Disseminated Intravascular Coagulation

in Infectious Disease
Marcel Levi, M.D., Ph.D.,1 Marcus Schultz, M.D., Ph.D.,2
and Tom van der Poll, M.D., Ph.D.1,3,4

ABSTRACT

Severe infection and inflammation almost invariably lead to hemostatic abnor-

malities, ranging from insignificant laboratory changes to severe disseminated intravascular
coagulation. Systemic inflammation as a result of severe infection leads to activation of

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coagulation, due to tissue factor–mediated thrombin generation, downregulation of
physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory
cytokines play a central role in the differential effects on the coagulation and fibrinolysis
pathways. Vice versa, activation of the coagulation system may importantly affect
inflammatory responses by direct and indirect mechanisms. Apart from the general
coagulation response to inflammation associated with severe infection, specific infections
may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The
relevance of the cross-talk between inflammation and coagulation is underlined by the
results of the treatment of severe systemic infection with modulators of coagulation and
inflammation.

KEYWORDS: Disseminated intravascular coagulation, infection, inflammation,

cytokines, tissue factor, antithrombin, protein C, fibrinolysis

V irtually all situations that lead to a systemic
inflammatory response are associated with some degree
of activation of coagulation. This may range from subtle
activation of coagulation that can only be detected by
sensitive markers for coagulation factor activation to
somewhat more robust coagulation activation that may
be evident by a small decrease in platelet count and
subclinical prolongation of global clotting times to (in its
most extreme form) fulminant disseminated intravascu-
lar coagulation (DIC), characterized by simultaneous
widespread microvascular thrombosis and profuse bleed-
ing from various sites.1 Patients with severe forms of
DIC may present with manifest thromboembolic disease
or clinically less apparent microvascular fibrin deposition
that may contribute to the development of multiple
organ dysfunction.2 DIC is not a disease in itself but
always secondary to an underlying condition. One of the
most studied underlying conditions that may lead to
DIC is infectious disease. Bacterial infection, in partic-
ular septicemia, is often associated with DIC. However,
systemic infections with other microorganisms, such as
viruses and parasites, may lead to DIC as well. Factors
involved in the development of DIC in patients with
infections may be bacterial endotoxins (e.g., from gram-
negative bacteria) or exotoxins (e.g., staphylococcal a
toxin). These components may cause a generalized in-
flammatory response, characterized by the systemic oc-
currence of cytokines. Cytokines are mainly produced by

1
Department of Medicine; 2Department of Intensive Care; 3Center for
Experimental and Molecular Medicine; 4Center for Infection and
Immunity Amsterdam (CINIMA), Academic Medical Center, Uni-
versity of Amsterdam, Amsterdam, The Netherlands.
Address for correspondence and reprint requests: Marcel Levi,
M.D., Department Internal Medicine (F-4), Academic Medical Cen-
ter, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam,
The Netherlands (e-mail: m.m.levi@amc.uva.nl).
Disseminated Intravascular Coagulation; Guest Editor, Marcel Levi,
M.D., Ph.D.
Semin Thromb Hemost 2010;36:367–377. Copyright # 2010 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0030-1254046.
ISSN 0094-6176.
367
368 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
activated mononuclear cells and endothelial cells and are
responsible for the derangement of the coagulation
system in DIC.
Abundant evidence indicates that the activation
of coagulation is mediated by inflammatory activity.3
Activation of coagulation and deposition of fibrin as a
consequence of inflammation can be considered instru-
mental in containing inflammatory activity to the site of
injury or infection, rendering this relationship physio-
logically efficient. However, there is increasing evidence
that extensive cross-talk between the systems of inflam-
mation and coagulation exists, whereby inflammation
not only leads to activation of coagulation, but coagu-
lation also markedly affects inflammatory activity. This
coagulation-driven modulation of inflammatory activity
is driven by specific cell receptors on inflammatory cells
and endothelial cells. In addition, systemic activation of
coagulation and inflammation in critically ill patients can
have some tissue- or organ-specific consequences perti-
nent to the development of multiorgan failure in the
setting of severe sepsis.4
The relevance of the interaction between coagu-
lation and inflammation as a response to severe infection,
in its most extreme form manifesting as DIC and
multiple organ failure, is becoming increasingly clear.2,5
In recent years the various mechanisms that play an
important role in this interaction have been elucidated,
and this knowledge has indeed been demonstrated to be
applicable for the improvement of our understanding of
the pathogenesis of severe infection or sepsis and, even
more importantly, the clinical management of these
patients.6 In this article the mechanisms that play a
role in the interaction between inflammation and coag-
ulation are reviewed, and specific features of infectious
disease-mediated effects on the coagulation system are
highlighted. In addition, the cross-talk between acti-
vated coagulation and inflammatory mediators is dis-
cussed.
