%). Mean age was 66.6 ([58.4-74.9], I2 = 95.1%), 65.6% was male (61/93 patients). Mean days from symptom onset of COVID-19 to stroke was 8.0 ([4.1-11.9], p< 0.001, I2 = 93.1%). D-dimer was 3.3 μg/mL ([1.7-4.9], I2 = 86.3%), and cryptogenic stroke was most common as etiology at 50.7% ([31.0-70.4] I2 = 64.1%, 39/71patients). Case fatality rate was 44.2% ([27.9-60.5], I2 = 66.7%, 40/100 patients).

      Conclusions

      This systematic review assessed the frequency and clinical characteristics of stroke in COVID-19 patients. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% and associated with older age and stroke risk factors. Frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in COVID-19 associated with high mortality. Further study is needed to elucidate the pathophysiology and prognosis of stroke in COVID-19 to achieve most effective care for this population.

      Keywords

      Introduction

      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused ongoing worldwide pandemic.
      • Zhu N.
      • Zhang D.
      • Wang W.
      • et al.
      A novel coronavirus from patients with pneumonia in China, 2019.
      Clinical features of COVID-19 range from asymptomatic to fever, cough, shortness of breath, and even death.
      • Zhou P.
      • Yang X.L.
      • Wang X.G.
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      Associated neurological manifestation included mild disease such as dizziness, headache, impaired sense of smell and taste, and polyneuropathy, as well as impaired consciousness, stroke, seizure, and encephalitis.
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      • Sedaghat Z.
      • Karimi N.
      Guillain Barre syndrome associated with COVID-19 infection: A case report.
      • Zhao H.
      • Shen D.
      • Zhou H.
      • Liu J.
      • Chen S.
      Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
      • Toscano G.
      • Palmerini F.
      • Ravaglia S.
      • et al.
      Guillain-Barre Syndrome Associated with SARS-CoV-2.
      • Camdessanche J.P.
      • Morel J.
      • Pozzetto B.
      • Paul S.
      • Tholance Y.
      • Botelho-Nevers E.
      COVID-19 may induce Guillain-Barre syndrome.
      • Alberti P.
      • Beretta S.
      • Piatti M.
      • et al.
      Guillain-Barre syndrome related to COVID-19 infection.
      • Padroni M.
      • Mastrangelo V.
      • Asioli G.M.
      • et al.
      Guillain-Barre syndrome following COVID-19: new infection, old complication?.
      • Virani A.
      • Rabold E.
      • Hanson T.
      • et al.
      Guillain-Barre Syndrome associated with SARS-CoV-2 infection.
      • Poyiadji N.
      • Shahin G.
      • Noujaim D.
      • Stone M.
      • Patel S.
      • Griffith B.
      COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features.
      Increasing evidence suggests that coagulopathy due to COVID-19 leads to systemic arterial and venous thromboembolism including but not limited to acute ischemic stroke.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.
      • Helms J.
      • Tacquard C.
      • Severac F.
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      Initial case reports with stroke and COVID-19 were alarming consisted of young patients without comorbidities,
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.
      however, there were also reports of older patients with stroke risk factors and worse outcome.
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • et al.
      COVID-19 presenting as stroke.
      There were mixed laboratory data and case fatality rate in case series making it difficult to apprehend the overall characteristics of stroke with COVID-19. Herein, this systematic review and meta-analysis were conducted to illustrate the reported frequency of stroke in hospitalized COVID-19 patients, as well as the demographic and the clinical characterization of all reported patients with COVID-19 and stroke.

      Methods

      Protocol and registration

      A review protocol does not exist for this analysis.

      Eligibility criteria

      Included studies met the following criteria: the study design was an observational study or a case series or report, the study population was patients with COVID-19 patients and stroke. Articles that do not contain original data of the patients (e.g. guideline, editorial, review, and letter) were excluded from the secondary review.

      Information sources and search

      All observational studies, case series, and case reports which included patients with COVID-19 and stroke (ischemic or hemorrhagic) were identified using a 2-level strategy. First, databases including PubMed and EMBASE were searched through June 10th, 2020. Search terms included ((SARS-CoV2) OR (COVID-19)) AND ((stroke) OR (cerebrovascular accident) OR (cerebral infarction)). We did not apply language limitations.

      Study selection and data collection process

      Relevant studies were identified through a manual search of secondary sources including references of initially identified articles, reviews, and commentaries. All references were downloaded for consolidation, elimination of duplicates. Two independent authors (M.Y. and T.K.) reviewed the search results separately to select the studies based on present inclusion and exclusion criteria. Disagreements were resolved by consensus.

      Data items

      Outcomes included age, sex, comorbidities, symptoms, days from COVID-19 symptom onset to stroke, laboratory data such as d-dimer, C-reactive protein (CRP), and cardiac troponin, etiology, treatment, and case fatality rate. Among symptoms of stroke, any change in mental status such as lethargy, confusion, and coma were summated as altered mental status; this included patients who presented with new change in mental status, and those who continued to be comatose after weaning off of sedation for mechanical ventilation. Fall or syncope was not included in this category. Corresponding authors were contacted individually if there were any values suspicious for a misspelling.

      Risk of bias in individual studies

      Risk of bias in individual studies was reviewed using assessment of risk of bias in prevalence studies.
      • Hoy D.
      • Brooks P.
      • Woolf A.
      • et al.
      Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement.

