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Coagulopathy in COVID-19: Connecting the Dots Together

Authors:
  • Werfen Academy India
  • TEM Innovations GmbH, Munich

Abstract

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus has spread quickly and become a public health emergency of global concern. Originating in the Wuhan district of China, which has reportedly been declared free of it now, the rest of the world continues to struggle with its severity and spread. While a lot of scientific publications and clinical data are available, newer clinical investigations and experiences continue to evolve, thereby depicting the dynamic nature of the disease and the knowledge around it. Researchers and clinical professionals continue to collect scientific information, clinical data, and evidence to help build a knowledge pool and guidance for the health care professionals to manage those affected with this pandemic disease. As significant and new data emerge, a lot of already available information gets confirmed and updated, while some of it also getting rejected or disapproved. In this article, we aim to put together the scientific and clinical information that is proven so far and the areas where more data or evidence is needed before a clear understanding can be achieved and guidance can be developed.
THIEME
Point of Technique
1
Coagulopathy in COVID-19: Connecting the Dots
Together
Ajay Gandhi1 Klaus Görlinger2
1Clinical Affairs, Instrumentation Laboratory India Private Limited,
New Delhi, India
2Department of Anesthesiology and Intensive Care Medicine,
University Hospital Essen, Essen, Germany
Address for correspondence Ajay Gandhi, Clinical Affairs,
MD (Pathology), Instrumentation Laboratory India Private
Limited, 1471-76, Agrawal Millennium Tower II, Plot Number
E-4, Netaji Subhash Place, Pitampura, New Delhi,India 110034
(e-mail: agandhi@werfen.com).
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (severe acute respiratory
syndrome coronavirus 2) virus has spread quickly and become a public health emer-
gency of global concern. Originating in the Wuhan district of China, which has report-
edly been declared free of it now, the rest of the world continues to struggle with its
severity and spread. While a lot of scientific publications and clinical data are available,
newer clinical investigations and experiences continue to evolve, thereby depicting the
dynamic nature of the disease and the knowledge around it. Researchers and clinical
professionals continue to collect scientific information, clinical data, and evidence to
help build a knowledge pool and guidance for the health care professionals to manage
those affected with this pandemic disease. As significant and new data emerge, a lot
of already available information gets confirmed and updated, while some of it also get-
ting rejected or disapproved. In this article, we aim to put together the scientific and
clinical information that is proven so far and the areas where more data or evidence is
needed before a clear understanding can be achieved and guidance can be developed.
Abstract
Keywords
coagulopathy
COVID-19
COVID-19-associated
coagulopathy
DOI https://doi.org/
10.1055/s-0040-1712739
ISSN 2457-0206.
©2020 Official Publication of
The Simulation Society (TSS),
accredited by International Society of
Cardiovascular Ultrasound (ISCU).
Background
Of the several viral epidemics that occurred in the past,
such as the severe acute respiratory syndrome coronavirus
(SARS-CoV) in 2002, H1N1 influenza in 2009, and Middle
East respiratory syndrome coronavirus (MERS-CoV) in Saudi
Arabia in 2012, the SARS-CoV-2 virus and the associated
Coronavirus disease 2019 (COVID-19) disease has been the
most contagious one, with a rapid spread across the globe.1
As far as the available data suggests, most of the infected
patients either have subclinical or mild clinical symptoms,
and a small patient population suffers from severe disease
manifestations, with viral sepsis leading to single or multiple
organ failure or even death being the most common issue.2
COVID-19-associated coagulopathy (CAC), as has become a
prevalent term now, is one of the most common hemostase-
ology findings and is associated with adverse outcomes.3
Accordingly, coagulopathy is one of the most significant
prognostic factors in COVID-19. Risk stratification and triage
based on predictive laboratory parameters such as D-dimer,
IL-6, lymphocyte count, and LDH, as well as clinical scoring
systems such as the Sequential Organ Failure Assessment
(SOFA) score, Sepsis-Induced Coagulopathy (SIC) score,
and International Society of Thrombosis and Haemostasis
Disseminated Intravascular Coagulation (ISTH DIC) score, can
help health care professionals and institutions in managing
COVID-19 patients and hospital resources such as intensive
care unit (ICU) beds, intubation, and ventilator therapy, as
well as extracorporeal membrane oxygenation (ECMO) in
the best way, particularly in times of exponential growth of
infected people and limited hospital resources.