INFLAMMATION-INDUCED
COAGULATION MODIFICATION
Vascular endothelial cells and cells of the innate immune
system (notably mononuclear cells) play a central role in
all mechanisms that contribute to inflammation-induced
activation of coagulation (Fig. 1).7 Endothelial cells
respond to the cytokines expressed and released by
activated leukocytes but can also release cytokines them-
selves.8 Furthermore, endothelial cells are able to express
adhesion molecules and growth factors that may not only
promote the inflammatory response further but also
affect the coagulation response. However, it has recently
become clear that, in addition to these mostly indirect
effects of the endothelium, endothelial cells interfere
directly with the initiation and regulation of fibrin
formation and removal during severe infection.4,9
2010
Inflammation-induced coagulation activation is
characterized by widespread intravascular fibrin deposi-
tion, which appears to be a result of enhanced fibrin
formation and impaired fibrin degradation.2,10 En-
hanced fibrin formation is caused by tissue factor
(TF)–mediated thrombin generation and simultaneously
occurring depression of inhibitory mechanisms, such as
the protein C and S system. The impairment of endog-
enous thrombolysis is mainly due to high circulating
levels of plasminogen activator inhibitor (PAI)-1, the
principal inhibitor of plasminogen activation. These
derangements in coagulation and fibrinolysis are medi-
ated by differential effects of various proinflammatory
cytokines.11
Tissue Factor
The initiating factors comprise the molecule TF and the
plasma protein factor VII(a).12 TF is a membrane-bound
4.5-kDa protein that is constitutively expressed on
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several cells throughout the body. These cells are mostly
in tissues not in direct contact with blood, such as the
adventitial layer of larger blood vessels. The subcuta-
neous tissue also contains substantial amounts of TF,
and histologically TF appears to be present in all blood
tissue barriers.13 Upon expression at the cell surface, TF
can interact with factor VII, either in its zymogen or
activated form.14 Upon complexing, factor VII is acti-
vated, and the TF-factor VIIa complex catalyzes the
conversion of both factors IX and X.15 Factors IXa and
Xa enhance the activation of factors X and prothrombin,
respectively. Inducible TF is predominantly expressed by
monocytes and macrophages. The expression of TF on
monocytes is markedly stimulated by the presence of
platelets and granulocytes in a P-selectin–dependent
reaction.16 This effect may be the result of nuclear factor
k B activation induced by binding of activated platelets
to neutrophils and mononuclear cells. TF has also been
localized on polymorphonuclear cells (PMN) in whole
blood and ex vivo perfusion systems, suggesting an
additional pool of ‘‘blood-borne’’ TF,17 but it is unlikely
that PMN actually synthesize TF in detectable quanti-
ties. Finally, TF and associated procoagulant activity in
vitro has been detected on microvesicles derived from
predominantly platelets and granulocytes in patients
with meningococcal sepsis.18 The localization on micro-
vesicles may imply a highly efficient pool of procoagulant
material assembling not only the initiating TF-factor
VIIa complex but also the phospholipid surface, facili-
tating the development of the tenase and prothrombi-
nase complexes. In addition, a soluble form of TF is
detectable in plasma from humans, and its levels are
elevated in DIC.19 In humans with infection and an
activated coagulation system, monocytes expressing en-
hanced levels of TF and procoagulant activity have been
demonstrated. The tissue expression of TF appears to be
 DISSEMINATED INTRAVASCULAR COAGULATION IN INFECTIOUS DISEASE/LEVI ET AL 369

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Figure 1 Role of the endothelium in the interaction between coagulation and inflammation. As shown in the upper panel,
endothelial cells harbor physiological anticoagulants, often in relation to the endothelial cell coating (i.e., the glycocalyx). During
systemic inflammatory response syndromes (lower panel), perturbed endothelial cells may produce proinflammatory cytokines
that mediate coagulation activation and further inflammation. Increased platelet aggregation facilitates activation of coagulation,
and a downregulation of physiological anticoagulant mechanisms leads to amplification of this coagulant response. Endothelial
cell perturbation also leads to decreased nitric oxide (NO) availability and increased oxidative stress.