      Summary measures and synthesis of results

      To attempt to calculate frequency of stroke in hospitalized COVID-19 patients, retrospective cohort studies focused on hospitalized COVID-19 patients were utilized. For other estimates (age, days from symptom onset of COVID-19 to stroke diagnosis, d-dimer, CRP, troponin, and case fatality rate), retrospective cohort studies which targeted other population and case series as well as case reports were added to the studies above and combined using one-group meta-analysis in a random-effects model using DerSimonian-Laird method for continuous value and Wald method for discrete value with OpenMetaAnalyst version 12.11.14 (available from http://www.cebm.brown.edu/openmeta/). The frequency of common comorbidities (hypertension, dyslipidemia, diabetes mellitus, acute coronary syndrome /coronary artery disease), atrial fibrillation, stroke/transient ischemic attack, and malignancy), etiology of stroke if specified in the articles, and treatment (tissue plasminogen activator (tPA), mechanical thrombectomy, and anticoagulation were calculated by summation of events divided by the number of total patients from all studies whose information is available for each value. Any anticoagulation therapy except prophylaxis for deep venous thrombosis preceding the stroke diagnosis was included in the calculation, and whether it was intended for treatment of stroke, therapeutic anticoagulation for other thromboembolic complication, or part of treatment protocol for acute respiratory distress syndrome in COVID-19, was delineated in the result section when available. The ProMeta 3 software was used to perform funnel plots (https://idostatistics.com/prometa3/) for age. We did our systematic review and meta-analysis according to PRISMA guidelines.

      Results

      Study selection and study characteristics

      The database search identified 215 articles that were reviewed based on the title and abstract. Of those, 186 articles were excluded based on article type (clinical guidelines, consensus documents, reviews, systematic reviews, and conference proceedings), conference abstracts, irrelevant topics, and articles without stroke with COVID-19. Twenty-nine articles met the inclusion criteria and were assessed for the systematic review (Fig. e-1). Nine articles were excluded for reasons including duplicate reports and article type. Six articles were added after the second search on June 10, 2020. There were 10 retrospective cohort studies, 6 case series, and 10 case reports with patients of interest.
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
      ,
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.
      ,
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • et al.
      COVID-19 presenting as stroke.
      ,
      • Cantador E.
      • Nunez A.
      • Sobrino P.
      • et al.
      Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients.
      • Co C.O.C.
      • Yu J.R.T.
      • Laxamana L.C.
      • David-Ona D.I.A.
      Intravenous Thrombolysis for Stroke in a COVID-19 Positive Filipino Patient, a Case Report.
      • Moshayedi P.
      • Ryan T.E.
      • Mejia L.L.P.
      • Nour M.
      • Liebeskind D.S.
      Triage of Acute Ischemic Stroke in Confirmed COVID-19: Large Vessel Occlusion Associated With Coronavirus Infection.
      • Sharifi-Razavi A.
      • Karimi N.
      • Zarvani A.
      • Cheraghmakani H.
      • Baghbanian S.M.
      Ischemic stroke associated with novel coronavirus 2019: a report of three cases.
      • Tunc A.
      • Unlubas Y.
      • Alemdar M.
      • Akyuz E.
      Coexistence of COVID-19 and acute ischemic stroke report of four cases.
      • Valderrama E.V.
      • Humbert K.
      • Lord A.
      • Frontera J.
      • Yaghi S.
      Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke.
      • Wang A.
      • Mandigo G.K.
      • Yim P.D.
      • Meyers P.M.
      • Lavine S.D.
      Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics.
      • Alay H.
      • Can F.K.
      • Gozgec E.
      Cerebral Infarction in an Elderly Patient with Coronavirus Disease.
      • Hossri S.
      • Shadi M.
      • Hamarsha Z.
      • Schneider R.
      • El-Sayegh D.
      Clinically significant anticardiolipin antibodies associated with COVID-19.
      • Malentacchi M.
      • Gned D.
      • Angelino V.
      • et al.
      Concomitant brain arterial and venous thrombosis in a COVID-19 patient.
      • Radmanesh A.
      • Raz E.
      • Zan E.
      • Derman A.
      • Kaminetzky M.
      Brain Imaging Use and Findings in COVID-19: A Single Academic Center Experience in the Epicenter of Disease in the United States.
      • Escalard S.
      • Maier B.
      • Redjem H.
      • et al.
      Treatment of acute ischemic stroke due to large vessel occlusion with COVID-19: Experience From Paris.
      • Kihira S.
      • Schefflein J.
      • Chung M.
      • et al.
      Incidental COVID-19 related lung apical findings on stroke CTA during the COVID-19 pandemic.

      Risk of bias in individual studies

      Summary of risk of bias for prevalence studies for each retrospective cohort study was shown in Table e-1.

