PRIMER

Disseminated intravascular coagulation

Satoshi Gando1, Marcel Levi2 and Cheng-Hock Toh3
Abstract | Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by
widespread intravascular activation of coagulation that can be caused by infectious insults (such as
sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC
are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient
control of anticoagulant pathways and plasminogen activator inhibitor 1mediated suppression of
fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular
thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent
observations have pointed to an important role for extracellular DNA and DNA-binding proteins,
suchas histones, in the pathogenesis of DIC. The International Society on Thrombosis and
Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test
parameters. This scoring system has now been well validated in diverse clinical settings. The
theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying
conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH
guidance for the treatment of DIC recommends treatment strategies that are based on current
evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and
management of DIC and discuss the future directions of basic and clinical research in this field.

Since it was described a half-century ago, the concept
of disseminated intravascular coagulation (DIC) and
its underlying pathogenesis have taken shape in accord-
ance with the understanding of the mechanisms of blood
coagulation and the advancement of laboratory tests1.
At the beginning of the 1980s, Spero and colleagues2
correctly proclaimed that DIC is a sign that death is
coming. Since then, DIC has been recognized as a seri-
ous, well-defined and life-threatening condition, which is
elicited by diverse infectious and non-infectious insults.
The Scientific and Standardization Committee (SSC)
on DIC of the International Society on Thrombosis and
Haemostasis (ISTH) defined DIC as an acquired syn-
drome characterized by the intravascular activation of
coagulation with a loss of localization arising from differ-
ent causes. It can both originate from and cause damage
to the microvasculature, which, if sufficiently severe, can
produce organ dysfunction3. Importantly, this definition
Correspondence to S.G.
Department of
highlights that the core features of DIC are indicative of
Anesthesiology and Critical systemic thrombin generation that is not restricted to the
Care Medicine, Hokkaido site of insult and endothelial cell injury, which gives rise to
University Graduate School of organ dysfunction. Combined with these changes, inhib
Medicine, N15W7, Kita-ku,
ition of fibrinolysis synergistically results in microvascular
Sapporo, 060-8638, Japan.
gando@med.hokudai.ac.jp thrombosis that in concert with haemodynamic and
metabolic derangements contributes to organ dysfunc-
Article number: 16037
doi:10.1038/nrdp.2016.37 tion. DIC is therefore an independent predictor of mortal
Published online 2 June 2016 ity in critical illness3. On the basis of these insights into
the pathogenesis of DIC, the ISTH has further contrib-
uted to the establishment of diagnostic criteria and better
strategies for the clinical management of DIC3,4.
DIC is an old concept that still attracts a substan-
tial amount of attention among physicians worldwide.
In this Primer, we provide an updated overview of the
pathophysiology, diagnosis and management of DIC and
discuss the future directions of basic and clinical research
in thisfield.
Epidemiology
DIC is a frequent complication of a systemic inflamma-
tory response syndrome (SIRS)5,6. SIRS can be caused
by infectious insults (for example, sepsis, which islife-
threatening organ dysfunction caused by a dysregulated
host response to infection) and non-infectious insults
(for example, trauma); indeed, sepsis and trauma are two
predominant clinical conditions associated with DIC2,3.
For example, two validation studies of the ISTH and the
Japanese Association for Acute Medicine (JAAM) DIC
diagnostic criteria revealed the prevalence of sepsis or
infection (3051% of patients) and trauma or major sur-
gery (45% of patients) as underlying conditions of DIC7,8.
Other important underlying DIC-associated disorders
include organ destruction (such as severe pancreatitis),
malignancy (solid tumours and haematological cancers),
obstetrical calamities (such as amniotic fluid embolism,

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Author addresses but declined to 56% in 1998 (REFS9,10). In addition, a

1
Department of Anesthesiology and Critical Care
Medicine, Hokkaido University Graduate School of
Medicine, N15W7, Kita-ku, Sapporo, 060-8638, Japan.
2
Department of Medicine, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands.
3
Institute of Infection and Global Health, University of
Liverpool, Liverpool, UK.
placental abruption, serious pre-eclampsia and post
partum haemorrhage), fulminant hepatic failure and
severe toxic or immunological reactions2,3,8.
The incidence and mortality of DIC vary according to
the period, country, place of treatment (ward or intensive
care unit), diagnostic criteria and underlying disorders
(TABLE1). The differences in mortality between patients
who are diagnosed according to the ISTH (a mortality
rate of 46%) and the JAAM scoring system (a mortal-
ityrate of 22%) depend on the differences in the nature of
the two diagnostic criteria7,8. The ISTH criteria diagnose
full-blown DIC, whereas the JAAM criteria diagnose DIC
that has not yet reached the stage of decompensation8.
Rough estimations show an improvement in mortality
due to DIC over the past two decades. For instance, a
nationwide epidemiological survey by the Ministry of
Health, Labour and Welfare of Japan showed that the
mortality of patients with DIC was as high as 65% in1992
study based on the Japanese national administrative
database demonstrated that mortality due to DIC further
declined to 46% between 2010 and 2012 (REF.11). This
study also showed a significant decrease in mortality due
to DIC in patients with infectious diseases in the same
period. The same trend was observed in population-
based studies in the United States, where mortality due
to DIC decreased from 76% to 51% between 2006 and
20042010 (REFS12,13). However, it is not clear whether
these better outcomes are owing to better understanding
of DIC or to improvements in the general m anagementof
patients who are criticallyill.
The clinical progression from SIRS to sepsis to severe
sepsis and septic shock has been recognized to accompany
an increase in the incidence of DIC. Progression to DIC,
in turn, leads to organ dysfunction, which is associated
with increased mortality 14. In fact, DIC is an indepen
dent predictor of morbidity, 28day mortality and hos-
pital mortality in patients with severe sepsis15. Subgroup
analyses of large studies in patients with severe sepsis,
such as the PROWESS and the KyberSept trials, showed
that when activated proteinC (APC) or antithrombin
treatments were not allocated, the incidence of DIC was
28.9% and 40.7%, and the mortality was 43% and 40%,
respectively 16,17. A multicentre, prospective validation
study of the JAAM DIC scoring system in patients with
severe sepsis demonstrated that the incidence of DIC was

Table 1 | Epidemiology of DIC

Time frame* Design Setting Centre n Criteria Incidence Mortality Evaluation Refs
(%) (%)
Various underlying disorders
1992 Questionnaire survey Ward Multicentre 123,231 JMHW 1.04 65.2 Hospital 9
1998 Questionnaire survey Ward Multicentre 108,792 JMHW 1.87 56 Hospital 10
20102012 Retrospective Various Multicentre 34,717 Various NA 46 Hospital 11
2006 Retrospective ICU Single centre 1,461 ISTH 18
76 Hospital 12
20042010 Retrospective ICU Single centre 8,089 ISTH 1.9 50.6 Hospital 13
2004 Prospective ICU Single centre 217 ISTH 32 46|| 28-day 7
2005 Prospective ICU Multicentre 3,864 JAAM 8.5 21.9 28-day 8
Severe sepsis
19982000 Retrospective Various Multicentre 1,568 Modified ISTH 28.9 30.543# 28-day 16
19972000 Retrospective Various Multicentre 563 Modified ISTH 40.7 25.440# 28-day 17
20102011 Prospective ICU Multicentre 624 JAAM 46.8 38.4 Hospital 18
ISTH 18.1 38.1
Severe trauma
20002007 Retrospective ED or ICU Single centre 314 JAAM 44.9 34 ED or ICU 19
ISTH 8.9 71.4
2014 Retrospective ED or ICU Multicentre 562 JAAM 54.2 25.2 Hospital 20
ISTH 16.9 43.2
Obstetrical calamities
19802009 Retrospective Ward Single centre 151,678 ISTH 0.03 6.1 Hospital 21
DIC, disseminated intravascular coagulation; ED, emergency department; ICU, intensive care unit; ISTH, International Society on Thrombosis and Haemostasis;
JAAM, Japanese Association for Acute Medicine; JMHW, Japanese Ministry of Health, Labour and Welfare; NA, not available. *When studies were conducted or
published. Only patients diagnosed with DIC were included. Per 100,000 population. ||Calculated using presented figure. #Trial drug and placebo.

