Review
org
OBSTETRICS
Disseminated intravascular coagulation
in pregnancy: insights in pathophysiology,
diagnosis and management
Offer Erez, MD; Salvatore Andrea Mastrolia, MD; Jecko Thachil, MD
U ncontrolled peripartum bleeding,
resulting in disseminated intra-
vascular coagulation (DIC), is one of the
leading causes for maternal mortality
worldwide.1 This is in spite of an
adaptive physiological mechanism that
generates a physiological prothrombotic
state during gestation2,3 and the ad-
vanced medical and surgical hemostatic
capabilities that have evolved during
the past decades for controlling acute
obstetrical blood loss.
The rate of DIC during pregnancy
differ among cohorts and range from
0.03%4 to 0.35%.5 A series of pregnancy
complications have been associated with
DIC including the following: (1) acute
peripartum hemorrhage (uterine atony,
cervical and vaginal lacerations, and
uterine rupture); (2) placental abrup-
tion; (3) preeclampsia/eclampsia/hemo-
lysis, elevated liver enzymes, and low
platelet count (HELLP) syndrome; (4)
retained stillbirth; (5) septic abortion
and intrauterine infection; (6) amniotic
fluid embolism; and (7) acute fatty liver
of pregnancy.1,6
From the Department of Obstetrics and
Gynecology, Soroka University Medical Center,
Faculty of Health Sciences, Ben Gurion
University of the Negev, Beer Sheva, Israel
(Dr Erez and Dr Mastrolia), Department of
Obstetrics and Gynecology, Azienda
Ospedaliera Universitaria Policlinico di Bari,
Universitá degli Studi di Bari “Aldo Moro”, Bari,
Italy (Dr Mastrolia), and Department of
Haematology, Manchester Royal Infirmary,
Manchester, United Kingdom (Dr Thachi).
Received Jan. 20, 2015; revised March 26,
2015; accepted March 29, 2015.
The authors report no conflict of interest.
Corresponding author: Offer Erez, MD.
erezof@bgu.ac.il
0002-9378/$36.00
ª 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.03.054
ajog.
Disseminated intravascular coagulation (DIC) is a life-threatening situation that can arise
from a variety of obstetrical and nonobstetrical causes. Obstetrical DIC has been
associated with a series of pregnancy complications including the following: (1) acute
peripartum hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine
rupture); (2) placental abruption; (3) preeclampsia/eclampsia/hemolysis, elevated liver
enzymes, and low platelet count syndrome; (4) retained stillbirth; (5) septic abortion and
intrauterine infection; (6) amniotic fluid embolism; and (7) acute fatty liver of pregnancy.
Prompt diagnosis and understanding of the underlying mechanisms of disease leading to
this complication in essential for a favorable outcome. In recent years, novel diagnostic
scores and treatment modalities along with bedside point-of-care tests were developed
and may assist the clinician in the diagnosis and management of DIC. Team work and
prompt treatment are essential for the successful management of patients with DIC.
Key words: acute fatty liver of pregnancy, endothelial dysfunction, hemolysis, elevated
liver enzymes, and low platelet count (HELLP) syndrome, hemorrhage, score, trophoblast
The proportion of each disorder varies impaired synthesis coagulation as well as
among the different reports. In a cohort5 anticoagulation proteins; (2) the diag-
including 24,693 pregnancies, among nosis of DIC with special attention to the
those who developed DIC, 49.4% had available scores adding prognostic value
placental abruption, 29.9% postpartum to the laboratory parameters in patients
hemorrhage (PPH), 12.6% severe pre- with this dangerous condition or are at
eclampsia, and 5.7% a uterine rupture, risk for its development; and (3) the
whereas in a different cohort including principles of the treatment of DIC
151,678 deliveries, the proportion of (the latter is discussed extensively in
these complications in those who had the literature).6,8-17
DIC was placental abruption (37%),
postpartum hemorrhage or hypovolemia What is disseminated intravascular
(29%), preeclampsia/HELLP syndrome coagulation?
(14%), acute fatty liver (8%), sepsis (6%), DIC represents a life-threatening condi-
and amniotic fluid embolism (6%).4 tion that is the endpoint of uncontrolled
In most of these pregnancy compli- systemic activation of the hemostatic
cations, DIC is associated with adverse system, leading to a simultaneous
maternal outcome including massive widespread microvascular thrombosis,
blood products transfusion, hysterec- that can compromise the blood supply to
tomy, and even maternal death.7 There- different organs and may lead to
fore, prompt diagnosis and treatment are organ failure.18 This process is associated
needed to reduce the morbidity and with increased degradation of coagula-
mortality that is associated with DIC. tion factors as well as anticoagula-
In this review, we aim to discuss the tion proteins and followed by their
following: (1) the pathophysiology of impaired synthesis, leading to uncon-
DIC focusing on the triad represented trolled bleeding.
by exaggerated activation of coagula- Acute, severe DIC is characterized by
tion, consumption of coagulopathy, and diffuse multiorgan bleeding, hemorrhagic
MONTH 2015 American Journal of Obstetrics & Gynecology 1
Review Obstetrics
necrosis, microthrombi in small blood
vessels, and thrombi in medium and large
blood vessels.12 This condition may occur
in the setting of sepsis, major trauma, and
obstetric calamities. The final scenario is
represented by the exhaustion of coagula-
tion/anticoagulation factors and platelets,
leading to profuse uncontrollable bleeding
and often death.