Pathogenesis
SARS-CoV-2 virus primarily affects epithelial cells in the
respiratory tract as well as vascular endothelial cells in case
of viremia. The virus enters the cells through the angioten-
sin-converting enzyme 2 (ACE2) receptors, which are most
J Card Crit Care
Published online: 2020-05-19
2
Journal of Cardiac Critical Care TSS
Coagulopathy in COVID-19 Gandhi, Görlinger
commonly found in the alveolar epithelial cells followed by
endothelial cells.4 Other organs presenting these receptors are
the renal and the gastrointestinal tracts. Furthermore, trans-
membrane protease serine subtype 2 (TMPRSS2) is a critical
factor enabling cellular infection by coronaviruses including
SARS-CoV-2 and is also the most frequently altered gene in
primary prostate cancer. The modulation of its expression
by sex steroids could contribute to the male predominance
of severe COVID-19.5,6 At the same time, this is the rationale
for serine protease inhibitors such as camostat as a potential
therapeutic intervention (NCT04321096 and NCT04338906).
The incubation period for COVID-19 is around 5 to
14 days.7 The viral infection is capable of triggering an exces-
sive immune reaction in the host, which can, in some patients,
result in a “cytokine storm” presenting clinically as hyper-
inflammation.8 The effect is extensive tissue damage and
vascular leakage. One protagonist of this “cytokine storm” is
interleukin-6 (IL-6). IL-6 is produced by activated leukocytes
and endothelial cells and acts on multiple cells and tissues.9,10
Furthermore, IL-6 is also involved in the pathogenesis of the
cytokine release syndrome (CRS), which is an acute systemic
inflammatory syndrome characterized by fever and multiple
organ dysfunction.
The pathological and clinical changes manifested in patients
with COVID-19 can be ascribed mostly to the innate immune
response. Here, an imbalance between the non-specific innate
immune response (hyperinflammation and activation of mac-
rophages and neutrophil granulocytes) and the specific adap-
tive immune response (production of specific antibodies by
lymphocytes) seems to play an important role.11,12 Accordingly,
high IL-6 levels and low lymphocyte counts are associated with
poor outcome in COVID-19.13,14 This immunological imbalance
is typical for older patients (immunosenescence) and patients
with chronic inflammatory diseases (inflammaging).15-18
Clinicopathological Manifestations
Hypercoagulability
There is a growing body of evidence that hypercoagulability
is one of the most common pathological manifestation of
COVID-19.7 However, the real incidence of macro- or micro-
thrombosis is not known yet. A potential mechanism is the
upregulation of tissue factor expression on circulating mono-
cytes, thrombopoietin, and fibrinogen, as well as downreg-
ulation of plasminogen activator inhibitor type 1 (PAI-1) by
IL-6.19 This results in increased and delocalized thrombin
generation as well as increased clot firmness and stability
(fibrinolysis resistance). Accordingly, increased D-dimer
levels (> 1µg/mL) are a good predictor for poor outcome in
COVID-19.20,21 Due to hemoconcentration, vascular endothe-
lial cell injury, and hypercoagulable state of patients with
COVID-19—particularly in patients with obesity, advanced
age, and other risk factors—risk of thrombosis is increased
in this patient population. Therefore, the risk of venous
thromboembolism cannot be ignored during the course and
treatment of COVID-19.22 Thromboprophylaxis is recom-
mended in all hospitalized COVID-19 patients.23 Tang et al
reported that patients with SIC score ≥ 4 or D-dimer > 3 µg/
mL (sixfold of the upper limit of normal) showed a significant
reduction in 28-day mortality (40 vs. 64.2%, p = 0.029; and
32.8 vs. 52.4%, p = 0.017, respectively).24 No difference in
28-day mortality was found between heparin users and
nonusers in the overall population of severe COVID-19
patients (30.3 vs. 29.7%; p = 0.910). Therapeutic antico-
agulation was performed by administering low molecular
weight heparin (40–60 mg enoxaparin/day) or unfraction-
ated heparin (10,000–15,000 U/day) for at least 7 days. As a
matter of fact, data is not available for direct oral anticoagu-
lants in COVID-19 patients.
