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ADC Online First, published on August 18, 2016 as 10.1136/archdischild-2016-311053
1
Paediatric Haemato-Oncology,
Department of Paediatrics,
University of Malaya, Kuala
Lumpur, Malaysia
2
Department of Haematology,
Manchester Royal Infirmary,
Manchester, UK
3 Neonates
Department of Clinical
Haematology, Royal Children’s
Hospital Melbourne,
Melbourne, Australia
4
Department of Paediatrics,
University of Melbourne,
Melbourne, Australia
5
Haematology Research,
Murdoch Children Research
Institute, Melbourne, Australia
Correspondence to
Professor Paul Monagle,
Department of Paediatrics,
University of Melbourne, 50
Flemington Road, Parkville, VIC
3052, Australia;
Paul.Monagle@rch.org.au
Received 18 April 2016
Revised 21 July 2016
Accepted 27 July 2016
To cite: Rajagopal R,
Thachil J, Monagle P. Arch
Dis Child Published Online
First: [ please include Day
Month Year] doi:10.1136/
archdischild-2016-311053
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Review
Disseminated intravascular coagulation
in paediatrics
Revathi Rajagopal,1 Jecko Thachil,2 Paul Monagle3,4,5
ABSTRACT
Disseminated intravascular coagulation (DIC) in
paediatrics is associated with significant morbidity and
mortality. Although there have been several recent
advances in the pathophysiology of DIC, most of these
studies were done in adults. Since the haemostatic
system is very different in early life and changes
dramatically with age, creating a variety of challenges for
the clinician, delay in the diagnosis of DIC can happen
until overt DIC is evident. In this review article, we report
the aetiology, pathophysiology, clinical manifestations,
diagnostic tests and a management algorithm to guide
paediatricians when treating patients with DIC.
INTRODUCTION
Disseminated intravascular coagulation (DIC) is a
serious, acquired clinical condition that is charac-
terised by systemic activation of the haemostatic
system resulting in excess thrombin deposition
leading to microvascular thrombi.1–3 In addition,
the consumption of platelets and depletion of
plasma clotting factors from ongoing activation of
coagulation and the imbalance between the fibrino-
lytic and antifibrinolytic systems can also induce
severe bleeding.2 This intravascular coagulation can
disseminate to the different organs and cause a
spectrum of clinical effects. This concept is encap-
sulated by the International Society of Thrombosis
and Haemostasis (ISTH) DIC subcommittee defin-
ition of DIC: “an acquired syndrome characterized
by intravascular activation of coagulation with loss
of localization arising from different causes. It dis-
rupts the microvascular endothelium and leads to
multi-organ dysfunction syndrome (MODS) if the
process is sufficiently severe”.2 The presence of
concomitant thrombosis and bleeding in DIC com-
plicate the treatment strategies.
Even though DIC is a well-known thrombo-
haemorrhagic condition, data in paediatric popula-
tion with regard to incidence, laboratory findings
and prognosis are lacking due to limited number of
clinical trials.1 The ISTH diagnostic scoring system
for DIC has been used widely in adult intensive
care units (ICU), but controversies exist in paediat-
ric population in relation to normal range for
laboratory parameters and choice of diagnostic
coagulation tests.4 This review article focuses on
the pathogenesis, diagnostic tests and principles of
management of DIC in children. Congenital throm-
botic disorders ( protein C (PC), protein S (PS),
antithrombin (AT) and disintegrin-like and metallo-
proteinase with thrombospondin type 1 motifs 13
deficiencies) will not be discussed in this review.
Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
AETIOLOGICAL FACTORS FOR DIC
DIC is a secondary effect caused by various under-
lying clinical conditions. In paediatric population,
the aetiological factors vary based on age group.