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Tissue factor Tissue factor

Factor VIIa pathway Factor X
+ inhibitor
Factor VII
Tissue factor Antithrombin

Factor IX Factor IXa Factor II

+ (prothrombin)
Factor VIII Factor VIIIa

Activated
protein C
Factor Xa
+
Factor XIa Factor V
Platelets

Factor IIa Antithrombin

(thrombin)
+ Activated
Factor Va protein C

Factor XI Fibrinogen Fibrin

Figure 1 | Schematic representation of coagulation physiology. Coagulation activationNature starts via the tissue
Reviews factorPrimers
| Disease
factorVII pathway (green arrows). Although tissue factor is a membrane-associated glycoprotein present at subendothelial
sites that is not in contact with the blood under physiological conditions, disruption of blood vessel structure can expose
itto the blood. In addition, tissue factor can be present in the blood through the expression by mononuclear cells or
endothelial cells in response to stimuli, such as inflammatory mediators. Once exposed, tissue factor can form a complex
with factor VII. The formation of this complex results in the conversion of factor VII into its active form (factor VIIa). The
tissue factorfactor VIIa complex subsequently binds to and activates factor X, resulting in factor Xa. Next, factor Xa, along
with the cofactor factor V, converts prothrombin (factor II) to thrombin (factor IIa) (black arrows). This step is most efficient
in the presence of a suitable phospholipid surface, such as that provided by activated platelets. Alternatively, factor Xa can
be generated by factor IXa in combination with factor VIIIa. Generation of factor IXa requires the tissue factorfactor VIIa
complex (orange arrows). A third amplifying pathway of the blood coagulation system involves positive feedback of
thrombin generation, such that thrombin activates factor XI. Factor XIa subsequently activates factor IX, resulting in further
factor Xa and thrombin generation. In addition, factor Va can activate factor XI, which amplifies the production of factorIXa
(blue arrows). Regulation of coagulation activation (red inhibitory lines) occurs by three distinct natural anticoagulant
pathways: antithrombin (which blocks factor Xa and thrombin), tissue factor pathway inhibitor (which inhibits the tissue
factorfactor VIIa complex) and activated protein C (which proteolytically degrades factor Va and factor VIIIa).

46.8% and the mortality in patients with both severe sep-
sis and DIC was 38.4%, a rate that was almost twofold
higher than patients without DIC18. Moreover, other stud-
ies have shown that, in severely injured trauma patients,
the incidence of DIC was 4554% in patients diagnosed
with the JAAM criteria19 and 917% in patients diag-
nosedusing the ISTH criteria20. These studies also showed
that the mortality of trauma patients with DIC ranged
from 2534%; these rates doubled in patients who met
the ISTH criteria for DIC19,20. Finally, a Canadian study
using the ISTH criteria found that the incidence of DIC
in obstetrical calamities was as low as 0.03% from 1980
to 2009, whereas the DIC-related maternal mortality
rate was 3%21. New data on the incidence of DIC in other
underlying conditions have been insufficient.
Mechanisms/pathophysiology
Thrombi (blood clots) are formed as the result of coagu
lation and comprise fibrin and activated platelets. The
coagulation cascade involves a series of proteolytic
reactions in which inactive serine proteases become
activated and, in turn, activate subsequent proteases
in the pathway. According to recent insights, the tradi-
tional division of the coagulation system into an intrinsic
and extrinsic pathway seems outdated. An abbreviated
scheme demonstrating the contemporary model of activ
ation of coagulation invivo is shown in FIG.1. Initiation
of activation of blood coagulation occurs through the
tissue factorfactorVII pathway (formerly known as the
extrinsic system) and ultimately results in the gener
ation of thrombin. Thrombin is the central protease in
the activation of coagulation. Generation of thrombin
is not only crucial for the conversion of fibrinogen into
fibrin but thrombin also augments its own generation by
activating various other coagulant enzymes and cofactors
(such as factor VIII, factor IX and factor XI). In addition,
thrombin is a potent agonist of platelet aggregation. The
creation of crosslinked fibrin is the eventual step in the
activation of coagulation. Thrombin-induced cleavage of
small fragments from fibrinogen leads to the formation of
fibrin monomers and, successively, polymers. To further
strengthen the clot, crosslinking of fibrin is mediated by

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thrombin-activated factor XIII (factorXIIIa). Activation in patients with DIC have become increasingly clear in
of coagulation is regulated by three main anticoagulant recent decades. Specifically, it seems that various mech-
pathways: antithrombin, the proteinC system and tissue anisms at different sites in the haemostatic balance act
factor pathway inhibitor(TFPI). simultaneously towards a procoagulant state. Although
DIC is a complication of various underlying disorders
Pathogenetic pathways in DIC (BOX1), once initiated, the mechanisms that lead to this
Innate immunity and coagulation are closely related coagulopathy follow similarlines.
and regulate each other when activated by diverse
insults22. These processes, which consist of inflamma- Triggers of coagulation activation in DIC. In sepsis and
tion,haemostasis and immunothrombosis, maintain trauma, the pathogenesis of DIC is triggered by the sys-
body homeostasis and promote recovery from the temic inflammatory response, in which inflammatory
insults22,23. However, severe insults perturb these con- cytokines are the most important mediators24. Increasing
trol mechanisms, leading to the systemic activation of evidence supports that extensive crosstalk between
coagulation and the inflammatory cascade, followed inflammation and coagulation occurs, such that inflam-
by DIC. Inturn, DIC gives rise to multiple organ dys- mation leads to the activation of coagulation and coagu
function and affects patient outcomes. The mechanisms lation also considerably affects inflammatory activity 25
involved in the pathological derangement of coagulation (FIG.2). Interestingly, some organ dysfunctions in DIC are
specific to severe sepsis owing to the systemic activation
of coagulation and inflammation that occurs in sepsis26.
Box 1 | Clinical conditions associated with DIC In other specific underlying disorders that cause DIC,
the activation of coagulation can initially be triggered by
Sepsis or severe infection other routes, such as the expression of procoagulant fac-
Potentially from any microorganism, including malaria tors (including tissue factor or factor X-activating cysteine
Trauma protease) in patients with cancer 27 or the release of
Serious tissue injury coagulation-initiating molecules in obstetrical calamities,
Head injury such as placental abruption or amniotic fluid embolism28.
The principal initiator of thrombin generation in
Fat embolism
DIC is tissue factor. For example, it has been shown that
Burns
a moderate systemic inflammatory challenge such as
Liver diseases low-dose endotoxaemia in humans results in an 125fold
Fulminant hepatitis increase in tissue factor mRNA levels in blood monocytes
Severe liver cirrhosis and consequent activation of coagulation29. In addition,
Heat stroke the expression of tissue factor on human monocytes can
be induced in response to experimental systemic exposure
Organ destruction to microorganisms30. In line with this finding, in animals
Severe pancreatitis challenged with microorganisms or lipopolysaccharides
Malignancy (which are found on the surface of Gram-negative bac-
Solid tumours teria), inhibition of the tissue factorfactor VIIa pathway
Haematological cancers by specific antibodies or agents that block the activity
of tissue factor or factor VIIa attenuated both thrombin
Obstetrical calamities
formation and coagulopathy, thereby decreasing mortal-
Pre-eclampsia or eclampsia ity 31,32. Similarly, in patients with severe trauma or cancer,
Placental abruption studies have shown that DIC is triggered by the tissue
Amniotic fluid embolism factorfactor VIIa pathway 33,34. In addition to monocytes,
HELLP (haemolysis, elevated liver enzymes and low perturbed epithelial cells might be a source of tissue fac-
platelet count) syndrome tor 35,36. Furthermore, tissue factor may be present on the
Acute fatty liver surface of other leukocytes, particularly neutrophils37,
Sepsis during pregnancy although it is doubtful whether these cells are capable of
Vascular abnormalities producing tissue factor38. It is more likely that other leuko
cytes acquire surface-bound tissue factor exogenously,
Haemangioma
such as from microparticles that are shed from activated
Leaking or ruptured aneurysm (such as in the aorta)
mononuclear cells and possibly endothelial cells39.
Aortic aneurysm Platelets have a pivotal role in the pathogenesis of
KasabachMerritt syndrome coagulation abnormalities in DIC36. Platelets can be activ
Other vascular malformations ated directly, for example, by pro-inflammatory mediators
Severe toxic or immunological reactions such as platelet-activating factor40. In addition, the expres-
Snake bite sion of tissue factor results in the generation of throm-
Recreational drug use bin, which may further activate platelets. The activated
platelet membrane then forms a perfect scaffold on which
Severe transfusion reaction
further coagulation activation can occur 41. Another path-
Transplant rejection
way by which activated platelets may stimulate thrombin

