REVIEW ARTICLE

Acute pulmonary embolism in childhood

C. Heleen Van Ommen
*
, Marjolein Peters
Department of Pediatric Hematology, Emma Childrens Hospital AMC, PO Box 22700, 1100 DE Amsterdam,
The Netherlands
Received 4 January 2005; received in revised form 11 March 2005; accepted 19 May 2005
Available online 29 June 2005
Abstract Pulmonary embolism is an uncommon, but potentially fatal disease in
children. Most children with pulmonary embolism have underlying clinical condi-
tions, of which the presence of a central venous catheter is the most frequent. The
clinical presentation is often subtle, or masked by the underlying clinical condition.
Diagnostic as well as therapeutic strategies for pulmonary embolism in children are
mostly extrapolated from studies in adults. Pulmonary angiography is still the gold
standard in diagnosing pulmonary embolism, but several other radiographic tests can
be used to diagnose pulmonary embolism, including ventilation-perfusion lung
scanning, helical computed tomography, magnetic resonance imaging and echocar-
diography. The choice of treatment depends on the clinical presentation of the
patient. Anticoagulation is the mainstay of therapy for children with pulmonary
embolism. However, thrombolytic therapy can be considered for patients with
hemodynamic instability. The outcome of pediatric pulmonary embolism is uncertain
and needs to be studied.
D 2005 Elsevier Ltd. All rights reserved.
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2005.05.013
Abbreviations: CT, Computed tomography; MR, Magnetic resonance; PIOPED, Prospective Investigation of Pulmonary Embolism
Diagnosis; APTT, Activated partial thromboplastin time; HIT, Heparin-induced thrombocytopenia; INR, International normalized ratio;
mSv, MilliSievert; tPA, Tissue plasminogen activator.
* Corresponding author. Tel.: +31 20 566 2727; fax: +31 20 691 7735.
E-mail address: c.h.vanommen@amc.uva.nl (C.H. Van Ommen).
KEYWORDS
Pulmonary embolism;
Child;
Incidence;
Diagnosis;
Therapy;
Outcome
Thrombosis Research (2006) 118, 1325
intl.elsevierhealth.com/journals/thre
Clinical diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Radiographic diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Pulmonary angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Ventilation-perfusion lung scanning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Helical computed tomography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Magnetic resonance angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Unfractionated heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Low-molecular-weight heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Vitamin K antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
New anticoagulant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Thrombolytic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Embolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Introduction
The first report of pulmonary embolism in child-
hood was made in 1861 by Stevenson and Stevenson
[1]. Since that time, mostly case reports and case
series have been published about this potentially
fatal disease in childhood. Pulmonary embolism is a
rare disorder in children, but the incidence will
probably rise as result of improvements in pediatric
care, especially the use of central venous cathe-
ters. This article reviews the current knowledge of
the pathophysiology, incidence, diagnosis, treat-
ment and outcome of pulmonary embolism in
children.
Pathophysiology
The effects of pulmonary embolism depend on the
extent to which it obstructs the pulmonary circu-
lation, coexistent cardiopulmonary disease, and
vaso-active mediators [2]. Patients with pre-exist-
ing cardiopulmonary disease will be more sensitive
to the effects of pulmonary embolism than previous
healthy patients. Some vaso-active mediators, such
as serotonin or thromboxane from activated plate-
lets, can probably produce vasospasm in non-
embolised parts of the lung contributing to pulmo-
nary hypertension [3].
If an embolus suddenly obstructs less than 50% of
the pulmonary circulation, symptoms do not often
occur [4]. For example, more than 50% of all adult
patients with deep-vein thrombosis, but without
symptoms and signs of pulmonary embolism, have
abnormal perfusion lung scans [5,6]. Usually, pul-
monary artery mean pressure remains low and as
the right ventricle is not compromised, cardiac
output and systemic arterial pressure are well
maintained. If symptoms do occur, the most
common symptoms are dyspnoea and pleuritic
chest pain [7,8]. However, in children with coexis-
tent cardiopulmonary disease, such as pulmonary
hypertension or congenital cardiac defects treated
with Fontan surgery, even small emboli may cause
severe symptoms, including cardiac failure.
