Venous Thromboembolism in Children: Is It

Preventable?
Tina T. Biss, BMedSci, BMBS, MD, MRCP, FRCPath1

1 Department of Haematology, The Newcastle upon Tyne Hospitals
NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Semin Thromb Hemost
Address for correspondence Tina T. Biss, BMedSci, BMBS, MD, MRCP,
FRCPath, Department of Haematology, Royal Victoria Infirmary, The
Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon
Tyne, Tyne & Wear, NE1 4LP, United Kingdom
(e-mail: tina.biss@nuth.nhs.uk).

Abstract The incidence of venous thromboembolism (VTE) in children is increasing. Hospitalized

infants and adolescents are at highest risk, and most individuals who have VTE have
multiple thrombotic risk factors. The presence of a central venous catheter (CVC) is the
most frequent risk factor for childhood thrombosis. Childhood VTE has significant
consequences in relation to the thrombotic event and the anticoagulant therapy used

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for its treatment. Identification of the most prevalent risk factors for VTE, particularly
Keywords among adolescents, has moved the focus toward prevention of thrombosis. Risk
► anticoagulants assessment models have been developed to identify individuals who are at higher
► pediatrics risk with a view to employing preventative strategies such as mechanical and chemical
► risk assessment thromboprophylaxis (TP). There is currently little evidence to support the efficacy of
► thromboprophylaxis such strategies for preventing either CVC-associated thrombosis or thrombosis at other
► venous sites. In addition, there are concerns about adverse consequences of mechanical and
thromboembolism chemical TP in a population where the overall incidence of VTE remains low.

Although childhood venous thromboembolism (VTE) is a
relatively infrequent occurrence, it has significant implica-
tions in terms of mortality, short- and long-term morbidity,
and health care costs, as a consequence of both the throm-
botic event itself and the anticoagulant therapy that is
required for its treatment. In addition, the incidence of
childhood VTE is increasing, particularly among hospitalized
children.
A marked reduction in the rate of VTE in relation to the
hospitalization of adults has been noted since the introduc-
tion of VTE risk assessment as standard of care, with mechan-
ical and/or chemical thromboprophylaxis (TP) being
administered to those who are deemed to be at sufficiently
enhanced risk. A similar approach has been extrapolated to
children, particularly adolescents, in some pediatric centers.
However, the safety and efficacy of TP, either mechanical or
chemical, as a means of preventing VTE in a pediatric
population remains uncertain.
This review aims to evaluate current preventative strate-
gies for childhood VTE, in particular to answer the question as
to whether sufficient data exist to support the role of
mechanical and/or chemical TP in this age group. The discus-
sion will focus on the prevention of venous thrombotic events
in children aged 28 days to less than 18 years and will
therefore not consider the prevention of neonatal or arterial
thrombosis.
Venous Thromboembolism in Childhood
Epidemiology of Venous Thromboembolism in
Childhood
Childhood VTE has an incidence of 0.7 to 4.9 per 100,000
children in the general population.1–3 The incidence of
thrombosis is highest among hospitalized children, occurring
in
50 per 10,000 admissions.3 An increasing incidence of
childhood VTE within all age groups has been recorded over
the last decade.4 This most likely relates to thrombosis as a
consequence of successful medical/surgical intervention for
disorders of childhood such as prematurity, malignancy, and
congenital heart disease, which are well-established pro-
thrombotic conditions. It may also reflect an increase in the
use of central venous catheters (CVCs) to treat these

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VTE Prevention in Children Biss

Fig. 1 Age distribution of venous thrombotic events occurring in childhood. These data were obtained from the Newcastle upon Tyne Hospitals

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NHS Foundation Trust pediatric thrombosis registry and represent 139 consecutive cases of venous thrombosis occurring in children aged 0 to less
than 18 years.