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Fibrinplatelet Propagation of coagulation activation. During sepsis-

Activated clot induced activation of coagulation, the function of all three
platelet physiological anticoagulant pathways can be impaired.
First, antithrombin, which forms complexes with and
inhibits thrombin and factor Xa (FIG.1), is one of the
Inammatory
most important inhibitors of coagulation, and reduced
cells levels of antithrombin are a characteristic feature of DIC.
Plateletvessel Reductions in the levels of antithrombin are caused by
wall interaction Fibrinogen to brin a combination of processes, including reduced protein
conversion
synthesis, increased clearance through the formation of
TLR4
proteaseantithrombin complexes, extravascular loss due
P-selectin
to increased vascular permeability and degradation by
neutrophil elastase36. In addition, heparin sulfate increases
Thrombin generation
the activity of antithrombin, and, in DIC, cytokines might
Mononuclear PAR1 impair proteoglycan synthesis in the vessel wall and
cell PAR3
PAR4 thereby reduce the availability of heparinsulfate47.
Second, APC and its cofactor protein S form an
Tissue factor-mediated
coagulation activation additional line of defence against the excessive activa-
PAR2 tion of coagulation. Thrombin forms a complex with
the endothelial cell membrane-associated molecule
thrombomodulin, and this complex converts proteinC
Pro-inammatory to its active form, APC48. Furthermore, after binding to
cytokines and chemokines thrombin, thrombomodulin stimulates the activation of
the thrombin activatable fibrinolysis inhibitor (TAFI),
which impairs endogenous fibrinolysis and stimulates
Vascular
endothelium sustained fibrin deposition. APC proteolytically degrades
Impairment of natural Shut down
anticoagulant pathways of brinolysis factor Va and factor VIIIa, attenuating thrombin gener-
ation and fibrin formation (FIG.1). Vascular endothelial
Figure 2 | Interaction of inflammation and coagulation in DIC. Expression of tissue cells express endothelial proteinC receptor (EPCR),
factor by mononuclear cells and subsequent exposure toNature blood Reviews Disease
results in|the Primers
generation which binds to and enhances the activation of proteinC
of thrombin followed by the conversion of fibrinogen to fibrin. Simultaneously, platelet at the cell surface49. In addition to its anticoagulant activ-
vessel wall interactions and activation of platelets contribute to the formation of vascular ity, APC exerts anti-inflammatory effects on leukocytes.
(or microvascular) clots. Platelet-derived P-selectin further enhances the expression of Several studies have demonstrated anti-inflammatory
tissue factor. The binding of tissue factor, thrombin and other activated coagulant
effects of APC invivo 50. By contrast, impairment of
proteases to specific protease-activated receptors (PARs) and the binding of fibrin to
Toll-like receptor 4 (TLR4) on inflammatory cells affect inflammation through the the proteinC system increases the severity of systemic
consequent release of pro-inflammatory cytokines and chemokines, which further inflammation and DIC. In clinical studies, decreased lev-
modulates coagulation and fibrinolysis. els of proteinCand protein S are associated with reduced
survival51. Furthermore, abrogation of protein C activity
by administration of C4binding protein converted a
generation involves P-selectin. Platelets express P-selectin sublethal sepsis model in baboons into a fatal model52.
on their surface, which regulates the adhesion of plate- Inhibition of EPCR by specific antibodies also reduced
lets to leukocytes and the vascular endothelium and also survival in this septic baboon model53. Conversely,
boosts the expression of tissue factor on mononuclear administration of protein C in this sepsis model pre-
cells42. This increased expression is caused by the binding vented DIC and mortality. Hence, it seems that the pro-
of platelets to mononuclear cells and the subsequent activ tein C pathway is of crucial relevance in the host defence
ation of nuclear factor-B (NF-B). P-selectin is released response that causesDIC.
from the platelet surface, and soluble P-selectin is a precise A third coagulation-regulating system is based on
marker of systemic inflammation42. In addition, disrup- TFPI. This inhibitor is present at the surface of the vas-
tion of the endothelium both enhances plateletvessel cular endothelium or is bound to lipoproteins in the cir-
wall interactions and involves the substantial release culation and inhibits tissue factor that is in a complex
of ultra-large von Willebrand factor (vWF) multimers with factor VIIa. Observations in patients with sepsis
from the endothelium. vWF is an important mediator of have not generated conclusive results regarding the rele
platelet adhesion and coagulation, and its degradation is vance of this inhibitory system in DIC, as plasma con-
usually catalysed by a disintegrin and metalloproteinase centrations of TFPI were not lower in most patients than
with thrombospondin motifs 13 (ADAMTS13). Relative in normal controls54. Despite this finding, two lines of
insufficient cleavage of vWF multimers due to consump- evidence from animal models demonstrate the relevance
tion of ADAMTS13 might contribute to DIC43. Indeed, of TFPI in DIC. First, deficiency of TFPI increased the
ultra-large vWF multimers have been detected in patients sensitivity of rabbits to DIC induced by tissue factor 55.
with DIC and ADAMTS13 deficiency, and the association Second, administration of TFPI diminished the detri-
between low levels of ADAMTS13 and the severity of DIC mental effects of experimental bacteraemia in baboons.
in sepsis has been confirmed4446. In this trial, TFPI not only prevented DIC but, in all

