review
Disseminated intravascular coagulation: epidemiology,
biomarkers, and management
Kasper Adelborg,1,2,3 Julie B. Larsen1 and Anne-Mette Hvas1,3
1
Department of Clinical Biochemistry, Aarhus University Hospital, 2Department of Clinical Epidemiology, Aarhus University Hospital,
and 3Department of Clinical Medicine, Aarhus University, Denmark
Summary
Disseminated intravascular coagulation (DIC) is a systemic
activation of the coagulation system, which results in
microvascular thrombosis and, simultaneously, potentially
life-threatening haemorrhage attributed to consumption of
platelets and coagulation factors. Underlying conditions, e.g.
infection, cancer, or obstetrical complications are responsible
for the initiation and propagation of the DIC process. This
review provides insights into the epidemiology of DIC and the
current understanding of its pathophysiology. It details the
use of diagnostic biomarkers, current diagnostic recommen-
dations from international medical societies, and it provides
an overview of emerging diagnostic and prognostic biomark-
ers. Last, it provides guidance on management. It is concluded
that timely and accurate diagnosis of DIC and its underlying
condition is essential for the prognosis. Treatment should pri-
marily focus on the underlying cause of DIC and supportive
treatment should be individualised according to the underly-
ing aetiology, patient’s symptoms and laboratory records.
Keywords: disseminated intravascular coagulation, thrombo-
sis, haemorrhage, sepsis, neoplasms.
Introduction
Since the first descriptions of disseminated intravascular
coagulation (DIC), appearing from the 19th century onward,
DIC has been considered a serious and life-threatening dis-
ease entity affecting the coagulation system.1 The most
widely used definition of DIC was issued by a subcommittee
of the Scientific and Standardization Committee (SSC) of the
International Society on Thrombosis and Haemostasis in 2001.2
According to this landmark definition, DIC is ‘an acquired
syndrome characterized by the intravascular activation of
Correspondence: Kasper Adelborg, Department of Clinical
Biochemistry, Aarhus University Hospital, Palle Juul-Jensens
Boulevard, 8200 Aarhus N, Denmark.
E-mail: kade@clin.au.dk
ª 2020 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2021, 192, 803–818
coagulation with a loss of localization arising from different
causes.’ DIC is always a complication to one or more under-
lying clinical conditions. Infection is the most frequent cause
of DIC, followed by malignancies, obstetrical complications,
or trauma, particularly head trauma. DIC also occurs sec-
ondary to vascular disorders e.g. Kasabach–Merritt syndrome
and aortic aneurisms, in which local activation of the coagu-
lation system propagates to the systemic circulation.
The clinical presentation of DIC is highly variable and
depends on the dynamic balance between clot formation in
the microvasculature and degree of consumption of coagula-
tion factors, inhibitors, and platelets. Based on the severity
and stage, DIC is categorised as non-overt (early) and overt
(decompensated).2 DIC can present either acutely or chroni-
cally, and it can be subclinical. In general, DIC patients can
suffer from both bleeding and thrombosis, although throm-
bosis often is not readily apparent, because clot formation
primarily involves the microvasculature, manifesting as organ
failure. It may be difficult to differentiate whether organ fail-
ure is a consequence of the underlying aetiology and/or is a
manifestation of clot formation in the small vessels, and this
may cause diagnostic delay. In a study of around 100 DIC
patients,3 64% had bleeding, renal dysfunction was present
among 25%, while hepatic dysfunction (19%), lung injury
(16%) and cerebral dysfunction (2%) also were observed
among the patients. Thromboembolic manifestations of large
arteries and venous vessels are less commonly observed, and
may also be a diagnostic challenge in patients with multiple
organ failures. The universal activation of the coagulation
system in DIC may lead to consumptive coagulopathy and
therefore bleeding from more than one site, e.g. dermatologi-
cal bleeds (petechiae and ecchymosis), gastrointestinal bleeds,
respiratory bleeds, urogenital bleeds, and bleedings in vicinity
of surgical sites, and/or serous cavities is particularly sugges-
tive of DIC. The intensity of symptoms varies from mild to
massive and life-threatening. DIC may present differently
according to aetiology. One study including 204 DIC patients
showed that patients with cancer-related DIC were more
likely to develop clinically significant bleeding (30–50%
depending on cancer type) than sepsis-related DIC, where
bleeding was a less common (15%) and often a late manifes-
tation.4 Conversely, in sepsis-related DIC, organ dysfunction
First published online 8 February 2021
doi: 10.1111/bjh.17172
Review
indicating microthrombus formation was predominant
(70%), while this was less pronounced in cancer patients.
Despite an increasing understanding of DIC over the past
decades, it remains a major challenge to clinicians within
most medical specialities. In this review, we first present an
updated overview of the epidemiology of DIC and its patho-
physiology. After this, we discuss current diagnostic criteria
for DIC, including a focus on emerging new biomarkers. Last,
we provide a guidance on contemporary treatment options.
Epidemiology
Preceding an overview that addresses the occurrence (inci-
dence and prevalence) of DIC, some important issues should
be noted. The occurrence of DIC varies considerably and it
depends on the type of hospital, geographical coverage, selec-
tion of study participants, diagnostic criteria, underlying dis-
eases and severity, physicians’ attitude to DIC, and the extent
of diagnostic work-up for coagulation abnormalities. As
such, the occurrence of DIC is not directly comparable
between studies. For example, diagnostic scoring systems for
DIC are not systematically implemented in all hospitals and
different criteria have been applied to diagnose DIC. Some
studies may underestimate the true burden of DIC, especially
mild, subclinical, and transient episodes. In addition, many
studies on DIC epidemiology pertained to single-centre stud-
ies, were small in sample sizes, lacked separate data on all
DIC aetiologies, were published more than 15 years ago, and
did not provide evidence on presence of microthrombus for-
mation or symptoms of bleeding accompanying the coagula-
tion abnormalities.
In one study, DIC occurred in 1286 of 123 231 (1%)
patients hospitalized at university hospitals in Japan.5 This
number is around 10–30% in the intensive-care unit (ICU)
setting.6–10 Similarly, DIC is frequent among patients with
infections, particularly among patients with severe sepsis
(~30–60%) (Table I).8,11 Among patients with solid tumours,
DIC is present among 10%, increasing in prevalence with
advancing cancer stage and in patients suspected for thrombo-
sis.12,13 DIC is also observed in a significant number of
patients with haematological cancers, most often in acute leu-
kaemia, particularly acute promyelocytic leukaemia. Studies
also suggested that DIC is relatively frequent in patients resus-
citated from out-of-hospital cardiac arrest (~10–30%),14,15
and in patients with head trauma (~30–40%). The prevalence
of DIC is considerably lower during pregnancy and among
women giving birth in general (<0
5%),16,17 but increases
markedly among patients with pregnancy complications such
as placental abruption or amniotic fluid embolism.
DIC is a devastating condition with a poor prognosis. The
clinical course is largely determined by the age of the
patients, presence of comorbidities, identification and treat-
ment of underlying aetiologies, initial treatment response,
and severity of organ dysfunction, including the degree of
haemostatic abnormalities. For example, 30-day mortality
804
rates following septic DIC was found to be around 20%,8
while the 30-day mortality was 45% in a heterogeneous DIC
population.7
Despite sparse available evidence on temporal trends in the
incidence of DIC, one study from the United States suggested
that the overall incidence of DIC, mainly covering DIC
related to sepsis, was stable or slightly decreasing over time.18
Covering all hospitalisations with overt DIC, the incidence
rates per 100 000 person-years were 26
2 in 2004 and 18
6 in
2010. A declining trend was apparent for men, but not for
women. The case fatality rate was relatively unchanged over
time. In contrast, a large study on 34 711 patients with DIC
from Japan reported an improvement in in-hospital survival
from 2010 to 2012.19 In the same study, in-hospital survival
did not improve for DIC accompanying solid tumours,
haematological cancers, acute pancreatitis or other diseases.
While the incidence of sepsis-associated DIC seems stationary
or decreasing over time, an upward trend has been observed
in maternal postpartum hospitalisations for DIC.20 Although
the incidences were low, rates of DIC per 10 000 delivery hos-
pitalisations were 9
2 in 1998–1999, increasing to 12
5 in
2008–2009.20 Whether the trends in incidence or mortality of
DIC extend to more recent years is less clear. Future studies
on DIC occurrence and prognosis, including longitudinal
trends should preferably be performed in a geographically
well-defined population-based setting using standardised cri-
teria adapted to the study question of interest.
Pathophysiology
Increased tissue factor activity and thrombin generation
Regardless of the underlying condition, an increased global
tissue factor (TF) expression is inherent to DIC (Fig 1). TF
is expressed on circulating activated monocytes in sepsis-re-
lated DIC21 and on the surface of the malignant cells or cir-
culating tumour-derived microparticles in cancer-related
DIC.22,23 In obstetric DIC, placental abruption and amniotic
fluid embolism expose the circulating blood to TF. Through
activation of coagulation factor (F) VII and FX, increased TF
activity leads to thrombin generation. This initially confers a
prothrombotic phenotype, as thrombin induces platelet acti-
vation, amplification of the coagulation cascade, and fibrin
formation. As DIC progresses, however, consumption of
coagulation factors and platelets leads to hypo-coagulability,
and subsequently an increased bleeding tendency.
Platelets
Increased platelet activation in DIC occurs through interac-
tion with activated endothelium and the direct action of
thrombin on platelets.24,25 In sepsis-related DIC, inflamma-
tory cells, cytokines and pathogens interact directly with pla-
telets and contribute to their activation,26 while cross-talk
between tumour cells and platelets induces platelet activation
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British Journal of Haematology, 2021, 192, 803–818
 Review