The haemostatic system in neonates is significantly
different from children and adults, yet is dynamic
and balanced. Neonates are more vulnerable to
DIC than older infants and children.5 Platelets and
coagulation factors are first detectable at 56 and
10 weeks7 of gestation, respectively. Platelets reach
normal range of 150–450×109/L at 22 weeks of
gestation6 and most coagulation factors achieve
adult values by 6 months of postnatal age, with a
few notable exceptions.5 Platelets are found to be
hyporeactive and aggregation is impaired due to
deficiency of α-adrenergic receptors on platelet
membrane, especially in preterm infants <30 weeks
of gestation, but this dysfunction is balanced by ele-
vated von Willebrand factor levels.5 6 Andrew et al8
found that the mean values of procoagulant factors
and anticoagulant factors in healthy preterm
infants between 30 and 36 weeks of gestation were
low, with a range of 25%–70% of adult values.7
Given the significant differences in the value of
coagulation factors, it is important for neonatolo-
gists to understand the development of haemostasis
and interpret the results with caution.
The main causes of DIC in neonates are given in
table 1.5 9 Dairaku et al reported that 24 neonates
were histopathologically confirmed to have DIC
with microthrombi involving three or more organs
during autopsies, but only 1 of the neonates was
diagnosed with clinical DIC. Whereas Schmidt
et al10 found abnormal coagulation results in 57
out of 100 sick neonates diagnosed with DIC.5 The
discrepancy in the incidence of neonatal DIC in
these reports highlights the difficulty in diagnosing
this condition in neonates.5 9 10 Also, there are no
universally accepted DIC diagnostic criteria specific
for neonates.
Older infants and children
Sepsis is the most common cause of DIC in older
infants and children. Other factors are detailed in
table 1. Oren et al documented an incidence of
1.12% for DIC in children between 1 month and
18 years. Sepsis (95%) was the most common aetio-
logic factor followed by major trauma (5%). The
incidence of DIC in this report was probably
underestimated as paediatric ICU and emergency
care patients were not included.1 The incidence of
DIC in childhood acute lymphoblastic leukaemia
and acute promyelocytic leukaemia (APML) were
reported as 14%11 and 4%–8%,12 respectively.
1
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Review

CLINICAL ASPECTS OF DIC

Table 1 Aetiological factors associated with DIC in neonates, DIC is classically described as a thrombo-haemorrhagic disorder.
older infants and children Although mixed thrombotic-haemorrhagic picture is characteristic
Neonates Sepsis Group B streptococcus, neonatal of DIC, very often either bleeding or thrombotic manifestations
cytomegalovirus and enterovirus, predominate at one particular time (box 1).3 It is unfortunate in this
necrotising enterocolitis, systemic context to note that most paediatricians tend to entertain the possi-
candidiasis
Perinatal Birth asphyxia, respiratory distress bility of DIC only when there is extensive and uncontrollable bleed-
syndrome, meconium aspiration ing from multiple sites. Thrombi in the microvasculature leading to
syndrome MODS may represent the onset of DIC. Occasionally, the throm-
Others Single-twin demise, hypothermia, botic process can be dramatic as in the case of meningococcal sepsis-
acidosis
related DIC with the development of Waterhouse-Friderichsen syn-
Older infants Sepsis Bacteria: Gram-positive (group B
drome, which is associated with high mortality.15
and children streptococcus) and Gram-negative
(Neisseria meningitidis, Haemophilus The haemostatic derangement in children with DIC results
influenzae) bacterial infection from cumulative effects of hypercoagulation and hyperfibrinoly-
Fungus: Candida, Aspergillus sis. When hypercoagulation is dominant, organ failure is the
Virus: cytomegalovirus, varicella zoster, main clinical manifestation and this is frequently seen in infec-
dengue
Malaria tion and trauma.3 16 If hyperfibrinolysis is the predominant
Injury Accidents: neuro-trauma, crush injury, mechanism, bleeding will be the primary presentation, for
electrocution example, in APML.3 Consumptive coagulopathy with massive
Massive burns bleeding is observed when both hypercoagulation and hyperfi-
Drowning: hypoxia with profound shock
brinolysis are simultaneously activated.3 Oren et al1 found that
Malignancy Acute lymphoblastic leukaemia, acute
promyelocytic leukaemia the frequency of bleeding and thrombosis were 48.8% and
Solid tumours 4.8%, respectively in the setting of DIC.