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animals that had received a lethal dose of Escherichia coli,
TFPI treatment also resulted in a marked amelioration of
vital functions and survival of the bacterial challenge56.
In further support of a role for TFPI in DIC, a study
in healthy humans showed the ability of TFPI to block
endotoxin-induced coagulation57.
Experimental and clinical studies have demonstrated
that, at the peak of thrombin generation in s epsis,
endogenous fibrinolysis is almost completely turned
off 58. Plasminogen is the inactive form of plasmin, which
is an enzyme that proteolytically degrades fibrin clots.
The immediate fibrinolytic reaction to inflammatory
mediators is a sharp increase in plasminogen activa-
tors (mainly tissue-type plasminogen activator (t-PA)
and urokinase-type plasminogen activator (u-PA))
due to their release from the endothelium. However,
this intensification of plasminogen activation and sub-
sequent plasmin generation is followed by a persistent
increase in the levels of plasminogen activator inhibitor1
(PAI1)59. This increase results in a sustained impairment
of fibrinolysis in sepsis. Important experimental studies
have confirmed the role of fibrinolysis in removing fibrin
from various organs. In experimental sepsis models,
fibrin deposition in the kidneys, lungs, liver and adrenal
glands was greatly reliant on a reduction in the activity of
plasminogenactivator 60.
Inflammation and coagulation in DIC. The derange-
ment of coagulation and fibrinolysis in DIC is mediated
by several cytokines. High cytokine concentrations have
been detected in the circulation of patients with sepsis
and coagulopathy and, in experimental models of sepsis,
serum levels of these cytokines are increased36. Inthe
course of sepsis, tumour necrosis factor (TNF) first
reaches a peak, which is followed by a rise in serum levels
of IL6 and IL1. Several studies have been performed to
elucidate the roles of these cytokines in the pathogenesis
ofDIC.
As TNF is the first cytokine that peaks in experimen-
tal bacteraemia or endotoxaemia and has potent pro
coagulant properties invitro, it was initially hypothesized
that coagulation activation was caused by TNF. However,
a trial that used various strategies to inhibit the activity
of TNF showed that, although the effects of sepsis on
coagulation inhibitors and fibrinolytic activity seemed to
be mediated by TNF, complete blockage of sepsis-induced
enhancement of TNF did not affect the activation of
coagulation36. In addition, in a lethal bacteraemia model
in baboons, an anti-TNF antibody had only a marginal
effect on fibrinogen consumption61. Furthermore, stud-
ies in patients with sepsis who were administered an anti-
TNF monoclonal antibody did not show any effect of this
treatment on survival62. By contrast, the administration
of a specific anti-IL6 antibody resulted in the complete
inhibition of lipopolysaccharide-induced activation of
coagulation in primates63. Similarly, patients with cancer
who received recombinant IL6 showed a marked increase
in the levels of thrombin64. Taken together, these results
indicate that IL6 rather than TNF is important in mediat-
ing the procoagulant response in DIC. IL1 is also a potent
stimulator of tissue factor expression invitro; however,
its role invivo has not been elucidated. In support of a
role for IL1 in mediating DIC in sepsis, infusion of an
IL1 receptor antagonist partly inhibited the procoagulant
response in an experimental sepsis model. In addition,
administration of an IL1 receptor inhibitor to patients
with sepsis reduced thrombin generation65. However, as
the endotoxin-induced effects on coagulation occur well
before the levels of IL1 become increased in the circula-
tion, the question of whether IL1 has a direct role in the
coagulopathy associated with sepsis remains unresolved.
Activated coagulant factors and coagulation inhib-
itors not only interact with other coagulation proteins
but also with specific cellular receptors that subsequently
turn on signalling pathways. In particular, the binding
of proteases to receptors that influence the activation of
inflammation might be important in sepsis and DIC.
The most relevant pathway by which coagulant proteases
affect inflammatory activity is by binding to protease-
activated receptors (PARs), which are transmembrane
domain, Gprotein-coupled receptors66. An unusual
property of PARs is that they act as their own ligand,
which is in contrast to most other receptors. Binding
and cleavage by an activated coagulant protease results
in the exposure of a neo-amino terminus that in turn
activates the same receptor (and possibly neighbouring
receptors), causing transmembrane signalling. There are
four different PARs: PAR1, PAR3 and PAR4 are throm-
bin receptors, whereas PAR2 is activated by factor Xa,
the tissue factorfactorVIIa complex and trypsin. PAR1
can also act as a receptor for factorXa and the tissue
factorfactor VIIacomplex.
Recent observations have pointed to an important
role for extracellular DNA and DNA-binding proteins
(such as histones and high mobility group proteinB1
(HMGB1)) in the pathogenesis of DIC. This cell-free
DNA and DNA-binding components are released from
nucleosomes of degraded cells and might form a surface
on which the assembly of activated coagulant factor com-
plexes could be greatly facilitated67. In addition, histones
activate platelets and stimulate thrombin generation68.
The activation and binding of neutrophils by DNA
components result in the formation of neutrophil extra
cellular traps (NETs), which have recently been identified
as important contributors to vascular thrombosis and
inflammation69. NETs mainly trap and kill pathogens70,71
by using their contents: histones, DNA and potent pro-
teases. However, NETs have been found to promote
excessive thrombosis by multiple mechanisms, including
activation of factor XII72, inactivation of TFPI73 and pro-
vision of a mesh for platelet binding and aggregation74.
NETs might also provide the availability of inflammatory
cells that express tissue factor 72. Activation of coagulation
is further enhanced by the proteolytic cleavage of physio
logical anticoagulants by neutrophil elastase, which is
abundant in NETs75. NETs might also induce endothelial
cell death and detrimental inflammatory activity, effects
that are probably mediated by NET-associated proteases
or cationic proteins, such as histones69,76.
In addition to the role of inflammation in promoting
coagulation, considerable crosstalk between regulatory
anticoagulant systems and inflammatory mediators

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Thrombin
an underlying disease-specific process, its pathogenetic
effects and systemic dissemination that lead to multiple
organ dysfunction and death are probably governed by
somewhat independent pathophysiological pathways and
Procoagulant Antibrinolytic Anticoagulant Probrinolytic mediators. Such pathways might include, for e xample,
acute phase reactants from the liver that are often
remotely linked to coagulation or to the inciting and
Thrombosis Bleeding
triggering effectors. Thus, it is often a major challenge
to identify the predominant mechanism that is driving
Figure 3 | Diverse and opposing effects of thrombin. Excess thrombin generation in
Nature Reviews | Disease Primers DIC from the heterogeneous, overlapping effects of the
disseminated intravascular coagulation leads to bleeding and/or thrombosis depending condition that can vary with time. The pathology associ
on the dominant change affecting the dynamic balance in both coagulant and
ated with DIC is further complicated by the presence of
fibrinolytic consequences.
several intertwined feedback loops between coagulation,
inflammation, complement and immune systems. This
might occur. For instance, antithrombin can act as an interplay between mechanisms tends to vary over the
anti-inflammatory mediator by directly binding to leuko- course of the clinical presentation and can be further
cytes and reducing their cytokine and chemokine recep- exacerbated by the underlying disease-specific process.
tor expression77. Indeed, in experimental animal models, Emerging evidence also suggests a pivotal role for sys-
the administration of antithrombin can reduce DIC temic cellular activation and death through the release of
intensity and mortality, and these effects are accompan damage-associated molecular patterns (DAMPs), includ-
ied by a decrease in the levels of IL6 and IL8. In addi- ing nuclear breakdown products such as DNA and his-
tion, convincing evidence supports that the proteinC tones that can be found in NETs, among other locations,
system plays a crucial part in modulating inflamma- making the management of this devastating condition
tion78. APC has been shown to block endotoxin-induced particularly challenging.
increases in the levels of TNF, IL1, IL6 and IL8 To understand the mechanisms of multiple organ
invitro and invivo 79,80. Inline with these results, the dysfunctions in DIC, a clear appreciation of the main
inhibition of APC in animals with experimental sepsis themes in the pathophysiology of DIC is required in the
has been shown to aggravate the systemic inflammatory approach to the patient with DIC. These themes need
host response, as indicated by enhanced levels of pro- to explain the mixed pathology, which includes micro
inflammatory cytokines, increased leukocyte infiltration vascular thrombosis, haemorrhages and oedema caused
and tissue destruction in various organs81. Furthermore, a by vascular leakage (summarized below).
study showed that targeted disruption of the gene encod-
ing protein C in mice (causing a heterozygous proteinC Multifaceted consequences of thrombin generation
deficiency) resulted in a more severe coagulopathy invivo. Regardless of the underlying disease-specific
after the administration of endotoxin than in wild-type process, the excessive generation of thrombin and
mice and that this increase in coagulopathy severity its systemic dissemination is usually the hallmark of
was associated with a markedly increased inflamma- DIC development 88. This mainly relates to the central
tory response, as shown by enhanced levels of several physiological role of thrombin and the multiple well-
pro-inflammatorycytokines82. orchestrated coagulant89,90, anticoagulant89,91, profibrino-
lytic92 and antifibrinolytic93,94 functions of thrombin in
Pathophysiology of organ dysfunction the coagulation cascade (FIG.3). The main theme in DIC
As DIC is an intermediary condition that arises on the pathophysiology is the loss of these opposing effects
background of other disorders (such as sepsis, trauma, owing to the excessive generation of thrombin, which
obstetrical calamities and cancer), it has frequently been not only disrupts this balance but also results in the dis
classified as a haemostatic complication of these under- proportionate consumption of these different compo-
lying disorders83. Nonetheless, the observations that DIC nents at rates that are difficult to predict, tend to vary
increases the risk of mortality to levels that are higher over the course of the illness and may be shaped by the
than that of the initiating disorder and that DIC is an underlying inciting pathology 95. One example of disease-
independent predictor of mortality regardless of the specific tailoring of DIC is the loss of the proteinC recep-
underlying condition84,85 suggest that the triggering of tors (thrombomodulin and EPCR) from endothelial
distinct processes that culminate in multiple organ dys- surfaces at vulnerable vascular sites, as has been shown
function as a prelude to death represent a distinct patho- in the case of DIC in cerebral malaria, which involves
logical entity. In sepsis that is not complicated by DIC, the cytoadherence of Plasmodium falciparum-infected
for example, DIC increases the risk of death from 27% to erythrocytes in microvessels within the brain96. Cerebral
43%86. DIC is therefore a development that has net liabil- malaria can result in localized cerebral microvascular
ity to the patient regardless of the inciting factors. This thrombosis, especially as infected erythrocytes bind to
concept is further demonstrated and strengthened by the EPCR, thereby reducing the generation of APC97,98. The
fact that removing or treating the primary disease does loss of EPCR can also contribute to compromised vascu-
not necessarily result in a better outcome or indeed in the lar endothelial barrier function, vascular leakage, oedema
resolution of DIC87. Altogether, these points indicate that, and microhaemorrhages due to the loss of cytoprotective
although the DIC process can be triggered and shaped by signalling through the APCEPCRPAR1 pathway 99.