Fig 1. Pathophysiological pathways in disseminated intravascular coagulation (DIC). TF on leukocytes, tumour-derived microparticles and the vessel
wall induces thrombin generation, which: (1) activates platelets; (2) induces coagulation amplification through positive feedback; and (3) induces fib-
rin formation. Endothelial anticoagulant surface proteins and glycans are shed, and endogenous anticoagulant activity is further impaired due to
decreased production and increased turnover of antithrombin, protein C and protein S. VWF release is increased while simultaneously ADAMTS13
levels decrease. This further enhances platelet adhesion at the endothelial surface and contributes to microthrombus formation. Fibrinolysis is
impaired due to increased PAI-1 release from activated endothelium and platelets as well as TAFI activation through thrombin. ADAMTS13, a disin-
tegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; AT, antithrombin; F, coagulation factor; PAR1, protease-activated
receptor 1; PAI-1, plasminogen activator inhibitor-1; PC, protein C; PS, protein S; TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor;
TM, thrombomodulin; tPA, tissue plasminogen activator.

in various cancer types.27 Circulating cell-free DNA and his-
tones, released from neutrophils during inflammation (neu-
trophil extracellular traps, or NETs), also induce platelet
aggregation and coagulation cascade activation,28 and have
been found to correlate with DIC severity and mortality.29
Increased release of von Willebrand factor and decreased cir-
culating levels of ADAMTS13 (a disintegrin and metallopro-
teinase with a thrombospondin type 1 motif, member 13)
also contribute to increased platelet adhesion during sepsis.30
Platelet aggregation in the microcirculation leads to
microthrombus formation. Further, it promotes pro-coagu-
lant activity, as activated platelets present a negatively
charged phospholipid surface where coagulation propagates
through activation of FXI, FIX and FX.31
Loss of regulation: endothelial disruption and decreased
anticoagulant activity
Under normal physiological circumstances, the endothelial
surface enhances the effect of endogenous anticoagulant
proteins antithrombin and protein C. Heparan sulphates in
the glycocalyx potentiate the inhibitory effect of antithrombin
on thrombin.32 Endothelial protein C receptor (EPCR) and
thrombomodulin are expressed on the resting endothelial cell
surface and are necessary for protein C activation.33 However,
trauma or inflammatory stimuli lead to endothelial activation
or damage and increased vascular permeability. This exposes
subendothelial activators such as TF and collagen to the blood.
Anticoagulant proteins can also decrease due to extravasation
through the permeable endothelium.34 Furthermore, upon
endothelial activation or damage, glycocalyx and surface pro-
teins are cleaved from the endothelial cells by proteases and
shed into the circulation35 and thus, the endothelium loses its
anticoagulant properties. High plasma levels of endothelial
proteins including soluble thrombomodulin, syndecan-1, and
heparan sulphate are related to coagulation disturbances and
increased mortality in sepsis.36 Furthermore, plasma levels of
antithrombin, protein C and protein S decrease due to con-
sumption, decreased synthesis in the liver, and degradation by
neutrophil elastase.37