      Results of individual studies and synthesis of results

      Extracted data as above is shown in Tables 1 and 2 for the retrospective cohort studies, and in Table e-2 for the case series and case reports.
      Table 1Results of Systematic Review with Cohort Studies of COVID-19 Positive Patients - Basic Characteristics.
      StudyCountryPopulationNumber of HospitalsCohort sizeStroke, % (N)AgeMale, % (N)Comorbidities, % (N)
      HTNDLPDMACS/CADAFStroke/TIAMalignancy
      Mao et al.ChinaHospitalized patients with COVID-19 infection between 1/16-2/19, 202032142.8% (6)NANANANANANANANANA
      Lodigiani et al.ItalyHospitalized patients with COVID-19 infection between 2/13-4/10, 202013382.7% (9)68.4±5.966.7% (6)NANANANANANA11.1% (1)
      Yaghi et al.USAHospitalized patients with COVID-19 infection between 3/15-4/19, 2020335560.9% (32)63±25NA56.3% (18)59.4% (19)34.4% (11)15.6% (5)18.8% (6)3.1% (1)NA
      Cantador et al.SpainHospitalized patients with COVID-19 infection between 2/1-4/21, 2020114190.56% (8)76.4±7.187.5% (7)100% (8)87.5% (7)50% (4)37.5% (3)25% (2)25% (2)62.5% (5)
      Romero Sanchez et al.SpainHospitalized patients with COVID-19 infection in March 202028411.3% (11)NANANANANANANANANA
      Merkler et al.USAPatients with emergency department visits or hospitalizations with COVID-19 infection between 3/4-5/2, 2020221321.5% (31)69±16.258.1% (18)96.8% (30)54.8% (17)74.2% (23)51.6% (16)54.8% (17)NANA
      Klok et al.NetherlandICU patients with COVID-1911842.7% (5)NANANANANANANANANA
      Radmanesh et al.USACOVID 19 positive patients who underwent MRI or CT in 3/1-3/31 at NYU12425.4% (13)NANANANANANANANANA
      Escalard et al.FrancePatients who had stroke with LVO from 3/1 to 4/1513727% (10)*59.5 [54, 71]80% (8)NANANANANANANA
      Kihira et al.USAPatients who had confirmed stroke in 3/16-4/564837.5% (18)*NANANANANANANANANA
      Value is shown as median [Q1, Q3] or mean±SD unless specified otherwise. Abbreviations: ACS/CAD – acute coronary syndrome/coronary artery disease; AF – atrial fibrillation; DM – Diabetes; HTN – hypertension; DLP – dyslipidemia; LVO: large vessel occlusion; NA – non-applicable; TIA – transient ischemic attack. * - who were COVID-19 positive.
      Table 2Results of Systematic Review with Cohort Studies of COVID-19 Positive Patients – Characteristics of Stroke, Treatment, and Mortality.
      StudyIschemic, % (N)Days from COVID-19 symptom onsetLaboratory dataEtiologyTreatmentMortality, % (N)
      D-dimer (μg/mL)CRP (mg/L)Cardiac troponin (ng/mL)CryptogenicCardioembolicAtherothrombictPAMechanical thrombectomyAC
      Mao et al.83.3% (5)9 [range 1-18]*NANANANANANANANANANA
      Lodigiani et al.100% (9)NA3.6 [0.4, 6.3]NANANANANA22.2% (2)22.2% (2)88.9% (8)NA
      Yaghi et al.100% (32)10 [5, 16.5]3.913 [2.549-10.000]101.1 [38.8, 214.3]0.7 [0.3125, 1.36]*365.6% (21)21.9% (7)6.3% (2)12.5% (4)21.9% (7)78.1% (25)37.5% (12)
      Cantador et al.100% (8)6.3±5.42.589 [0.735, 8.156]100.5 [27, 206]NA25% (2)25% (2)37.5% (8)12.5% (1)NAProphylactic 37.5% (3), therapeutic 12.5% (2)25% (2)
      Romero Sanchez et al.NA10⁎29.929±28.286NANANANANANANANANA
      Merkler et al.NA16 [5, 28]1.93 [0.559, 5.285]NA0.03 [0.03, 0.09]51.6% (16)41.9% (13)NA9.7% (3)6.5% (2)NA29% (9)
      Klok et al.NANANANANANANANANANANANA
      Radmanesh et al.100% (13)NANANANANANANANA23.1% (3)NANA
      Escalard et al.100% (10)6 [range 2-18]*NANANANANANA50% (5)100% (10)NA60% (6)
      Kihira et al.NANANANANANANANANANANANA
      Days from COVID-19 symptom onset, D-dimer, C-reactive protein (CRP), cardiac troponin – shown as median [Q1, Q3] or mean±SD unless specified otherwise. *1 – specified as “range” in the original article. *2 - mean. *3 - Only 15 patients out of 32 patients had available value in the article. AC – anticoagulation; NA – non-applicable; tPA – tissue plasminogen activator.
      Among the 10 retrospective cohort studies, 5 studies defined their population as hospitalized COVID-19 patients, 1 from China,
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      1 from Italy,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      2 from Spain,
      • Cantador E.
      • Nunez A.
      • Sobrino P.
      • et al.
      Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients.
      ,
      • Romero-Sanchez C.M.
      • Diaz-Maroto I.
      • Fernandez-Diaz E.
      • et al.
      Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry.
      and 1 from USA,
      • Yaghi S.
      • Ishida K.
      • Torres J.
      • et al.
      SARS2-CoV-2 and Stroke in a New York Healthcare System.
      with total of 6,368 individuals. The reported frequency of stroke in hospitalized COVID-19 patients was 1.1% ([95% confidential interval]: [0.6-1.6], I2=62.9%, 66/6,368 patients)
      • Mao L.
      • Jin H.
      • Wang M.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Cantador E.
      • Nunez A.
      • Sobrino P.
      • et al.
      Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients.