Toxin Snake bites, recreational drugs One of the key clinical features to note is the contribution of the
Gastrointestinal tract Acute and chronic liver disease liver to the DIC process. The consequences of liver disease that
disorder Reye’s syndrome
Immunological Acute haemolytic transfusion reaction, may develop due to the underlying cause of DIC or secondary to
insults transplant rejection microvascular ischaemia are manifold. These include consumption
Others Giant haemangioma, autoimmune of platelets and clotting factors due to endothelial damage,
disease impaired production of vitamin K-dependent coagulation factors,
DIC, disseminated intravascular coagulation. activation of platelet-coagulation-fibrinolytic system, hypersplen-
ism and sequestration of clotting factors in ascitic fluid.13 17

Acquired inhibitors of coagulation factors such as prothrom- DIAGNOSIS OF DIC

bin inhibitors in transient lupus anticoagulant following infec-
tion, factor VIII inhibitors in autoimmune disease and other
inhibitors post major surgery are other miscellaneous factors in
paediatric DIC.13
PATHOPHYSIOLOGY OF DIC
Understanding the pathogenesis of DIC is crucial to providing
optimal treatment to reverse the underlying condition.1
Sepsis, trauma, major surgery or severe hypoxia leads to
release of tissue factor (TF) from endothelial cells and mono-
nuclear cells, which activates extrinsic pathway involving factor
VIIa (FVIIa).13 TF-FVIIa complex initiates thrombin generation
and further augments the haemostatic cascade by platelet
activation-aggregation process, activation of factors VIII, V, XI
and XIII, thrombin-activatable fibrinolysis inhibitor and pro-
motes inflammatory effect of white blood cells. Neutrophil
extracellular traps in patients with sepsis promote the apoptosis
of endothelial cells, platelet aggregation and decompose tissue
factor pathway inhibitor (TFPI) in order to augment thrombo-
genesis.3 Hence, TF pathway is the primary triggering factor of
DIC. This mechanism results in the consumption of the
endogenous anticoagulants AT, PC, PS and downregulation of
thrombomodulin and TFPI activity to promote thrombosis.3 In
addition, elevated cytokines such as interleukin-1 and tissue
necrosis factor-α in bloodstream stimulate the production of
plasminogen activator inhibitor type 1 and further impair the
fibrinolytic process (figure 1).3 The inflammatory process that
activates the coagulation system also plays a crucial role in the
organ damage of DIC. More recent advances in DIC have
focused on this inflammation-coagulation cross-link.14
2 Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
Laboratory tests for DIC
DIC is a clinico-laboratory diagnosis.4 The diagnosis is consid-
ered only in patients with an underlying disorder, which is
known to be associated with DIC in conjunction with several
laboratory features. The laboratory tests commonly used are
platelet count, coagulation screen, serum fibrinogen and
D-dimer or fibrin degradation products (FDP). These tests are
easily available in most laboratories and can identify the pro-
coagulant and fibrinolytic processes activated in DIC.
Prothrombin time (PT), activated partial thromboplastin time
(aPTT), platelet count and fibrinogen provide important infor-
mation on the procoagulant system, whereas D-dimer or FDP
measures fibrin formation and fibrinolysis.2 These parameters
should never be considered in isolation and also a single set of
these values should be deemed diagnostic. A reduction in plate-
let count, prolongation of the clotting screen, decrease in
fibrinogen level and an increase in the D-dimer values all point
towards extreme coagulation activation and uncontrolled throm-
bin generation.5 Table 2 outlines the most frequently used inves-
tigations in DIC. In conjunction with the clinical picture,
monitoring of the results over time helps to determine the tran-
sition from non-overt to overt DIC.
Additional investigations such as haemoglobin level, white
blood cell count, blood film (looking for red cell fragmentation
or schistocytes), liver and renal function tests, lactic dehydro-
genase level, arterial blood gas, blood culture and appropriate
imaging (eg, chest X-ray, brain MRI) may provide clues on pre-
cipitating factors and extent of organ involvement.
