Coagulopathy in COVID-19: Connecting the Dots Together

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.

Full text

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

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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

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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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