      ,
      • Romero-Sanchez C.M.
      • Diaz-Maroto I.
      • Fernandez-Diaz E.
      • et al.
      Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry.
      ,
      • Yaghi S.
      • Ishida K.
      • Torres J.
      • et al.
      SARS2-CoV-2 and Stroke in a New York Healthcare System.
      (Fig. 1A). The other 5 retrospective cohort studies set their population differently and thus were excluded from the calculation of the frequency of stroke in hospitalized COVID-19 patients.
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
      ,
      • Merkler A.E.
      • Parikh N.S.
      • Mir S.
      • et al.
      Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza.
      ,
      • Radmanesh A.
      • Raz E.
      • Zan E.
      • Derman A.
      • Kaminetzky M.
      Brain Imaging Use and Findings in COVID-19: A Single Academic Center Experience in the Epicenter of Disease in the United States.
      • Kihira S.
      • Schefflein J.
      • Chung M.
      • et al.
      Incidental COVID-19 related lung apical findings on stroke CTA during the COVID-19 pandemic.
      Figure 1
      Figure 1Forest plots for characteristics of stroke patients with COVID-19 (random-effects model); (A): The frequency of stroke in hospitalized COVID-19 patients; (B): Days from COVID-19 symptom onset to stroke; (C): D-dimer; (D): Case fatality rate.
      All 10 retrospective cohort studies and 16 case series and case reports were included for further analysis regarding age, symptoms of stroke, symptoms of COVID-19, days from COVID-19 onset to stroke diagnosis, d-dimer, CRP, troponin, the frequency of cryptogenic stroke as etiology if it is specified in the article, location of affected major intracranial arteries if specified, and mortality using one-group meta-analysis in a random-effects model (Fig. 1B-D, Fig. e-2). Mean age was 66.6 ([58.4-74.9], I2=95.2%). There was slight male preponderance at 65.6% (61/93 patients). The frequency of comorbidities and stroke risk factors were hypertension 69.4% (75/108 patients), dyslipidemia 44.4% (48/108 patients), diabetes 43.5% (47/108 patients), acute coronary syndrome/coronary artery disease 26.9% (29/108 patients), atrial fibrillation 23.1% (25/108 patients), prior stroke/transient ischemic attack 10.4% (8/77 patients), and malignancy 14.8% (8/54 patients). Of note, prior anticoagulation status for patients with atrial fibrillation was not available in majority of included studies, and thus was not included in this analysis.
      Of those who stroke type (ischemic vs hemorrhagic) were described, 96.6% (113/117 patients) had ischemic stroke. The three most common presenting symptoms of stroke gathered mainly from case series and case reports were unilateral weakness (65.7%, 23/35 patients), altered mental status (51.4%, 18/35 patients), and dysarthria (34.3%, 12/35 patients). As for symptoms of COVID-19, cough was most common (77.6%, 59/76 patients), followed by fever (63.2%, 48/76 patients) and dyspnea or hypoxia (62.1%, 41/66 patients). Mean days from symptom onset of COVID-19 to stroke was 8.0 ([4.1-11.9], I2=93.1%) (Fig. 1B). Mean d-dimer was 3.3 μg/mL ([1.7-4.9], I2=86.3%) (Fig. 1C) and elevated, mean CRP was 127.8 mg/L ([100.9-154.6], I2 = 0%) also elevated, however, mean troponin was 0.051 ng/mL ([0.002-0.099], I2 = 91.5%) and was not significantly high. In regards to the etiology of stroke specified by the authors, 50.7% was cryptogenic ([31.0-70.4] I2=64.1%, 39/71patients). Affected major intracranial arteries were middle cerebral arteries (30.5%, 25/82 patients), internal carotid arteries (18.3%, 15/82 patients), vertebrobasilar arteries (7.3%, 6/82 patients), posterior cerebral arteries (3.7%, 3/82 patients). Of those patients whose detail of stroke localization was available, 29.2% had multifocal stroke (14/48 patients). As for acute treatment, 21.8% (24/110 patients) received tPA, 28.3% (34/120 patients) underwent mechanical thrombectomy. Anticoagulation was documented in 61.3% (46/75 patients); of those, 1 patient was getting therapeutic anticoagulation for pulmonary embolism before diagnosis of stroke,
      • Beyrouti R.
      • Adams M.E.
      • Benjamin L.
      • et al.
      Characteristics of ischaemic stroke associated with COVID-19.
      and another patient was started on therapeutic anticoagulation as part of treatment for acute respiratory distress syndrome from COVID-19, however the timing of anticoagulation in relation to the stroke occurrence was unavailable.
      • Deliwala S.
      • Abdulhamid S.
      • Abusalih M.F.
      • Al-Qasmi M.M.
      • Bachuwa G.
      Encephalopathy as the sentinel sign of a cortical stroke in a patient infected with coronavirus disease-19 (COVID-19).
      Other patients were started on anticoagulation therapy for stroke treatment. Case fatality rate was 44.2% (40/100 patients) ([27.9-60.5], I2=66.7%) (Fig. 1D). Funnel plot for age is shown in Supplemental Figure e-3 (Egger's test: p=0.97).