Some of the practical issues faced in the laboratory diagnosis
of DIC are (a) difficult venous or arterial access in sick children
to obtain adequate blood volume for repeated tests, especially in
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Review

Figure 1 Pathophysiology of disseminated intravascular coagulation (DIC). AT, antithrombin; F, factor; FVIIa, activated factor VII; PAI-1,
plasminogen activator inhibitor-1; PARs, protease-activated receptors; PC, protein C; PS, protein S; TAFI, thrombin-activatable fibrinolysis inhibitor;
TF, tissue factor; TFPI, tissue factor pathway inhibitor.

neonates, (b) standardisation of reference range is hard for vari-
ables like fibrinogen and D-dimer and (c) low levels of normal
physiological coagulation factors in neonates may be misinter-
preted as abnormal results.
Diagnostic scores for DIC
Three separate guidelines for diagnosis of DIC have been pub-
lished by the British Committee for Standards in Haematology,
Japanese Society for Thrombosis and Haemostasis and Italian
Society for Haemostasis and Thrombosis. These are broadly
similar but some variations in the recommendations were noted.
Hence, the ISTH Subcommittee harmonised these differences
and published a standardised DIC scoring system.2 3
The ISTH criteria recommended five-step diagnostic algo-
rithm to calculate the DIC score by using four laboratory tests
(table 3).2 The criteria have 91% sensitivity with 97% specificity
among adults and demonstrated strong correlation between DIC
score with incidence of mortality.18 Unfortunately, data on valid-
ation of ISTH DIC criteria in children are limited, even though
it has been used universally in paediatric patients.4 Furthermore,
to our knowledge no studies have evaluated the sensitivity and
specificity of ISTH DIC criteria in neonates.
Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
Data on the use of diagnostic scores in paediatrics
Kutny et al19 evaluated the predictive value of ISTH DIC score
in newly diagnosed paediatric patients with APML treated on
Children’s Oncology Group study AAML0631. In this study,
DIC score of ≥6 was used to assess the correlation of ISTH DIC
score with haemorrhagic death. This cut-off score of ≥6 was
based on the previous study by Mitrovic et al.20 DIC score ≥6
was significantly associated with a high incidence of fatal bleed-
ing compared with score of <6 (13% vs 0%, p=0.025) and also
an increased rate of coagulopathy (32% vs 9%, p=0.015).
However, the sensitivity and specificity of the DIC score in pre-
dicting at least one coagulopathy event during induction was
low with the rate of 66.7% and 65.6%, respectively.19 The
authors concluded that other investigations are essential to
improve the predictive value, but did not address the reason for
using the diagnostic score of ≥6 instead of ≥5 as per the ISTH
DIC recommendation.
Soundar et al retrospectively compared the Texas Children’s
Hospital (TCH) DIC modified criteria and the ISTH DIC
scoring system. TCH criteria used serial platelets and fibrinogen
levels in DIC diagnosis. The sensitivity of this scoring system
was significantly higher than the ISTH DIC score (82% vs 65%,
3
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Review

Table 3 ISTH DIC scoring criteria

Box 1 Clinical features of DIC
Step 1: Risk Does the patient have an underlying If yes: proceed
assessment disorder known to be associated If no: do not use
Typical haemorrhagic features of DIC with overt DIC? this algorithm
▸ Bleeding venepuncture sites Step 2: Order global PT, platelet count, fibrinogen, fibrin-related marker
▸ Oozing of blood from indwelling catheters coagulation tests
▸ Spontaneous or minimal trauma-related generalised Step 3: Score the Platelet count
test results >100×109/L 0
ecchymoses
<100×109/L 1
▸ Development of large, bullous haemorrhagic skin lesions on <50×109/L 2
previous viral exanthematous sites Elevated fibrin marker (eg, D-dimer, fibrin degradation
▸ Mucosal bleeding from gingiva, gastrointestinal or renal products)
tracts No increase 0
Moderate increase 1
▸ Unexpected and major bleeding around drain sites or Strong increase 2
surgical wounds postsurgery in postoperative states Prolonged PT
Typical thrombotic features of DIC <3 s 0
▸ Thrombophlebitis at unusual sites >3 s but <6 s 1
>6 s 2
▸ Renal impairment in the absence of other explanations
Fibrinogen level
▸ Fluctuating central nervous system disturbances like >1 g/L 0
confusion, and seizures—consistent with the <1 g/L 1
microcirculatory ischaemia Step 4: Calculate ≥5 compatible with overt DIC Repeat score
▸ Respiratory distress syndrome with no obvious explanation score daily
▸ Dermal infarcts and skin necrosis <5 suggestive for non-overt DIC Repeat next
1–2 days
▸ Greyish discolouration of finger tips, toes or ear lobes, which
has been termed ‘acral cyanosis’; usually seen in extreme DIC, disseminated intravascular coagulation; ISTH, International Society of Thrombosis
and Haemostasis; PT, prothrombin time.