confined to certain organs and vascular beds, but it is
uncertain whether its expression is genetically controlled
in an organ specific way.4
Physiological Anticoagulant Pathways
Systemic activation of coagulation upon inflammation is
counteracted by several mechanisms. First, coagulation
inhibitors are present to slow down the coagulation
mechanism.20 Soluble inhibitors constitute antithrom-
bin (AT), proteins C and S, and tissue factor pathway
inhibitor (TFPI).21 Antithrombin inhibits coagulation
proteases by a 1:1 complex formation, which, in the case
of thrombin-antithrombin complexes, can be detected
by immunoassay in plasma from patients with DIC.19
AT is thought to be one of the most important inhibitors
of the activated coagulation system, and markedly low-
ered plasma levels are found in sepsis.22 In the course of
DIC, the function of AT may be influenced in several
ways. First, a reduced absolute amount of the inhibitor
may occur due to reduced protein synthesis on the one
hand and clearance on the other. Clearance may be
either in the form of protease-inhibitor complex or due
to proteolytic cleavage by proteolytic enzymes including
granulocyte elastase.23 Second, the function of AT may
be impaired due to the possibly reduced availability of
370 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
glycosaminoglycans, which may act as the physiological
heparin-like cofactor of AT.24 Under the influence of
cytokines, the synthesis of glycosaminoglycans by endo-
thelial cells may be reduced, impairing the inhibitory
potential of AT.25 In animal models of experimental
bacteremia, an antithrombin concentrate prolonged sur-
vival and reduced the severity of DIC.26 This protective
effect may have been distinct from the anticoagulant
effect as such because in one of these models, an active
site-blocked factor Xa preparation reduced the severity
of DIC but did not protect the animals from dying due
to sepsis.27 The protective effect of antithrombin may
have resulted from an anti-inflammatory effect. Infusion
of recombinant antithrombin at very high concentrations
(about 10-fold higher than the basal plasma concentra-
tion) markedly reduced mortality due to lethal Escher-
ichia coli infusion but also caused a significant reduction
in the plasma levels of interleukin (Il)-6 and Il-8.28
Protein C and its cofactor protein S form a second
line of defense.29 Thrombin binds to the endothelial cell
membrane associated molecule thrombomodulin, and
this complex converts protein C to its active form,
protein Ca (PCa).30 In addition, the thrombin-throm-
bomodulin complex accelerates the conversion of the
thrombin activatable fibrinolytic inhibitor (TAFI).31
PCa inactivates factors Va and VIIIa by proteolytic
cleavage, thus slowing down the coagulation cascade.
Endothelial cells, primarily of large blood vessels, express
an endothelial protein C receptor (EPCR), which aug-
ments the activation of protein C at the cell surface.32
Activated protein C has anti-inflammatory effects on
mononuclear cells and granulocytes, which may be dis-
tinct from its anticoagulant activity. An anti-inflamma-
tory effect of PCa was demonstrated by Hancock et al,33
showing reduced tumor necrosis factor (TNF)a produc-
tion in rats challenged with endotoxin. In patient stud-
ies, lowered levels of protein C and protein S are
associated with increased mortality. Blockade of the
activity of protein C by infusion of C4 binding protein
turns a sublethal model of E. coli in baboons into a lethal
model.34 Blockade of EPCR by a neutralizing mono-
clonal antibody also increased mortality in the E. coli
baboon model.35 Vice versa, infusion of PC in the same
model protected against DIC and dying.36 Thus it
appears that the protein C mechanism is of great
importance in the host defense against sepsis and coag-
ulation activation. In situations associated with DIC and
systemic inflammation, TNFa and IL-1 may signifi-
cantly downregulate the cellular expression of thrombo-
modulin, as suggested by cell culture experiments.37
A third inhibitory mechanism constitutes TFPI.
