Published online: 2019-08-23

89

Sepsis-Induced Coagulopathy and Disseminated

Intravascular Coagulation
Toshiaki Iba, MD1 Marcel Levi, MD2 Jerrold H. Levy, MD3

1 Department of Emergency and Disaster Medicine, Juntendo Address for correspondence Toshiaki Iba, MD, PhD, Department of
University Graduate School of Medicine, Tokyo, Japan Emergency and Disaster Medicine, Juntendo University Graduate
2 Department of Medicine, University College London Hospitals NHS School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan
Foundation Trust, London, United Kingdom (e-mail: [email protected]).
3 Department of Anesthesiology, Critical Care, and Surgery, Duke
University School of Medicine, Durham, North Carolina

Semin Thromb Hemost 2020;46:89–95.

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Abstract Disseminated intravascular coagulation (DIC) has been recognized as a deadly compli-
cation in sepsis, and its early recognition followed by appropriate management of the
underlying infection are the current management strategies. The activation of
coagulation, inflammation, and other pathways are fundamental host responses
against infection but also produce injury to the host. Recent advances have helped
define the critical roles of thrombus formation in overcoming infection. In addition to
activation of coagulation induced by pathogens, other important pathways including
damage-associated molecular patterns, neutrophil extracellular traps, extracellular
vesicles, and glycocalyx damage are involved in the pathogenesis of sepsis-induced
DIC. The hallmark of DIC is thrombosis in the microvasculature; however, sepsis-
induced DIC is a laboratory diagnosis based on coagulation test results and clinical
Keywords setting. Although simplified criteria were recently introduced, DIC should be distin-
► sepsis guished from other similar conditions such as thrombotic microangiopathy and
► disseminated heparin-induced thrombocytopenia. In DIC, treating the underlying cause is crucial,
intravascular and additional adjunct therapies including antithrombin, thrombomodulin, and
coagulation heparins may have potential benefit, but evidence supporting their use in terms of
► antithrombin improvement of clinically relevant outcomes continues to be debated. In this review,
► thrombomodulin we introduce recent findings regarding the pathophysiology, diagnosis, and treatment
► heparin of sepsis-induced DIC. In addition, we also discuss future potential therapeutic
► coagulation approaches regarding this complex, life-threatening complication.

The activation of coagulation and inflammation are essential tissue factor on monocytes and macrophages by binding to
reactions for host defense during sepsis. Engelmann and pattern-recognizing receptors on immune cells. Tissue factor
Massberg1 introduced the concept of “immunothrombosis,” has been recognized as the main initiator of coagulation in
referring to the close interaction between coagulation and sepsis, together with the clotting factors, factor VIIa, factor Xa,
innate immunity. In sepsis, activation of the coagulation thrombin, and fibrin.2 These components are known to induce
system is common and can lead to disseminated intravascular proinflammatory responses via protease-activated receptors.3
coagulation (DIC), which is associated with organ dysfunction However, recombinant tissue factor pathway inhibitor (TFPI)
and/or hemorrhage. Microorganisms and their components administration failed to produce a positive result in Phase 3
such as lipopolysaccharides, described as pathogen-associated trials performed in patients with severe sepsis.4 The failure of
molecular patterns, are known to induce the expression of the TFPI trial was suggested to be due to the inability of a single

published online Issue Theme Perioperative Hemostasis; Copyright © 2020 by Thieme Medical DOI https://doi.org/
August 23, 2019 Guest Editors: Beverley J Hunt, FRCP, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1694995.
FRCPath, MD, and Jerrold H Levy, MD, New York, NY 10001, USA. ISSN 0094-6176.
FAHA, FCCM Tel: +1(212) 584-4662.
90 Sepsis-Induced Coagulopathy and DIC Iba et al.