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Altered fibrinolysis
Disturbed fibrinolysis is an important contributor to the
pathophysiology of DIC. Fibrinolysis can be either impaired
(hypofibrinolysis) or enhanced (hyperfibrinolysis) according
to the pathophysiology of the underlying disease.38 Both tis-
sue plasminogen activator (tPA) and plasminogen activator
inhibitor-1 (PAI-1) are released from the activated endothe-
lium.39 PAI-1 is also synthesised in platelets and is released
upon platelet activation. In sepsis, the net effect is impaired
fibrinolysis in most cases,40 but the degree of fibrinolytic
shutdown may be variable and depends on disease sever-
ity.41,42 Besides increased circulating PAI-1, other factors
contributing to hypo-fibrinolytic DIC are decreased produc-
tion and increased consumption of plasminogen, as well as
increased thrombin-activatable fibrinolysis inhibitor (TAFI)
activity. In contrast, cancer is often associated with increased
fibrinolytic activity.43 This may be secondary to increased
pro-coagulant activity and fibrin formation, which in turns
leads to increased plasmin activity. Primary hyper-fibrinolysis
is a common feature of acute promyelocytic leukaemia.
These patients often present with severe hyper-fibrinolysis
and bleeding due to increased plasminogen activation on the
malignant cell surface.44 Hyper-fibrinolysis has also been
described among patients with solid tumours, e.g. prostate
cancer.45 In trauma patients, dynamic changes in fibrinolysis
also occur, characterised by initial hyper-fibrinolysis and a
subsequent shift towards a hypo-fibrinolytic state.46
Current diagnostics
Timely diagnosis of DIC is essential but can be challenging.
The diagnosis is based on the presence of one or more relevant
underlying conditions, symptoms indicative of DIC, and
abnormal laboratory test results. These tests include measures
of platelet count, activated partial thromboplastin time
(aPTT), prothrombin time (PT), fibrinogen, fibrin breakdown
products, and, where available, antithrombin activity. A low or
rapidly decreasing platelet count is suggestive of overt DIC. PT
and aPTT are usually prolonged, while fibrinogen and
antithrombin levels are decreased as a result of consumption.
Fibrin D-dimer and other fibrin breakdown products are ele-
vated, reflecting increased fibrin formation and degradation.
Though not necessarily specific for DIC, normal circulating
fibrin D-dimer has a high negative predictive value.
Routine coagulation tests are relatively sensitive markers
for DIC, but as single markers, they are not specific for DIC.
To facilitate early diagnosis, several international medical
societies have developed scoring systems for decompensated
DIC (Table II). Most of these include a range of different
routine coagulation tests and assign a total DIC score to the
patient based on the results of the individual biomarkers.
While much focus has been on the diagnosis of overt DIC,
some scoring systems have also been developed for the diag-
nosis of non-overt DIC. Several studies have reported high
806
sensitivities and specificities of DIC scoring systems. There-
fore, the use of one or more scoring systems is generally rec-
ommended. However, the scoring systems also have some
drawbacks. Clinical use may be challenging due to their com-
plexity and diversity. Often multiple laboratory test results
are recorded in critically ill patients each day at different
timepoints, which may result in changing DIC scores. In one
prior study, DIC scores were calculated every 48 h.7 How-
ever, as the laboratory test results may rapidly change in
DIC, this interval may be too infrequent in some clinical sit-
uations. Moreover, local translation of the scoring systems is
often required depending on the available laboratory equip-
ment and analysis methods, e.g. in some hospitals PT ratio
or international normalised ratio is used rather than PT. For
some of the analyses, there is large variation in the analysis
principles of the biomarkers. For example, fibrin breakdown
products can be measured using different methods (e.g.
enzyme-linked immunosorbent assay or latex agglutination
assay), resulting in interhospital variation in reference inter-
vals and units. Last, prior studies of DIC scoring systems
have seldom been validated against a detailed and standard-
ised gold standard, including information on microthrombus
formation and bleedings.
Several clinical conditions may also influence the labora-
tory tests included in the DIC score, and these should be
kept in mind when interpreting the result of the score. An
overview of differential diagnostic considerations is presented
in Table III. In acutely ill patients, thrombocytopenia may
also be caused by bleeding, colloids, resuscitation, medica-
tion, and concurrent conditions such as liver cirrhosis, bone
marrow suppression, or pregnancy-related thrombocytopenia.
It has been estimated that between 20% and 50% of ICU
patients present with some degree of thrombocytopenia at
admission.47 The differential diagnosis between DIC and
other thrombotic microangiopathies, such as thrombotic
thrombocytopenic purpura (TTP), haemolytic uraemic syn-
drome (HUS) and heparin-induced thrombocytopenia (HIT)
can also be challenging (Table III). In these conditions, plate-
let consumption predominates over coagulation activation,
which will reflect in thrombocytopenia with normal or only
slightly abnormal coagulation markers. Intravascular haemol-
ysis is a prominent feature of TTP and HUS, indicated by
increased lactate dehydrogenase and the presence of schisto-
cytes. In HIT, timing in relation to heparin treatment should
be considered, and the ‘4T score’ can guide diagnosis.48 Con-
versely, platelet counts may be within the reference range
during the early stages of DIC, as circulating platelet levels
increase as part of an acute-phase reaction.49 Thus, a single
normal platelet count cannot exclude presence of DIC, and
longitudinal evaluation of the platelet count yields important
diagnostic and prognostic information.50,51 This is accounted
for in some DIC scoring systems, such as the Japanese Associ-
ation of Acute Medicine (JAAM) DIC score.52 Prolonged PT
and aPTT can be indicative of DIC but can also be caused
by decreased coagulation factor synthesis, e.g. due to liver
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British Journal of Haematology, 2021, 192, 803–818
 Review

Table I. Prevalence of disseminated intravascular coagulation in selected subgroups of patients.