The relevance of TFPI in sepsis-induced coagulation
activation is illustrated by two lines of experimentation.
First, deficiency of TFPI sensitized rabbits to develop a
more severe DIC. Second, TFPI infusion protected
against the harmful effects of E. coli in primates. In
2010
this study, TFPI not only blocked DIC, but all baboons
challenged with lethal amounts of E. coli showed a
marked improvement in vital functions and survived
the experiment without apparent complications.38 A
study in human volunteers confirmed the potential of
TFPI to block the procoagulant pathway triggered by
endotoxin.39 However, in this study in healthy subjects,
there was no reduction in cytokine levels, in contrast to
the apparent anti-inflammatory effect of TFPI in the
baboon study. There are several possible explanations for
this discrepancy, which all relate to the marked differ-
ences between the endotoxin and E. coli sepsis models in
which the effects of TFPI were investigated. In the
beneficial effects of TFPI on survival, anti-inflammatory
effects rather than antithrombotic activity may be prom-
inent.38
In general, the presence of intact function and
normal plasma levels of inhibitors appears to be impor-
tant in the defense against DIC. It should be noted
however, that there are no strong indications that
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individuals with congenital deficiencies of inhibitors
would suffer a greater chance of developing DIC, but
this issue remains to be explored. In addition, the
influence of inhibitors in modifying the interaction
between coagulation and inflammation deserves further
attention.
Fibrinolysis
In experimental models of severe infection, fibrinolysis is
activated, demonstrated by an initial activation of plasmi-
nogen activation, followed by a marked impairment
caused by the release in blood of PAI-1.40 The latter
inhibitor strongly inhibits fibrinolysis, causing a net
procoagulant situation. The molecular basis is cytokine-
mediated activation of vascular endothelial cells; TNFa
and IL-1 decreased free tissue plasminogen activator and
increased PAI-1 production, TNFa increased total uro-
kinase plasminogen activator (uPA) production in endo-
thelial cells.41 Endotoxin and TNFa stimulated PAI-1
production in liver, kidney, lung and adrenals of mice.
The net procoagulant state is illustrated by a late rise in
fibrin breakdown fragments after E. coli challenge of
baboons. Endotoxin induced fibrin formation in kidneys,
and adrenals was most dependent on a decrease in uPA.42
PAI-1 knockout mice challenged with endotoxin did not
develop thrombi in the kidney in contrast to wild-type
animals.43 Endotoxin administration to mice with a func-
tionally inactive thrombomodulin gene (TMProArg mu-
tation) and defective protein C activator cofactor function
caused fibrin plugs in the pulmonary circulation, whereas
wild-type animals did not develop macroscopic fibrin.44
Fibrinolytic activity is markedly regulated by PAI-1, the
principal inhibitor of this system. Several studies have
shown that a functional mutation in the PAI-1 gene, the
4G/5G polymorphism, not only influenced the plasma
 DISSEMINATED INTRAVASCULAR COAGULATION IN INFECTIOUS DISEASE/LEVI ET AL
levels of PAI-1 but was also linked to clinical outcome of
meningococcal septicemia. Patients with the 4G/4G
genotype had significantly higher PAI-1 concentrations
in plasma and an increased risk of death.45 Further
investigations demonstrated that the PAI-1 polymor-
phism did not influence the risk of contracting meningitis
as such, but probably increased the likelihood of develop-
ing septic shock from meningococcal infection.46 These
studies are the first evidence that genetically determined
differences in the level of fibrinolysis influences the risk of
developing complications of a gram-negative infection. In
other clinical studies in cohorts of patients with DIC, high
plasma levels of PAI-1 were one of the best predictors of
mortality.47 These data suggest that activation of coagu-
lation contributes to mortality in this situation, but as
indicated earlier, the fact that PAI-1 is an acute-phase
protein, a higher plasma concentration may also be a
marker of disease rather than a causal factor. Interestingly,
platelet a-granules contain large quantities of PAI-1 and
release PAI-1 upon their activation. Because platelets
become activated in case of severe inflammation and
infection, this may further increase the levels of PAI-1
and contribute to the fibrinolytic shutoff.