Acute pulmonary embolism, obstructing more
than 50% of the pulmonary circulation, increases
right ventricular afterload. As the thin-walled right
ventricle is not used to work against a sudden
obstruction, right ventricular dilatation occurs and
the right ventricular and pulmonary artery systolic
pressure rise. Dilatation leads to tricuspid regurgi-
tation, and may compromise the filling of the left
ventricle. In addition, right ventricular enlarge-
ment causes a leftward shift of the interventricular
septum, resulting in an impaired left ventricular
filling during diastole. Cardiac output falls and the
patient becomes hypotensive [9]. Furthermore,
increased right ventricular pressure compresses
the right coronary artery, decreases subendocardial
perfusion, and as a consequence, cardiac ischemia
may develop.
In patients with acute massive pulmonary em-
bolism, arterial hypoxemia is the result of mis-
matching of ventilation and perfusion, shunting and
low pressure of oxygen in venous blood [2,4].
Mismatching of ventilation and perfusion is the
most common cause of hypoxemia. Perfusion of the
normal lung areas is relatively increased. Ventila-
tion of these areas may be insufficient to oxygenate
fully the extra blood flow. Shunting occurs when
venous blood comes into the systemic arterial
circulation without getting oxygenated in the lung.
C.H. Van Ommen, M. Peters 14
In patients with a patent foramen ovale, increased
right atrial pressure may open the foramen and
cause intracardiac right-to-left shunting. Shunting
through the lungs may occur in areas of collapse
and infarction, which are not ventilated but still
have some blood flow. Furthermore, venous blood
with a low pressure of oxygen caused by low
cardiac output may also add to arterial hypoxemia,
as it cannot be fully saturated in the over-perfused
areas of the lungs.
Incidence
In a large retrospective review study, the overall
average age- and sex-adjusted annual incidence of
pulmonary embolism in the United States was
estimated to be 69 per 100,000 individuals [10].
The incidence increased markedly with age. While
the annual pulmonary embolism incidence rate for
females and males younger than 15 years was 0 and
0.3 per 100,000, respectively, the rate increased to
690 and 758 per 100,000 for females and males
above 85 years. Hence, the incidence of pulmonary
embolism is decreased in children compared to
adults.
In prospective Canadian and Dutch pediatric
registries, incidence rates of pulmonary embolism
were 0.86 per 10,000 pediatric hospital admissions
and 0.14 per 100,000 children (ages 0 to 18 years)
annually [11,12]. These incidences are probably an
underestimation. Pulmonary embolism frequently
is clinically silent or presents with symptoms that
can be explained by underlying diseases. Buck et al.
showed that in children with clinically significant
pulmonary embolism, 50% had documented signs
and symptoms of embolism. The clinical diagnosis
was considered in only 15% of these children [13].
The incidence of pulmonary embolism will probably
rise as result of increased survival of children with
chronic diseases and increased use of central
venous catheters. Future registry studies are need-
ed to investigate whether this hypothesis is true.
In selected pediatric patient populations, the
incidences of pulmonary embolism varied between
less than 1% and 40%, reflecting different suspicion
index, diagnostic tests and underlying clinical
conditions. (Table 1) Pulmonary embolism is not
often recognized clinically in pediatric trauma
patients (0.0069%) [14]. However, 40% of children
with nephrotic syndrome and elevated plasma D-
dimer were diagnosed with pulmonary embolism
Table 1 Incidence of pulmonary embolism in childhood
A. General autopsy studies
Author Year Study design n Age (year) Diagnostic method Incidence
Emery [95] 1962 Retrospective 2,000 07 Autopsy 1.25%
Jones [96] 1966 Retrospective 10,000 016 Autopsy 0.73%
Buck [13] 1981 Retrospective 019 Autopsy 4.2%
Byard et al. [97] 1990 Retrospective 17,500 013 Autopsy 0.05%
B. In selected underlying clinical conditions
Author Year Study design n Clinical condition Diagnostic method Incidence
Hoyer et al. [98] 1986 Retrospective 26 Asymptomatic NS V/Q 27%