Diffuse Microvascular Damage
Multiple organ failure caused by diffuse microvascular
damage and microthrombosis is an important cause of
death in critically ill patients with COVID-19 and may be
related to CRS and immune imbalance.25 Around 70% of
COVID-19 nonsurvivors and 0.6% of survivors meet the
ISTH DIC diagnostic criteria during their hospital stay.26
Most of them present a hypercoagulable state. However,
it is unclear whether the pathophysiology of SIC, DIC,
and CAC is the same and whether the terms can be used
interchangeably.27
Bleeding Risk
Notably, some COVID-19 patients may also have an increased
bleeding risk due to imbalances in platelet production and
consumption and other coagulation disorders.28,29 However,
bleeding complications have been reported rarely in COVID-19
patients. It is under investigation whether bleeding complica-
tions might occur in a specific subset of COVID-19 patients
(medication, comorbidities) or at a specific stage of the dis-
ease (severe, late stage).
Laboratory Investigations for Coagulopathy
in COVID-19
D-Dimer
Elevated D-dimers can occur in 50% of patients with
COVID-19, and fibrinogen degradation products and
D-dimers are significantly higher in severe patients and
nonsurvivors compared with mild patients and survivors.30
Accordingly, elevated D-dimers have to be considered
as a marker of poor outcome in patients with COVID-19
infection.20,25 In patients with markedly increased D-dimers
(which may be arbitrarily defined as three- to fourfold of the
upper limit of normal), admission to hospital should be con-
sidered even in the absence of other severity symptoms since
it has to considered as a marker of poor outcome.31
Platelet Count
Thrombocytopenia is a prominent marker of severity or mor-
tality associated with sepsis. However, most patients with
COVID-19 have platelet count in the normal range,7 although
the incidence of thrombocytopenia varies, the numbers fall-
ing with increasing severity.32
3
Coagulopathy in COVID-19 Gandhi, Görlinger
Journal of Cardiac Critical Care TSS
Prothrombin Time
A slight prolongation of prothrombin time (PT) has been
observed in severe stages of COVID-19 or in nonsurvivors
at the time of admission.1,2,31,33 This is one of the commonly
available laboratory coagulation parameters that could serve
as predictor of ICU admission.
Fibrinogen
As an acute response protein, fibrinogen may be increased in
the course of mild disease and in the early stages of severe
patients and can be significantly reduced in the late stages
of severe patients. However, the increase in fibrinogen levels
is usually less pronounced in viral compared with bacterial
sepsis. Nonetheless, fibrinogen forms another significant
marker while monitoring DIC or CAC.33
Hence, for specific monitoring of evolving or established
coagulopathy, coagulation laboratory parameters such as
D-dimer, platelet count, PT, and fibrinogen are required not
only at the time of hospital admission but also during hospital
stay for all patients with suspected or confirmed COVID-19.34
Actually, data on the utility of viscoelastic testing devices
such as rotational thromboelastometry (ROTEM) and throm-
boelastography (TEG) in CAC are limited. The value of ROTEM
in predicting the clinical course, need for hospital resources
(ICU beds, respiratory therapy, ECMO, etc.), and outcomes in
hospitalized patients with COVID-19 will be assessed in the
ongoing Rotterdam cohort study (ROHOCO). Further research
is needed to investigate whether ROTEM/TEG is useful in
identifying COVID-19 patients who might benefit from ther-
apeutic anticoagulation and to guide hemostatic therapy in
patients with hyper- and hypocoagulability.
Conict of Interest
None.
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... 49 Other strategies could include the use of intravenous unfractionated heparin or direct thrombin inhibitors 44 if heparin induced thrombocytopenia occurs 18,24 Currently, data on the usefulness of VET devices in CAC is still limited. 50 Further research is needed to investigate whether ROTEM ® /TEG ® are useful in identifying COVID-19 patients who might benefit from therapeutic anticoagulation, in order to guide hemostatic therapy, 33,[35][36][37]50 and to determine whether an abnormal VET alone or in combination with other findings can identify a group of patients with increased thrombotic risk. 17,19,37 ...