In contrast to the acutely ill patient
with complicated severe DIC, other pa-
tients may have mild or protracted
clinical manifestations of consumption
or even subclinical disease manifested
by only laboratory abnormalities.19 The
clinical picture of subacute to chronic
DIC is exemplified by the chronic
hypercoagulability that may accompany
malignancy, in particular with mucin-
producing adenocarcinomas and acute
promyelocytic leukemia. However, cur-
rently there are no reports in the litera-
ture regarding the occurrence of mild
subacute DIC in pregnant women.
The development of DIC as a result
of predisposing conditions can be a
life-threatening complication and is
considered one of the leading causes
for maternal morbidity and mortality
worldwide.7 However, it is important to
emphasize that DIC is not a disease by
itself; it is always secondary to an un-
derlying disorder that causes the un-
controlled activation of coagulation.
What are the mechanisms leading to
DIC during pregnancy?
The development of DIC during preg-
nancy can be either abrupt as in acute
abruption or PPH or continuous as can
be observed in a retained dead fetus. Of
interest, obstetric complications such
as placental abruption, amniotic fluid
embolism, and acute fatty liver of preg-
nancy are associated with severe early-
onset DIC that is accompanied by
maternal coagulopathy. The DIC in ob-
stetric hemorrhage activates coagulation
and triggers fibrinolysis. Activation of
fibrinolysis leads to the production of
D-dimers and fibrin-degradation prod-
ucts. These will interfere with platelet
function and can impair myometrial
contractility.20
Clinical presentation of DIC may be
the results of the following mechanisms.
2 American Journal of Obstetrics & Gynecology MONTH 2015
Endothelial dysfunction and platelet
activation
Intact, dysfunctional, or activated cells,
as well as remnants of cell surfaces,
inflammatory mediators, and coagula-
tion proteins are all part of an interplay
in which uncontrolled activation of
coagulation cascade leads to DIC.21
Endothelial cells, platelets, but in some
cases also leucocytes and cancer cells can
participate in the genesis of the process
leading to DIC by releasing proin-
flammatory cytokines, propagating the
activation of coagulation on their surface
or inducing tissue factor (TF) expression
on their membrane.10,22-28 A systemic
inflammatory response that is associated
with markedly increased circulating pro-
inflammatory cytokines such as tumor
necrosis factor-a, interleukin-1 (IL-1),
and interleukin-6 (IL-6) can lead to
exaggerated expression of TF by leuko-
cyte and endothelial cells.24 This will
generate an uncontrolled coagulation
response that will eventually deteriorate
into DIC. Lastly, the initiation of coagu-
lation leading to thrombin generation in
DIC, is mediated by the TF/factor VIIa
pathway, also known as the extrinsic
coagulation pathway.12
The most significant source of TF is
not completely clear in all situations.
Tissue factor may be expressed not only
in mononuclear cells in response to
proinflammatory cytokines (mainly IL-
6) but also by vascular endothelial or
cancer cells.27-29 Despite the potent
initiation of coagulation by TF, the acti-
vation of coagulation cannot be propa-
gated if the physiological anticoagulant
pathways function properly. However, in
DIC all major natural anticoagulant
pathways (ie, antithrombin III, protein
C system, and TF pathway inhibitor
[TFPI]) appear to be impaired.30
Plasma concentrations of anti-
thrombin III, the most important
inhibitor of thrombin, are markedly
reduced during DIC because of a com-
bination of consumption,31 degradation
by elastase from activated neutrophils,32
and impaired synthesis.10
A significant depression of the protein
C system may further compromise an
adequate regulation of activated coagu-
lation.33 This impaired function of the
ajog.org
protein C system is caused by a combi-
nation of impaired protein synthesis,
cytokine-mediated down-regulation of
endothelial thrombomodulin, and a fall
in the concentration of the free fraction
of protein S (the essential cofactor of
protein C), resulting in reduced activa-
tion of protein C.33
Lastly, there seems to be a misbalance
of TFPI function in relation to the
increased TF-dependent activation of
coagulation.34
All these anticoagulant pathways are
linked to the endothelium, and it is likely
that endothelial cell activation and
dysfunction are an important compo-
nent of the imbalance between coagula-
tion and anticoagulation systems. Of
interest, experimental and clinical
studies indicate that during DIC, the
fibrinolytic system is largely suppressed
at the time of maximal activation of
coagulation.10,11 This inhibition of
fibrinolysis is caused by a sustained rise
in the plasma concentrations of plas-
minogen activator inhibitor (PAI)-1, the
principal inhibitor of the fibrinolytic
system.
Activation of platelets may also accel-
erate fibrin formation.35 The expression
of TF in monocytes is markedly stimu-
lated by the presence of platelets and
granulocytes in a P-selectinedependent
reaction.29 This effect may be the result
of nuclear factor kappa B activation
induced by binding of activated platelets
to neutrophils and mononuclear cells.36
During pregnancy maternal leukocytes
are in a higher state of activation than in
nonpregnant women37 and have charac-
teristics akin to sepsis.38 However, they
are well controlled during pregnancy, and
it has been proposed that the trophoblast
plays a role in the maintenance of the
balanced systemic maternal inflamma-
tion during gestation.39 Nevertheless, in
cases of sepsis caused by an infectious
agent or septic abortion and at least in
some of the cases of amniotic fluid em-
bolism,40 this equilibrium is disturbed
and the mother develops DIC.