disorders, as well as the recent epidemics of novel pathogens,
especially viruses. In addition, improvements in vascular
imaging technology and an increasing recognition among
physicians of VTE as a disorder of childhood as well as
adulthood are likely to play a part.
Previous registry studies have identified two peaks in
incidence of thrombosis occurring during childhood: infancy
and adolescence1,2,5 (►Fig. 1). The majority of thrombotic
events during infancy occur within the first month of life. The
presence of a CVC is an important factor, which probably
contributes to >90% of neonatal thrombosis.2 The incidence
of thrombosis is low during younger childhood, but then rises
during adolescence. Many of the risk factors for VTE within
this age group are common to both adolescents and adults,
and include immobility, surgery, malignancy, smoking, in-
fections, and hormonal factors such as the combined oral
contraceptive pill (COCP) and pregnancy. In addition, the
index thrombotic event in an individual with a significant
thrombophilic abnormality or a congenital venous anomaly
may occur during adolescence.6
Risk Factors for Venous Thromboembolism in
Childhood
Patient-related, disease-related, and treatment-related risk
factors for thrombosis in childhood are shown in ►Table 1.
The presence of a CVC is the most important risk factor,

Table 1 Risk factors for venous thrombosis in childhood

Patient-related factors Disease-related factors Treatment-related factors

Infancy/adolescence
Thrombophilic abnormality
Congenital venous anomaly
Personal history of VTE
Family history of VTE
Smoking
Obesity
Pregnancy/postpartum
Recent long-haul travel
Reduced mobility Central venous catheter
Malignancy Surgeryc
Prematurity Asparaginase therapy
Congenital heart disease Steroid therapy
a
Trauma Estrogen-containing hormonal therapy
Paraplegia/spinal cord injury Admission to ICU
Severe infections/sepsis Total parenteral nutrition
Dehydration
Others: Severe burns, IBD, nephrotic syndrome, anti-
phospholipid antibodies, autoimmune disease, sickle
cell anemia, hemolysis, low-output cardiac failure,
head/neck infection,b heparin-induced
thrombocytopenia

Abbreviations: IBD, inflammatory bowel disease; ICU, intensive care unit; VTE, venous thromboembolism.
a
Particularly major trauma, lower limb or pelvic fracture.
b
Implicated in the etiology of neck vein thrombosis or cerebral venous sinus thrombosis.
c
Particularly major orthopedic surgery, neurosurgery, major abdominal surgery, surgery for malignancy, and prolonged surgical procedure.

Seminars in Thrombosis & Hemostasis

 VTE Prevention in Children Biss

particularly in infants and neonates.1,2 Idiopathic VTE is rare
in childhood, with <5% of individuals having no identifiable
risk factor. According to the traditional multifactorial patho-
genesis of VTE,7 childhood thrombosis is also multifactorial in
essence, the majority of children having two or more risk
factors for thrombosis at the time of the event.1,2 A throm-
bophilic abnormality is more likely to be present in older
children who present with VTE than in younger children,
infants, neonates, or those with CVC-associated thrombosis.2
For those with an inherited thrombophilic abnormality, there
may be a family history of thrombosis in a first-degree
relative. Acquired thrombophilic abnormalities include anti-
thrombin deficiency due to asparaginase therapy, protein-
losing enteropathy, nephrotic syndrome, liver disease or
disseminated intravascular coagulation, protein S deficiency
due to varicella-zoster virus infection, pregnancy or COCP use,
and the presence of antiphospholipid antibodies.
Site of Thrombosis in Childhood
in children are cerebral venous sinus thrombosis, renal vein
thrombosis, and portal vein thrombosis.10,11
Current Management of Venous Thromboembolism in
Childhood
Published guidelines provide advice on the choice of antico-
agulant, intensity of therapy, nature and frequency of moni-
toring, and duration of therapy for management of
thrombosis in children. However, many of the recommenda-
tions are based on limited evidence or are extrapolated from
adult data.12,13 Provoked thrombotic events are treated for a
minimum of 3 months, while unprovoked events are treated
for 6 to 12 months or longer. Anticoagulant therapy may be
continued long term in individuals with ongoing risk
factors.12,13
Consequences of Venous Thromboembolism in
Childhood
The potential consequences of childhood VTE are shown