inhibitor of coagulation activation to regulate an overactivated factor VII-activating protease.7 DNA released from cells con-
coagulopathy. Multiple factors influence sepsis-induced coa- tributes to coagulopathy by initiating hemostatic activation,
gulopathy (SIC) and therapy requires a multimodal approach platelet aggregation, and fibrinolytic inhibition that together
in addition to the underlying infection.5 interfere with clot stability. After neutrophil extracellular trap
(NET) formation, DNA released intravascularly is both procoa-
Damage-Associated Molecular Patterns gulant and cytotoxic. Proteins that bind to DNA including
Sepsis induces cellular damage and cell death, releasing various histones and HMGB1 are also procoagulant and contribute
cellular components that further propagate inflammation.6 to DIC pathogenesis.8
Host-released proinflammatory substances are known as dam-
age-associated molecular patterns (DAMPs) that play key roles Neutrophil Extracellular Traps
in the innate immune system and tissue repair.6 DAMPs also Coagulation activation induced by NETs represents impor-
contribute to the pathogenesis of inflammation and thrombo- tant host defense mechanisms that contribute to the
genesis that can lead to microcirculatory abnormalities and compartmentalization and killing of bacteria but may also
organ dysfunction.6 The aforementioned DAMPs, which initiate DIC.9 An in vitro study has shown that fibrin is

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include histones, chromosomal DNA, mitochondrial DNA, colocalized with free DNA in blood clots, and increased levels
nucleosomes, high-mobility group box 1 protein (HMGB1), of free DNA occur with deep vein thrombosis.10 These
and heat shock protein, are all important initiators of coagula- findings suggest that NET formation plays important roles
tion and have the potential to induce DIC (►Fig. 1).6 in promoting thrombogenesis. This concept is supported by
Damage-associated molecular patterns can be highly inju- the inability of a knockout mouse model of peptidyl arginine
rious to the host, and as a result, they are released in a regulated deiminase type 4, an essential enzyme for NETs formation, to
process catalyzed by serine proteases that include DNase1 and form thrombi.11 Interestingly, the disintegration of NETs by

Fig. 1 Complex mechanisms for the activation of coagulation during sepsis. Pathogens and their components stimulate monocytes through
specific receptors on the cell surface. Activated monocytes release cytokines, chemokines, and several chemical mediators that activate
platelets, neutrophils, and endothelial cells. Monocytes and other cells release extracellular vesicles that express procoagulant tissue factor and
phosphatidylserine on their surfaces. Damaged endothelial cells change their anticoagulant properties to procoagulant through the disruption
of the glycocalyx and the expression of ultralarge von Willebrand factor (VWF). Neutrophils play major roles in the activation of coagulation by
expressing tissue factor and releasing granule proteins and mediators. Neutrophils also activate coagulation by expelling neutrophil extracellular
traps (NETs), composed of procoagulant DNA, histones, and other damage-associated molecular patterns (DAMPs).

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 Sepsis-Induced Coagulopathy and DIC Iba et al. 91

DNAse1 limited the efficacy of bacterial killing and pre- released into the circulation.21 Similar structures penetrate the
vented thrombosis in mice.12 An inverse correlation between intercellular clefts and play important roles in the regulation of
DNase activity and thrombosis also suggests a pathogenic vascular permeability. Structures expressed in the spaces
role of NETs in thrombosis.12 Coagulation activation that between the endothelial cell and basement membrane are
occurs with NETs is important in sepsis and DIC. For example, also known to function as a foothold for cells. The glycocalyx on
extracellular tissue factor release by NETs favors factor VIIa– the luminal surface of endothelial cells is extremely important
mediated thrombin formation, and the polyanionic surface for the maintenance of antithrombogenicity in the vascular
of NETs also activates contact activation proteins, including lumen. Under inflammatory conditions, reactive oxygen
factor XII (Hageman factor). Neutrophil elastase in NETs also species, heparanases, and other proteases disrupt the glyco-
upregulates the coagulopathic response through the proteo- calyx to produce shedding. Once this occurs, E-selectin, inter-
lytic cleavage of serine protease inhibitors including α2- cellular adhesion molecule 1, and other adhesion molecules
antiplasmin, antithrombin, and C1-esterase inhibitor. Histo- that are exposed on the denuded endothelium recruit platelets
nes can also bind via the A1 domain to von Willebrand factor and neutrophils causing thrombus and fibrin formation.
to initiate GPIbα-mediated platelet adhesion. In septic DIC, Microvascular dysfunction occurs due to the loss of the glyco-