Country Criteria Prevalence of DIC Comments

Infectious diseases
Severe sepsis Japan (JAAM JAAM DIC 51% DIC prevalence was estimated at ICU
FORECAST admission.
Sepsis study)118
Japan (JSEPTIC- JAAM DIC 61% DIC prevalence was estimated at ICU
DIC study)11 ISTH DIC 29% admission.

Cancer
Solid tumours United States12 Symptoms Overall = 7% The study population consisted of
(thrombosis or Lung cancer = 7% cancer patients referred to haematology
bleeding) and at Breast cancer = 5% or oncology departments. Thus,
least 3 routine Prostate cancer = 6% patients with early cancer requiring
coagulation Colorectal cancer = 8% surgery only were not included
abnormalities Pancreas cancer = 9% Risk factors for DIC were advancing
Brain cancer = 10% age, advanced malignancies, breast
Ovarian = 10% cancer, and necrosis in the tumour
Stage I-II = 4% specimen
Stage III-IV = 9%
Liver metastases = 12%
Adenocarcinoma = 8%
Squamous cell = 5%
Advanced Japan13 ISTH DIC Overall = 21% The study population comprised
malignant Lung cancer = 5% advanced cancer patients with
diseases Breast cancer = 23% symptoms of or routine laboratory tests
Urinary tract cancer = 25% indicative of thrombosis
Colon cancer = 2%
Pancreas cancer = 14%
Ovarian cancer = 8%
Hepatic cell
carcinoma = 22%
Haematological
cancers = 21%

Haematological cancers
Acute India and ISTH DIC Overall = 15–17% The prevalence was estimated at the
leukaemia United States119,120 ALL = 16% time of diagnosis
AML = 21%
APL = 75%
Malignant Japan121 ISTH DIC Overall = 3% The prevalence was estimated prior to
lymphoma chemotherapy or radiotherapy among
incident patients or patients in relapse
DIC was mainly observed in patients
with stage IV disease
Non-Hodgkin Japan122 JMHLW DIC Overall = 11% The prevalence was estimated at the
lymphoma time of diagnosis
DIC was only observed among patients
with stage IV disease

Obstetrical conditions
HELLP Turkey and Coagulation 5–20% The prevalence was estimated during
syndrome and United States123,124 abnormalities hospitalization.
pre-eclampsia indicative of DIC
Amnion fluid United States125 ICD-9 codes for 66% The prevalence was estimated during
embolism DIC hospitalization.

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Table I. (Continued)
Country Criteria
Others
Out-of-hospital Vienna and Japan14,15 ISTH DIC
cardiac arrest
Aortic aneurysm China126 ISTH DIC
Head trauma China, Malaysia, ISTH or modified
and United ISTH DIC
States127–129
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; DIC, disseminated intravascular coagu-
lation; HELLP, haemolysis, elevated liver enzymes and low platelet count; ICD, International Classification of Diseases; ICU, intensive care unit;
ISTH, International Society on Thrombosis and Haemostasis; JAAM, Japanese Association for Acute Medicine; JMHLW, Japanese Ministry of
Health, Labour and Welfare.
cirrhosis or vitamin K antagonist treatment. Antithrombin is
often also decreased in patients with liver dysfunction, which
may complicate differential diagnosis further. One study
found elevated PT and fibrin D-dimer in 92% and 99% of
severe sepsis patients at study enrolment,53 which limits the
specificity of these markers for sepsis-related DIC. This is
reflected in most DIC scoring systems where more points are
assigned for a more pronounced increase in fibrin break-
down products. Likewise, fibrinogen is an acute-phase reac-
tant and may stay within or even above reference range until
late in the course of DIC, and thus, its sensitivity for DIC
during an ongoing acute-phase response is low.7 Fibrinogen
and fibrin D-dimer levels are also elevated in pregnancy.54 In
cancer patients, a more chronic, ‘low-grade’ DIC may be pre-
sent. In this case, PT and fibrinogen can be within the refer-
ence intervals, and moderate thrombocytopenia and an
elevated fibrin D-dimer may be the earliest sign of DIC.43
However, since elevated fibrin D-dimer is a common finding
in patients with advanced disease, the specificity of fibrin D-
dimer as a single marker for DIC in cancer patients is low.
Nonetheless, an elevated fibrin D-dimer in cancer patients is
indicative of ongoing coagulation activation and is a predic-
tor for venous thromboembolism,55 as well as mortality.56
To compensate for the afore-mentioned issues, some scoring
systems have been adapted to certain subgroups of patients
or have been developed to apply different weights in patients
with e.g. haematopoietic disorders, sepsis, or obstetric DIC
(Table II).
Taken together, in patients suspected for DIC, it is advis-
able to use a combination of laboratory tests, preferably in
the form of a validated scoring system, and to use sequen-
tial changes in laboratory test parameters at regular time
points (e.g. every 6 h) rather than single measurements. The
presence of an underlying condition known to be associated
with DIC is a prerequisite for most scoring systems to ensure
808
Prevalence of DIC Comments
8–33% The prevalence was estimated at
admission
4% The prevalence was estimated at
admission
36–41% The prevalence was estimated at
admission. In some of the reports, it
may be difficult to differentiate between
the contribution of trauma/bleeding
associated coagulopathy from DIC
occurring secondary to the head trauma
a high positive predictive value. Other potential causes of
coagulation disturbances, which may lead to spurious calcula-
tion of the DIC score, should be taken into account.
Potential for future biomarkers
As there are some limitations to the current diagnostic
biomarkers for DIC, much interest has been given to the
development of supplementary biomarkers to support the
DIC diagnosis, predict DIC, diagnose overt DIC, and aid in
prognostication. Below and in Table IV, the role of the most
important potential biomarkers is discussed.
Thrombin generation markers
Excess thrombin formation is an important component of
DIC regardless of aetiology, and thus markers of thrombin
generation (TG) could be a specific measure of DIC and its
severity. The most widely used markers of thrombin formation
are the ex vivo TG assay, levels of thrombin–antithrombin
(TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2).
The TG assay has been described in detail elsewhere.57 It
measures ex vivo thrombin formation over time in plasma
upon activation with TF and allows calculation of peak and
total thrombin generation, as well as time to initial and peak
thrombin generation. Thus, this assay can identify both
decreased and excess TG, indicating either hypo- or hyper-
coagulability. Studies investigating associations between the
TG assay and DIC have found reduced ex vivo thrombin
generation in patients with overt DIC according to the ISTH
DIC score compared with patients without DIC.58–60 The
individual parameters had moderate ability to discriminate
between patients with and without DIC but were only weakly
associated with mortality. Limitations of the TG assay are
lack of standardisation and automatisation, relatively long
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British Journal of Haematology, 2021, 192, 803–818