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a b

Figure 4 | Purpura fulminans in a patient with DIC due to meningococcal septicaemia. Shoulder
Nature (parta)
Reviews and hand
| Disease Primers
(partb). DIC, disseminated intravascular coagulation. Reproduced from Disseminated intravascular coagulation:
olddisease, new hope, Toh, C. H. & Dennis, M., 327, 974977, 2003 with permission from BMJ Publishing Group Ltd.

The excessive generation of thrombin in DIC can
manifest as varying phenotypes, which are not neces-
sarily restricted to excessive thrombosis (FIGS3,4). This is
exemplified by an early hyperfibrinolyic (haemorrhagic)
phase, which is a response to the surge of thrombin in the
early stages following severe trauma100,101. The haemor-
rhagic phase is followed by a procoagulant (thrombotic)
phase after 2448hours102, which is mainly attributable
to the excessive expression of PAI1 on the surface of
platelets and activated endothelial cells, as well as to the
suppression of the protein C anticoagulant pathway 101.
Mechanisms that disseminate thrombin generation.
InDIC, organ dysfunction typically occurs distant to the
site of injury, for instance, acute lung injury in severe
trauma and necrotizing pancreatitis. As such, factors that
disseminate and increase the generation of thrombin are
particularly important. These factors include abnormal
and excessive expression of tissue factor on the surfaces
of activated cells and derived microparticles103,104, plate-
let polyphosphate-dependent activation of factor XI68,105,
increased consumption (and reduced production) of
anticoagulant factors (proteinC and antithrombin),
increased exposure of negatively charged surfaces that
dramatically enhance thrombin generation106,107 and,
finally, the newly recognized role of DAMPs in promot-
ing and fuelling thrombin generation68,108. DAMPs are
discussed in more detailbelow.
The generation and dissemination of microvascular
thrombi in DIC leads to organ ischaemia and ischaemia
reperfusion injury, which in turn results in nonspecific
body responses with inflammation and further coagula
tion activation, fuelling a vicious circle that substantially
contributes to multiple organ dysfunction109. Thus,
the development of multiple organ dysfunction in the
course of DIC is directly linked to the systemic dissemin
ationof thrombin generation that overwhelms the fine
balance between the opposing physiological effects con-
trolled by thrombin and the phenotype (thrombotic or
haemorrhagic) that follows thrombin generation during
the DIC process. This phenotype relies on the predomi-
nant pathway that overwhelms the haemostatic balance
and might be partly, but not completely, shaped by the
underlying pathology.
Immunothrombosis and DAMPs in multiple organ
dysfunction. Although clot formation was classically
described as a function of activated clotting factors,
subendothelial collagen and platelets, recent evidence
suggests that the picture is much wider and involves
activated neutrophils and monocytes what has
come to be known as immunothrombosis (REFS22,23).
As described above, monocyte-derived tissue factor
expression is believed to be an important mediator
of immunothrombosis103,104. Furthermore, the inter-
actions between neutrophils, monocytes and plate-
lets to generate and propagate thrombosis invivo is
increasinglycompelling 72,110.
Emerging evidence also highlights the pivotal part
played by DAMPs, such as the individual components
of NETs (histones and DNA) in mediating not only
immunothrombosis74,108 but also direct cellular toxicity
that contributes to organ injury and multiple organ
dysfunctions111114. For example, circulating histones
have been found to directly induce features of thrombo-
sis and DIC invivo111,115 and to mediate specific organ
injuries, such as lung 111, cardiac112,116, liver 113, renal117 and
endothelial injury 111,114. Specific functional consequences
of circulating histones include platelet aggregation and
thrombocytopaenia118, thrombi that are particularly
resistant to lysis119, vascular leakage and the release of
pro-inflammatory cytokines and extracellular traps by
leukocytes, especially neutrophils111. Furthermore, evi-
dence suggests that increased levels of circulating histones
are observed in patients with DIC115 and that histone
DNA complexes (nucleosomes) might be important clin-
ical prognostic markers and predictors of multiple organ
dysfunctions and mortality in patients withDIC120.