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varying degrees of thrombocytopenia can occur, and the calyx, and results in acute inflammation, increased capillary
magnitude of the platelet drop is reportedly associated with permeability, and loss of vascular responsiveness.21 Moreover,
disease severity and mortality.13 Thrombocytopenia in sep- the loss of the glycocalyx accelerates the devastating hyper-
tic patients also occurs due to activated platelets adhering to coagulation that occurs during sepsis. Subsequently, the
neutrophils stimulated by NETs13 and is considered to be an decreased blood flow and the impaired oxygen delivery result
effect of NETs formation with DIC. in multiorgan failure. Therefore, even if the global oxygen
delivery is increased, the tissue capillary beds cannot receive
Extracellular Vesicles an adequate oxygen supply because of endothelial injury.
Extracellular vesicles (EVs) are a generic name for submicron-
sized spherical particles that are enclosed by bilayer phospho-
Diagnosis of Disseminated Intravascular
lipid membranes released from most cell types into plasma or
Coagulation
other sites.14 Several subclasses of EVs exist based on their
biogenesis and phenotypic origin, including apoptotic bodies, Diagnostic Criteria
exosomes, and microvesicles.15 Research on EVs began with the In 1991, DIC was defined by the Scientific Subcommittee (SSC)
exploration of their procoagulant properties,5,15 as primarily on DIC of the International Society on Thrombosis and Haemo-
expressed through the expression of tissue factor and phospha- stasis (ISTH) as “an acquired syndrome characterized by the
tidylserine on their surfaces. Although platelet-derived EVs intravascular activation of coagulation with loss of localization
were initially reported to be the main type in SIC, endothelial arising from different causes. It can originate from and cause
cells, leukocytes, red blood cells, and other cell types contribute damage to the microvasculature, which if sufficiently severe,
to proinflammatory and procoagulant reactions during sepsis.16 can produce organ dysfunction.”22 Although the cause may
Sepsis is associated with a massive release of leukocyte-derived differ, the systemic activation of coagulation is a common
EVs, particularly neutrophil-derived EVs that retain DNAs, feature of DIC; thus, a diagnosis is possible using diagnostic
histones, and other DAMPs from neutrophils, contributing to criteria obtained from a combination of coagulation tests, and
the procoagulant activity.17 As a result, DIC is associated with the ISTH DIC-SSC has released a set of overt DIC diagnostic
neutrophil-derived EVs generation because they contain pro- criteria.22 However, these diagnostic criteria are not widely
coagulant NETs components. Delabranche et al18 reported an used because of their complexity.23 Recent progress in DIC
increase in NETs and nucleosomes in EVs during sepsis-induced research has shown that the characteristics of DIC differ
DIC. Hence, it is reasonable to think that components of NETs according to the underlying disease. For example, transient
that contain EVs contribute to the pathogenesis of sepsis- excess fibrinolysis is seen in trauma-induced DIC and is viewed
induced DIC.19 as a counter-response to massive thrombotic events.24 In
sepsis, coagulation activation occurs with inhibition of fibri-
Glycocalyx and Endothelial Damage nolysis. The clarification of these differences in pathogenesis
The vascular endothelial surface is covered by the glycocalyx, a has enabled the establishment of simple but additional diag-
gel-like layer that exhibits important properties such as antith- nostic criteria for sepsis-induced DIC as follows.
rombogenicity and anti-inflammation.20 The endothelial gly- The Japanese Association for Acute Medicine (JAAM) re-
cocalyx is composed of three structures: membrane-binding leased the JAAM-DIC diagnostic criteria for acute DIC by
proteoglycans (such as syndecan and glycan), glycosaminogly- eliminating fibrinogen as a criterion,25 and the clinical utility
can (GAG) side chains conjugated with core proteoglycans, and of the JAAM-DIC has been repeatedly reported.26 Recently,
plasma proteins (such as albumin and antithrombin). Each active members of the ISTH DIC-SSC recently proposed a
glycocalyx component is critical to its physiologic functions: simpler version for the diagnosis of SIC that is composed of
syndecans act as mechanosensors, GAGs contribute to antith- only three items: sepsis-3 definitions (infection with organ
rombogenicity, and plasma proteins regulate vascular perme- dysfunction), platelet count, and the prothrombin time ratio27
ability. The glycocalyx is synthesized by vascular endothelial (►Table 1). The usefulness of these SIC diagnostic criteria has
cells and covers the endothelial cell surface, and subsequently been validated, and Iba et al28 reported that it provides an

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92 Sepsis-Induced Coagulopathy and DIC Iba et al.