Trophoblast properties and activation
of the coagulation system
During normal gestation the trophoblast
has 2 hemostatic functions: (1) to allow
ajog.org Obstetrics Review
the laminar flow of maternal blood in the
intervillous space and prevent it from FIGURE 1
clotting during that time; and (2) to Comparison between normal endothelium and placental trophoblast
prevent bleeding at the maternal fetal
interface.6
To address these contradicting chal-
lenges, the syncytiotrophoblast acquires
endothelial-cell like properties (Figure 1).
As a consequence, first, in human normal
placenta, syncytiotrophoblast strongly
expresses TF, and its activity is higher if
compared with human umbilical vein
endothelial cells. On the contrary, the
trophoblast is able to synthesize protein
C, protein S, and protein Z as well as
a specific inhibitor of the tissue factor
pathway known as TFPI-2 (placental
protein 5)41-43 that will prevent unnec-
essary activation of the coagulation
cascade.44-47
Second, the placenta produces PAI-2
in addition to the gradual increase of
PAI-1, observed during normal preg-
nancy and becomes markedly elevated
in the third trimester to prevent fibri-
nolysis.48 These changes are associated
with relatively unchanged tissue plas-
minogen activator concentrations, con-
tributing to a state of reduced clot
lysis and a prothrombotic bias in the
pregnant woman.49 This mechanism is
further mediated through thrombin
activatable fibrinolysis inhibitor.50,51
The evidence brought herein supports
the fact that any condition that disrupts
the integrity of the throphoblast
(Figure 2) can lead to a release of a large
amount of potent TF that will activate
the coagulation cascade and propagate Comparison between normal endothelium (top) and placental trophoblast (bottom). The placenta is in
an inflammatory response that can easily a heightened state of coagulation activation through increased TF production. This increases pro-
become systemic, leading to uncon- thrombin (II) to thrombin (IIa) conversion for cleavage of fibrinogen into fibrin. Increased amounts of
trolled thrombin generation and the TAFIa is generated, which together with increased levels of PAI-1 and PAI-2 reduce fibrinolytic
subsequent development of DIC.25,52 activity that would normally occur through tPA-induced generation of Pm from Pg in generating fdp.
There are several conditions that are The bold arrows signify increased generation, and the dotted arrows signify inhibition.
associated with DIC in which the current fdp, fibrin-degradation products; II, prothrombin; IIa thrombin; PAI, plasminogen activator inhibitor; Pg, plasminogen; Pm, plasmin;
TAFIa, thrombin-activatable fibrinolysis inhibitor activation; TF, tissue factor; tPA, tissue plasminogen activator.
evidence suggests that the systemic Reproduced, with permission, from Thachil et al.6
maternal response is the result of endo- Erez. Disseminated intravascular coagulation in pregnancy. Am J Obstet Gynecol 2015.
thelial activation. The classical one is
abruption, especially that with concealed
bleeding and fetal demise. These patients as a problem of consumption coagulop- that this complication is associated with
have a combination of consumption athy, it seems that there is more to it, the release of procoagulating factors, such
coagulopathy and discharge of throm- meaning that often patients with a retro- as thromboplastin, into the maternal
boplastin (tissue factor) into the placental clot have a much lower blood circulation.6
maternal circulation.10 loss than those who developed PPH, In addition, local hypoxia and hy-
Although the DIC developed in pa- yet the DIC of in these patients is much povolemia trigger endothelial response
tients with placental abruption is regarded more severe. A probable explanation is leading to increased expression of

MONTH 2015 American Journal of Obstetrics & Gynecology 3

Review Obstetrics
FIGURE 2
Disruption of trophoblast integrity
Disruption of trophoblast integrity, as classically observed in placental abruption, leading to a release
of a large amount of tissue factor in maternal circulation. This can activate the coagulation cascade
and propagate an inflammatory response that can easily become systemic leading to uncontrolled
thrombin generation and subsequent development of DIC.
Erez. Disseminated intravascular coagulation in pregnancy. Am J Obstet Gynecol 2015.
vascular endothelial growth factor,
which causes an increased endothelial
expression of TF.53 Evidence in support
of this view is brought by Erez at al,25
who demonstrated that in women with
fetal death, those who had abruption
had a higher amniotic fluid of TAT
complexes. These events result in the
consumption of coagulating factors,
fibrin deposition in microcirculation,
and thrombus formation on maternal
surface of the placenta at the site of
abruption. This is followed by fibrino-
lysis and the release of fibrin degrada-
tion products further contributing to
the development of DIC.
Of interest, if the abruption in con-
cealed or it is severe enough to cause
fetal demise, it is at much higher risk for
the development of DIC because of a
4 American Journal of Obstetrics & Gynecology MONTH 2015
continuous release of TF in the maternal
circulation. The probable mechanism
leading to this observation is similar to
that observed in amniotic fluid embo-
lism with systemic release of TF that
leads to systemic activation of coagula-
tion and subsequent DIC.