CROSS-TALK BETWEEN COAGULATION
AND INFLAMMATION
Coagulation activation yields proteases that not only
interact with coagulation protein zymogens but also
with specific cell receptors to induce signaling pathways.
In particular, protease interactions that affect inflamma-
tory processes may be important in the development of
DIC. Factor Xa, thrombin, and the TF-factor VIIa
complex have each been shown to elicit proinflammatory
activities.48 Fibrinogen/fibrin is important to the host
defense mechanism and probably has an additional role
that is not directly related to clotting per se.49
Thrombin has been shown to induce a variety of
noncoagulant effects, some of which may influence DIC
by affecting cytokine levels in blood. It induces produc-
tion of monocyte chemotactic protein 1 and IL-6 in
fibroblasts, epithelial cells, and mononuclear cells in
vitro.50 Endotoxin-stimulated whole blood produces
significant IL-8, which has a procoagulant effect that
is TF and thrombin dependent. Thrombin also induces
IL-6 and IL-8 production in endothelial cells. These
effects of thrombin on cell activation are probably
mediated by protease-activated receptors (PARs) 1, 3,
and 4.51 PARs are cellular receptors for activated pro-
teases that may contribute to intracellular signaling.
Several studies have indicated that the TF-factor VIIa
complex also activates cells by binding to PARs, and it
appears that PAR2 in particular is involved. Binding of
the catalytic TF-factor VIIa complex elicits a variety of
inflammatory effects in mononuclear cells that may
influence their contribution to coagulation activity.52 A
371
direct indication of the relevance of these phenomena in
vivo comes from a recent study showing that infusion of
recombinant factor VIIa into healthy human volunteers
causes a rise, albeit small, in plasma levels of IL-6 and
IL-8.53 Although the plasma concentrations of factor
VIIa in this experiment were much higher than endog-
enous factor VIIa concentrations in patients with sepsis,
it is possible that the mechanism by which VIIa causes
cytokine induction (direct or factor Xa/thrombin-medi-
ated) is of physiological importance.
Another link between inflammation and coagu-
lation is formed by the protein C system. Activated
protein C has anti-inflammatory effects on mononuclear
cells and granulocytes that may be distinct from its
anticoagulant activity.54 The anti-inflammatory effect
of activated protein C was confirmed in vivo by the
demonstration of reduced TNFa production in rats
challenged with endotoxin.33 In addition, we have re-
cently shown that mice with a one-allele targeted dele-
tion of the protein C gene (heterozygous protein C–
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deficient mice) not only develop more severe DIC and
increased fibrin deposition upon systemic endotoxemia,
but they also have significantly higher circulating levels
of proinflammatory cytokines compared with wild-type
littermates.55 These experimental data are corroborated
by the observations in the Protein C Worldwide Eval-
uation in Severe Sepsis (PROWESS) trial that recombi-
nant human activated protein C (drotrecogin alfa
[activated]) accelerated the decrease in levels of IL-6 in
patients with severe sepsis.56 For high doses of antith-
rombin, similar interactions with the inflammatory cas-
cades were seen.28 Taken together, several coagulation
proteases can induce proinflammatory mediators that
have procoagulant effects, which may amplify the cas-
cade that leads to DIC. Effects at the cellular level will
be determined by the capacity of the coagulation inhib-
itors to inactivate these enzymes.