      Discussion

      This systematic review of 26 studies identified 183 COVID-19 patients with stroke. The salient findings of the study can be summarized as the followings; (1) the frequency of stroke in hospitalized COVID-19 patients was 1.1%, with mean days from COVID-19 symptom onset to stroke at 8 days, most commonly cryptogenic; (2) even with early case series with younger patients without a pre-existing medical condition, the mean age was 66.6, with slight male preponderance (65.6%); (3) stroke risk factors such as hypertension, dyslipidemia, and prior strokes were common as comorbidities; altered mental status was as frequent as 51.4% as presenting symptom of stroke; (4) elevation of d-dimer and CRP were reproduced after synthesis of results; (5) case fatality rate was as high as 44.2% in patients with COVID-19 and stroke.
      We revealed the frequency of stroke in hospitalized COVID-19 patients was 1.1%. Stroke incidence in general population is estimated from 0.6 to 0.8%.
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association.
      Infection, particularly systemic upper respiratory illness is an important precipitating risk factor for acute ischemic stroke.
      • Boehme A.K.
      • Luna J.
      • Kulick E.R.
      • Kamel H.
      • Elkind M.S.V.
      Influenza-like illness as a trigger for ischemic stroke.
      • Elkind M.S.
      • Carty C.L.
      • O'Meara E.S.
      • et al.
      Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study.
      • Smeeth L.
      • Thomas S.L.
      • Hall A.J.
      • Hubbard R.
      • Farrington P.
      • Vallance P.
      Risk of myocardial infarction and stroke after acute infection or vaccination.
      Notably, Boehme et al. reported that risk of acute stroke increases 9 times in young population aged 18-45 within 15 days from onset of influenza-like illness.
      • Boehme A.K.
      • Luna J.
      • Kulick E.R.
      • Kamel H.
      • Elkind M.S.V.
      Influenza-like illness as a trigger for ischemic stroke.
      Furthermore, patients with emergency department visits and hospitalizations with COVID-19 were reported to be approximately seven times as likely to have an acute ischemic stroke as compared to patients with emergency department visits or hospitalizations with influenza.
      • Merkler A.E.
      • Parikh N.S.
      • Mir S.
      • et al.
      Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza.
      Previous study revealed that stroke risk increases after a systemic respiratory tract infection at most within 3 days from symptom onset.
      • Smeeth L.
      • Thomas S.L.
      • Hall A.J.
      • Hubbard R.
      • Farrington P.
      • Vallance P.
      Risk of myocardial infarction and stroke after acute infection or vaccination.
      On the contrary, the days from symptom onset to stroke with COVID-19 in our study was 8 days, longer than other systemic respiratory infection in pre-COVID-19 era,
      • Smeeth L.
      • Thomas S.L.
      • Hall A.J.
      • Hubbard R.
      • Farrington P.
      • Vallance P.
      Risk of myocardial infarction and stroke after acute infection or vaccination.
      potentially supporting late thromboembolism complications caused by immune-mediated coagulopathy of COVID-19.
      • McFadyen J.D.
      • Stevens H.
      • Peter K.
      The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.
      However, this duration between symptom onset of COVID-19 and stroke was variable as represented by a high heterogeneity, and it is notable that some patients presented with stroke even without COVID-19 symptoms.
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.
      Most common etiology of stroke was cryptogenic up to 50.7% which is twice as high as that of general population at 25%.
      • Saver J.L.
      Cryptogenic stroke.
      29.2% had multifocal stroke among patients whose detail of stroke was available. Collectively, SARS-CoV-2 is potentially a higher precipitating factor for acute ischemic stroke compared to other classic respiratory infection such as influenza, possibly via immune mediated coagulopathy.
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      • Helms J.
      • Tacquard C.
      • Severac F.
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      Early in the course of the pandemic, several cases of younger patients without comorbidities were reported
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.
      ,
      • Gonzalez-Pinto T.
      • Luna-Rodriguez A.
      • Moreno-Estebanez A.
      • Agirre-Beitia G.
      • Rodriguez-Antiguedad A.
      • Ruiz-Lopez M.
      Emergency room neurology in times of COVID-19: malignant ischaemic stroke and SARS-CoV-2 infection.
      ,
      • Gunasekaran K.
      • Amoah K.
      • Rajasurya V.
      • Buscher M.G.
      Stroke in a young COVID -19 patient.
      ; however, our synthesized results re-demonstrated classic demographics of the population who are at risk for stroke even in COVID-19 patients, including older age, male gender, and pre-existing medical condition such as hypertension, dyslipidemia, and diabetes. Altered mental status was seen in 51.4% as presenting symptom of stroke, which is more frequent than stroke in general (15–23% in one study).
      • Lisabeth L.D.
      • Brown D.L.
      • Hughes R.
      • Majersik J.J.
      • Morgenstern L.B.
      Acute stroke symptoms: comparing women and men.
      Decreased level of consciousness is reported to be a risk factor for missed diagnosis of stroke in emergency room.
      • Madsen T.E.
      • Khoury J.
      • Cadena R.
      • et al.
      Potentially Missed Diagnosis of Ischemic Stroke in the Emergency Department in the Greater Cincinnati/Northern Kentucky Stroke Study.
      Along with delayed presentation and concurrent fever, this could potentially explain the relatively low rates of tPA administration; however, further investigation is needed to depict the safety and effectivity of tPA in patients with stroke and COVID-19.