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The most common site of thrombotic event in childhood is
extremity (limb) deep vein thrombosis (DVT). Due to the
frequent use of upper venous system CVCs, approximately
one-third of extremity DVTs in children affects the vessels of
the neck, upper limb, and/or the superior vena cava, a much
greater proportion than is seen in adults.1,8 Isolated pulmo-
nary embolism (PE) accounts for 5 to 10% of thrombotic
events in childhood, and may also complicate upper or lower
venous system DVT.1,2,5,8,9 Less common thrombotic events
in ►Table 2. In addition to the potential for mortality,
morbidity, thrombosis recurrence, psychological and lifestyle
implications, and health-related cost, childhood thrombosis
can have an adverse impact on other therapy. The manage-
ment of surgery requires careful decision-making about the
safe duration of interruption of anticoagulant therapy and the
need for bridging anticoagulation and/or inferior vena cava
filter placement. In children with malignancy, bleeding dur-
ing periods of thrombocytopenia induced by chemotherapy

Table 2 Consequences of venous thrombosis in childhood

Consequence of venous thrombosis Details

Mortality
All-cause mortality 10 to 15%2,14
Mortality related to VTE 2% (predominantly death due to PE or CVST)2,9,11,14
Morbidity
Deep vein thrombosis
Post-thrombotic syndrome Occurs in 10 to 25% of children with extremity DVT.15 Occurs in 6% of those
with CVC for treatment of malignancy but no symptomatic DVT16
Loss of venous access
Superior vena cava obstruction
Pulmonary embolism Chronic thromboembolic pulmonary hypertension17
Cerebral venous sinus thrombosis Neurological morbidity, including hemiplegia, seizures, headaches,
and cognitive/behavioral deficits18
Portal vein thrombosis Portal hypertension
Renal vein thrombosis Hypertension, renal impairment
Thrombosis recurrence 7 to 10%2,14
Psychological and lifestyle implications Restriction of physical activities, needle phobia, burden of anticoagulant
monitoring, fear of recurrent thrombosis or bleeding, dietary and alcohol
restrictions, changes in physical appearance19,20
Health-related cost Extended hospital stay, outpatient monitoring of anticoagulant therapy,
loss of productivity of parent/caregiver

Abbreviations: CVST, cerebral venous sinus thrombosis; CVC, central venous catheter; DVT, deep vein thrombosis; PE, pulmonary embolism.