This view is supported by the ex-
periment reported by Schneider,54
which demonstrated that the intrave-
nous injection of placental extracts
into mice leads to the death of the
animal through DIC, which can be
prevented by the administration of
heparin.54 The author identified thro-
mboplastin as the causative agent
through its effect on the clotting time
and its chemical properties and
measured its activity by the 1-stage
prothrombin-time method.54
ajog.org
Hemorrhage
Acute obstetrical bleeding is being
considered by many4,6,18,23,55-58 as a
leading cause for DIC. This form of
consumption coagulopathy is classically
related to PPH as a result of uterine
atony, retained placenta or membranes,
uterine rupture, placenta accreta, or se-
vere cervical or vaginal lacerations.5 In
all of these cases, the mother is losing a
large volume of blood and coagulation
factors in a short time interval, and these
patients are usually hemodynamically
compromised.
Currently there is a debate whether
this form of consumption coagulopathy
is truly DIC or just a massive blood loss
that depletes the patient’s coagulation
factors and can lead to death because
of exsanguination.9 However, massive
maternal bleeding may not be that
straightforward as a pure loss of coagu-
lation factors. During the time of
parturition and postpartum period,
there is substantial activation of coagu-
lation cascade and generation of
thrombin as a result of the release of
TF to the maternal circulation following
the separation of the membranes and
the placenta.59,60 Thus, these women
already have increased thrombin gener-
ation61 and indeed are regarded as high-
risk patients for the development of
deep vein thrombosis during the
puerperium.62
The evidence brought herein, that
parturients with PPH have a higher acti-
vation of coagulation cascade even above
the physiological threshold, suggests that
the clinicians who treat these patients
must regard them as a high-risk group for
DIC, even though the fundamental pa-
thology is a rapid and massive loss of
blood as well as coagulation factors.52
Therefore, patients with PPH need to be
treated promptly, pharmacologically,
and/or surgically and by blood products
as well as volume expanders to sustain
the maternal circulation and perhaps
to prevent the subsequent development
of DIC.
Disruption of liver function
Acute fatty liver of pregnancy
Acute fatty liver of pregnancy is a rare
(an estimated incidence between 6 and
ajog.org
14 per 100,000 pregnancies63-65) but
potentially fatal complication of preg-
nancy. It is characterized by fatty mi-
crovascular infiltration of hepatocytes
with progressive loss of liver function,66
without alteration of the overall struc-
ture of the liver. Women who develop
this complication have abnormal renal
function67 and DIC.68 The mechanisms
by which DIC develops in this compli-
cation is a combination of reduced liver
production of fibrinogen as well as
coagulation proteins and hemorrhage.
Evidence in support of this view is
presented by Nelson et al,69 who studied
51 women with acute fatty liver of preg-
nancy. Their hemostatic condition was
classified according to the International
Society of Thrombosis and Haemostasis
DIC score,70,71 and 80% of these women
had unequivocal DIC defined as com-
posite score of 5 or greater. The authors
studied the hepatic and hemostatic
function of these patients including fib-
rinogen, fibrin-fibrinogen split products,
coagulation studies, and cholesterol.
Those who developed DIC had abnor-
mally low plasma fibrinogen concentra-
tions that persisted for the first several
days after delivery along with only mild to
moderately elevated fibrin degradation
products.69
At the same time, there was also evi-
dence for continuing increased proco-
agulant consumption caused by ongoing
DIC provided by the modestly elevated
levels of fibrin degradation products
in the face of depressed plasma fibrin-
ogen concentrations. This observation
was in contrast to that of patients with
abruption in whom the fibrinogen con-
centration recovered into normal range
several hours after the acute event.
Collectively the continuous low fibrin-
ogen concentration and abnormal func-
tion of the coagulation cascade is the
result of the liver dysfunction associated
with acute fatty liver of pregnancy,
leading to a lower production of coagu-
lation factors, anticoagulation proteins,
and fibrinogen by the liver.
HELLP syndrome
This condition is an additional cause for
DIC in obstetric patients that may involve
the liver. The relationship between acute
fatty liver of pregnancy and HELLP syn-
drome has not been clearly established.
There are obviously common clinical
and biological features between these 2
entities.68 Indeed, some authors66,72 have
suggested that acute fatty liver of preg-
nancy and HELLP syndrome are the
2 faces of the same coin. However,
others73,74 found that a difference in liver
histopathology (fatty microvascular in-
filtration of hepatocytes vs fibrin deposi-
tion or hemorrhage in the periportal
areas75,76) makes an overlap between
these 2 entities not possible.
One of the major differences between
acute fatty liver of pregnancy and HELLP
syndrome is the prevalence of DIC. In a
study by Vigil-De Gracia,68 DIC was
present in more than 70% of patients
with acute fatty liver of pregnancy and
less than 15% of those with HELLP
syndrome. Thus, although women with
HELLP syndrome have a reduced pro-
duction of fibrinogen and other coagu-
lating as well as anticoagulation factors
that can lead to the development of
DIC,77 this is not the central feature of
this disease. From the evidence brought
herein, DIC is a central feature of acute
fatty liver and in a way reflects the
severity of the hepatic injury, whereas in
HELLP syndrome, it is present in only a
fraction of the patients, probably those
with a more severe form of the micro-
angiopathic hemolytic anemia associ-
ated with this syndrome.
How can we diagnose DIC?