      D-dimer and CRP were elevated on average at 3.3 μg/mL and 127.8 mg/L respectively in our study. Previous report pointed out d-dimer greater than 1 μg/mL is a risk factor for severe COVID-19 and mortality.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Lippi G.
      • Cervellin G.
      • Casagranda I.
      • Morelli B.
      • Testa S.
      • Tripodi A.
      D-dimer testing for suspected venous thromboembolism in the emergency department. Consensus document of AcEMC, CISMEL, SIBioC, and SIMeL.
      Other report demonstrated d-dimer >2.5 μg/mL and CRP >200 mg/L were related to critical illness of COVID-19, which may be associated with higher risk of hyper-inflammatory states and hypercoagulability and resultant pulmonary emboli and microscopic emboli.
      • Petrilli C.M.
      • Jones S.A.
      • Yang J.
      • et al.
      Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.
      As a marker for acute inflammation and coagulopathy, elevated d-dimer was an adverse prognostic factor in H1N1 influenza in 2009
      • Wang Z.F.
      • Su F.
      • Lin X.J.
      • et al.
      Serum D-dimer changes and prognostic implication in 2009 novel influenza A(H1N1).
      ,
      • Davey Jr., R.T.
      • Lynfield R.
      • Dwyer D.E.
      • et al.
      The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies.
      and also in acute ischemic stroke.
      • Sato T.
      • Sato S.
      • Yamagami H.
      • et al.
      D-dimer level and outcome of minor ischemic stroke with large vessel occlusion.
      Since elevated d-dimer could be used as a risk assessment biomarker of recurrent stroke in general
      • You L.R.
      • Tang M.
      The association of high D-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: A retrospective study.
      ,
      • Choi K.H.
      • Seo W.K.
      • Park M.S.
      • et al.
      Baseline D-Dimer Levels as a Risk Assessment Biomarker for Recurrent Stroke in Patients with Combined Atrial Fibrillation and Atherosclerosis.
      and previous observational study showed that anticoagulation might be associated with improved outcomes among patients hospitalized with COVID-1956, patients with stroke and COVID-19 might benefit from anticoagulation therapy, especially with cryptogenic stroke.
      • Paranjpe I.
      • Fuster V.
      • Lala A.
      • et al.
      Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19.
      However, patients who are intubated under sedation with poor neurological exam warrant extra caution before initiating anticoagulation, since those patients could be at higher risk of ischemic stroke that could have hemorrhagic conversion undetected.
      • Dogra S.
      • Jain R.
      • Cao M.
      • et al.
      Hemorrhagic stroke and anticoagulation in COVID-19.
      Neuroimaging should be considered in this population prior to anticoagulation to avoid iatrogenic hemorrhagic conversion of undiagnosed ischemic stroke.
      Lastly, the case fatality rate in this population with stroke and COVID-19 was conspicuously high at 44.2%. It is higher than mortality from stroke in general population that differs significantly by age; according to a report of Medicare beneficiaries over the time period 1995 to 2002, the 30-day mortality rate was: 9% in patients 65 to 74 years of age, 13.1% in those 74 to 84 years of age, and 23% in those older than 85 years of age.
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association.
      Mortality in hospitalized COVID-19 patients reported in the early course of pandemic ranged from 4 to 28%.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Chen N.
      • Zhou M.
      • Dong X.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      • Chen T.
      • Wu D.
      • Chen H.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      This discrepancy in mortality of COVID-19 patients with and without stroke could be secondary to withdrawal of medical care when the neurological prognosis is grave
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • et al.
      COVID-19 presenting as stroke.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Wang A.
      • Mandigo G.K.
      • Yim P.D.
      • Meyers P.M.
      • Lavine S.D.
      Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics.
      ; another possibility is that stroke is part of multi-organ failure and systemic coagulopathy whose mortality is higher than COVID-19 patients in general. Notably, prior stroke has been described as a risk factor for severe disease in COVID-19 patients even without concurrent acute stroke, which could potentially support vulnerability of patients with cerebrovascular disease to COVID-19 from undetermined cause.
      • Aggarwal G.
      • Cheruiyot I.
      • Aggarwal S.
      • et al.
      Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis.
      The cause of death in this population remains unclear with our study due to limited details about the cause of death from large cohort studies. Further study is needed to elucidate pathophysiology and risk factors for stroke as well as outcome and best treatment measures in hope to lower mortality in COVID-19 patients with stroke.
      This study has several limitations. First, this systematic review covered a brief period, and therefore the sample size may still be limited. Second, only limited value was available ubiquitously in the reviewed studies. Third, there was a substantial heterogeneity in patient population given high I2 and different inclusion criteria of the studies used in this analysis, such as hospitalization, requirement of intensive care, and large vessel occlusion that warranted mechanical thrombectomy. In addition, the case reports and case series that were included in this review could potentially have publication bias that more severe cases in a younger population without risk factors with large stroke burden tend to be published as this type of articles, compared to those who had stroke risk factors as comorbidities and suffered small lacunar strokes and COVID-19. Furthermore, reported incidence of acute stroke could be lower than actual, since subtle signs of small stroke could have been missed by the providers especially when patients with COVID-19 were sedated and intubated.