... 49 Other strategies could include the use of intravenous unfractionated heparin or direct thrombin inhibitors 44 if heparin induced thrombocytopenia occurs 18,24 Currently, data on the usefulness of VET devices in CAC is still limited. 50 Further research is needed to investigate whether ROTEM ® /TEG ® are useful in identifying COVID-19 patients who might benefit from therapeutic anticoagulation, in order to guide hemostatic therapy, 33,[35][36][37]50 and to determine whether an abnormal VET alone or in combination with other findings can identify a group of patients with increased thrombotic risk. 17,19,37 ...
... Prospective clinical trials, ideally RCT, could underline the additional value of VET in predicting the clinical course, guidance of anticoagulation, and the risk stratification of COVID-19 patients for CAC. 20,47,48 Clinical trials in hospitalized COVID-19 patients are actually underway, such as the Rotterdam cohort study using ROTEM ® (ROHOCO trial) 50 and the evaluation of hemostasis by TEG ® , platelet function testing, and biomarker analysis (TARGET-COVID Study 37 -ClinicalTrials.gov: NCT04493307). ...
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COVID-19 associated coagulopathy is a dysfunction of severe SARS-CoV-2 infection, characterized by significantly increased fibrinogen, D-dimer and C reactive protein and normal to near-normal prothrombin time, activated partial thromboplastin time and platelet count. Hypercoagulopathy and hypofibrinolysis coexist and are detected by viscoelastic tests. These features, when associated with immobilization and intrinsic risk factors (age, obesity, comorbidities, drugs) of the patient, can trigger thromboembolic events, despite thromboprophylaxis. The lungs are the first and most severely damaged organ. To date, most patients have exhibited hypercoagulability on viscoelastic tests not detected by standard coagulation tests. A high rate of thrombotic events was reported, suggesting that it should be considered as a cause of clinical deterioration in intensive care and potentially other clinical settings. In advanced stage, COVID-19 associated coagulopathy, fibrinogen and platelet count can decrease significantly, depending on the severity of clinical status resembling consumptive coagulopathy. In this stage, bleeding events can occur, especially if the patient is under extracorporeal membrane oxygenation (ECMO). Viscoelastic tests are very useful tools to assess hypercoagulability and hypofibrinolysis (not detectable by standard coagulation tests) in critically ill SARS-CoV-2 patients with COVID-19 associated coagulopathy and look like very promising tools for anticoagulation management. However, further research needs to be carried out to determine whether abnormal viscoelastic tests alone or in combination with other clinical or laboratory findings can identify patients at increased thrombotic risk. Clinical trials to evaluate hypercoagulability using viscoelastic tests and the need for personalized dosage of anticoagulation in SARS-CoV-2 patientsare quickly emerging.
... Increased coagulation in very severe COVID-19 patients has been reported in various articles. Based on the evidence, increasing coagulation is one of the most common manifestations of COVID-19 and plays an important role in patient mortality (6). This is rare for other coronavirus infections, but also has been reported in severe influenza. ...
Preprint
COVID-19 induces coagulopathy at the base of SIC (sepsis-induced coagulopathy) and it is an important cause of death in the patients. Cytokine storm causes imbalance in coagulation and fibrinolytic system. A combination of hypercoagulability state, decrease or inhibition of fibrinolytic and endothelialopathy causes thromboembolic events. Underlined disease with a high rate of mortality in COVID-19 like diabetes, hypertension and some conditions like aging and obesity are the main disorders with hemostatic disturbance and increase of coagulopathy. Therefore, it seems that the combination of COVID-19 infection and these risk factors increase the risk of thromboembolic all together.
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Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19.
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Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with droplets and contact as the main means of transmission. Since the first case appeared in Wuhan, China, in December 2019, the outbreak has gradually spread nationwide. Up to now, according to official data released by the Chinese health commission, the number of newly diagnosed patients has been declining, and the epidemic is gradually being controlled. Although most patients have mild symptoms and good prognosis after infection, some patients developed severe and die from multiple organ complications. The pathogenesis of SARS-CoV-2 infection in humans remains unclear. Immune function is a strong defense against invasive pathogens and there is currently no specific antiviral drug against the virus. This article reviews the immunological changes of coronaviruses like SARS, MERS and other viral pneumonia similar to SARS-CoV-2. Combined with the published literature, the potential pathogenesis of COVID-19 is inferred, and the treatment recommendations for giving high-doses intravenous immunoglobulin and low-molecular-weight heparin anticoagulant therapy to severe type patients are proposed.