Desai et al. [99] 1989 Retrospective 178 Fatal burns Autopsy 1.7%
Hsu et al. [100] 1991 Cross-sectional 62 Pre-heart transplantation V/Q, PA 9.7%
Marraro et al. [101] 1991 Prospective 205 Leukemia Perfusion scan, PA 3.4%
Uderzo et al. [102] 1993 Retrospective 67 BMT for leukemia V/Q, PA 4.5%
Uderzo et al. [103] 1993 Prospective 452 Leukemia and respiratory
failure
Perfusion scan, PA 2.7%
McBride et al. [14] 1994 Retrospective 28,692 Trauma Clinical 0.0069%
Dollery et al. [104] 1994 Cross-sectional 34 Long-term TPN V/Q, CRX 32%
Andrew et al. [11] 1994 Prospective 137 Venous thrombotic event V/Q 16%
Nuss et al. [105] 1995 Retrospective 61 Thrombotic event V/Q 20%
Derish et al. [17] 1995 Retrospective 21 Intensive care unit deaths Autopsy 24%
Massicotte et al. [18] 1998 Prospective 244 Catheter-related thrombosis V/Q 16%
Huang et al. [15] 2000 Prospective 20 NS and elevated D-dimer V/Q, CRX 40%
Monagle et al. [106] 2000 Prospective 405 Venous thrombosis V/Q 17%
van Ommen et al. [12] 2001 Prospective 100 Venous thrombosis V/Q 10%
Levy et al. [107] 2003 Retrospective 24 SLE with positive LAC V/Q 8.3%
Abbreviations: n number, NS nephrotic syndrome, V/Q ventilation-perfusion lung scan, PA pulmonary angiography, BMT bone
marrow transplantation, TPN total parenteral nutrition, CRX chest radiograph, SLE systemic lupus erythematosus, LAC lupus
anticoagulants.
Acute pulmonary embolism in childhood 15
after performing ventilation-perfusion scans and
chest radiographs routinely [15].
Diagnosis
Clinical diagnosis
The clinical diagnosis of pulmonary embolism is
confounded by a clinical presentation that may be
very subtle, mimics many other diseases or is
obscured by an underlying clinical condition. In-
creased clinical suspicion is needed to prevent
delay in diagnosis. In teenagers, pleuritic chest
pain appeared to be the most common presenting
complain, mentioned in 84% of the patients [7].
Other complaints included dyspnoea (58%), cough
(47%), and hemoptysis (32%). Presenting signs in
teenagers were arterial hypoxemia, physical signs
of a deep-vein thrombosis of the lower extremity,
abnormal chest radiograph, tachypnea and fever.
Unexplained persistent tachypnea can be an im-
portant indication of pulmonary embolism in pedi-
atric patients of all age-categories [16]. In
children, receiving artificial ventilation, an in-
crease in oxygen requirements, may be a sign of
pulmonary embolism [17]. Other signs, which have
been reported to occur in children with acute
pulmonary embolism, include acute right heart
failure, cyanosis, hypotension, arrhythmia, pallor,
syncope, or sudden death.
Based on these signs and symptoms, however, it
is impossible to differentiate those patients with
pulmonary embolism from those without [7,8]. The
presence of one or more risk factors may lower the
threshold for consideration of a diagnostic evalua-
tion. Registry studies showed that more than 95% of
children with venous thromboembolic disease have
at least one underlying clinical condition [11,12].
Central venous catheters are the most frequent
clinical risk factor. Catheter-related venous throm-
bi are an important source of pulmonary embolism
in children [17]. In a prospective registry study of
children with catheter-related venous thrombosis,
the incidence of pulmonary embolism was about
16% [18]. This was probably an underestimation, as
most children did not undergo investigation for
pulmonary embolism. Other underlying clinical
conditions associated with pediatric venous throm-
boembolic disease are congenital heart disease,
infection, surgery, malignancy, kidney disease,
trauma, immobility, hypovolemia, systemic lupus
erythematosus, obesity, sickle cell disease, the
presence of lupus anticoagulants, ventriculo-atrial
shunts and medication, including estrogens and L-
asparaginase [19]. The role of congenital prothrom-
botic disorders in paediatric pulmonary embolism
remains uncertain, and is discussed in detail
elsewhere in this journal edition. In adults, the
combination of clinical signs and symptoms and the
presence of risk factors is used to assess the pre-
test probability of pulmonary embolism. During the
last decade, several sets of prediction rules were
published, which varied in complexity [2023].