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Diagnosis, screening and prevention
Clinically, the disordered coagulation associated with
DIC can manifest at any point in the spectrum between
bleeding and thrombosis (FIG.3). Although bleeding
ranging from oozing at venipuncture sites to major organ
haemorrhage is one manifestation of DIC, organ dys-
function from microvascular thrombosis is usually evi-
dent. The archetypal expression of this organ dysfunction
is the skin manifestation of purpura fulminans, which
appears bruised owing to bleeding under the surface, but
also ischaemic owing to the reduced blood supply (FIG.4).
Equally, the underlying and predisposing clinical condi-
tion is likely to influence the balance between thrombosis
and bleeding and affect the resulting phenotype (BOX1).
As such, the diagnosis of DIC is always made in the
context of the underlying clinical condition121 and this
is typically in the setting of acute clinical deterioration.
Thus, diagnostic tests should be simple, robust and rapid
to keep pace with the DIC process. As increased invivo
thrombin generation is central to the pathogenesis of
DIC, assays can detect its generation (such as the throm-
bin generation assay and the detection of increased lev-
els of thrombinantithrombin complexes), the activation
of the protein C pathway (such as measuring increased
levels of APC and detecting APCinhibitor complexes)
and its activity on fibrinogen (such as measuring the
levels of fibrinopeptide A or soluble fibrin monomer).
However, none of these sensitive indicators of thrombin
generation meet the practical challenges present in the
acute diagnostic laboratory of turning out such results
rapidly. Moreover, serial testing of these molecular mark-
ers to monitor evolving DIC is unlikely to be cost and
clinicallyeffective.
As falling levels of the endogenous anticoagulants
(protein C and antithrombin) have been linked to clin-
ical outcome in DIC51,122, measuring the levels of anti-
coagulants might offer a more practical approach to
establishing coagulation activation at the molecular
level. Results can now be generated in real time, but the
sensitivity of this approach for non-overt DIC is not
quite clear. Moreover, overt DIC may already be evident
Box 2 | The ISTH scoring criteria for DIC
1. In a patient with an underlying disorder that is associated with overt disseminated
intravascular coagulation (DIC), attain results from the global coagulation tests
(prothrombin time, platelet count, fibrinogen and fibrin-related marker levels)
2. Score the test results
Platelet count (>100=0 points, <100=1 point and <50=2 points)
Increased fibrin marker levels (such as D-dimer and fibrin degradation products; no
increase=0 points, moderate increase=2 points and strong increase=3 points)
Prolonged prothrombin time (<3 seconds=0 points, >3 and <6 seconds=1 point and
>6 seconds=2 points)
Fibrinogen level (>1g per l=0 points and <1g per l=1 point)
3. Calculate score
A score of 5 points is compatible with overt DIC: repeat score daily
A score of <5 points is suggestive of non-overt DIC: repeat score daily
ISTH, International Society on Thrombosis and Haemostasis. Adapted with permission from from
Taylor Jr. FB, Toh CH, Hoots WK, et al. Towards Definition, Clinical and Laboratory Criteria, and a
Scoring System for Disseminated Intravascular Coagulation. Thromb Haemost 2001; 86: 132730.
through routinely available tests of global coagulation
(prothrombin time and activated partial thromboplastin
time) by the timethat levels of protein C and anti
thrombin fall to <50% of normal2. Prognostically, stud-
ies have shown that the more-readily available measures
of prothrombin time (a global measure of the extrinsic
pathway of coagulation that can be increased in DIC)
and D-dimer changes (ameasure of lysis of crosslinked
fibrinand an increase in DIC), rather than levels of pro-
tein C and antithrombin, relate significantly to mortality
in DIC when analysed as continuous variables123.
As such, diagnosing DIC is still very much reliant on
a composite of simple, rapid and practical tests of global
coagulation, such as the prothrombin time, activated
partial thromboplastin time (aPTT; which is a global
measure of the intrinsic pathway of coagulation) and the
number of platelets in circulation (which can fall as part
of DIC consumption) alongside the levels of fibrinogen
and markers of fibrin formation and its lysis, such as
D-dimer. None of these markers are sufficiently sensitive
or specific in isolation, and a combination of results at
different time points is particularly helpful in determin-
ing the presence of DIC. However, normal prothrombin
time or aPTT do not exclude coagulation activation124
and it is more useful to look for time-dependent longitu-
dinal changes to capture the typically evolving nature of
DIC. Nonetheless, it is well validated that the degree of
abnormality in global coagulation tests has pathogenetic
relevance in indicating the degree of multiple organ fail-
ure and the likelihood of death, which has led the ISTH
SSC on DIC to develop and harmonize a composite
scoring framework of global haemostatic tests, in which
a score of 5 is indicative of overt DIC3,125 (BOX2).
Once overt DIC can be identified, the condition
might already be at a stage of irreversible decompensa-
tion and, therefore, late from a therapeutic perspective.
With this in mind, a standardized method of identifying
non-overt DIC at a point when haemostatic dysfunction
is subtle but starting to decompensate would be impor-
tant clinically and for inclusion criteria in clinical trials.
Screening for this has been proposed within the ISTH
DIC guidelines through scoring for abnormal trends and
abnormal results in global coagulation tests3. Although
this approach needs prospective validation, similar
approaches for capturing worsening coagulopathy have
been shown to correlate with clinical deterioration,
increasing number and severity of organ dysfunctions
and adverse outcome in general. As such, a high index
of suspicion of abnormal changes in the global coagu-
lation tests is the mainstay for alerting the clinician to
identify the trigger so that its removal can prevent the
overt transformation ofDIC.
Point-of-care tests that can assess the combined effect
of the different haemostatic components, including plate-
lets and the fibrinolytic system, would be advantageous if
truly indicative of the predominant effect of multifaceted
thrombin generation invivo. In this regard, automated
thromboelastographic techniques have the potential
for real-time capture of the evolving DIC process126; no
prospective studies have been conducted on their sen-
sitivity or specificity in DIC. The only evidence for the

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cost and clinical effectiveness of these techniques relates
to predicting blood loss in cardiovascular surgery 127,128.
Inaddition to coagulation-based tests, there is a potential
for improving DIC diagnosis by incorporating biomark-
ers of the crosstalk between coagulation, inflammation
and innate immune activation, suchas DAMPs, that have
a pathogenetic link to increasing thrombin generation
invivo111,115. However, none of these assays are sufficiently
simple and rapid, and their robustness in DIC needs to be
comprehensively evaluated.
Management
Rationale
As presented in FIG.5, the theoretical cornerstone of
DIC management is the specific and vigorous treat-
ment of the underlying conditions (the insults)4. DIC
should be simultaneously well managed to improve a
patients outcome. Discrimination between controlled
and uncontrolled DIC is important. In controlled DIC,
the endothelial regulatory network for coagulation
control is temporarily overridden and DIC will reverse
quickly when the predisposing condition is removed
or stopped (such as in cases of transfusion reactions or
placental abruption). By contrast, uncontrolled DIC is
characterized by the overriding of the regulatory factors
and the degradation of the endothelial network (which
occurs, for instance, in sepsis and trauma)3. Thus, in
cases ofuncontrolled DIC, in addition to the manage-
ment of underlying disorders, it is essential to install
supportive treatment aimed at DIC itself. The timing of
the start of treatment is also important. Early treatment,
before DIC is diagnosed, might deteriorate physiologi-
cal haemostasis and immunothrombosis against injuries
and pathogens and exacerbate the underlying condi-
tions. Indeed, Fourrier 129 demonstrated that anticoagu
lant factor concentrates only improve the outcome of
severe s epsis when administered to patients with DIC.
Insults Treatment
Innate immunity Systemic inammation
Inammation DIC
Immunothrombosis
Organ dysfunction
Thesame results were obtained from the subgroup
analyses of two large-scale trials in which anticoagulant
factor concentrates were used for the treatment of severe
sepsis16,17. These results suggest that the target of these
concentrates is not severe sepsis, but severe sepsis with
established DIC and that DIC should be treated after its
definitive diagnosis (FIG.6). Finally, during treatment,
repeated evaluation of the DIC score is required to
monitor the DIC status, which will improve the diag-
nostic accuracy and the ability of the DIC scoring system
to predict c linical outcomes3,18,100.
Substitution therapy
Although the evidence-based benefits of the transfusion
of platelets, fresh frozen plasma (FFP) and coagulant
factor concentrates have not yet been established in
randomized controlled trials, these therapies seem to be
supported in patients who are at risk of bleeding or those
with bleeding due to consumption coagulopathy. The
recommended treatment thresholds for transfusion of
platelets, FFP, fibrinogen concentrates or cryoprecipitates
have been presented in the ISTH guidance for treatment
ofDIC4.
The ISTH guidance recommends the use of pro-
thrombin complex concentrate (PCC) in actively bleed-
ing patients to promote clotting; however, the following
should be considered: PCC is a concentrated product
composed of three or four vitaminK-dependent coagu-
lant factors and contains no (or a very small amounts) of
anticoagulant proteins, such as protein C, protein S and
antithrombin130. This means that, at least theoretically,
the extremely high ratio of procoagulants to anticoagu
lants in PCC might induce both thromboembolism
and DIC130132. In fact, PCC increases thrombin gener-
ation and this is accompanied by a decrease in platelet
count, a decrease in the levels of antithrombin and a
prolonged prothrombin time, which are hallmarks of
the development of DIC132,133. As such, PCC should be
used carefully alongside monitoring of the DIC score
and the measurement of antithrombin and/or proteinC
levels. Finally, the effect of recombinant human activ
ated factorVII (rhFVIIa) in DIC with severe bleeding is
unknown. A recent Cochrane review 134 concluded that
the use of rhFVIIa to promote haemostasis does not
have proven effectiveness and that it increases the risk of
arterial events. On the basis of these findings, the review
concluded that rhFVIIa should not be used outside its
current licensed indications, except for in clinical trials134.

Anticoagulants
Outcome Outcome Anticoagulant treatment is an appropriate approach
based on the ISTH definition of DIC, in which DIC is
characterized by extensive activation of coagulation
Recovery Death due to systemic thrombin generation. However, the
use of anticoagulants in patients with bleeding due to
Figure 5 | Management strategies for DIC. Diverse
Nature Reviewsof| Disease consumption coagulopathy or increased fibrinolysis
insults induce the pathological reactions systemicPrimers
inflammation and disseminated intravascular coagulation (orfibrinogenolysis) is controversial. Anticoagulants
(DIC), which synergistically give rise to multiple organ are contraindicated in DIC caused by severe trauma and
dysfunctions that severely affect patient outcomes. traumatic shock accompanied by critical bleeding due to
Toimprove outcomes, DIC and the underlying insults both consumption coagulopathy and hyperfibrinolysis
should be treated simultaneously. (or hyperfibrinogenolysis)101.