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TMPRSS2 is both the most frequently altered gene in primary prostate cancer and a critical factor enabling cellular infection by coronaviruses, including SARS-CoV-2. The modulation of its expression by sex steroids could contribute to the male predominance of severe infections and given that TMPRSS2 has no known indispensable functions, and inhibitors are available, it is an appealing target for prevention or treatment of respiratory viral infections.
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The novel corona virus infection (now classified as COVID‐19), first identified in December 2019 in Wuhan, China, has contributed to significant mortality in several countries with the number of infected cases increasing exponentially worldwide.¹ The majority of the most severely ill patients initially present with single organ failure (i.e. respiratory insufficiency) but some of them progress to more systemic disease and multiple organ dysfunction. One of the most significant poor prognostic features in those patients is the development of coagulopathy.² In patients who develop sepsis from various infectious agents, development of coagulopathy is one of the key and persistent features which is associated with poor outcomes.³ In this context, the role of International Society of Thrombosis and Haemostasis (ISTH) would be crucial in guiding health care professionals how to manage the coagulopathy of COVID‐19. A simple and easily follow‐able algorithm for the management of COVID‐19 coagulopathy would currently be useful in both the well‐resourced and less‐resourced settings as a guide in managing this complication. This pragmatic statement should clearly be considered as an interim guidance since the clinical experience of managing this pandemic is increasing. The authors are certain that this statement will be modified with developing knowledge and therapeutics in managing COVID‐19. The aim of this guidance document is to provide a risk stratification at admission for a COVID‐19 patient and management of coagulopathy which may develop in some of these patients, based on easily available laboratory parameters.
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The role of clinical laboratory data in the differential diagnosis of the severe forms of COVID‐19 has not been definitely established. The aim of this study was to look for the warning index in severe COVID‐19 patients. We investigated forty‐three adult patients with COVID‐19. The patients were classified into mild group (28 patients) and severe group (15 patients). Comparison of the haematological parameters between the mild and severe groups showed significant differences in IL‐6, D‐Dimer, GLU, TT, FIB and CRP (P <0.05). The optimal threshold and area under the ROC curve of IL‐6 were 24.3 pg/mL and 0.795 respectively, while those of D‐Dimer were 0.28 µg/L and 0.750, respectively. The area under the ROC curve (AUC) of IL‐6 combined with D‐Dimer was 0.840. The specificity of predicting the severity of COVID‐19 during IL‐6 and D‐Dimer tandem testing was up to 93.3%, while the sensitivity of IL‐6 and D‐Dimer by parallel test in the severe COVID‐19 was 96.4%. IL‐6 and D‐Dimer were closely related to the occurrence of severe COVID‐19 in the adult patients, and their combined detection had the highest specificity and sensitivity for early prediction of the severity of COVID‐19 patients, which has important clinical value. This article is protected by copyright. All rights reserved.
Article
Background As the number of patients increases, there is a growing understanding of the form of pneumonia sustained by the 2019 novel coronavirus (SARS-CoV-2), which has caused an outbreak in China. Up to now, clinical features and treatment of patients infected with SARS-CoV-2 have been reported in detail. However, the relationship between SARS-CoV-2 and coagulation has been scarcely addressed. Our aim is to investigate the blood coagulation function of patients with SARS-CoV-2 infection. Methods In our study, 94 patients with confirmed SARS-CoV-2 infection were admitted in Renmin Hospital of Wuhan University. We prospectively collect blood coagulation data in these patients and in 40 healthy controls during the same period. Results Antithrombin values in patients were lower than that in the control group (p < 0.001). The values of D-dimer, fibrin/fibrinogen degradation products (FDP), and fibrinogen (FIB) in all SARS-CoV-2 cases were substantially higher than those in healthy controls. Moreover, D-dimer and FDP values in patients with severe SARS-CoV-2 infection were higher than those in patients with milder forms. Compared with healthy controls, prothrombin time activity (PT-act) was lower in SARS-CoV-2 patients. Thrombin time in critical SARS-CoV-2 patients was also shorter than that in controls. Conclusions The coagulation function in patients with SARS-CoV-2 is significantly deranged compared with healthy people, but monitoring D-dimer and FDP values may be helpful for the early identification of severe cases.
Article
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/L (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/L 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.
Article
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.