Early and accurate recognition of DIC is
the hallmark of success in the treatment
of this dire complication. Unfortunately,
in the majority of the cases, the diagnosis
of DIC is based on the clinical assess-
ment of the patient. Indeed, there is
no single laboratory or clinical test that
is sensitive and specific enough to di-
agnose DIC. Also, the effect of the pa-
thologies on the coagulation profile of
the patients cited previously and the risk
to develop DIC is not evident in all
cases.4,6,8,9,23,40,78
For these reasons, and the need to
provide the clinician a tool for early
identification of DIC as well as the need
for a common language and definition
of DIC, efforts have been made to create
MONTH 2015 American Journal of Obstetrics & Gynecology
Obstetrics Review
scoring systems to identify patients at
high risk for this dangerous complica-
tion. All these scores use simple and
readily available coagulation tests in-
cluding platelet count, prothrombin time
(PT) prolongation, fibrinogen, and fibrin
split products/D-dimer concentrations.
One key message is that the tests
should be repeated to reflect the dynamic
changes on the basis of laboratory results
and clinical observations. In the order
of relative importance in patients with
DIC, the tests are platelet count
(decreasing), PT (prolongation), fibrin-
related marker (increasing), and fibrin-
ogen (decreasing).13,14,79
Thrombocytopenia is the most com-
mon laboratory diagnostic feature for
DIC.80 However, the platelet count may
not always be very low and may even be
in the normal range in patients who have
recently started developing DIC. On the
other hand, the gestational thrombocy-
topenia of the third trimester may
confuse the thrombocytopenia of DIC.
To determine whether the thrombocy-
topenia is due to DIC, a downward trend
in the platelet count is most important,
even if the count remains in the normal
range.
It is useful to bear in mind that
thrombocytopenia in preeclampsia and
hypertensive disorders of pregnancy may
also be related to platelet aggregation or
increased adhesion to the vascular
endothelium. This is consistent with the
finding that A disintegrin and metal-
loproteinase with thrombospondin-like
repeats-13, the Von Willebrand cleaving
protease enzyme that typically shows
reduced concentration in thrombotic
thrombocytopenic purpura, is also lower
in women with preeclampsia or HELLP
syndrome in comparison with normal
pregnant women.35,81-84 Stepanian et al81
suggested that it may even play a role in
the pathophysiology of this obstetrical
syndrome and, as a consequence, this
might worsen the clinical course of pa-
tients with DIC.
A diagnosis of DIC is often considered
when the PT and activated partial
thromboplastin time (APTT) are con-
siderably prolonged. However, in preg-
nant women, normal ranges for these
tests are considerably shorter than that
5
Review Obstetrics
for the general population. For example,
even after significant PPH (up to 1500
mL), because of uterine atony, genital
tract trauma, and retained placenta, PT
and APPT were normal in 98.4% and
98% of cases, respectively, whereas in the
case of placental abruption, they were
normal in all cases.85
Prolongation of PTand APTTmay not
occur until the underlying condition has
progressed considerably. This is espe-
cially true in the case of APTT, which can
be shortened because of increased con-
centrations of factor VIII seen in preg-
nancy. It is important that in the correct
clinical context, attention is paid to
prolongation of the PT and APTT, even
in the normal range, because suggestive
of thrombin generation and clinical
worsening and treatment commenced
when they are even mildly prolonged.86
Low fibrinogen concentration is often
considered in the diagnostic algorithm
for DIC. However, because of the fact
that it is an acute-phase reactant, it is
very uncommon for the fibrinogen levels
to be low in pregnant women unless in
the setting of massive PPH.86 At the same
time, in comparison with the other
clotting factors, fibrinogen levels fall
below the normal pregnancy range
sooner, with reports suggesting a
decrease in serum fibrinogen is an ac-
curate biomarker for progression from
moderate to severe PPH.87-89
The pivotal study in this area came
from Charbit et al,87 who demonstrated
that, in women with uterine resistant
atony, a fibrinogen less than 2 g/L had a
positive predictive value of 100% for
progression to severe PPH, whereas a
level greater than 4 g/L had a negative
predictive value of 79%. For this reason,
importance once again should be given
to a decreasing fibrinogen level rather
than an absolute value with a threshold
value of 1.5 g/dL or even higher recom-
mended for replacement.86
Fibrin degradation product measure-
ments also have its problems in preg-
nancy because D-dimers are already
raised, even before pathological states set
in. Repeated measurements showing
increasing values may be helpful.
Point-of-care testing using devices
like thromboelastography (Haemonetics,
6 American Journal of Obstetrics & Gynecology MONTH 2015
Braintree, MA) or thromboelastometry
(TEM GmBH, Munich, Germany) is
useful in the obstetrical coagulopathic
disorders to achieve rapid results and
decide intervention. Normal ranges have
been published for women at the time of
delivery compared with the standard
ranges.90
Collins et al85 reported the throm-
boelastometry Fibtem A5 assay as a
very useful marker for monitoring he-
mostasis in this setting. In addition,
Sharma and Saxena91 have proposed a
thromboelastographic score, studying 21
patients classified following the Inter-
national Society for Haemostasis and
Thrombosis (ISTH) score. They de-
monstrated that parameters arising from
this technique may reach a sensitivity of
95.2% and specificity of 81.0%, with the
highest receiver operating characteristic
area under the curve of all parameters of
0.957 for identifying overt DIC.