cases
DIC, disseminated intravascular coagulation.
significant impact in the diagnosis of DIC. Fibrinogen is an
insensitive indicator of DIC as it acts as an acute-phase reactant.
Therefore, serial fibrinogen measurement is more useful in pre-
Table 2 Laboratory investigations in paediatric DIC dicting an overt DIC.4
Khemani et al analysed the association between ISTH DIC
Test Abnormality Difficulties in children score and the risk of mortality in children admitted with shock.
Platelet count Decreased Platelet clumping due to inability Paediatric index of mortality (PIM 2) and 12-hour paediatric risk
to achieve free-flowing venous mortality III (PRISM III) score were used along with ISTH DIC
sample in paediatrics score. The analysis demonstrated that a unit increase in DIC score
Prothrombin time/ Prolonged Age-dependent values; blood was strongly associated with 1.3-fold increase in mortality rate.
activated partial sample from heparin containing Most of the children achieved peak ISTH DIC score within
thromboplastin time indwelling lines in critically ill
patients; difficulty in filling blood
2 hours and 75% within 6 hours of paediatric ICU admission.
sample in specimen tube with Mortality in patients with DIC score ≥5 was 50% compared with
sodium citrate to the correct level; 20% in patients with DIC score <5 (p=0.0003). The ISTH DIC
high haematocrit level especially in score predicted mortality better than other validated paediatric
neonates causes excessive sodium mortality scores such as PIM 2 and PRISM III.21
citrate concentration in plasma
after centrifuge In contrast, a recent retrospective study by Jhang et al on
INR Prolonged Age-dependent values; INR values evaluation of DIC scores in 191 critically ill patients showed that
derived from control values of the ISTH and the Japanese Association of Acute Medicine
adult plasma, hence paediatric scoring systems correlate well with other severity scores including
results fall outside the normal PRISM III, modified sequential organ failure assessment and
range
paediatric multiple organ dysfunction syndrome. Among them,
Fibrinogen Decreased Acute-phase reactant and falsely
elevated; Clauss fibrinogen assay is
15.7% and 29.8% of the patients were diagnosed with DIC by
useful as it provides accurate ISTH and the Japanese Association of Acute Medicine scoring
quantification of low levels of systems, respectively. In addition, ISTH and Japanese Association
fibrinogen in DIC of Acute Medicine scoring systems showed higher mortality rate
D-dimer Elevated Not well described in paediatrics in patients with DIC than patients without DIC, suggesting that
with regard to normal reference these scores could be promising prognostic factors.22
range
The contradicting recommendations from several analyses in
DIC, disseminated intravascular coagulation; INR, international normalised ratio. paediatric population warrant further validation of ISTH DIC
scoring system in this age group. However, the data to date
suggest that a single time point analysis of laboratory test is of
p≤0.05), whereas the specificity was lower (29% vs 43%, no value and should not be relied on to make the diagnosis of
p≤0.05). This suggests that ISTH score is only able to identify DIC.
overt DIC and not evolving DIC in paediatric population.
Platelets, PT and D-dimer are important parameters in predict- TREATMENT OF DIC IN PAEDIATRICS
ing DIC in both scoring systems but fibrinogen did not show The basic principles of DIC treatment are outlined in box 2.