Table II. Overview of the most frequently used diagnostic scoring systems used for disseminated intravascular coagulation and sepsis-associated
coagulopathy.
Scoring system
International Society on Thrombosis
and Haemostasis (ISTH) scores
Japanese Association for
Thrombosis and
Hemostasis (JSTH)
Japanese Ministry of Health,
Labor and Welfare (JMHLW)
DIC score133
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Parameters Overt DIC diagnosis
Basic2
≥5
• Platelet count level
• Prothrombin time
• Fibrin-related markers
• Fibrinogen
Pregnancy16
• Platelet count level
• Prothrombin time difference
• Fibrinogen (different levels and weights than above)
Sepsis-induced coagulopathy (SIC) score130
• Platelet count level
• Prothrombin time
• Total sequential organ failure assessment (SOFA) score
Basic131 ≥6
• Platelet count level
• PT ratio
• Fibrin-related markers
• Fibrinogen
• Antithrombin activity
• Thrombin–antithrombin complexes/soluble
fibrin/prothrombin F1 + 2
• Liver failure
Hematopoietic disorders131
• PT ratio
• Fibrin-related markers ≥4
• Fibrinogen
• Antithrombin activity
• Thrombin–antithrombin complexes/soluble
fibrin/prothrombin F1 + 2
• Liver failure
Infection131
• PT ratio
• Fibrin-related markers
• Antithrombin activity
• Thrombin–antithrombin complexes/soluble ≥6
fibrin/prothrombin F1 + 2
• Liver failure
Simplified criteria for sepsis-associated DIC132
• Platelet count level ≥4
• PT ratio
• Fibrin-related markers
• Antithrombin activity
• Platelet count level ≥7
• PT ratio
• Fibrin-related markers
• Fibrinogen
• Underlying disease
• Clinical symptoms (bleeding and organ failure)
809
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Table II. (Continued)

Scoring system Parameters Overt DIC diagnosis

Chinese Society of Thrombosis • Clinical presentation (abnormal bleeding, unexplained organ ≥7

and Hemostasis scoring failure, shock, independent of original disease)
system for DIC (CDSS)134 • PT and aPTT Some modifications of the score in
• Fibrin D-dimer haematologic malignancies
• Fibrinogen
• Platelet count

Japanese Association for Acute Basic135 ≥6

Medicine (JAAM) score
• Platelet count level or change
• Prothrombin time
• Fibrin-related markers
• Systemic inflammatory response syndrome criteria
Revised-JAAM (R-JAAM)52
• Platelet count level or change ≥4
• PT
• Fibrin-related markers
• Antithrombin
Unified criteria based on JAAM criteria136
• Platelet count level ≥9
• Prothrombin time
• Fibrin-related markers
• Systemic inflammatory response syndrome criteria
• Protein C activity
• Plasminogen activator inhibitor 1

Korean Society on Thrombosis • Platelet count ≥3

and Hemostasis (KSTH) score137 • PT or aPTT
• Fibrin D-dimer
• Fibrinogen

aPTT, activated partial thromboplastin time; PT, prothrombin time.

Table III. Differential diagnostic considerations in patients with thrombocytopenia or affected global coagulation parameters.

Platelet count Global coagulation tests (PT, aPTT) Other findings

Hepatic cirrhosis Stable or only ↑ Global decrease of coagulation

mild decrease factors (except FXIII)
↑ ALAT, ALP
Thrombotic microangiopathies(HUS, TTP) ↓↓ Normal or only slightly prolonged Schistocytes
Haemolysis
TTP: ↓↓ ADAMTS13
Heparin-induced thrombocytopenia ↓ Normal or only slightly prolonged Heparin exposure
Large-vessel thrombosis
Antiheparin-PF4-antibodies
Pregnancy-related thrombocytopenia
Benign ↓ Normal
HELLP ↓↓ May be prolonged in case of liver failure Haemolysis, ↑ ALAT
Bone marrow suppression ↓↓ Normal ↓RBC and WBC counts
Inherited or acquired haemophilia Normal ↑ aPTT, normal PT Isolated FVIII or FIX deficiency;
FVIII or FIX antibodies

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALAT, alanine aminotransferase; ALP, alkaline
phosphatase; aPTT, activated partial thromboplastin time; F, coagulation factor; HELLP, haemolysis, elevated liver enzymes and low platelet
count; HUS, haemolytic uraemic syndrome; PF, platelet factor; PT, prothrombin time; RBC, red blood cell; TTP, thrombotic thrombocytopenic
purpura; WBC, white blood cell.

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British Journal of Haematology, 2021, 192, 803–818
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Table IV. Potential future biomarkers in disseminated intravascular coagulation (DIC) diagnosis.