Seminars in Thrombosis & Hemostasis

VTE Prevention in Children Biss
may be exacerbated by the anticoagulant therapy. In children
who develop thrombosis during treatment of acute lympho-
blastic leukemia (ALL), the therapy for the underlying malig-
nancy may be compromised by delaying or withholding
intrathecal chemotherapy due to a reluctance to interrupt
anticoagulant therapy or by deferring further doses of aspar-
aginase for concern about recurrent thrombosis.21
Preventing Venous Thromboembolism in
Childhood
Principles of Thromboprophylaxis
The successful prevention of VTE relies on the ability (1) to
identify those who are at increased risk by recognizing the
presence of specific thrombotic risk factors and (2) to employ
effective and safe preventative strategies in those individuals.
Thrombosis in adults occurs with an incidence of 1 per 1,000
in the general population and, prior to the routine introduc-
tion of TP for hospitalized adults, 10 to 15% in medical
patients and 40 to 50% in surgical patients. Dependent on
the clinical setting, the use of low-molecular-weight heparin
(LMWH) TP results in a relative decreased VTE risk ( 0.4 to 0.7)
compared with no TP.22 There is limited evidence to support
thrombotic risk assessment in children or adolescents, and
even less to support the use of mechanical and/or chemical TP
in this age group. The available evidence for prevention of VTE
in children and adolescents is presented below.
Potential Means of Venous Thromboembolism
Prevention in Childhood
Simple Measures to Prevent Venous Thromboembolism
Simple measures to prevent VTE in all age groups include
early mobilization after surgical or medical admission, ade-
quate hydration, and interruption of the COCP in adolescent
females in preparation for surgery. It is recommended that
CVCs are removed as soon as they are no longer required.13
Type and Site of Central Venous Catheter
The presence of a CVC is the most frequent risk factor
associated with childhood VTE. Some studies have shown
variation in incidence of CVC-associated VTE with different
types of catheter, site of insertion, and insertion procedure.23
The majority of the evidence is for children who require a CVC
for the treatment of malignancy. In terms of type of CVC, the
use of heparin-bonded catheters in children was evaluated in
two randomized controlled trials (RCTs) with conflicting
results. The former recruited 209 children and showed a
consistent reduction in CVC-associated thrombosis (i.e., 0% in
heparin-bonded catheters vs. 8% in non–heparin-bonded
catheters, respectively).24 Nevertheless, the latter study
failed to show a reduction in CVC-associated thrombosis
using heparin-bonded catheters in 87 infants with congenital
heart disease (VTE in 44.7% with heparin-bonded catheters
vs. 42.5% in those without, respectively).25 Thrombosis
occurs less frequently with internal CVCs, such as the porta-
cath, than external tunneled lines (i.e., Hickman or Broviac
catheter).26 A study of 307 children showed a higher risk of
Seminars in Thrombosis & Hemostasis
CVC-associated thrombosis in children with a peripherally
inserted central catheter than with an external tunneled line,
with a hazard ratio of 8.7 at 6 to 12 months’ follow-up.27 A
greater thrombotic risk of multiple- versus single-lumen
CVCs is probably due to the CVC occupying a greater propor-
tion of the vessel lumen. In terms of site of CVC placement, a
prospective multicenter study of 158 general pediatric
patients requiring central venous access showed the highest
incidence of CVC-associated thrombosis in relation to femo-
ral venous access (odds ratio [OR], 5.41), followed by subcla-
vian venous access (OR, 4.28). Brachial or jugular venous
access was associated with the lowest incidence of thrombo-
sis.28 The CVC insertion technique affected the incidence of
VTE in 85 children with ALL and a CVC placed in the upper
venous system during induction chemotherapy. Percutane-
ous insertion was associated with a higher risk of VTE than
venous cut-down (OR, 3.5).29 The timing of CVC insertion has
been studied in relation to induction therapy for ALL, the
period of treatment that is associated with the highest
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incidence of thrombosis. Some centers delay CVC insertion
until after the end of induction in an attempt to prevent CVC-
associated VTE. There are, however, no recommendations to
support this practice, and studies have failed to confirm a
higher rate of CVC-associated thrombosis in lines placed
early in induction therapy when compared with those placed
later.26,30
Mechanical Thromboprophylaxis
Mechanical approaches to TP include antiembolism stockings
and intermittent pneumatic compression devices. There are
no data on efficacy or safety of either in children or adoles-
cents. Adult data support the use of physical methods as a
means of reducing risk of lower limb DVT in trauma patients
and those with hip fracture, although not the risk of PE or
death.31,32 There is no evidence that mechanical TP reduces
VTE in adult medical inpatients.33 The use of mechanical TP
could be considered in older children and adolescents, of an
appropriate size, who are at higher risk of VTE (i.e., trauma
patients and/or those who have a high risk of bleeding) and
are hence precluded from receiving chemical TP. Contra-
indications to mechanical TP include acute fracture, periph-
eral intravenous access, vascular insufficiency, or poor skin
condition of the extremity on which the stocking/device is to
be worn.34 There are anecdotal reports of ulceration due to
antiembolism stockings that have been incorrectly fitted, and
it is imperative that they are applied by staff who have had the
appropriate training and experience in their use.
Chemical Thromboprophylaxis
Evidence to support the efficacy and safety of chemical TP for
the prevention of childhood thrombosis is also limited.
A summary of the published RCTs is shown in ►Table 3.
Most of the available evidence is in relation to the preven-
tion of CVC-associated thrombosis. Many centers administer a
low-dose infusion of unfractionated heparin (UFH), usually 5
to 10 U/kg/h, to maintain CVC patency in infants in the
intensive care unit (ICU) setting.35 This practice is not sup-
ported by a single-center RCT that evaluated a 10 U/kg/h UFH
 VTE Prevention in Children Biss

infusion against placebo in 90 children younger than 1 year

Abbreviations: ALL, acute lymphoblastic leukemia; CVC, central venous catheter; INR, international normalized ratio; MRI, magnetic resonance imaging; USS, ultrasound scan; VTE, venous thromboembolism.
bin arm versus one major bleed
Two minor bleeds in antithrom-