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Severe sepsis A Cochrane review 144 concluded that antithrombin

Immunothrombosis DIC Anticoagulant
Physiological responses Pathological responses factor
Homeostasis Organ dysfunction concentrates
Figure 6 | Anticoagulant factor concentrate treatment for DIC. Anticoagulant factor
Nature Reviews | Disease Primers
concentrates do not target severe sepsis alone; rather, they target severe sepsis with
established disseminated intravascular coagulation (DIC). Treatment of severe sepsis
before the emergence of DIC can lead to the deterioration of the physiological responses
that maintain body homeostasis. Thus, DIC should be treated after it is definitively
diagnosed using the DIC diagnostic criteria.
The ISTH guidance recommends the use of unfrac-
tionated heparin or low-molecular-weight heparin
(LMWH) in DIC with the thrombotic phenotype4.
However, there have been no randomized controlled
trials demonstrating a clinically relevant outcome
for patients with DIC who are treated with heparin.
Unfractionated heparin was found to target sepsis, but
not sepsis with DIC, in a failed randomized trial135. No
significant differences in DIC scores or mortality of
patients with DIC who received unfractionated heparin
or LMWH were noted in a small randomized trial136.
Importantly, the prophylaxis of venous thromboembo-
lism with unfractionated heparin or LMWH is advocated
in critically ill, non-bleeding patients with DIC4,137.
Anticoagulant factor concentrates
The escape of thrombin from the site of insult into the
circulation is inhibited by anticoagulant mechanisms,
including TFPI, antithrombin and the thrombomodulin
protein C systems of the endothelium. When anticoagu
lant mechanisms are overwhelmed by severe insults,
systemic thrombin generation ensues138. In DIC, endo
thelial injury as well as the consumption and dysfunction
of these anticoagulant proteins enhance disseminationof
thrombin generation; thus, the use of agents that are
capable of restoring impaired anticoagulant pathways is
recommended4,139. Three large trials of antithrombin140,
TFPI141 and APC142 for severe sepsis have failed. However,
it is important to note that, in these trials, although the
treated patients had severe sepsis, the majority did not
have both severe sepsis and DIC. In addition, the sub-
group analyses of patients with or without DIC16,17 and
the analyses across the subgroup that was diagnosed
with DIC at entry 129 showed significant efficacy of anti
thrombin and APC in decreasing mortality in patients
with severe sepsis associated with DIC. Accordingly,
studies that focus on the treatment of anticoagulant factor
concentrates for severe sepsis with DIC, but not for severe
sepsis without significant coagulopathy, are required.
Recombinant APC has been removed from the
market based on the results of the PROWESS-SHOCK
study 142. Plasma-derived APC is still available and a
double-blind, randomized trial of the use of APC and
unfractionated heparin in the treatment of DIC has been
conducted143. APC significantly improved 28day mortal
ity (20.4% forAPC versus 40% for placebo; P<0.05) and meta-analysis found beneficial effects of rhTM
without increasing bleeding. However, this drug is locally
approved and cannot be used worldwide.
did not significantly reduce overall mortality compared
with a control group of patients who were critically
illwith various underlying conditions. Several subgroup
analyses did not investigate the effects of antithrombin
in patients with DIC; no data on the effects of anti
thrombin in DIC were available for this review. By con-
trast, a meta-analysis on mortality in patients with DIC
and sepsis, and a systematic review and meta-analysis on
mortality due to DIC in severe sepsis showed significant
reduction in mortality with antithrombin treatment145,146.
The systematic review and meta-analysis146 included a
subgroup analysis of the KyberSept trial, which showed
the efficacy of antithrombin in the treatment of DIC17.
In addition, a randomized controlled study of the effects
of antithrombin on DIC in s epsis in patients who had
initial antithrombin levels of 5080% of normal showed
that antithrombin significantly improved DIC scores
and doubled the rate of recovery from DIC without
any risk of bleeding 147. The small sample sizes and the
low mortality in the control (13.3%) and antithrombin
(10%) groups explain why there was no improvement in
the 28day mortality. Furthermore, a multicentre survey
showed that patients with sepsis and DIC who had an
initial antithrombin level of <40% of normal and had
received a high dose of antithrombin (3,000IU per day)
had a higher DIC recovery rate and 28day survival rate
than patients who received a lower dose of antithrombin
(1,500IU per day), without an increase in the bleeding
risk148. Moreover, two large nationwide database studies
have been published149,150, the first with 2,194 patients
and the second with 518 patients, which used propen-
sity scores and instrumental variable analyses. In these
studies, the administration of antithrombin was associ-
ated with significant reductions in 28day mortality in
patients with severe pneumonia and sepsis-induced DIC
and in patients with sepsis-induced DIC after emergency
laparotomy for intestinal perforation. Together, these
results suggest the need for a randomized controlled
trial of antithrombin without adjuvant heparin and good
bias protection in patients who meet prespecified criteria
forDIC144.
Although somewhat varied, the data on the efficacy
of using recombinant human soluble thrombomodulin
(rhTM) to treat DIC are generally positive. Following
the study that demonstrated the efficacy and safety of
rhTM in DIC151, many studies confirmed these results;
however, the results of these subsequent studies have
been heterogeneous. For example, one study showed
little or no association between the use of rhTM and
mortality in patients with severe pneumonia and sepsis-
associated DIC152. By contrast, a historical control study
and a multicentre propensity score-matched study on
sepsis-induced DIC showed that rhTM led to significant
improvements in organ dysfunction, DIC and hospital
mortality 153,154. In addition, rhTM has been shown to
improve mechanical ventilation times and the length
of stay in the intensive care unit. A systematic review
on 2830day mortality and the resolution of DIC
in patients with sepsis-induced DIC155. Importantly,

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Table 2 | Studies on anticoagulant factor concentrates

Drug Trial Design Subject Result Refs

Antithrombin KyberSept Double-blind, placebo- Severe sepsis Failed 140

controlled, multicentre
KyberSept Retrospective subgroup DIC in severe sepsis Significant mortality reduction (P=0.024) 17
analysis of the
KyberSepttrial
JAAMDICAT Prospective multicentre DIC in sepsis and Significant improvement of DIC (P=0.015) 147
severe sepsis anddoubling the recovery rate of DIC without
riskof bleeding
Tissue factor OPTIMIST Double-blind, placebo- Severe sepsis Failed 141
pathway inhibitor controlled, multicentre
Recombinant PROWESS- Double-blind, placebo- Septic shock Failed 142
activated proteinC SHOCK controlled, multicentre
PROWESS Retrospective subgroup DIC in severe sepsis A trend towards greater risk reduction in mortality 16
analysis of the
PROWESStrial
Plasma-derived NA Randomized, prospective, DIC in various Significant mortality reduction without increasing 143
activated proteinC double-blind, multicentre underlying diseases bleeding (P<0.05)
Recombinant NA Randomized, prospective, DIC in haematological Significant improvement of DIC without risk 151
soluble double-blind, multicentre malignancy or of bleeding (Pvalue is not provided, but the
thrombomodulin infection resolution rate with 95% CI was described)
NA Double-blind, placebo- Suspected DIC in Evidence suggestive of efficacy supporting further 157
controlled, multicentre sepsis development of this drug in sepsis-associated DIC
NA Double-blind, placebo- Severe sepsis and Ongoing 177
controlled, multicentre coagulopathy
DIC, disseminated intravascular coagulation; NA, not available.