Biomarker Advantages Limitations

Thrombin formation
Thrombin generation
assay
Thrombin–antithrombin
complexes
Viscoelastic tests
Plasminogen activator
inhibitor-1
Sensitive to both increased and decreased
thrombin formation
Sensitive to increased thrombin formation in vivo
Potential value as an early DIC marker
Detects hypo-coagulability and hyper-fibrinolysis
in patients suspected of DIC
Can guide haemostatic treatment in the bleeding patient
High levels associated with sepsis-related DIC and mortality
Ex vivo assay; does not discriminate between
decreased thrombin generation due to decreased
prothrombin synthesis (e.g. liver failure) and
increased consumption (DIC)
Influenced by antithrombin levels
Both thrombin generation assay and thrombin-
antithrombin complexes: Not fully automated,
high cost and turnover time. Inter-laboratory
variation
Mainly investigated in sepsis-related DIC
May not be available in all routine laboratories
Not sensitive to hypo-fibrinolysis: potential for
modified assays
Mainly investigated in sepsis-related DIC
Not fully automated; Inter-laboratory variation

DIC, disseminated intravascular coagulation.

turnover times, and that specialised training for interpreta-
tion of results is required.
In vivo TG can be quantified through measurement of cir-
culating F1 + 2 or TAT complex, of which the latter has
been studied most extensively. Studies found higher mean
TAT levels in patients with DIC at inclusion60,61 or patients
who subsequently developed DIC62,63 than in patients with-
out DIC. Two studies showed that TAT had moderate accu-
racy to predict DIC development within five days in patients
with sepsis, adjusted for APACHE-II score62 and patients
with combined DIC aetiology.62,63 In both studies, a combi-
nation of TAT and other biomarkers performed better than
TAT alone (PAI-1 and protein C)62 or PAI-1, plasmin-an-
tiplasmin complex and thrombomodulin.63 High TAT levels
at ICU admission were associated with increased mortality in
sepsis patients62 but not in one study including patients with
mixed DIC aetiology.61 Thus, TAT could represent a measure
of early coagulation disturbances and may be useful to sup-
plement early DIC diagnosis. Precautious interpretation of
TAT is recommended if the plasma level of antithrombin
(decreased synthesis or protease degradation) is low, as TAT
complex formation may decrease and thus does not accu-
rately reflect thrombin formation.
Fibrinolysis
Hypo-fibrinolysis aggravates microthrombus formation in
DIC, but current routine coagulation parameters are not
sensitive to impaired fibrinolysis. One potential biomarker
for hypo-fibrinolysis may be the anti-fibrinolytic protein
PAI-1. The role of PAI-1 is most extensively investigated in
sepsis-related DIC. Multiple studies have found higher PAI-
1 plasma levels in sepsis patients with DIC, with moderate
to good ability to discriminate between DIC and no
DIC36,64,65 or predict DIC development.62,63,66 Similar to
TAT, a combination of PAI-1 and other haemostatic mark-
ers performed better than PAI-1 alone.62,63 Furthermore, a
recent meta-analysis found that high PAI-1 levels are asso-
ciated with increased mortality in severe sepsis.67 Thus,
PAI-1 could be a useful biomarker for diagnosis and prog-
nostication in sepsis-related DIC. However, PAI-1, like TG
markers, is currently not implemented in the routine labo-
ratory, and automatisation and inter-laboratory standardisa-
tion would be necessary to facilitate wider use of these
biomarkers.
Viscoelastic tests
Dynamic viscoelastic point-of-care tests [thromboelastogra-
phy (TEG) or thromboelastometry (ROTEM)] provide
another potential laboratory method in the diagnostic work-
up and prognostication of DIC. In addition to clotting time,
these assays measure velocity, clot firmness and lysis index
and therefore provide more detailed information on clot for-
mation capacity than aPTT and PT. However, the ability of
standard viscoelastic tests to detect early pro-coagulant activ-
ity preceding overt DIC has not yet been convincingly
demonstrated.68 In contrast, decreased clot formation capac-
ity assessed with TEG/ROTEM, indicated by prolonged
clotting times and decreased maximal clot firmness has been
associated with overt DIC defined by International Society
on Thrombosis and Haemostasis (ISTH) DIC score and with
higher mortality in several sepsis cohorts.69–71 However,
other authors reported no such association, or found that
TEG/ROTEM parameters were within reference range in
all patients.72,73 This may be due to the fact that standard
assays are designed mainly to detect severe coagulation dis-
turbances and guide treatment in the bleeding patient.

ª 2020 British Society for Haematology and John Wiley & Sons Ltd 811
British Journal of Haematology, 2021, 192, 803–818
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Fig 2. Flow chart summarizing treatment recommendations in DIC based on expert recommendation and guidelines from international medical
societies.77,78,83–85 aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; LMWH,
low-molecular-weight heparin; PPH, postpartum haemorrhage; PT, prothrombin time; VTE, venous thromboembolism; UFH, unfractionated
heparin.

Modified assays with lower TF concentrations may be more

sensitive to increased pro-coagulant activity.
Besides clot formation, viscoelastic tests are sensitive to pro-
nounced hyper-fibrinolysis, which may inform treatment deci-
sions on the use of anti-fibrinolytic agents in DIC patients
presenting with bleeding. The ability of viscoelastic tests to
detect impaired fibrinolysis has also been explored, and high
ROTEM lysis indices, indicating fibrinolytic shutdown, have
been associated with mortality in sepsis.41,74 However, the
absolute differences in standard lysis index are negligible and
patients with hypo-fibrinolysis may still be within the reference
range.41 As such, the implementation of clinically useful cut-
off limits seems difficult. Modified viscoelastic assays with
added tPA are potentially more sensitive to hyper- and hypo-
fibrinolysis,42,75,76 but this warrants further confirmation.
Management
The main principle of DIC treatment is management of the
underlying cause (Fig 2). For example, treatment of infection
implies urgent and sufficient antibiotic treatment with ongoing
adjustment according to microbial cultivation. Drainage of the
infection focus is needed as well as surgical resection of avital
tissue. Management of DIC also includes supportive treatment
to mitigate the coagulopathy, including formation of micro-
thrombi and subsequent supportive treatment of the bleeding
occurring due to consumption of platelets and coagulation fac-
tors. During the accelerated coagulation process, the natural
anticoagulants also suffer from consumption, which is why
substitution by these proteins is also discussed. The supportive
treatment varies according to the underlying aetiological