0 major bleeds in warfarin arm

versus 44.7% in no prophylaxis

53.3% in reviparin-sodium arm
who had had cardiac surgery and showed no difference in rate

versus two major bleeds in no

of CVC-associated thrombosis.36 In the cancer setting, the
PARKAA (Prophylactic Antithrombin Replacement in Kids

in no prophylaxis arm
incidence of bleeding
with Acute Lymphoblastic Leukemia Treated with Asparagi-
No difference in

prophylaxis arm
nase) trial randomized 85 children with ALL being treated

arm, p ¼ 0.3
with asparaginase to receive antithrombin concentrate or no
Safetya

therapy. Fewer of those treated with antithrombin concen-

trate developed asymptomatic thrombosis on screening
(28 vs. 37%), but the study lacked power to confirm efficacy.37
A study of chemical TP with low-dose warfarin (international
28% (7/25) VTE in antithrombin

48% VTE in warfarin arm versus

14.1% (11/78) VTE in reviparin-

15% VTE in heparin arm versus

sodium arm versus 12.5% (10/

arm versus 37% (22/66) in no

normalized ratio [INR], 1.3–1.9) versus no therapy for pre-

36% in no prophylaxis arm,

80) in no prophylaxis arm,

prophylaxis arm, p ¼ 0.43
16% in placebo, p ¼ 0.89

vention of CVC-associated thrombosis in 73 children with

malignancy failed to demonstrate a benefit of warfarin.38
Randomization of 158 children with a recently inserted
CVC to receive prophylactic reviparin-sodium or no prophy-
p ¼ 0.44

p ¼ 0.82 laxis (the PROTEKT study) showed no difference in VTE rate,

Efficacy

although the study was underpowered due to early closure for

slow accrual39 (►Table 3). Anticoagulant therapy with a

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vitamin K antagonist (VKA), with target INR range of 1.4 to
diagnosed by screening Doppler

detected by venogram at day 30

Table 3 Summary of randomized controlled trials of chemical thromboprophylaxis for the prevention of VTE in children

venography or upper body MRI

CVC-associated thrombosis, di-
agnosed by serial Doppler USS

1.8 or 2.0 to 3.0, for the prevention of CVC-associated throm-

Symptomatic VTE or asymp-

CVC-associated jugular vein

bosis in children receiving long-term total parenteral nutri-

at 1 to 4 mo from start of

or time of CVC removal

tion (TPN) has been evaluated in a cross-sectional and a

diagnosed by bilateral

USS at 1, 3, or 6 mo

CVC-associated VTE

prospective study. Both studies involved small numbers of

Primary outcome

children (n ¼ 12 and 8), but supported VKA as a means of

tomatic VTE

thrombosis,

prolonging duration of CVC patency.40,41 A further study in

induction

the setting of long-term TPN showed a cumulative 5-year

thrombosis-free survival of 48% in children without TP versus
93% in those receiving TP, predominantly nadroparin with a
Continuous intravenous heparin

target anti-Xa activity of 0.1 to 0.3 IU/mL, with no increase in

Twice daily 30 to 50 IU/kg revi-
1.3–1.9) versus no prophylaxis
Low-dose warfarin (target INR,
10 units/kg/h versus placebo
Antithrombin infusions once

bleeding. However, this was again a small study of only

during induction versus no

32 children.41 There is, therefore, no evidence to support

parin-sodium versus no

the routine use of chemical TP in children with indwelling

CVCs, although VKA therapy may be useful in children
weekly for 4 wk
Randomization

requiring long-term central venous access for the adminis-

prophylaxis

prophylaxis

tration of TPN.12,23,42
Evidence for the efficacy of chemical TP in adolescents
and children with trauma is limited. A study of 260,078
pediatric trauma patients between 2001 and 2008 showed
subjects
No. of

that prescriptions of enoxaparin for TP doubled over the

All bleeds combined, major and minor, unless otherwise stated.
158
90

85

73

studied time period but without a change in the incidence

of VTE, which remained at around 0.25%.43 A further study
0 to <18 y
Age range

Not stated

of 546 children admitted to a pediatric trauma center

to <18 y
<12 mo

>6 mo

evaluated the effectiveness of instituting a clinical guide-

line for chemical TP in reduction of VTE. The incidence of
VTE was 5.2% prior to introduction of the guideline and 1.8%
CVC in a jugular vein,
from cardiac surgery