Table 1 ISTH overt DIC and sepsis-induced coagulopathy therapy. Thus, the SIC diagnostic criteria for SIC may be
scoring systems valuable for detecting sepsis patients who are candidates for
anticoagulant therapy.
Points ISTH overt SIC
DIC Differential Diagnoses
Platelet count 2 < 50 < 100 The early diagnosis of sepsis-induced DIC is important for
(
109/L) management and may potentially improve outcomes.30 While
1 3 50, < 100 3 100, < 150
the use of a simplified diagnostic criteria is desirable, there is
FDP or D-dimer 3 Strong 
increase also the possibility of misdiagnosing diseases that mimic DIC
and delay appropriate management. Important examples
2 Moderate 
increase include heparin-induced thrombocytopenia (HIT), thrombotic
thrombocytopenic purpura (TTP), hemolytic uremic syndrome
1  
(HUS), hemophagocytic syndrome, antiphospholipid syn-
Prothrombin time 2 36s > 1.4 drome, and other conditions associated with thrombocytopenia

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or INR (elevation)
1 3 3, < 6 s > 1.2, 2 1.4 and organ dysfunction as shown in ►Table 2. HIT is a pro-
Fibrinogen (g/mL) 1 < 100  thrombotic disease that requires the immediate termination of
heparin and treatment with nonheparin anticoagulants. Simi-
Total SOFA score 32  2
larly, thrombotic microangiopathy, which includes both HUS
1  1 and TTP, is a broad pathophysiologic process that requires
Abbreviations: DIC, disseminated intravascular coagulation; FDP, fibrin urgent management. A high mortality rate has been reported
degradation products; INR, international normalized ratio; ISTH, Inter- for both diseases unless adequate treatment using either C5
national Society on Thrombosis and Haemostasis; SIC, sepsis-induced inhibitor or plasma exchange is performed at an appropriate
coagulopathy; SOFA, sequential organ failure assessment. time. Recently, ISTH DIC-SSC published guidance information
Note: ISTH overt DIC diagnosis: total score is 5 or more; SIC diagnosis:
important for the differential diagnosis of these diseases.31
total SIC score is 4 or more with sum of SOFA score and coagulation
criteria exceeding 2. Total SOFA score is the sum of four items
(respiratory SOFA, cardiovascular SOFA, hepatic SOFA, and renal SOFA).
Treatment for Disseminated Intravascular
Coagulation
earlier diagnosis and includes most cases of ISTH overt DIC. An Antithrombin
additional analysis of septic patients from Japan evaluated Antithrombin is one of the most important physiological anti-
associations between in-hospital mortality and anticoagulant coagulants that is thought to suppress acute inflammatory
therapy according to the SIC or ISTH overt DIC sets of criteria. reactions in sepsis. However, antithrombin is rapidly consumed
They reported the rate for ISTH overt DIC was about half of that by thrombin, cleaved by neutrophil elastase and the bacterial
for SIC, while the mortality rates for the two sets of criteria enzyme thermolysin, resulting in its inactivation. Thus, the
were comparable.29 Beneficial effects of anticoagulant therapy supplementation of antithrombin for the treatment of septic
were observed in patients with coagulopathy as defined using DIC is included in recommendations.32 Unfortunately, the effi-
both sets of criteria, suggesting that some patients who do not cacy of antithrombin supplementation was not confirmed in a
meet the criteria for overt DIC may benefit from anticoagulant large-scale randomized controlled trial (RCT) known as

Table 2 Major differential diagnoses of the sepsis-induced DIC

Causes Clinical symptoms and laboratory findings

HIT Presence of antiplatelet factor Thrombocytopenia, bleeding tendency, thrombosis
4-heparin antibodies
TTP Decrease of ADAMTS-13 activity Thrombocytopenia, thrombosis, fever, neurological manifestation,
organ dysfunction
aHUS Dysregulation of alternative Hemolytic anemia, thrombocytopenia, renal dysfunction, thrombosis
complement pathway
STEC-HUS STEC infection Bloody diarrhea, hemolysis, thrombocytopenia, renal dysfunction
HPS Epstein–Barr virus infection, Persistent high fever, thrombocytopenia, splenomegaly,
malignant lymphoma, cancer, etc. hemophagocytosis in bone marrow
APS Presence of antiphospholipid antibodies Multiorgan dysfunction due to arterial thrombosis,
venous thrombosis
SFTS SFTS virus infection High fever, leukopenia, thrombocytopenia, bleeding tendency

Abbreviations: ADAMTS-13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13; aHUS, atypical HUS; APS,
antiphospholipid syndrome; HIT, heparin-induced thrombocytopenia; HPS, hemophagocytic syndrome; HUS, hemolytic uremic syndrome; SFTS,
severe fever with thrombocytopenia syndrome; STEC, Shiga toxin-producing Escherichia coli; TTP, thrombotic thrombocytopenic purpura.