These prediction rules classify patients in three
clinical probability categories: low, intermediate
and high. The prevalence of pulmonary embolism in
the low, intermediate and high probability-group is
expected to be V10%, about 25% and z60%,
respectively [24]. The combined use of the clinical
probability and the results of one or more non-
invasive radiographic tests improve the precision of
diagnosis for pulmonary embolism, as compared
with either assessment alone. In children, clinical
prediction rules have not yet been validated.
Radiographic diagnosis
As the clinical diagnosis lacks sensitivity and
specificity, objective diagnostic imaging is neces-
sary to establish or to rule out the presence of
pulmonary embolism. Diagnostic imaging includes
pulmonary angiography, ventilation-perfusion lung
scanning, computed tomography (CT), magnetic
resonance (MR) imaging and echocardiography. As
there are no studies determining the sensitivity and
specificity of these tests in children, recommenda-
tions for the use and interpretation of these tests
are extrapolated from adult data. After diagnosis
and subsequent treatment of pulmonary embolism,
a follow-up imaging study can be used to establish a
new baseline for subsequent episodes of suspected
pulmonary embolism and to assess the efficacy of
anticoagulation treatment.
An electrocardiogram, a chest radiograph, and
arterial blood gases are useful in ruling out other
diseases, but these tests cannot be relied on to
confirm or exclude a diagnosis of pulmonary
embolism [25]. They may show many non-specific
abnormalities or may be completely normal even in
the presence of a significant pulmonary embolism.
The measurement of the breakdown product of
cross-linked fibrin (D-dimer) in plasma is a sensitive
but non-specific test for suspected venous throm-
bosis. In nearly all patients with pulmonary embo-
lism, the levels of D-dimer are elevated. However,
elevated levels are also present in patients with
underlying clinical conditions, such as trauma,
surgery, infection, and malignancy [26]. In adults,
studies showed that it is safe to exclude pulmonary
embolism in patients with a normal D-dimer level
C.H. Van Ommen, M. Peters 16
and a low clinical suspicion of embolism [22,27].
Such management studies have not been performed
in children. As most pediatric patients with pulmo-
nary embolism have underlying clinical conditions,
the usefulness of D-dimer testing seems to be less
likely in children than in adults.
Pulmonary angiography
Pulmonary angiography is the gold standard for the
diagnosis of pulmonary embolism. Direct angio-
graphic signs for pulmonary embolism are contrast
filling defects or non-filling of pulmonary arteries
with abrupt termination of the contrast agent. This
method has its limitations. It is invasive, expensive,
and unavailable in some centers, and requires
expertise in performance and interpretation, espe-
cially when performed in children. Furthermore, it
has associated risks. In the Prospective Investiga-
tion of Pulmonary Embolism Diagnosis (PIOPED)
study, death occurred in 5 of the 1111 adult
patients (0.5%), and the overall major complication
rate was 1% [28]. Relative contraindications include
renal insufficiency, significant bleeding risk, preg-
nancy, and known right heart thrombus [4]. The
diagnostic validity of angiography appeared to be
high. Definitive diagnosis was established in 1064 of
1111 patients (96%) by angiography. Angiograms
were non-diagnostic in 35 of 1111 patients (3%),
and studies were incomplete in 12 of the 1111 (1%)
patients [28]. Nevertheless, many clinicians are
reluctant to use pulmonary angiography and prefer
less invasive tests.
Ventilation-perfusion lung scanning
Ventilation-perfusion lung scanning has been the
usual initial diagnostic test in adults and children
with suspected pulmonary embolism for more than
3 decades. It is an indirect method and visualizes
effects of thrombosis on perfusion and ventilation.
This test is easy to perform, even in small children
[29]. However, some underlying diseases may
hamper the interpretation of the scans. In children
with congenital heart disease, the blood flow may
be imbalanced between both lungs, or within each
lung, influencing the perfusion scan results [30,31].
Furthermore, in children with left-to-right shunts,
the distribution of the isotope may be variable as
result of mixture of arterial blood in the pulmonary
artery.
It is a valuable test when the results are
definitive. A normal perfusion scan rules out the
diagnosis of a clinically relevant recent pulmonary
embolism; and if a patient has a high probability
ventilation-perfusion lung scan (mismatched perfu-
sion defects that are segmental or larger), there is
a more than 85% chance that the patient has
pulmonary embolism. However, the majority of
patients with clinically suspected pulmonary em-
bolism who undergo lung scanning have low or
intermediate probability scans which are non-
diagnostic, as shown by the PIOPED investigators
[32]. In these patients, additional diagnostic test-
ing is needed.