COAGULATION AND VASCULAR
COMPLICATIONS IN INFECTIOUS
DISEASES
Apart from the generalized response upon systemic in-
flammation as already discussed, specific infections may
result in thrombohemorrhagic syndromes, hemolytic
uremic syndrome (HUS), thrombotic thrombocytopenic
purpura (TTP), or vasculitis.57 Symptoms and signs may
be dominated by bleeding, thrombosis, or both.2 Clin-
ically overt infection-induced activation of coagulation
may occur in 30–50% of patients with gram-negative
sepsis.58 Remarkably, this may appear as common in
patients with gram-positive sepsis as in those with
gram-negative sepsis. Activation of the coagulation sys-
tem has also been documented for nonbacterial patho-
gens (i.e., viruses,59 protozoa (Malaria),60,61 fungi,62 and
spirochetes).63
372 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
Thrombosis and Bleeding in Viral Infections
Viral and bacterial infections may result in an enhanced
risk for local thromboembolic disease (i.e., deep venous
thrombosis or pulmonary embolism). In a thromboem-
bolic prevention study of low-dose subcutaneous stand-
ard heparin for hospitalized patients with infectious
diseases, morbidity due to thromboembolic disease was
significantly reduced in the heparin group compared
with the group receiving no prophylaxis. There was,
however, no beneficial effect of prophylaxis on mortality
due to thromboembolic complications.64 In chronic viral
diseases, such as cytomegalovirus (CMV) or human
immunodeficiency virus (HIV) infection, the risk of
thromboembolic complications is relatively low.65
Viral hemorrhagic fever is complicated by DIC in
the most severe cases.66,67 DIC is not frequently en-
countered in other viral infections but has been reported
in cases of infection with rotavirus, varicella, rubella,
rubeola, and influenza.68–71 TTP and HUS, triggered by
a viral or bacterial infection,72 frequently lead to bleeding
symptoms, but also platelet and fibrin thrombi may be
generated in various organs, leading to prominent symp-
toms with organ dysfunction. In specific infections, such
as viral hemorrhagic fever, bleeding complications are
prominent.66 In other viral and bacterial infections
associated with TTP or HUS, bleeding also is often
the prominent and presenting symptom (Table 1).73
Infections Leading to Vasculitis
Bacterial and viral infections may result in a vasculitis-
like syndrome with either bleeding manifestations or
ischemic injury.74 Vasculitis is a well-documented phe-
nomenon in CMV infection, occurring predominantly
in the vasculature of the gastrointestinal tract where it
causes colitis, the central nervous system where it causes
cerebral infarction, and the skin where it results in
petechiae, purpura papules, localized ulcers, or a diffuse
maculopapular eruption.75,76 HIV infection may be
accompanied by vasculitis syndromes (e.g., polyarteritis
nodosa, Henoch-Schönlein purpura, and leukocytoclas-
tic vasculitis).77,78 Hepatitis B and C infection may cause
polyarteritis-like vasculitis.79 Parvovirus B19 has been
Table 1 Viral Hemorrhagic Fevers
Virus Geographic Distribution
Dengue HF Southeast Asia, Mid/South America, China
Chikungunya Southeast Asia
Ebola Zaire, Sudan
Marburg HF Zimbabwe, Kenya, Uganda
Lassa fever West Africa
Yellow fever South America, Africa
Omsk HF Former Soviet Union
Hantaan Central Europe, former Soviet Union, Asia
HF, hemorrhagic fever.
2010
suggested to be associated with vasculitis-like syndromes
including Kawasaki’s disease, polyarteritis nodosa, and
Wegener’s granulomatosis.80,81
SPECIFIC FEATURES OF THE
PATHOGENESIS OF COAGULATION
DISORDERS IN INFECTIOUS DISEASE
Much of our knowledge on the mechanisms that play a
role in infection-associated activation of coagulation
comes from observations in clinical and experimental
infectious disease. Essentially, and as outlined in detail in
the preceding paragraphs, several pathways appear to
play a role, including TF-mediated generation of throm-
bin, impairment of physiological anticoagulant mecha-
nisms, and a depression of the fibrinolytic system, due to
elevated levels of PAI-1. In addition, specific features of
coagulation activation in patients with infectious disease
may be appreciated.
Endothelial cells may turn into a procoagulant
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state either by stimulation of cytokines in concert with
circulating blood cells, such as lymphocytes or platelets,
or by direct infection (viruses) of endothelial cells. The
role of endothelial cells seems to be crucial in the
development of shock and activation of coagulation.82,83
Endothelial cell injury is a common feature of viral
infection and can alter hemostasis in a direct or indirect
manner. The endothelial cell can be directly infected by
different viruses, for example, HSV, adenovirus, para
influenzavirus, poliovirus, echovirus, measles virus,
mumps virus, CMV, human T-cell lymphotropic virus
1 and HIV.84,85 The ability to infect endothelial cells has
also been demonstrated in hemorrhagic fevers due to
dengue virus, Marburg virus, Ebola virus, Hantaan virus,
and Lassa virus.86 Such infections may result in a
procoagulant state, mainly by inducing TF expression
on the endothelial surface, probably mediated by cyto-
kines such as IL-1, TNFa, and IL-6.87 However, not all
viral infections affecting endothelial cells result in acti-
vation of coagulation, which may indicate that activation
of endothelium is one factor in a multifactorial process.