thereafter, which was a significant reduction. All VTE in the

Children with newly
asparaginase, with
Children with ALL,

diagnosed cancer,
Infants recovering

recently inserted

latter group occurred in children who did not receive

Children with a
treatment for

LMWH due to a perceived high risk of bleeding. None of

anticipated
Population

CVC in situ
receiving

those treated with LMWH developed VTE. There was no

>6 mo

increase in hemorrhagic complications or overall LMWH

CVC

use, suggesting that children had been appropriately risk

stratified.44
(PARKAA study)37

(PROTEKT trial)39
Schroeder et al 36

Massicotte et al

Use of the direct oral anticoagulants (DOACs) in the

Mitchell et al

Ruud et al 38

prevention and management of childhood thrombosis is

undergoing evaluation in clinical trials.45 The potential
Study

advantages of the DOACs in children include oral administra-

tion, minimal drug and dietary interactions, and, most
a

Seminars in Thrombosis & Hemostasis

VTE Prevention in Children Biss
significantly, predictable pharmacokinetics which are likely
to allow the administration of a weight-adjusted dose with-
out the need for monitoring. Two of the factor Xa inhibitors,
rivaroxaban and apixaban, and a direct thrombin inhibitor,
dabigatran, are being evaluated against standard of care for
the treatment of VTE in children in ongoing phase II/III
studies. In terms of prevention of VTE, a randomized phase
III study of apixaban versus placebo in the prevention of
venous thrombosis in individuals aged 1 to less than 18 years,
who are receiving pegylated asparaginase for treatment of
ALL, is currently recruiting (NCT02369653). A further trial is
evaluating the efficacy and safety of rivaroxaban versus
aspirin for prevention of thrombosis in children aged 2 to
8 years with a Fontan circulation. A potential disadvantage to
the use of the DOACs is the lack of licensed reversal agents for
children with significant bleeding, an urgent need for surgery,
or overdose, although idarucizumab has recently been
approved for the reversal of dabigatran in adults and agents
to reverse the factor Xa inhibitors are currently in phase III
trials in the adult population.45
Potential Adverse Consequences of Thromboprophylaxis
The use of mechanical TP may be complicated by discomfort,
lack of tolerance, or skin ulceration. The major concern in
relation to the use of chemical TP is bleeding. There are few
reports of the frequency of bleeding in a pediatric population.
Two single-center studies identified a major bleed rate of 2.2
and 4.3% in children and adolescents receiving LMWH TP. In a
study by Cavo et al, of the 650 individuals aged 18 years who
received LMWH TP, the majority were trauma patients which
made it difficult to determine whether bleeding was due to
LMWH or the injury itself. In addition, those who had
bleeding were almost all receiving what would have been
considered a therapeutic dose of enoxaparin.46 A study by
Stem et al evaluated 89 individuals with a mean age of 16.6
years (range, 7–27 years): the two major bleeding events
occurred in individuals who had undergone major orthopedic
surgery with none in the remaining patients.47 These rates
are greater than the <1% major bleed rate that is reported in
adults receiving chemical TP following a general surgical
procedure.48
Prevention of Venous Thromboembolism in
Hospitalized Children: Current Practice
Detailed evaluation of thrombotic risk factors in hospital-
ized children has been largely limited to the trauma setting.
The incidence of VTE in pediatric trauma inpatients is low
at 0.08 to 0.27%,43,49–51 although one study reported a rate
of 6.2% in those admitted to an ICU.52 Among a cohort of
58,716 pediatric trauma patients, VTE occurred in 45
(0.08%) and was associated with older age (10 years)
and a higher injury severity score (ISS), in particular with
major vascular injury, pelvic fracture, and spinal cord