The use of thromboelastometry has
been further evaluated in patients with
DIC related to severe sepsis, showing it
can be a valuable tool in assessing whole
blood coagulation capacity in patients
with severe sepsis with and without overt
DIC.92
Data on thromboelastography and
thromboelastometry in pregnant women
are limited, especially during the peri-
partum period and in women with
PPH, so more research in this field is
needed. Moreover, preliminary data are
encouraging because these tests may be
able to detect early alteration of coagula-
tion pathways and hyperfibrinolysis,93
allowing, in combination with the other
diagnostic and prognostic means, like
DIC scores, an adequate surveillance and,
eventually, a prompt intervention in ob-
stetric not yet severely affected patients.94
The acutely bleeding patient does not
need any score evaluation but prompt
infusion of blood products according to
preexisting protocols. However, in many
cases, DIC develops gradually and
through different underlying mecha-
nisms that are described in the manu-
script. In the latter group, using such a
scoring system can alert the clinician
that his patient is deteriorating and
needs further attention and treatment.
In addition, the introduction of such a
ajog.org
scoring system into clinical work will
help to validate the diagnosis and
create a common language between
clinician and researchers that will assist
in the promotion of the understanding
and management of DIC during
pregnancy.
To address the task of facilitating the
diagnosis of DIC, in those conditions
that do not represent emergencies in
which only a clinical diagnosis can be
achieved, the use of scoring systems has
been introduced. The first DIC score has
been recommended by the ISTH in
200170 showing a correlation between
key clinical observations and outcomes.
Using the same parameters, the Japanese
Association for Acute Medicine pub-
lished an additional score in 2005,95 of-
fering a good predictive value for the
diagnosis of DIC and the identification
of critically ill nonpregnant patients.
These scores can be used not only as a
diagnostic but also as a prognostic tool.
Thus, in the nonpregnant state, a DIC
score is important in the diagnosis of
patients with DIC and carries a diag-
nostic and prognostic value.71,96-98
Because the physiological hemostatic
changes occurring in pregnancy affect
the application of these scores to gesta-
tion, an adjusted score for the pregnant
state was needed. Based on this consid-
eration, Erez et al5 have recently con-
structed a pregnancy modified DIC score
by using only 3 components of the ISTH
DIC score (platelet count, fibrinogen
concentrations, and the PT difference)
with an area under the curve of 0.975
(P < .001) and at a cutoff of 26 or more
points had a sensitivity of 88% and a
specificity of 96% for the diagnosis of
DIC. At this cutoff, the pregnancy-
modified DIC score showed a positive
likelihood ratio of 22 and a negative
likelihood ratio of 0.125 (Table).
To further validate these results,
the performance of this DIC score was
compared with that of a modified
version of the DIC score adopted by
the ISTH (D-dimer was excluded from
the score). Due to the differences in pa-
tient selection and definition, compa-
ring the above mentioned score to that
proposed by Terao99 in 2007 was not
possible.
ajog.org Obstetrics Review

TABLE
Comparison among the pregnancy-modified DIC score by Erez et al5 and the other DIC scores in current clinical
use
Parameters ISTH score JAAM score Modified ISTH score
Platelet count, 10 /L 9
>100 ¼ 0 <80 or >50% decrease <50 ¼ 1
within 24 h ¼ 3
<100 ¼ 1 80 but <120 or >30% 50e100 ¼ 2
decrease within 24 h ¼ 1
<50 ¼ 2 >120 ¼ 0 100e185 ¼ 2
>185 ¼ 0
Fibrin-related markers No increase: 0 25 ¼ 3
(eg, soluble fibrin monomers/fibrin
degradation products)
Moderate increase: 2 10 ¼ 1 /
Strong increase: 3 < 10 ¼ 0
Prothrombin time (value <3 sec ¼ 0 1.2 ¼ 1 <0.5 ¼ 0
of patient/normal value)
3 sec but <6 sec ¼ 1 <1.2 ¼ 0 0.5e1 ¼ 5
6 sec ¼ 2 1.0e1.5 ¼ 12
>1.5 ¼ 25
Fibrinogen level, g/L >1.0 ¼ 0 3.0 ¼ 25
<1.0 ¼ 1 3.0e4.0 ¼ 6
/ 4.0e4.5 ¼ 1
>4.5 ¼ 0
SIRS criteria 3 ¼ 1
/ 0-2 ¼ 0 /
Calculated score >5: compatible with overt 4: suggestive of disseminated >26 high probability for DIC
DIC; repeat scoring daily intravascular coagulation
<5: suggestive (not affirmative) for
nonovert DIC; repeat next 1e2 d
DIC, disseminated intravascular coagulation; ISTH, International Society for Thrombosis and Haemostasis; JAAM, Japanese Association for Acute Medicine; SIRS, systemic inflammatory response
syndrome.
Erez. Disseminated intravascular coagulation in pregnancy. Am J Obstet Gynecol 2015.

Because abruption was the most
prevalent cause for blood transfusion
and DIC in their population, Erez et al5
used these patients for the comparison
between the DIC scores. Of 684 women
with abruption, 150 (21.93%) needed
blood transfusion and 43 (6.29%) had
DIC. The first comparison was in the
ability to identify patients with abrup-
tion who needed blood and blood
product transfusion. Their DIC score
had an area under the curve of 0.98
(95% confidence interval, 0.96e0.99)
at a cutoff point of 26, a sensitivity of
88%, and a specificity of 96%. The
modified ISTH score at a cutoff point
of 0.5 had an area under the curve
of 0.85 (95% confidence interval,
0.78e0.91), a sensitivity of 74%, and
a specificity of 95%.
