Understanding COVID-19-associated coagulopathy

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Abstract

COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC.

Abstract

Here, the authors consider our emerging understanding of COVID-19-associated coagulopathy. They focus on the complex interactions between innate immune, coagulation and fibrinolytic pathways that can lead to potentially life-threatening thrombosis following SARS-CoV-2 infection.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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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

Kyung Moon:

ORCID: http://orcid.org/0000-0001-5809-1601

kyung.moon@nih.gov

James H. Morrissey:

ORCID: http://orcid.org/0000-0002-1570-1569

jhmorris@umich.edu

Journal

Journal ID (nlm-ta): Nat Rev Immunol

Journal ID (iso-abbrev): Nat Rev Immunol

Title: Nature Reviews. Immunology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1733

ISSN (Electronic): 1474-1741

Publication date (Electronic): 5 August 2022

Pages: 1-11

Affiliations

[1 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Centre for Blood Research, Life Sciences Institute, Department of Medicine, , University of British Columbia, ; Vancouver, British Columbia Canada

[2 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Medicine, UNC Blood Research Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[3 ]GRID grid.279885.9, ISNI 0000 0001 2293 4638, Molecular Cellular and Systems Blood Science Branch, Division of Blood Diseases and Resources, , National Heart, Lung, and Blood Institute, ; Bethesda, MD USA

[4 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Pathology and Laboratory Medicine, UNC Blood Research Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[5 ]GRID grid.214007.0, ISNI 0000000122199231, Department of Molecular Medicine, , The Scripps Research Institute, ; La Jolla, CA USA

[6 ]GRID grid.223827.e, ISNI 0000 0001 2193 0096, Department of Internal Medicine, Division of General Medicine, , University of Utah, ; Salt Lake City, UT USA

[7 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Epidemiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[8 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Internal Medicine, , Radboud University Medical Center, ; Nijmegen, the Netherlands

[9 ]GRID grid.30760.32, ISNI 0000 0001 2111 8460, Versiti Translational Glycomics Center, , Blood Research Institute and Medical College of Wisconsin, ; Milwaukee, WI USA

[10 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Department of Paediatrics, School of Medicine, , University of California at Irvine, ; Irvine, CA USA

[11 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Biological Chemistry, , University of Michigan Medical School, ; Ann Arbor, MI USA

[12 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Internal Medicine, , University of Michigan Medical School, ; Ann Arbor, MI USA

[13 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Present Address: Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, , National Institute of Allergy and Infectious Diseases, ; Bethesda, MD USA

Author information

Nigel Mackman http://orcid.org/0000-0002-9170-7700

Lisa E. Gralinski http://orcid.org/0000-0003-1374-8002

Kyung Moon http://orcid.org/0000-0001-5809-1601

James H. Morrissey http://orcid.org/0000-0002-1570-1569

Article

Publisher ID: 762

DOI: 10.1038/s41577-022-00762-9

PMC ID: 9362465

PubMed ID: 35931818

SO-VID: 5b7e9688-3ea6-49c2-8b62-c5c79c271b68

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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.

Understanding COVID-19-associated coagulopathy

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Novel Coronavirus Disease COVID-19

Most cited references 163

Clinical Characteristics of Coronavirus Disease 2019 in 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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