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British Journal of Haematology, 2021, 192, 803–818

features. Most literature evaluated supportive treatment of sep-
sis-related DIC. Regarding cancer-associated DIC, the support-
ive treatment depends on whether the DIC is pro-coagulant,
hyper-fibrinolytic, or subclinical,77 and in obstetric DIC the
major complication demanding supportive treatment may be
postpartum haemorrhage.78
Anticoagulant treatment of microthrombi or overt
thromboembolism
The purpose of anticoagulant treatment is to restore organ
perfusion and thereby prevent subsequent organ dysfunction
caused by microthrombi. Below, current evidence for the use
of different anticoagulants is summarised.
Unfractionated heparin and low-molecular-weight heparin.
Critically ill patients have a substantially increased risk of
venous thromboembolism, which is supported by the notion
that almost 10% of intensive-care patients experienced
venous thromboembolism during hospitalisation despite
thromboprophylaxis with unfractionated heparin (UFH).79
Hence, in critically ill patients, thromboprophylaxis with
UFH or low-molecular-weight heparin (LMWH) is recom-
mended regardless of the presence of DIC. Several studies
have investigated the effect of heparins, especially UFH, in
patients with sepsis. The results are summarised in meta-
analyses, reporting a reduced 28-day mortality but also with
some indication of increased bleeding risk.80–82
In patients with DIC, pharmacological thromboprophylaxis
should be paused in bleeding or high-risk bleeding patients or
if platelet counts drop below 20 9 109/l.83 In DIC patients
with acute promyelocytic leukaemia causation is advised as
regards thromboprophylaxis, and prophylactic platelet transfu-
sion is suggested to maintain platelet counts above 20 9 109/
l.83 As obstetric DIC primarily manifests with bleeding, the
role of UFH or LMWH is unclear and should be reserved to
patients in whom thrombosis predominates.78
Therapeutic doses of heparin should be reserved to
patients with venous thromboembolism and may in addition
be considered in patients with severe thrombotic manifesta-
tions as purpura fulminans or acral ischaemia.84,85 UFH
mainly inactivates thrombin and FXa, while LMWH targets
FXa. Theoretically, this could imply differences in the efficacy
and safety of UFH and LMWH. However, for therapeutic pur-
poses, use of LMWH is preferred to UFH.86 In patients with
concomitant bleeding, a vena cava filter should be considered
in parallel to transfusions given to ameliorate the coagulopa-
thy and thereby making LMWH treatment possible.77,83 It
remains to be elucidated whether treatment with heparin in
any form improves survival specifically in DIC patients.
Other anticoagulation drugs. Some experimental evidence
indicates that direct thrombin inhibitors may down-regulate
hyper-coagulability in DIC patients,87 but this has not been
tested in a controlled clinical setting. The anti-Xa agent fon-
daparinux has not been evaluated in DIC patients, while the
anti-Xa agent danaparoid sodium, which is available in
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British Journal of Haematology, 2021, 192, 803–818
Review
Japan, and synthetic protease inhibitors have been suggested
by the Japanese Society of Thrombosis and Haemostasis for
anticoagulant treatment during DIC.88 A recent retrospective
Japanese study compared the effect of danaparoid sodium
and synthetic protease inhibitors in patients with haemato-
logical malignancy complicated by DIC, but no difference in
DIC resolution was found between the two agents in the
multivariate analysis.89 As no randomised controlled trials
(RCTs) have evaluated the effect on mortality or resolution
of DIC, these anticoagulant agents need further investigation.
In addition, the efficacy and safety of direct oral anticoagu-
lants in the management of DIC are currently unclear.
Antithrombin. During the course of DIC, levels of
antithrombin drop due to consumption by thrombin, and in
sepsis-induced DIC antithrombin is inactivated due to cleav-
age by neutrophil elastase and the bacterial enzyme ther-
molysin.90 Several studies have reported an association
between reduced levels of antithrombin and poor clinical
outcome.91,92 Thus, it seems plausible that antithrombin sub-
stitution could be beneficial in DIC patients.
The landmark KyberSept study, a large-scale multicentre
RCT, tested the impact of high-dose antithrombin substitu-
tion on mortality in 2 314 patients with severe sepsis.93 The
study did not demonstrate improved survival in the interven-
tion group, but found a significantly increased bleeding inci-
dence among patients receiving antithrombin concentrate and
concomitant heparin.93 However, a post-hoc analysis demon-
strated that patients with sepsis and DIC who did not receive
concomitant heparin during study treatment with antithrom-
bin concentrate had a survival benefit with an absolute 28-
day mortality reduction of 14
6% compared to placebo.94
A meta-analysis published in 2016 challenged the use of
antithrombin in critically ill patients as no effect was found
on survival but an increased bleeding risk was demon-
strated.95 A following guideline thus recommended against
antithrombin substitution in critically ill patients including
DIC patients.96 However, a subsequent meta-analysis that
only included studies investigating patients with sepsis and
DIC and excluded studies with mixed populations of criti-
cally ill patients suggested that administration of antithrom-
bin concentrate in patients with sepsis and DIC reduced
mortality.97 More recently, an observational multicentre
study from Japan indicated clinical benefit in patients with
sepsis and DIC treated with antithrombin concentrate.98
Mainly based on the afore-mentioned results, the most
recent Japanese Clinical Practice Guidelines for Management
of Sepsis and Septic shock only weakly recommend
antithrombin substitution in patients with DIC and reduced
antithrombin levels.99 According to other guidelines from e.g.
the British Committee for Standards in Haematology and
ISTH, the use of antithrombin is not recommended. Still,
additional evidence is warranted.
Thrombomodulin. Thrombomodulin forms a complex with
thrombin and subsequently inhibits its activity in addition to
amplification of formation of activated protein C.100 Several
813
Review
studies from Japan have indicated clinical benefit of recombi-
nant human soluble thrombomodulin (rTM, ART-123) in
patients with DIC due to haematologic malignancy or infec-
tion.98,101–104 More recently, Vincent et al. published a RCT
(Sepsis Coagulopathy Asahi Recombinant LE Thrombomod-
ulin [SCARLET] study) investigating the effect of rTM on
28-day mortality in patients with sepsis-associated coagu-
lopathy, but demonstrated only a minor absolute risk reduc-
tion in the intervention group compared to the placebo
group (26
8% vs. 29
4%).105 Notably, no increased risk of