The modified DIC score showed a
high sensitivity and specificity to
identify patients with DIC in the gen-
eral obstetric population. The positive
likelihood ratio greater than 10 sug-
gested a high probability that a positive
test score would be really diagnostic
for DIC. This is also correct for the
negative likelihood ratio, suggesting
that a negative result is true, with a
very low probability of such patient
having DIC (Figure 3).
Two more studies have proposed
the application of scores of parameters
with diagnostic and prognostic value to
obstetrical practice. First, Terao et al99
suggested in 1987 a DIC score based
on 77 patients with DIC identified in
100 centers in Japan, of which their
score identified 70 (90%). The score
included 3 main categories: (1) etiology,
stating whether there is a prominent
etiology that can explain the develop-
ment of DIC; (2) clinical manifestation,
including bleeding and organ dysfunc-
tion; and (3) laboratory tests, including
PT, fibrinogen, fibrin degradation pro-
ducts, and platelets; a minimum

MONTH 2015 American Journal of Obstetrics & Gynecology 7

Review Obstetrics
FIGURE 3
Algorithm summarizing diagnosis and treatment of DIC
DIC, disseminated intravascular coagulation.
Erez. Disseminated intravascular coagulation in pregnancy. Am J Obstet Gynecol 2015.
score of 7 or greater was needed for
the diagnosis of DIC. However, this
score was not validated in comparison
with the normal obstetric population,
and it is currently not in wide clinical
use.
The second study was reported by
Windsperger and Lehner,100 who studied
the utility fibrinogen/C-reactive protein
ratio as a diagnostic and prognostic tool
for the development of overt DIC in
patients with underlying HELLP syn-
drome. Their population was composed
of 19,404 deliveries, with 111 cases of
HELLP syndrome, who were divided
into 2 groups because the diagnosis was
8 American Journal of Obstetrics & Gynecology MONTH 2015
based on the ISTH criteria. They also
used D-dimer concentration. An overt
DIC developed in 11.7% of these pa-
tients with HELLP syndrome. This study
showed that the fibrinogen/C-reactive
protein ratio could differ significantly
between patients who develop DIC and
those who do not, showing to be a better
indicator for predicting a DIC than is the
fibrinogen level.
The applicability of this parameter
into clinical practice is limited by the
very small number of patients included
who developed the studied condition.
Moreover, following the study by Erez
et al,5 we can no longer use coagulation
ajog.org
parameters of nonpregnant patients in
comparison with pregnant patients
because curves are different and point-
of-care tests perform differently during
pregnancy, parturition, and puerperium.
The comparison of a scoring system that
is not adjusted to pregnancy and to lab-
oratory testing taken during acute
obstetrical complications such as HELLP
syndrome needs to be taken with a grain
of salt.
What are the current treatments for
obstetrical DIC?
The basic principles for treating obstet-
rical DIC include the following6,13,14,86:
ajog.org
management of the underlying condi-
tion that predisposes to DIC; supportive
care with blood products and related
measures; regular clinical and laboratory
surveillance; and seeking assistance from
the relevant specialists at the earliest.
Management of the underlying
condition that predisposes to DIC
DIC is an intermediary mechanism of
disease and is always secondary to an
underlying process. This hypothesis is
supported by the fact that the mortality
of DIC associated with placental abrup-
tion is less than 1%, whereas that asso-
ciated with sepsis related to obstetrical
cases is 50e80%.13 For this reason,
appropriate management of the primary
condition is paramount in limiting the
excess thrombin generation.
Supportive care with blood products
and related measures
The term, consumption coagulopathy,
often classically used for DIC, suggests
the need for replacement of blood com-
ponents in the management of DIC. The
following principles are considered in this
context: in relation to the coagulation
factors, their reduction has to be consid-
ered in relation to their hemostatic levels,
especially if the patient is bleeding; in the
case of platelets, because an element of
platelet dysfunction exists, this may
contribute to the bleeding; fibrinogen as
an acute-phase reactant has recently been
shown to play an important role in he-
mostasis in obstetrics as discussed before;
an adequate hemoglobin concentration
needs to be maintained because severe
anemia can worsen the rheology by being
unable to push platelets toward the
endothelium and also reducing oxygen
delivery to already compromised tissues.
The thresholds for transfusing blood
components are those recommended
by the harmonized guidance from the
ISTH, except in the case of fibrin-
ogen.14,86 In bleeding patients or those
who need interventions, this should be
started in the following conditions:
fibrinogen less than 1.5 g/L (2 pools of
cryoprecipitate should raise the fibrin-
ogen level by 1.0 g/L in the absence of
continued bleeding; if available, fibrin-
ogen concentrate may be used); platelets
less than 50  109/L (1-2 adult doses of
platelets), but if ongoing hemorrhage is
occurring, a higher threshold of 75 
109/L may be a starting point; PT and
APTT prolonged outside normal ranges
(15e30 mL/kg of fresh frozen plasma,
higher volumes likely to replace more
coagulation factors and is preferred if
volume overload is not a concern).