      Conclusions

      This systematic review assessed the clinical characteristics of stroke in patients with COVID-19. The frequency of stroke in hospitalized COVID-19 patients was 1.1% and associated with older age and stroke risk factors. Frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in COVID-19 associated with high mortality. Further studies such as prospective collaborative international registries are helpful to decipher the pathophysiology and prognosis of stroke in COVID-19 to achieve the most effective care for this population to decrease mortality.

      Declaration of Competing Interest

      There is no conflict of interest of this study.

      Acknowledgments

      None

      Funding

      None.

      Appendix. Supplementary materials

      References

        • Zhu N.
        • Zhang D.
        • Wang W.
        • et al.
        A novel coronavirus from patients with pneumonia in China, 2019.
        N Engl J Med. 2020; 382: 727-733
        • Zhou P.
        • Yang X.L.
        • Wang X.G.
        • et al.
        A pneumonia outbreak associated with a new coronavirus of probable bat origin.
        Nature. 2020; 579: 270-273
        • Mao L.
        • Jin H.
        • Wang M.
        • et al.
        Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
        JAMA Neurol. 2020; 77: 683-690
        • Sedaghat Z.
        • Karimi N.
        Guillain Barre syndrome associated with COVID-19 infection: A case report.
        J Clin Neurosci Off J Neurosurg Soc Aust. 2020; 76: 233-235
        • Zhao H.
        • Shen D.
        • Zhou H.
        • Liu J.
        • Chen S.
        Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
        Lancet Neurol. 2020; 19: 383-384
        • Toscano G.
        • Palmerini F.
        • Ravaglia S.
        • et al.
        Guillain-Barre Syndrome Associated with SARS-CoV-2.
        N Engl J Med. 2020; 382: 2574-2576
        • Camdessanche J.P.
        • Morel J.
        • Pozzetto B.
        • Paul S.
        • Tholance Y.
        • Botelho-Nevers E.
        COVID-19 may induce Guillain-Barre syndrome.
        Rev Neurol (Paris). 2020; 176: 516-518
        • Alberti P.
        • Beretta S.
        • Piatti M.
        • et al.
        Guillain-Barre syndrome related to COVID-19 infection.
        Neurol(R) Neuroimmunol Neuroinflammation. 2020; 7: e741
        • Padroni M.
        • Mastrangelo V.
        • Asioli G.M.
        • et al.
        Guillain-Barre syndrome following COVID-19: new infection, old complication?.
        J Neurol. 2020; 267: 1877-1879
        • Virani A.
        • Rabold E.
        • Hanson T.
        • et al.
        Guillain-Barre Syndrome associated with SARS-CoV-2 infection.
        IDCases. 2020; : e00771
        • Poyiadji N.
        • Shahin G.
        • Noujaim D.
        • Stone M.
        • Patel S.
        • Griffith B.
        COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features.
        Radiology. 2020; : 201187
        • Lodigiani C.
        • Iapichino G.
        • Carenzo L.
        • et al.
        Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
        Thromb Res. 2020; 191: 9-14
        • Klok F.A.
        • Kruip M.
        • van der Meer N.J.M.
        • et al.
        Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
        Thromb Res. 2020; 191: 148-150
        • Zhang Y.
        • Xiao M.
        • Zhang S.
        • et al.
        Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.
        N Engl J Med. 2020; 382: e38
        • Helms J.
        • Tacquard C.
        • Severac F.
        • et al.
        High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
        Intensive Care Med. 2020; 46: 1089-1098
        • Oxley T.J.
        • Mocco J.
        • Majidi S.
        • et al.
        Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.
        N Engl J Med. 2020; 382: e60
        • Avula A.
        • Nalleballe K.
        • Narula N.
        • et al.
        COVID-19 presenting as stroke.
        Brain Behav Immun. 2020; 87: 115-119
        • Hoy D.
        • Brooks P.
        • Woolf A.
        • et al.
        Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement.
        J Clin Epidemiol. 2012; 65: 934-939
        • Cantador E.
        • Nunez A.
        • Sobrino P.
        • et al.
        Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients.
        J Thromb Thrombolysis. 2020;
        • Merkler A.E.
        • Parikh N.S.
        • Mir S.
        • et al.
        Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza.
        JAMA Neurol. 2020; (Published online July 2, (was preprint in medRxiv at the time of systematic review))https://doi.org/10.1001/jamaneurol.2020.2730
        • Romero-Sanchez C.M.
        • Diaz-Maroto I.
        • Fernandez-Diaz E.
        • et al.
        Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry.
        Neurology. 2020; 95: e1060-e1070
        • Yaghi S.
        • Ishida K.
        • Torres J.
        • et al.
        SARS2-CoV-2 and Stroke in a New York Healthcare System.
        Stroke. 2020; 51 (STROKEAHA120030335): 2002-2011
        • Beyrouti R.
        • Adams M.E.
        • Benjamin L.
        • et al.
        Characteristics of ischaemic stroke associated with COVID-19.
        J Neurol Neurosurg Psychiatry. 2020; 91: 889-891
        • Co C.O.C.
        • Yu J.R.T.
        • Laxamana L.C.
        • David-Ona D.I.A.
        Intravenous Thrombolysis for Stroke in a COVID-19 Positive Filipino Patient, a Case Report.
        J Clin Neurosci Off J Neurosurg Soc Aust. 2020; 77: 234-236
        • Deliwala S.
        • Abdulhamid S.
        • Abusalih M.F.
        • Al-Qasmi M.M.
        • Bachuwa G.
        Encephalopathy as the sentinel sign of a cortical stroke in a patient infected with coronavirus disease-19 (COVID-19).
        Cureus. 2020; 12: e8121
        • Gonzalez-Pinto T.
        • Luna-Rodriguez A.
        • Moreno-Estebanez A.
        • Agirre-Beitia G.
        • Rodriguez-Antiguedad A.
        • Ruiz-Lopez M.
        Emergency room neurology in times of COVID-19: malignant ischaemic stroke and SARS-CoV-2 infection.
        Eur J Neurol. 2020; 27: e35-e36
        • Gunasekaran K.
        • Amoah K.
        • Rajasurya V.
        • Buscher M.G.
        Stroke in a young COVID -19 patient.
        QJM Mon J Assoc Phys. 2020; 113: 573-574
        • Morassi M.
        • Bagatto D.
        • Cobelli M.
        • et al.
        Stroke in patients with SARS-CoV-2 infection: case series.
        J Neurol. 2020; 267: 2185-2192
        • Moshayedi P.
        • Ryan T.E.
        • Mejia L.L.P.
        • Nour M.
        • Liebeskind D.S.
        Triage of Acute Ischemic Stroke in Confirmed COVID-19: Large Vessel Occlusion Associated With Coronavirus Infection.
        Front Neurol. 2020; 11: 353