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 Sepsis-Induced Coagulopathy and DIC Iba et al. 93

KyberSept. This trial examined the effects of high-dose anti- Heparin and Heparinoids
thrombin for sepsis itself and did not target DIC specifically.33 As noted in the previous section, the usefulness of anticoagu-
However, a subanalysis demonstrated that antithrombin sup- lant therapy for sepsis-induced DIC remains controversial.
plementation could be effective in patients with sepsis and Research on the use of heparin and heparinoids is particularly
coagulopathy.34 Other than the earlier trial, some large-scale difficult because they are commonly administered for venous
clinical studies have consistently demonstrated favorable effects thromboembolic prophylaxis regardless of the presence of
of antithrombin supplementation in septic patients with DIC.26 DIC. Jaimes et al39 examined the effects of unfractionated
Antithrombin’s anticoagulant activity is known to heparin in a RCT and reported no survival benefit; however,
increase dramatically when it binds to heparan sulfate on this study was performed in patients suspected of having
the endothelial glycocalyx.35 One of the unique features of sepsis and not in the septic DIC patients. There have been
antithrombin is its ability to attenuate glycocalyx injury.36 three RCTs examining the effects of heparin in patients with
The mechanism is presumed to involve binding to heparan septic DIC. Aikawa et al40 used unfractionated heparin in 234
sulfate on endothelial cells.37 This phenomenon also can patients as a control for recombinant thrombomodulin, while
explain why the favorable effects of antithrombin were Aoki et al41 used unfractionated heparin as a control for

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canceled by the concomitant use of heparin. A recent topic activated protein C concentrate; no benefit of heparins com-
is the recombinant nonfucosylated antithrombin. This new pared with each of the therapeutic agents studied was
agent was developed in Japan, and its applications continue reported in these two trials. In contrast, Liu et al42 examined
to be explored.38 the effect of low-dose heparin in 37 sepsis-associated pre-DIC
patients and reported an improvement in the hypercoagulable
Thrombomodulin state, multiple organ dysfunction, and period of hospitaliza-
Thrombomodulin is an endothelial anticoagulant cofactor tion compared with saline control. However, this study was too
that promotes the thrombin-mediated activation of protein small to reach a definite conclusion. Regarding heparin use, the
C. Since the expression of thrombomodulin is down-regu- risk of HIT must be kept in mind, and caution is required when
lated during sepsis, supplementation with recombinant judging the benefit–risk balance (►Table 3).
soluble thrombomodulin was proposed as a therapeutic
modality, and recombinant thrombomodulin was devel- Other Anticoagulants
oped. Subsequently, the efficacy of recombinant thrombo- Recombinant activated protein C was the first anticoagulant
modulin in SIC was examined in a randomized Phase 2b approved for the treatment of sepsis after its success in a
study, and a nonsignificant reduction in mortality differ- large-scale RCT named PROWESS (Recombinant Human
ence of 3.8% was shown.38 Following this study, a multina- Activated Protein C Worldwide Evaluation in Severe Sep-
tional Phase 3 study was conducted, and the preliminary sis).43 PROWESS was performed for patients with severe
results have been reported (http://www.asahi-kasei.co.jp/ sepsis and resulted in a significant reduction in 28-day
asahi/en/news/2018/press.html). According to the article, a mortality. Dhainaut et al44 subsequently performed a sub-
nonsignificant mortality reduction of 2.6% was recognized group analysis of subjects with overt DIC and demonstrated
in 800 septic patients with coagulopathy. In addition, an even more profound favorable effect on mortality (relative
improvements were observed in D-dimer, thrombin–anti- risk, 0.71; 95% confidence interval, 0.55–0.91). Nevertheless,
thrombin complex, and prothrombin fragment F1 þ 2 levels recombinant activated protein C was withdrawn when sub-
and the platelet count. The unique feature of thrombomo- sequent trials showed less positive outcomes, generated
dulin is its lectin-like domain, which is thought to suppress some concern about potential bleeding complications, and
inflammatory responses through the inactivation of DAMPs finally, after the failure of a RCT performed in septic patients
such as histones and HMGB1. This activity consequently with shock.45 According to the report, unlike the results of
leads to the suppression of leukocyte adhesion to endothe- PROWESS, the use of recombinant activated protein C was
lial cells, the interference of complement activation, and not associated with reduced mortality but was associated
the inactivation of inflammatory reactions.6 with an increased risk of bleeding.