The evidence on different recom-
mendation transfusion protocols for
blood products is available in the litera-
ture,101-105 and we suggest the interested
reader to refer to them because a more
thorough evaluation of these protocols is
beyond the scope of this review.
Moreover, an interesting and novel
view regarding transfusion protocols
deserves to be mentioned to be critically
evaluated by the interested readers.
This is brought by Pacheco et al,106
who suggested how transfusion pro-
tocols may not be able to sustain patients
with massive bleeding because crystal-
loid resuscitation may actually worsen
bleeding before achieving surgical con-
trol of hemorrhage, increasing the
intravascular hydrostatic pressures (fa-
voring a dilutional coagulopathy) and
by dislodgement of fresh clots at sites
of endothelial injury. Following the evi-
dence,107 shared by patients with trauma
and obstetric patients with massive
bleeding, of an early coagulopathy oc-
curring before dilution and consump-
tion of clotting factors, they suggest a less
aggressive crystalloid therapy and an
early administration of fresh frozen
plasma, platelets, and packed red blood
cells in a condition of acute bleeding not
yet associated with catastrophic clinical
signs.106
Tranexamic acid has had resurgence
in recent years for the management of
massive hemorrhage. In the obstetrical
setting, the multinational World Maternal
Antifibrinolytic Trial (WOMAN) trial is
likely to improve the evidence regarding
this issue (www.thewomantrial.lshtm.ac.
uk). In their recently published review,
Sentilhes et al108 underlined the presence
of little evidence regarding the utilization
of tranexamic acid in the treatment of
PPH because of the lack of adequately
powered and high-quality randomized
controlled trials on this topic.109
MONTH 2015 American Journal of Obstetrics & Gynecology
Obstetrics Review
Moreover, the updated World Health Or-
ganization guidelines for PPH treat-
ment101 state a possible use of tranexamic
acid in case other measures (uterotonics,
uterine massage, fluid resuscitation) fail,
and this is suggested in the United
Kingdom as “recommended for consid-
eration” in cases of intractable PPH.110
A similar conclusion in terms of lack
of evidence has been suggested by
Wikkelsø et al111 for the use of pre-
emptive treatment with fibrinogen
concentrate for severe PPH in patients
with normofibrinogenemia.
Prothrombin complex concentrates
are avoided for the reasons that they
may promote thrombotic process and
do not replace all the clotting factors,
especially factor V. It is not an uncom-
mon practice worldwide to administer
recombinant activated factor VII
(rFVIIa) in patients who have massive
PPH. However, World Health Organi-
zation guidelines advise against the
use of this product outside the context
of clinical trials.112 Recombinant acti-
vated factor VII has been identified as
global hemostatic agent. Its use in
massive PPH decreased maternal mor-
tality because of hemorrhage.113
A recently published randomized
controlled trial,114 including 84 women
with severe PPH unresponsive to utero-
tonics, evaluated the use of human
rFVIIa in these patients. The authors
found that this molecule reduces the
need of specific second-line therapies
(interventional hemostatic procedures,
blood transfusions) in about one third of
the patients, with the occurrence of
nonfatal venous thrombotic events in 1
of every 20 patients. Guidelines suggest
its use before proceeding to hysterec-
tomy for massive PPH.
A review including 99 cases115 of DIC
treated with rFVIIa, of which 32 were
due to massive PPH, showed a median
dose of 67.2 mg/kg to be effective in
controlling hemorrhage. It was also
found useful in DIC related to malig-
nancy, whereas in the presence of meta-
bolic acidosis, the efficacy of rFVIIa in
DIC is much lower. Thus, the timing of
its administration during the course
of the management of DIC should be
considered carefully.
9
Review Obstetrics
Concerns have been raised about the
potential of arterial thrombosis associ-
ated with its use. It has been found that
its use is associated with a 2 times
increased risk for arterial thrombosis but
not with venous thrombosis.55 In addi-
tion, one must take into account the high
cost of this treatment.
Regular clinical and laboratory
surveillance
Because DIC is a dynamic process, close
monitoring of the patient is crucial to
evaluate clinical improvement or wors-
ening, to assess whether the process of
DIC is abated, and notice the develop-
ment of complications including organ
failure, allowing prompt intervention.
Repeated monitoring of the labora-
tory values including full blood count for
hemoglobin and platelet count and
clotting screen including fibrinogen is
needed.
Seeking assistance from the relevant
specialists at the earliest
DIC is a complex condition in which
dysfunction in multiple organ systems
contributes to the pathophysiology, and
as such, the obstetrician should not be
left alone in managing the patients but
he or she should be involved as the part
of a group of physicians from different
specialties. As a consequence, attending
surgeons, intensive care specialists, and
hematologists, but also all the people
involved in the patient care, including
nurses and support staff, must take part
in the case management (Figure 3).
Conclusions
DIC is a life-threatening situation that
can arise from a variety of obstetrical
and nonobstetrical causes. Prompt
diagnosis and understanding the un-
derlying mechanisms of disease leading
to this complication in essential for
favorable outcome. In recent years
novel diagnostic scores and treatment
modalities along with bedside point-of-
care tests were developed and may
assist the clinician in the diagnosis and
management of DIC. Team work and
prompt treatment are essential for the
successful management of patients with
DIC. - Pharmacol Sci 2008;12:19-31.
10 American Journal of Obstetrics & Gynecology MONTH 2015
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