The change of the endothelial cell from a resting
to a procoagulant state may be associated with expression
Source of Infection
Mosquito
Mosquito
Unknown
Unknown
Rodent
Mosquito
Tick
Rodent
 DISSEMINATED INTRAVASCULAR COAGULATION IN INFECTIOUS DISEASE/LEVI ET AL
of endothelial surface adhesion molecules.88 These mol-
ecules, that is, intercellular adhesion molecule, vascula
cell adhesion molecule, E selectin, and von Willebrand
factor, play an essential role in the binding of leukocytes,
resulting in a local inflammatory response, endothelial
cell damage, and subsequent plasma leakage and shock.89
The finding of increased plasma concentrations of these
endothelial surface adhesion molecules is thought to be a
reflection of the level of activation and perhaps damage
of the endothelial cell.
During sepsis, the protein C/S system is down-
regulated, as described earlier. Some viruses have the
ability to induce specific changes in the coagulation
inhibitory system. In the course of HIV infection the
protein C/S system may be impaired as a result of an
acquired protein S deficiency, whose pathogenesis is not
yet clarified.90,91 Increased plasma concentrations of the
C4b-binding protein, an acute-phase protein that binds
protein S, may result in decreased levels of free protein S.
Antiphospholipid antibodies, which may be present in
HIV patients, might interfere with the protein C/pro-
tein S complex and diminish its activity.92 In patients
with dengue hemorrhagic fever, we also found decreased
levels of both protein C and protein S activity.93 As in
dengue, HIV can affect the endothelial cell; hypotheti-
cally this could lead to decreased production of protein S.
Thrombocytopenia is seen in the course of many
viral infections but is only occasionally serious enough to
lead to hemostatic impairment and bleeding complica-
tions. It is assumed that thrombocytopenia is mainly
immune mediated.94 Alternative mechanisms are de-
creased thrombopoiesis, increased platelet consumption,
or a combination of both.95 Direct interaction of the
virus with platelets may lead to thrombocytopenia and/
or thrombocytopathy.96 Endothelial injury by the virus
may lead to increased adherence and consumption of
platelets.
Viral infections that have been associated with
thrombocytopenia are mumps, rubella, rubeola, varicella,
disseminated herpes simplex, CMV, infectious mono-
nucleosis, Hantaan virus infection, dengue hemorrhagic
fever, Crimean-Congo hemorrhagic fever, and Marburg
hemorrhagic fever.97–99
CLINICAL IMPLICATIONS OF THE
INCREASED INSIGHT INTO THE
MECHANISMS OF DIC IN INFECTIOUS
DISEASE
Management of DIC in infectious disease is based on
three important pillars: (1) establishing the diagnosis of
DIC, (2) appropriate treatment of the underlying in-
fection using appropriate antibiotics and source control,
and (3) initiation of supportive treatment, aimed at
circulatory and respiratory support, replacement of organ
function, and coagulation interventions.100–102 In par-
373
ticular, supportive measures to manage the coagulation
disorder may be considered if coagulation abnormalities
proceed, even after proper treatment has been initiated.
These interventions have been shown to be able to
positively affect morbidity and mortality.
In particular, in view of the deficient state of
physiological anticoagulant pathways in patients with
sepsis, restoration of these inhibitors seems to be a
rational approach.55 Because antithrombin is one of
the most important physiological inhibitors of coagula-
tion, and owing to successful preclinical results, several
larger clinical trials have addressed the use of antithrom-
bin III concentrates in patients with sepsis and/or DIC.