        • Sharifi-Razavi A.
        • Karimi N.
        • Zarvani A.
        • Cheraghmakani H.
        • Baghbanian S.M.
        Ischemic stroke associated with novel coronavirus 2019: a report of three cases.
        Int J Neurosci. 2020; : 1-5
        • Tunc A.
        • Unlubas Y.
        • Alemdar M.
        • Akyuz E.
        Coexistence of COVID-19 and acute ischemic stroke report of four cases.
        J Clin Neurosci. 2020; 77: 227-229
        • Valderrama E.V.
        • Humbert K.
        • Lord A.
        • Frontera J.
        • Yaghi S.
        Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke.
        Stroke. 2020; 51 (STROKEAHA120030153): e124-e127
        • Wang A.
        • Mandigo G.K.
        • Yim P.D.
        • Meyers P.M.
        • Lavine S.D.
        Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics.
        J Neurointerventional Surg. 2020; 12: 648-653
        • Alay H.
        • Can F.K.
        • Gozgec E.
        Cerebral Infarction in an Elderly Patient with Coronavirus Disease.
        Rev Soc Bras Med Trop. 2020; 53e20200307
        • Hossri S.
        • Shadi M.
        • Hamarsha Z.
        • Schneider R.
        • El-Sayegh D.
        Clinically significant anticardiolipin antibodies associated with COVID-19.
        J Crit Care. 2020; 59: 32-34
        • Malentacchi M.
        • Gned D.
        • Angelino V.
        • et al.
        Concomitant brain arterial and venous thrombosis in a COVID-19 patient.
        Eur J Neurol. 2020; 27: e38-e39
        • Radmanesh A.
        • Raz E.
        • Zan E.
        • Derman A.
        • Kaminetzky M.
        Brain Imaging Use and Findings in COVID-19: A Single Academic Center Experience in the Epicenter of Disease in the United States.
        AJNR Am J Neuroradiol. 2020; 41: 1179-1183
        • Escalard S.
        • Maier B.
        • Redjem H.
        • et al.
        Treatment of acute ischemic stroke due to large vessel occlusion with COVID-19: Experience From Paris.
        Stroke. 2020; 51 (STROKEAHA120030574): 2540-2543
        • Kihira S.
        • Schefflein J.
        • Chung M.
        • et al.
        Incidental COVID-19 related lung apical findings on stroke CTA during the COVID-19 pandemic.
        J Neurointerventional Surg. 2020; 12: 669-672
        • Benjamin E.J.
        • Blaha M.J.
        • Chiuve S.E.
        • et al.
        Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association.
        Circulation. 2017; 135: e146-e603
        • Boehme A.K.
        • Luna J.
        • Kulick E.R.
        • Kamel H.
        • Elkind M.S.V.
        Influenza-like illness as a trigger for ischemic stroke.
        Ann Clin Transl Neurol. 2018; 5: 456-463
        • Elkind M.S.
        • Carty C.L.
        • O'Meara E.S.
        • et al.
        Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study.
        Stroke. 2011; 42: 1851-1856
        • Smeeth L.
        • Thomas S.L.
        • Hall A.J.
        • Hubbard R.
        • Farrington P.
        • Vallance P.
        Risk of myocardial infarction and stroke after acute infection or vaccination.
        N Engl J Med. 2004; 351: 2611-2618
        • McFadyen J.D.
        • Stevens H.
        • Peter K.
        The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.
        Circ Res. 2020; 127: 571-587
        • Saver J.L.
        Cryptogenic stroke.
        N Engl J Med. 2016; 375: e26
        • Lisabeth L.D.
        • Brown D.L.
        • Hughes R.
        • Majersik J.J.
        • Morgenstern L.B.
        Acute stroke symptoms: comparing women and men.
        Stroke. 2009; 40: 2031-2036
        • Madsen T.E.
        • Khoury J.
        • Cadena R.
        • et al.
        Potentially Missed Diagnosis of Ischemic Stroke in the Emergency Department in the Greater Cincinnati/Northern Kentucky Stroke Study.
        Acad Emerg Med Off J Soc Acad Emerg Med. 2016; 23: 1128-1135
        • Zhou F.
        • Yu T.
        • Du R.
        • et al.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        Lancet. 2020; 395: 1054-1062
        • Lippi G.
        • Cervellin G.
        • Casagranda I.
        • Morelli B.
        • Testa S.
        • Tripodi A.
        D-dimer testing for suspected venous thromboembolism in the emergency department. Consensus document of AcEMC, CISMEL, SIBioC, and SIMeL.
        Clin Chem Lab Med. 2014; 52: 621-628
        • Petrilli C.M.
        • Jones S.A.
        • Yang J.
        • et al.
        Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.
        BMJ. 2020; 369: m1966
        • Wang Z.F.
        • Su F.
        • Lin X.J.
        • et al.
        Serum D-dimer changes and prognostic implication in 2009 novel influenza A(H1N1).
        Thromb Res. 2011; 127: 198-201
        • Davey Jr., R.T.
        • Lynfield R.
        • Dwyer D.E.
        • et al.
        The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies.
        PLoS One. 2013; 8: e57121
        • Sato T.
        • Sato S.
        • Yamagami H.
        • et al.
        D-dimer level and outcome of minor ischemic stroke with large vessel occlusion.
        J Neurol Sci. 2020; 413116814
        • You L.R.
        • Tang M.
        The association of high D-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: A retrospective study.
        Med (Baltimore). 2018; 97: e12622
        • Choi K.H.
        • Seo W.K.
        • Park M.S.
        • et al.
        Baseline D-Dimer Levels as a Risk Assessment Biomarker for Recurrent Stroke in Patients with Combined Atrial Fibrillation and Atherosclerosis.
        J Clin Med. 2019; 8: 1457
        • Paranjpe I.
        • Fuster V.
        • Lala A.
        • et al.
        Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19.
        J Am Coll Cardiol. 2020; 76: 122-124
        • Dogra S.
        • Jain R.
        • Cao M.
        • et al.
        Hemorrhagic stroke and anticoagulation in COVID-19.
        J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2020; 29104984
        • Chen N.
        • Zhou M.
        • Dong X.
        • et al.
        Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
        Lancet. 2020; 395: 507-513
        • Chen T.
        • Wu D.
        • Chen H.
        • et al.
        Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
        BMJ. 2020; 368: m1091
        • Huang C.
        • Wang Y.
        • Li X.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        Lancet. 2020; 395: 497-506
        • Wang D.
        • Hu B.
        • Hu C.
        • et al.
        Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
        JAMA. 2020; 323: 1061-1069
        • Aggarwal G.
        • Cheruiyot I.
        • Aggarwal S.
        • et al.
        Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis.
        Curr Probl Cardiol. 2020; 45100617