4 Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
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Box 2 Management of DIC
Basic principles of DIC management
1. Management of the underlying condition that predisposes to
DIC
2. Supportive care with blood products and related measures
3. Inhibition of the effects of excess thrombin
4. Regular clinical and laboratory surveillance
5. Always bearing in mind that the abnormal laboratory markers
may be due to several factors and not just DIC
6. Seeking treatment assistance from the relevant specialists early
DIC, disseminated intravascular coagulation.
Treatment of underlying disease
Diagnosis of DIC should be made based on the combination of
clinical condition and laboratory information. The key to DIC
treatment is vigorous management of the underlying condition
with optimal care.2 3
Blood products transfusion
There are lots of different practices and controversies related to
blood product management in DIC. Transfusion should be
reserved for bleeding patients with DIC and not to transfuse pri-
marily based on laboratory results. The Serious Hazards of
Transfusion Haemovigilance scheme has highlighted the
increased risk of adverse effects in transfused children as com-
pared with adults.13 These observational data are supported by
Khemani et al,21 where higher mortality rate was found in
patients who received more blood products. Platelets, fresh
frozen plasma (FFP) and cryoprecipitate are commonly used
blood components in patients with DIC.
In general, platelets are transfused in patients with bleeding
or high risk of bleeding requiring invasive procedures with
platelet count of <50×109/L. In non-bleeding patients and
patients with chronic DIC, prophylactic platelet transfusion is
not recommended and close monitoring of clinical status is
advisable. Thrombocytopenia is a common finding in sick
preterm neonates and there is no clear correlation between
severity of thrombocytopenia and risk of major bleeding. Thus,
the threshold for platelet transfusion, volume and appropriate
indication for transfusion in paediatric populations with DIC
are still unclear. Most of the guidelines are based on expert
opinion.
FFP is mainly indicated in bleeding patients with prolonged
PT and aPTT >1.5 times of upper limit of normal range.
However, PT and aPTT normal values in neonates vary accord-
ing to the gestational age. In this situation, serial monitoring is
indicated along with clinical observation to determine the sever-
ity of DIC. Generally, 10–20 mL/kg of FFP is recommended,
but strict haemodynamic status must be evaluated to prevent
fluid overload as these patients may require multiple blood com-
ponents. Risk of cardiomyopathy secondary to sepsis may com-
plicate the clinical condition.3 16 Occasionally, prothrombin
complex (PCC) can be considered if volume overload is an
issue. There are case reports on use of PCC in paediatrics,23 but
one should bear in mind that PCC should be used judiciously as
they may cause thrombosis and also lack certain coagulation
factors, especially factor V.16 In addition, the amount of anticoa-
gulants like AT, PC and PS in PCC may not be adequate for
replacement in patients with DIC, where these proteins are
markedly reduced.
Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
Review
Cryoprecipitate is used in bleeding patients when fibrinogen
level is <1.5 g/L.3 16 Some paediatric oncology centres practice
prophylactic transfusion of cryoprecipitate in non-bleeding
patients with APML when fibrinogen level is <1.5 g/dL in the
anticipation of coagulopathy, although this is not evidence-based.
Fibrinogen concentrates have been used instead of cryoprecipi-
tate, but are currently licensed only for congenital afibrinogen-
emia. However, there are several studies documenting their
efficacy in acquired hypofibrinogenemic conditions such as in
dilutional coagulopathy, trauma, cardiac and thoracic surgery and
liver failure in adults. It is difficult to make a strong recommenda-
tion in paediatrics based on anecdotal reports and small case
series. More clinical trials are needed focusing on DIC manage-
ment in children and on the dosing, efficacy and safety of this
blood component.
