Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium

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Abstract

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and d-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

Abstract

In this Consensus Statement, the authors delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess thrombotic risk in these patients. Consensus recommendations are made about the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombosis and in-hospital mortality.

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Fei Zhou, Ting Yu, Ronghui Du … (2020)

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Author and article information

Contributors

Diana A. Gorog:

ORCID: http://orcid.org/0000-0002-9286-1451

d.gorog@imperial.ac.uk

Journal

Journal ID (nlm-ta): Nat Rev Cardiol

Journal ID (iso-abbrev): Nat Rev Cardiol

Title: Nature Reviews. Cardiology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1759-5002

ISSN (Electronic): 1759-5010

Publication date (Electronic): 13 January 2022

Pages: 1-21

Affiliations

[1 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, National Heart and Lung Institute, Imperial College, ; London, UK

[2 ]GRID grid.5846.f, ISNI 0000 0001 2161 9644, School of Life and Medical Sciences, , University of Hertfordshire, ; Hatfield, UK

[3 ]GRID grid.11835.3e, ISNI 0000 0004 1936 9262, Cardiovascular Research Unit, Department of Infection, Immunity & Cardiovascular Disease, , University of Sheffield, ; Sheffield, UK

[4 ]GRID grid.415936.c, ISNI 0000 0004 0443 3575, Sinai Center for Thrombosis Research and Drug Development, , Sinai Hospital of Baltimore, ; Baltimore, MD USA

[5 ]GRID grid.240324.3, ISNI 0000 0001 2109 4251, New York University Grossman School of Medicine, ; New York, NY USA

[6 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Yong Loo-Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore

[7 ]GRID grid.488497.e, ISNI 0000 0004 1799 3088, National University Heart Centre, ; Singapore, Singapore

[8 ]GRID grid.5963.9, Cardiology and Angiology I and Medical Intensive Care, Faculty of Medicine, Medical Center, , University of Freiburg, ; Freiburg im Breisgau, Germany

[9 ]GRID grid.411778.c, ISNI 0000 0001 2162 1728, Cardiology, Medical Intensive Care, Angiology and Haemostaseology, , University Medical Centre Mannheim, ; Mannheim, Germany

[10 ]GRID grid.241054.6, ISNI 0000 0004 4687 1637, UAMS College of Medicine, , University of Arkansas for Medical Sciences, ; Little Rock, AR USA

[11 ]GRID grid.9909.9, ISNI 0000 0004 1936 8403, Leeds Institute of Cardiovascular and Metabolic Medicine, , University of Leeds, ; Leeds, UK

[12 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Cardiovascular Research Center-ICCC, Research Institute - Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, ; Barcelona, Spain

[13 ]GRID grid.510932.c, CiberCV, Institute Carlos III, ; Madrid, Spain

[14 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Universitat Autonoma de Barcelona, ; Barcelona, Spain

[15 ]GRID grid.415960.f, ISNI 0000 0004 0622 1269, St. Antonius Hospital, ; Nieuwegein, Netherlands

[16 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Cardiovascular Research Institute Maastricht (CARIM) and Thrombosis Expertise Center, , Maastricht University Medical Center, ; Maastricht, Netherlands

[17 ]GRID grid.410607.4, Center for Thrombosis and Haemostasis, , University Medical Center of Gutenberg University, ; Mainz, Germany

[18 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, ; Milan, Italy

[19 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Università degli Studi di Milano, Department of Pathophysiology and Transplantation, ; Milan, Italy

[20 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Medicine, Division of Infectious Diseases, , Stanford University, ; Stanford, CA USA

[21 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Microbiology and Immunology, , Stanford University, ; Stanford, CA USA

[22 ]GRID grid.499295.a, ISNI 0000 0004 9234 0175, Chan Zuckerberg Biohub, ; San Francisco, CA USA

[23 ]GRID grid.24827.3b, ISNI 0000 0001 2179 9593, Heart, Lung and Vascular Institute, , University of Cincinnati College of Medicine, ; Cincinnati, OH USA

Author information

Diana A. Gorog http://orcid.org/0000-0002-9286-1451

Robert F. Storey http://orcid.org/0000-0002-6677-6229

Lina Badimon http://orcid.org/0000-0002-9162-2459

Article

Publisher ID: 665

DOI: 10.1038/s41569-021-00665-7

PMC ID: 8757397

PubMed ID: 35027697

SO-VID: 910504a8-d2ca-4292-b1d5-7e858ecff2be

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium

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Novel Coronavirus Disease COVID-19

Most cited references 211

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

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