injury. The presence of a CVC was an additional indepen-
dent risk factor.51 Other studies have identified similar risk
factors for thrombosis in pediatric trauma patients, includ-
ing older age, CVC, higher ISS, reduced Glasgow coma score,
pelvic fracture, and ICU admission.43,49,50
Seminars in Thrombosis & Hemostasis
Surveys of practice among pediatric intensivists have
identified marked variation in practice, although most agree
that TP is not necessary in children <12 years of age. In a
survey of members of the Pediatric Orthopaedic Society of
North America (POSNA) in 2013, only 16% had a TP protocol
for pediatric patients, 23% had never used mechanical TP, and
45% had never used chemical TP in children.53 A survey of
pediatric intensivists in North America identified a higher
likelihood of prescribing LMWH TP to adolescents (when
compared with younger children and infants) and to those
with hypercoagulability, previous VTE, or cavopulmonary
anastomosis, despite a considerable variation in practice. In
this study, the presence of a CVC did not affect the likelihood
of prescribing LMWH.54 A multinational cross-sectional
study by the same group, which surveyed children in pediat-
ric ICUs in four continents, identified that 12.4% of children
were receiving chemical TP (low-dose infusion of UFH, aspi-
rin, or LMWH) and 23.8% of over 8-year-olds were using
mechanical TP. The use of chemical TP was highest at the
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extremes of age, whereas the use of mechanical TP rose with
increasing age beyond 8 years. Again, a marked variation in
practice was observed between centers.55 A further study of
260,078 pediatric trauma patients in the United States iden-
tified an increasing use of enoxaparin for TP between the
years of 2001 and 2008, rising from 0.75 to 1.54%. Use of
enoxaparin was highest for older children (>10 years) and
those with pelvic fractures, a CVC, and ICU admission. The rate
of VTE diagnosis did not change during this time period.43
Recent studies have focused on standardizing the assessment
of thrombotic risk in pediatric inpatients by development of risk
assessment models (summarized in ►Table 4). A single-center
study identified CVC, infection, and length of stay as the most
significant risk factors for VTE in noncritically ill hospitalized
children. A weighted risk score was proposed, in which the most
significant factor (i.e., the presence of a CVC) was allocated the
greatest number of points, the total score being used to deter-
mine thromboprophylactic strategy.56 This group has also
devised a score for critically ill children admitted to an ICU but
not undergoing cardiothoracic surgery, in which the same risk
factors were identified.57 Neither of these scores has been
validated and could hence be criticized for their lack of ability
to distinguish the different age groups among which the risk
factors for VTE are known to differ. In addition, individuals up to
the age of 21 years were included in these studies. A risk
prediction tool developed by Sharathkumar et al, the Peds-
Clot clinical Decision Rule (PCDR), was developed from a deriva-
tion cohort which identified positive bloodstream infection,
CVC, direct admission to ICU, hospitalization for 7 days,
immobilization for >72 hours, and use of a COCP as the most
important predisposing factors for VTE. Following validation
against a separate cohort, it is suggested that this tool may be
used to stratify VTE risk in hospitalized children but, again, it
does not distinguish between age groups and included individ-
uals up to the age of 20 years.58 All three risk models place
significant importance on the presence of a CVC as a risk factor
for thrombosis. However, the efficacy of chemical TP to prevent
CVC-associated thrombosis has not been confirmed,12 and this is
a further criticism of these models. Three further publications
 VTE Prevention in Children Biss