Anticoagulants—heparins
In patients with DIC with predominant thrombosis, therapeutic
dose of heparin should be considered.2 This approach was
clearly discussed by Fox in 13 patients with widespread DIC
and Waterhouse-Friderichsen syndrome following meningococ-
cal septicaemia.15 Continuous infusion of unfractionated
heparin (UFH) is a better option in paediatric population due to
its short half-life and reversibility with protamine sulfate.16 In
one study by Göbel et al, treatment of 40 newborns with DIC
and respiratory distress syndrome were randomised between
heparin infusion and placebo. The heparin group required sig-
nificantly shorter duration of mechanical ventilation and faster
normalisation of coagulation parameters even though mortality
rate was equal in both groups.5 24 Use of UFH is contraindicated
in patients with evidence of bleeding. In non-bleeding critically
ill patients with DIC, prophylaxis use of heparin is recom-
mended.2 Low molecular weight heparin (LMWH) is frequently
administered in adults due its predictive pharmacokinetics,
lesser bleeding risks and lower incidence of heparin-induced
thrombocytopenia. LMWH usage in paediatrics in acute DIC
with thrombosis is still limited and not commonly accepted
practice due to lack of evidence. When using UFH in DIC,
monitoring with aPTT may not be straightforward, since the
excess of thrombin generation may lead to shortening of the
aPTT. In the case of LMWH, abnormal renal function in chil-
dren with DIC further complicates the treatment because
LMWH accumulates in renal impairment.
Anticoagulants factor concentrates—AT
AT is depleted during excessive thrombin generation in DIC,
and AT levels are a predictor of outcome in septic DIC patients
and an independent predictor of 28-day mortality.16 Several ran-
domised controlled trials (RCT) assessing the effect of AT treat-
ment on mortality rate in adults have demonstrated statistically
significant reduction in mortality.1 There are no RCTs available
in the paediatric population, but several retrospective analyses
have been reported. Nowak-Göttl et al25 reported that adminis-
tration of AT in 21 preterm infants and 18 children has resulted
in the normalisation of platelets, PT, aPTT, fibrinogen, thrombin
time, AT within 24–48 hours and recovery from DIC without
adverse effects.5 However, this result has to be interpreted with
caution because all of the patients received blood components
simultaneously during the treatment. AT replacement is not
widely recommended in paediatric DIC.
5
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Anticoagulants factor concentrates—recombinant
activated PC
PC is markedly low in patients with sepsis and it has been sug-
gested that restoration of PC may help to reduce the severity of
DIC.13 26 Laterre26 has reviewed several clinical trials with
recombinant activated protein C (rAPC) in adults and paediat-
rics. In Protein C Worldwide Evaluation in Severe Sepsis trial,
usage of rAPC at a dose of 24 μg/kg/hour for 96 hours in
among 1960 adult patients showed absolute and relative reduc-
tions in the risk of death of 6.1% and 19.4%, respectively.
Mortality rate was only 24.7% in rAPC group as compared with
30.8% in placebo group ( p=0.005). In addition, rAPC-treated
adults demonstrated faster cardiovascular and respiratory recov-
ery. However, the incidence of major bleeding was noted to be
higher in rAPC group compared with placebo group (3.5% vs
2.0%; p=0.06), which resulted in premature interruption of the
study. Subsequent adult trials of rAPC in Extended Evaluation
of Recombinant Human Activated Protein C and Administration
of Drotrecogin alfa (activated) in early stage Severe Sepsis
revealed higher incidence of bleeding-related adverse events
with no significant reduction in 28-day mortality, especially in
latter trial.26 In children, a phase III randomised, double-blind,
placebo-controlled trial called Researching severe Sepsis and
Organ dysfunction in children: a global perspective was con-
ducted in 477 patients with sepsis (age >38 weeks of gestation
until <18 years) to evaluate the efficacy and safety of rAPC. This
study demonstrated that there was no significant difference in
28-day mortality between rAPC and placebo groups (17.2% vs
17.5%). Bleeding events were similar in both groups, but higher
incidence of intracranial bleeding occurred in rAPC group (4.6%)
than in placebo group (2.1%). This phenomenon was observed
predominantly in children younger than 60 days.13 26 27 Hence,
rAPC usage is not recommended in children.