nostudies have found an increased incidence of major
bleeding or transfusion associated with rhTM use151155.
A meta-regression analysis indicated that there was a
significant positive relationship between the probability
of benefit from rhTM and the increased risk of death
in control patients155. The same author group con-
firmed that rhTM treatment only had survival benefit
among patients with sepsis-induced DIC in a high-risk
subset of patients with acute physiology and chronic
health evaluation II (APACHEII) scores of >24 or
sepsis-related organ failure assessment (SOFA) scores
of >11 (REF.156). The results suggest that the survival
benefit of rhTM may only be experienced by patients
with sepsis-induced DIC involving a high risk of death.
The results also indirectly support the concept that the
target of anticoagulant factor concentrates is not severe
sepsis, but severe sepsis with established DIC. Based
on the results of a randomized, double-blind, placebo-
controlled, PhaseIIb study, a PhaseIII trial of rhTM in
patients with severe sepsis and coagulopathy was devel-
oped and is ongoing 157. Studies on anticoagulant factor
concentrates are summarized in TABLE2.
Antifibrinolytic treatment
In DIC, fibrinolysis is primarily blocked by increases in
the levels of PAI1. Thus, DIC should not be treated with
antifibrinolytic agents that may in fact cause deterior
ation of microvascular thrombosis4. In some cases,
DIC and pathological systemic hyperfibrinolysis (or
hyperfibrinogenolysis) may coexist known as DIC
with the hyperfibrinolytic phenotype158,159. Examples of
this clinical condition include acute promyelocytic leu-
kaemia (APL) and prostatic carcinoma. In these cases,
antifibrinolytic treatment may be applicable4.
Acute promyelocytic leukaemia. Massive plasmin is
formed on the assembly of plasminogen and t-PA on
cell surface-associated annexin II. Its formation leads
to the consumption of 2plasmin inhibitor by the
plasmin2plasmin inhibitor complex in the plasma,
which results in excess plasmin. In turn, excess plasmin
induces haemorrhagic disorder in patients with APL160.
A small double-blind study showed that tranexamic
acid (an antifibrinolytic agent that inhibits plasmin-
mediated degradation of fibrin) was effective for the
control of haemorrhage without thromboembolic com-
plications in APL161. However, after the introduction
ofall-trans retinoic acid (ATLA) as a front-line therapy
for APL, a recent historical control study showed no
potential benefit of the prophylactic use of tranexamic
acid in patients with APL who were treated with
ATLA162. Because of the complication of fatal throm-
bosis when ATLA and tranexamic acid treatments are
combined163, antifibrinolytic agents should only be
considered in cases of life-threatening bleeding 4,164.
Trauma. WeibelPalade bodies are storage granules of
endothelial cells. Upon traumatic shock-induced hypo
perfusion, these bodies release t-PA into the circulation,
which results in systemic fibrinolysis (or fibrinogeno
lysis) in addition to DIC-induced secondary fibrinoly
sis33,158,165. In contrast to the immediate t-PA release

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from the endothelium, the induction and expression of
PAI1 (also known as SERPINE1) mRNA usually takes
several hours166. Indeed, immediately after trauma, one
study showed that patients with DIC had significantly
higher levels of t-PA and plasmin than those without
DIC, whereas the levels of PAI1 were almost identical
between patients with and those without DIC33. These
studies suggest that an extreme imbalance between the
levels of t-PA and PAI1 are the main cause of hyper-
fibrinolysis in patients with DIC during the first few
hours after trauma. Tranexamic acid can reduce the risk
of death in patients with bleeding trauma167 and should
be given as early as possible because any delay reduces its
efficacy and might be harmful168. Although some debates
exist 169, these studies provide the theoretical basis for
antifibrinolytic therapy in DIC with the hyperfibrinolytic
phenotype in the early phase oftrauma.
In summary, the management of multiple organ
dysfunctions in general and in DIC specifically has had
many failed therapeutic dawns140142,170. Its complexity
as outlined above probably requires combination
treatment approaches that are biomarker guided to
target specific pathways and phases in the DIC process.
Quality of life
The quality of life of patients who develop DIC is highly
dependent on the conditions and prognoses of the dis-
orders underlying DIC. Similarly, the occurrence of
DIC markedly influences the prognoses of the various
disorders that underlie DIC and the development of
multiple organ dysfunctions8.
A logistic regression analysis demonstrated that, on
the day of diagnosis of severe sepsis, the complication of
DIC was an independent predictor of 28day and hospi-
tal mortality and that the DIC score could also predict a
patients prognosis15,18,100. Importantly, the KaplanMeier
method showed that the 1year survival rate of patients
with severe sepsis and DIC was significantly lower than
that in severe sepsis without DIC18. Another study has
shown that, on the day of the injury, the complication of
DIC was found to be an independent predictor of death
of patients with trauma19,171.
In addition, DIC could predict the need for massive
transfusions, and DIC scores on admission to the
emergency department were found to be significantly
correlated with the transfusion volume of platelet con-
centrates, packed red blood cells and FFP20,171. These
findings clearly indicate that the quality of life of patients
with DIC can be aided by the improvement of both the
underlying disease and DIC itself.
Outlook
Although insight into the mechanisms underlying the
development of DIC in various settings has improved
considerably in recent decades, important questions
remain. For instance, as it is likely that activation of
coagulation in DIC occurs at the surface of the endothe-
liumthat interacts with inflammatory cells and medi-
ators, we must gain more knowledge on the exact
interactions between these components at this surface
invivo. As most of our current insights are based on
invitro observations (for example, by using cultured
cells and isolated molecules), which may sometimes
lead to spurious results, and studies in experimental
animals and humans are mostly based on exvivo obser-
vations, the real challenge may be tobe able to more
directly and incisively analyse inflammatory-driven
activation of coagulation at the vascular wall surface
invivo. This approach could potentially yield new
targets for improved treatment strategies forDIC.
Current therapeutic interventions are mostly sup-
portive and only partly effective. Although these inter-
ventions can leadto improvement of the coagulopathy
or more-rapid resolution of DIC, they do not affect
clinically relevant outcomes, such as organ dysfunc-
tion or mortality. Further refinement of (support-
ive) treatment might come from the notion that the
effect of the coagulopathy in DIC might vary from
organ to organ172,173. Hypothetically, it could be argued
that therapy should be tailored to the organs that are
most affected. For example, if acute lung injury is
themost prominent feature of DIC, therapy should
be aimed at restoration of physiological anticoagulant
pathways, such as antithrombin or thrombomodulin.
In DIC presenting with purpura fulminans, there are
ample indications that restoration of the APC pathway
might be most effective. By contrast, in acute renal fail-
ure, interventions aimed at the deranged plateletvessel
wall interaction (for example, restoring the levels of
ADAMTS13) can be most helpful.
Management of DIC might also benefit from
improvement in early patient identification and risk
stratification. Although the diagnosis of DIC has been
greatly improved and facilitated after the introduction of
diagnostic scoring algorithms, these systems are particu-
larly effective in establishing overt DIC and less sensitive
and specific for DIC in its early stage. In addition, tests
that can be used to assess endothelial cell perturbation
in combination with early-stage systemic coagulopathy
would be helpful to identify patients at high risk of
developing uncontrolled DIC and would facilitate early
(and thereby potentially more effective) treatment.
In addition, genetic variation between patients
might be important in the vulnerability for the develop
ment of DIC and the severity of the coagulopathy 174.
For instance, genetic mutations and polymorphisms
have been shown to affect coagulation and fibrino
lysis in DIC. Mice with targeted disruption of one
allele of the gene that encodes protein C, which causes
heterozygous protein C deficiency, exhibited a more-
severe DIC and associated inflammatory response82.
In addition, factorV Leiden heterozygosity has been
associated with the incidence and outcome of DIC in
sepsis175. Furthermore, a functional mutation in PAI1
the 4G/5G polymorphism not only influences the
plasma levels of PAI1 but has also been linked to clin
ical outcome of meningococcal sepsis and DIC176. More
insight into the genetic variation that influences the host
response to conditions underlying DIC might be help-
ful for identifying patients who are more susceptible to
DIC and for individually tailoring therapy to the most
vulnerable patients.

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Acknowledgements
C.-H.T. has received funding from the US National Institute of
Health Research. The authors thank Y. Alhamdi (University
ofLiverpool, UK) for assistance in preparing the manuscript.
Author contributions
Introduction (S.G.); Epidemiology (S.G.); Mechanisms/
pathophysiology (C.-H.T. and M.L.); Diagnosis, screening and
prevention (C.-H.T.); Management (S.G.); Quality of life (S.G.);
Outlook (M.L.); Overview of Primer (S.G.).
Competing interests statement
The authors declare no competing interests.

16 | 2016 | VOLUME 2 www.nature.com/nrdp

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