major bleeding was found. Recently, a post-hoc analysis of
the SCARLET study indicated that the absolute mortality risk
reduction was most pronounced in subgroups of patients
with increased levels of TG markers (TAT and protrombin
fragment F1 + F2).106 A meta-analysis including 5 RCTs,
including the SCARLET study, evaluated the effect of rTM in
patients with sepsis-induced coagulopathy and demonstrated
a non-significant 13% mortality reduction in the intervention
groups compared to the controls.107
In conclusion, some studies suggest a potential beneficial
effect of anticoagulant treatment with rTM, but further stud-
ies are still needed.
Protein C. As the first natural anticoagulant, recombinant
activated protein C (rAPC) was approved for treatment of
sepsis after having proved beneficial effect in the large-scale
RCT including patients with severe sepsis, Recombinant
Human Protein C Worldwide Evaluation in Severe Sepsis
(PROWESS).108 Moreover, a subsequent subgroup analysis
showed an even more beneficial effect on survival in patients
with overt DIC.109 However, rAPC was later withdrawn from
the market and is no longer available for clinical use in DIC
patients, a decision that followed several RCTs failing to
demonstrate a beneficial effect of rAPC while showing a clin-
ically significant increased bleeding risk.110–112
Tissue factor pathway inhibitor. Tissue factor pathway inhi-
bitor (TFPI) inhibits factor Xa directly and is the main inhi-
bitor of the TF/FVII catalytic complex.113 Thus, theoretically
treatment by TFPI would be the most appropriate treatment
in DIC to inhibit the uncontrolled activation of the coagula-
tion system. Following successful animal studies and studies
in healthy individuals testing different doses of recombinant
TFPI,114 a phase II trial evaluated recombinant TFPI (ti-
facogin) in 210 patients with severe sepsis and reported a
non-significant reduced 28-day mortality.115 However, the
following optimised phase 3 tifacogin in multicentre interna-
tional sepsis trial (OPTIMIST) failed to show a survival ben-
efit in patients with severe sepsis receiving recombinant TFPI
compared to placebo.111
Supportive treatment of bleeding complications
Substitution with platelets and/or coagulation factors is indi-
cated in bleeding patients, in patients requiring invasive pro-
cedures, and/or if the patient otherwise is at particularly
814
increased risk of bleeding complications; hence, substitution
should not be initiated based solely on abnormal laboratory
results.43,83,84,86
The efficacy of platelet concentrates or substitution by
coagulation factors has not been evaluated in RCTs exclu-
sively investigating DIC patient. Thus, the recommendations
provided below and in Fig 2 are based on a summary of
expert opinions and international guidelines.
Platelet concentrate. Based on expert consensus, adminis-
tration of platelet concentrates is recommended with a
threshold at 50 9 109/l in DIC patients with major bleeding
or patient at high risk of bleeding.84,85 In obstetric DIC com-
plicated by postpartum haemorrhage, it is especially impor-
tant that the level is maintained above 50 9 109/l.116 In DIC
patients with minor or no bleeding, and also in cancer
patients, a threshold of 20 9 109/l is accepted.77,83,85,86
Coagulation factors. According to expert consensus, substi-
tution by coagulation factors is indicated in patients with
major bleeding and aPTT and/or PT more than 1
5 times the
normal value.83,85 First choice for substitution of coagulation
factors is fresh frozen plasma with an initial dose of 15–
30 ml/kg.77,85,86 Obviously, large volumes of fresh frozen
plasma may be needed to restore normal coagulation factor
levels implying a risk of volume overload. If volume overload
is considered to constitute a clinical problem, prothrombin
complex concentrate may be favoured.86 Most prothrombin
complex concentrates contain the vitamin K-dependent FII,
FVII, FIX and FX, and may as well contain the natural anti-
coagulants protein S, protein C, and antithrombin. However,
they lack important coagulation factors, e.g. FV, and no well-
defined dosing strategy exists. Vitamin K is a useful alterna-
tive to correction of vitamin K-dependent coagulation fac-
tors,84 but it will have no substantial effect until after more
than 6 h. If fibrinogen specifically is lacking, administration
of fibrinogen may be relevant either as fibrinogen concen-
trate or as cryoprecipitate. In bleeding patients, the goal is to
keep fibrinogen above 1
5 g/l (4
4 lmol/l),85 though with a
higher level (above 2
0 g/l) recommended for women with
concomitant postpartum haemorrhage.116 The level of fib-
rinogen will increase 1 g/l (2
9 lmol/l) after administration
of 30 mg fibrinogen concentrate per kilogram body
weight.117 For cryoprecipitate, two pools are recommended
to increase fibrinogen levels.77
Anti-fibrinolytics. As suppression of endogenous fibrinoly-
sis is the most common alteration of fibrinolysis in sepsis-in-
duced DIC, the use of anti-fibrinolytics is generally not
recommended in these patients.86 In cancer patients, hyper-
fibrinolysis secondary to DIC has been reported, especially in
patients with acute pro-myelocytic leukaemia, and DIC
induced by adenocarcinoma.43 In these situations, treatment
with anti-fibrinolytics as tranexamic acid may be appropri-
ate.77 However, it should be reserved to patients with ther-
apy-resistant bleeding with a clear picture of hyper-
fibrinolysis.43,77
ª 2020 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2021, 192, 803–818

The use of tranexamic acid in postpartum haemorrhage is
fully established,116 but in obstetric DIC, where suppressed
fibrinolysis may be dominating, caution is advised.
Conclusions
Despite recent advances in the understanding of the patho-
genesis of DIC, which have resulted in the use of several
potential therapeutic agents, the prognosis of patients with
DIC remains dismal. Diagnostic scoring systems may support
diagnosis; however, DIC remains difficult to diagnose early
in its course prior to the development of organ failure, uni-
versal formation of microthrombi, and bleedings. The man-
agement of DIC should be individualised according to the
underlying cause of DIC, clinical symptoms, and the bio-
chemical abnormalities. As most of the clinical treatment
studies were conducted in patients with sepsis, which also
included patients without DIC, implementation of emerging
biomarkers suggestive of microthrombus formation and
hyper-fibrinolysis would allow for improved prospective
RCTs and more personalised management of DIC.
Author contributions
KAD, JBL, and AMH all reviewed the literature and con-
tributed to the first draft of the paper. All authors con-
tributed to discussion of the literature and reviewed the
manuscript for intellectual content. All authors approved the
manuscript prior to submission.
Conflicts of interest
No conflicts of interest for any of the authors.
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