Table 4 Published risk assessment models for thrombotic risk in hospitalized children

Population Proposed risk assessment Predictive value of Proposed action

modela model
Atchison et al56 Noncritically ill hos- CVC: 5 points 8 points: 12.5% incidence 8 points: chemical TP
pitalized children, 0 Infection: 2 points of VTE 7 points: mechanical TPb
to 21 y LOS  4 days: 1 point 7 points: 1.1% incidence  6 points: no intervention
of VTE
 6 points: 0.1% inci-
dence of VTE
Arlikar et al57 Critically ill children CVC: 8 points 15 points: 8.8% incidence 15 points: chemical TP
not having cardio- LOS  4 d: 6 points of VTE 7 to 14 points:
thoracic surgery,c Infection: 1 point 7 to 14 points: 1.3% mechanical TPb
0–21 y incidence of VTE <7 points: no intervention
<7 points: 0.03%
incidence of VTE
Sharathkumar Hospitalized chil- Immobilization for  3 points, 70% Not specified
et al58 dren, 0 to <20 y >72 h: 3 points sensitivity,
LOS  7 d: 2 points 80% specificity
Birth control pill: 2 points
CVC: 1 point

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Positive blood
culture: 1 point
ICU admission: 1 point

Abbreviations: CVC, central venous catheter; ICU, intensive care unit; LOS, length of stay; TP, thromboprophylaxis; VTE, venous thromboembolism.
a
Points are summated to generate a total score.
b
Pneumatic compression device in children of appropriate size.
c
Admitted to ICU.

have each reported on a policy within a single institution, all of
which have focused the need for TP on postpubertal children,
highlighting the importance of general measures to reduce VTE
risk, reserving chemical TP for those with significant immobility
in addition to multiple risk factors.34,59,60 None of these
approaches have been validated. Specific to the setting of ALL
in children, an international multicenter study validated a model
that incorporated a combination of risk factors for treatment-
related thrombosis in children treated on three separate proto-
cols which included asparaginase treatment, steroid therapy,
CVC, and the presence of a thrombophilic abnormality. A high
risk group could be identified, with an incidence of symptomatic
VTE of 64.7% compared with 2.5% in the low-risk group. This
scoring system is limited to children with ALL, and is also likely to
be of less value in risk stratification of patients treated on the
same protocol.61
Prevention of Venous Thromboembolism in Children
Who Are Outpatients: Current Practice
There are many nonhospitalized children who are at a
potentially increased risk of thrombosis, due to either a
temporary risk factor or a long-term underlying prothrom-
botic condition. These include individuals with malignancy
who are undergoing ambulatory chemotherapy, those with
active inflammatory bowel disease (IBD) or nephrotic syn-
drome, and those who have reduced mobility following
recent lower limb surgery or trauma. The presence of a CVC
may further increase the risk. The role of TP in these settings
has not been evaluated, and decisions are usually made on a
case-by-case basis according to the assessment of thrombotic
risk factors balanced against the risk of bleeding.
Secondary Prophylaxis for Thrombosis in Childhood
Duration of anticoagulant therapy for VTE may be extended
beyond the recommended interval in individuals who have
ongoing risk factors for thrombosis, such as malignancy or the
presence of a CVC. Those who have prothrombotic relapsing-
remitting conditions, such as IBD or nephrotic syndrome, may
receive chemical TP during episodes of relapse.
Following a defined period of anticoagulant therapy for
VTE in childhood or adolescence, it may be appropriate to
provide TP for subsequent periods of increased thrombotic
risk, such as a surgical procedure, pregnancy, a long journey
(e.g., a flight of >6 hours’ duration), or a significant period of
immobility. Simple measures to prevent VTE should be taken
(as detailed above). In the absence of published guidance,
decisions regarding mechanical or chemical TP are made on
the basis of an individual risk–benefit analysis. Estrogen-
containing contraceptives are generally avoided in females
who have had a prior thrombotic event.
Conclusion
Although childhood thrombosis remains uncommon, the
incidence in hospitalized children is increasing over time.
This has resulted in a greater interest in the development of
preventative strategies, particularly for adolescents who have
the highest incidence of thrombosis after infancy. There is
reasonable evidence from retrospective studies that it is
possible to identify thrombotic risk factors in children—the
presence of a CVC, significant immobility, and older age being
the most important. There is no evidence to support the use of
mechanical TP in children. There is also a lack of evidence to

Seminars in Thrombosis & Hemostasis

VTE Prevention in Children Biss
support the safety and efficacy of chemical TP in either
adolescents or younger children—the low incidence of VTE
in hospitalized children not only means that it is challenging
to conduct adequately powered trials but also highlights the
importance of minimizing the risk of bleeding and other
complications due to an intervention. Any strategy for risk
assessment for thrombosis, with the provision of TP for
children who are felt to be at sufficient risk, will be compli-
cated by differences in the incidence of VTE and the nature of
thrombotic risk factors between age groups. Further research
is required to evaluate the safety and efficacy of TP, both
mechanical and chemical, prior to routine use in children.
Notably, interesting data will expectedly emerge from the
ongoing studies on DOACs for preventing thrombosis in
pediatric populations.
Acknowledgment
The author would like to acknowledge LEO Pharma UK for
providing an educational grant to support the develop-
ment of the Newcastle upon Tyne Hospitals NHS Founda-
tion Trust pediatric thrombosis registry.
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