Most of the randomized controlled trials concern pa-
tients with sepsis, septic shock, or both. All trials show
some beneficial effect in terms of improvement of
laboratory parameters, shortening of the duration of
DIC, or even improvement in organ function.6 How-
ever, a large-scale, multicenter, randomized controlled
trial to address this issue directly showed no significant
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reduction in mortality of patients with sepsis who were
treated with antithrombin concentrate.103 Interestingly,
post hoc subgroup analyses indicated some benefit in
patients who did not receive concomitant heparin and
who fulfilled the diagnostic criteria for DIC, but this
observation needs prospective validation.104
Based on the notion that depression of the
protein C system may significantly contribute to the
pathophysiology of DIC, supplementation of (acti-
vated) protein C (rhAPC) might be beneficial.55 A
beneficial effect of rhAPC was demonstrated in a phase
III trial (PROWESS) in patients with sepsis that was
stopped prematurely because of its efficacy in reducing
mortality in these patients.56 All-cause mortality at
28 days after inclusion was 24.7% in the rhAPC group
versus 30.8% in the control group (19.4% relative risk
reduction). The administration of rhAPC was demon-
strated to cause an amelioration of coagulation abnor-
malities, and rhAPC-treated patients had less organ
failure.105 In view of the previously described effects
that APC has on inflammation, part of the success may
have been caused by a beneficial effect on inflammatory
pathways. Interestingly, a post hoc analysis of this trial
demonstrated that patients with a diagnosis of DIC,
according to the DIC scoring system of the Interna-
tional Society on Thrombosis and Haemostasis, had a
relatively greater benefit of rhAPC treatment than
patients who did not have overt DIC.106 The relative
risk reduction in mortality of patients with sepsis and
DIC that received rhAPC was 38%, in comparison with
a relative risk reduction of 18% in patients with sepsis
who did not have DIC. This seems to underscore the
importance of the coagulation derangement in the
pathogenesis of sepsis and the point of impact that
restoration of microvascular anticoagulant pathways
may provide in the treatment of sepsis. Recombinant
374 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
human APC has been licensed in most countries for
treatment of patients with severe sepsis and two or
more organ failures. It was shown not to be effective in
patients with sepsis with less severe sepsis.107
Based on the results of PROWESS, rhAPC has
been approved for therapy by regulatory agencies in the
United States, Europe, and other parts of the world.
Indeed, its use in patients with severe sepsis and multiple
organ failure, and in the absence of major risk factors for
bleeding, has been advocated in guidelines for the treat-
ment of sepsis.108 However, there is currently debate on
the role of rhAPC in the treatment of sepsis.29 For
example, a meta-analyses of published literature con-
cluded that the basis for treatment with rhAPC, even in
patients with a high disease severity, is weak if not
insufficient.109,110 A series of negative trials in specific
populations of patients with severe sepsis has added to
the skepticism regarding the use of rhAPC. Taken
together, there is quite some uncertainty and doubt
surrounding the exact place of rhAPC in patients with
severe sepsis, and this equipoise has convinced the
manufacturer of this agent to start a new placebo-
controlled trial in patients with severe sepsis and septic
shock in the coming months.111 Certainly, the result of
this trial will be helpful to assess the effectiveness and
safety of rhAPC more precisely in the treatment of
patients with severe sepsis.
CONCLUSION
A bidirectional relationship between coagulation and
inflammation appears to play a pivotal role in the
mechanisms leading to organ failure in patients with
severe infection or sepsis. The endothelium plays a
central role in all major pathways involved in the
pathogenesis of hemostatic derangement during severe
inflammation. Endothelial cells appear to be directly
involved in the initiation and regulation of thrombin
generation and the inhibition of fibrin removal. Proin-
flammatory cytokines are crucial in mediating these
effects on endothelial cells, which themselves may
also express cytokines, thereby amplifying the coagu-
lative response. The interaction between inflammation
and coagulation involves significant cross-talk between
the systems. At all levels in the activated coagulation
system in sepsis, natural anticoagulant pathways are
defective and as a consequence incapable of containing
the ongoing thrombin formation. Pharmacological re-
storation of these anticoagulant mechanisms may be a
logical action in the (supportive) treatment of septic
patients with coagulation abnormalities. Indeed, exper-
imental and (initial) clinical studies show beneficial
results of this type of treatment, not only confined to
improvement of the coagulation status but also on
clinically relevant outcome parameters such as organ
function and survival.
2010
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