Table 3 Therapeutic agents for sepsis-induced disseminated intravascular coagulation

Agent Mechanism of action Clinical evidence Reference

31,32
Antithrombin Inhibits thrombin and other Although a large-scale RCT (KyberSept) did
coagulation factors. not show any efficacy, a meta-analysis
Protection of endothelium showed a beneficial effect in survival
36
Thrombomodulin Suppresses coagulation Although not statistically significant, there
through activation of protein C. are two RCTs that showed a trend toward
Suppresses inflammation by a favorable effect in survival
neutralizing DAMPs
38–40
Heparin and Suppress coagulation through No sufficient supportive data except for
heparinoids activation of antithrombin usefulness in venous thrombosis

Abbreviations: DAMPs, damage-associated molecular patterns; RCT, randomized controlled trial.

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94 Sepsis-Induced Coagulopathy and DIC Iba et al.

Regarding the use of recombinant TFPI, two RCTs 6 Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role
targeting sepsis and one RCT targeting pneumonia have of extracellular DNA and DNA-binding proteins in the pathogen-
been performed.5,46 First, a Phase 2 study reported a trend esis of DIC. Blood Rev 2016;30(04):257–261
7 Zeerleder S, Zwart B, te Velthuis H, et al. Nucleosome-releasing
toward a reduction in 28-day all-cause mortality in the
factor: a new role for factor VII-activating protease (FSAP). FASEB J
treatment group. A higher baseline prothrombin time was 2008;22(12):4077–4084
associated with a more pronounced beneficial effect. How- 8 Iba T, Ito T, Maruyama I, et al. Potential diagnostic markers for
ever, a subsequent Phase 3 trial failed to demonstrate such an disseminated intravascular coagulation of sepsis. Blood Rev 2016;
effect. Following these two trials, a third RCT was performed 30(02):149–155
9 Massberg S, Grahl L, von Bruehl ML, et al. Reciprocal coupling of
in the patients with community-acquired pneumonia. Again,
coagulation and innate immunity via neutrophil serine proteases.
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11 Martinod K, Demers M, Fuchs TA, et al. Neutrophil histone

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modification by peptidylarginine deiminase 4 is critical for
Conclusion deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013;
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Disseminated intravascular coagulation is a life-threatening 12 Jiménez-Alcázar M, Napirei M, Panda R, et al. Impaired DNase1-
complication characterized by the systemic activation of mediated degradation of neutrophil extracellular traps is associated
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suppression of fibrinolysis typical of DIC and can easily 14 Iba T, Ogura H. Role of extracellular vesicles in the development of
progress to multiple organ dysfunction and failure. Thus, sepsis-induced coagulopathy. J Intensive Care 2018;6(01):68
15 Nieuwland R, Berckmans RJ, McGregor S, et al. Cellular origin and
the early detection of DIC is extremely important. For this
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purpose, several sets of criteria have been proposed, each
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18 Delabranche X, Stiel L, Severac F, et al. Evidence of NETosis in
there is still no established treatment, appropriate diagnosis septic shock-induced disseminated intravascular coagulation.
remains important for judging the severity of each patient’s Shock 2017;47(03):313–317
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Conflicts of Interest coccus pyogenes. PLoS Pathog 2013;9(08):e1003529
Dr. Levi reports being a member of a scientific advisory 20 Iba T, Levy JH. Derangement of the endothelial glycocalyx in
sepsis. J Thromb Haemost 2019;17(02):283–294
board of Asahi Kasei Pharma America, outside the sub-
21 Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Thera-
mitted work; Dr. Levy reports other from Boehringer, CSL peutic strategies targeting the endothelial glycocalyx: acute
Behring, Instrumentation Labs, Octapharma, outside the deficits, but great potential. Cardiovasc Res 2010;87(02):300–310
submitted work. 22 Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific
Subcommittee on Disseminated Intravascular Coagulation (DIC)
of the International Society on Thrombosis and Haemostasis
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Seminars in Thrombosis & Hemostasis Vol. 46 No. 1/2020