Anticoagulants factor concentrates—thrombomodulin
Thrombomodulin is a vascular endothelial glycoprotein, which
binds to thrombin and enhances PC activation. Activated PC
with PS inhibits activated factors V and VIII to prevent further
thrombin generation. Recombinant soluble human thrombomo-
dulin (rTM) has similar pharmacological mechanism as rAPC.28
In Japan, a randomised double-blinded control trial in adults
comparing rTM with low-dose heparin showed a significant
improvement in DIC symptoms in rTM group as compared
with heparin group (66.1% vs 49.9%) and lower incidence of
bleeding-related adverse events (43.1% vs 56.5%).29 Even
though this study failed to demonstrate superior outcome in the
survival rate, its usage has been approved in Japanese population
since 2008. In the paediatric population, Yagasaki et al reported
their first experience of rTM in 25 patients (23=infants/chil-
dren; 2=neonates) with sepsis and haematological malignancy.
A dosage of 380 U/kg/day of rTM was recommended and dose
was reduced to 130 U/kg/day in patients with impaired renal
function. In this small cohort, 80% (20/25) of patients reco-
vered from DIC by day 7 and 88% (22/25) were alive on day
28 of treatment. Laboratory results, especially PT, FDP and AT
improved on day 4 and further improvement was documented
on day 7 of post-rTM treatment. The result was encouraging
but all the patients received FFP and platelet transfusion to
maintain fibrinogen >4.4 μmol/L and platelet >20×109/L. Two
neonates in this study died with intracranial bleeding. The
authors were uncertain whether the bleeding was associated
with rTM or as a sequelae of DIC as these newborns received
suboptimal treatment at initial presentation. Hence, it was
6 Rajagopal R, et al. Arch Dis Child 2016;0:1–7. doi:10.1136/archdischild-2016-311053
concluded that rTM must be used carefully in newborns.
Furthermore, low levels of PC in neonates pose a question
regarding the effectiveness of rTM in this age group.28
Subsequently, Shirahata et al investigated the effectiveness of
rTM in 60 neonates. This study demonstrated greater survival
rates in neonates as compared with children and adults, but
failed to show good DIC resolution rate. Only 31.7% neonates
received rTM as monotherapy and remaining 68.3% had
another anticoagulant concomitantly. The incidence of
bleeding-related adverse events in neonates (6.7%) was similar
to children (5.2%) and adults (7.0%). However, the result of
this trial has to be interpreted carefully because the clinical
assessment of DIC was made by the treating physicians. Sixteen
out of 60 neonates had DIC secondary to birth asphyxia but
with favourable outcome, onset of bleeding preceded the mani-
festation of DIC and blood products and other anticoagulants
were used concomitantly. Adult criteria of Japanese Ministry of
Health and Welfare was used to calculate the resolution rate in
this study.30 Even though rTM seems to be safe and more effect-
ive than other anticoagulants in paediatric population, further
trials are needed to confirm its efficacy as PC is required for
optimal action.
Others
Antifibrinolytic agents and recombinant FVIIa are not recom-
mended in the treatment of DIC. There are significant concerns
about the risk of thromboembolic events following administra-
tion of these components.
CONCLUSION
DIC in children is associated with high mortality. Clinical
manifestations in children and neonates vary and management
strategies should be individualised. Early involvement of multidis-
ciplinary teams is crucial to initiate appropriate treatments
adequately. In paediatrics, the challenge is in implementing
evidence-based diagnostic criteria according to the clinical and
laboratory results for each patient. The diagnosis of DIC should
not be interpreted based on a single result and careful observation
on the patterns of clinical signs and serial results are mandatory.
However, difficulty in obtaining blood samples from critically ill
children is a major challenge. Treating the underlying condition
and supportive treatment with blood components in bleeding
patients are the mainstay of treatment. UFH is generally recom-
mended in non-bleeding patients. Administration of other
pharmaceutical agents is not routinely recommended, but
requires advice from a haematologist in specific situations. Most
of the treatment strategies in DIC are extrapolated from adult
studies. Hence, further trials are needed to validate the ISTH DIC
diagnostic criteria and management approach in paediatrics.
Contributors RR drafted the initial manuscript and approved the final manuscript.
JT and PM reviewed and revised the manuscript, and approved the final manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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Disseminated intravascular coagulation in

paediatrics
Revathi Rajagopal, Jecko Thachil and Paul Monagle

Arch Dis Child published online August 18, 2016

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