Helical computed tomography
Helical (spiral) CT is becoming the first choice
diagnostic test for pulmonary embolism in many
centres. It makes a volumetric image of the chest
by rotating the detector around the patient. A
contrast agent that is injected in a peripheral
vessel visualizes the pulmonary vessels. Pulmonary
embolism is seen as partial or complete filling
defects in pulmonary arteries. Besides visualisation
of the emboli, it can also identify other chest
disorders, which should be differentiated from
pulmonary embolism. Another advantage is that it
can be performed quickly in critically ill patients.
Important disadvantages are the use of iodinated
contrast media and, especially in children, the
large radiation exposure. In growing children, the
thyroid gland, breast tissue, and gonads have an
increased sensitivity to radiation [33]. Further-
more, small children receive a greater radiation
dose than larger children or adults from the same
CT settings. Although the radiation dose is less for
children than for adults, the organs are even
smaller and therefore the actual organ dose is
higher. In addition, children have a longer lifetime
in which cancer may occur. Finally, there is still a
lack of size-based adjustments in CT technique.
The radiation dose of one CT examination ranges
from b1.0 milliSievert (mSv) to N27.0 mSv. Follow-
up of atomic bomb survivors showed that there is a
significant increased risk of fatal cancer from low-
dose radiation in the range of 50 to 100 mSv, and
possibly 10 to 50 mSv. It has been estimated that
the percentage increase in the cancer mortality
rate over the natural background is about 0.35% as
result of CT [34]. Strategies to minimize radiation
exposure include breast shielding, limited exami-
nation to region in question, and settings based on
indication, size of the child and body region
scanned.
In adults, several studies assessed the sensitivity
and specificity of the helical CT for pulmonary
embolism, which shown overall sensitivities ranging
from 60% to 100%, and specificities ranging from 81%
to 100% [35,36]. The helical CT seemed especially
less sensitive for detection of subsegmental emboli.
At present, these subsegmental emboli cannot be
classified as clinically unimportant. Thus, a normal
helical CT reduces the probability of pulmonary
Acute pulmonary embolism in childhood 17
embolism, but it does not exclude the diagnosis.
However, recent management studies in adults
suggest that anticoagulant therapy could be safely
withheld on the basis of negative results of helical
CT in patients with adequate cardiopulmonary
reserve [3740].
A recent advance in helical CT technology was
the replacement of single-detector helical CT by
multi-detector helical CT. Advantages of the multi-
detector CT are shorter imaging time, leading to
less respiratory motion artefacts, and thinner
imaging sections, resulting in greater interobserver
agreement and improvement in peripheral pulmo-
nary arterial visualisation [41,42].
Magnetic resonance angiography
MR angiography offers an important advantage over
helical CT: the absence of radiation exposure that is
especially relevant to pediatric patients. Further-
more, it uses safer contrast agents. In addition, it
can potentially be used to image the upper and
central venous system, as well as the pulmonary
arteries during the same examination. This might be
an advantage for children, as venous thrombi are
usually located in the upper or central venous
system as result of insertion of central venous
catheters. MR angiography, however, is more ex-
pensive, less available, has a long examination
time, requires more technical expertise to perform
and to interpret, does not provide optimal image
quality in patients who are unable to hold their
breath and may need anesthesia in small children.
Like helical CT, it can reveal an alternative diagnosis
that explains patients signs and symptoms.
A recent review showed that the diagnostic
accuracy of contrast-enhanced MR angiography for
detection of pulmonary embolism in adult patients
is similar to helical CT: MR angiography is sensitive
and specific for segmental and larger pulmonary
embolism, whereas the diagnosis of subsegmental
pulmonary embolism is more difficult [43]. Until
now, clinical management studies using MR angiog-
raphy are lacking, making the role of this test in the
evaluation of patients with suspected pulmonary
embolism uncertain.
MR imaging technology continues to improve.
Real-time MR imaging allows visualisation of the
pulmonary vasculature without the need for breath
holding or contrast media application, an attractive
method for detection of pulmonary embolism in
pediatric patients [44]. Very recently, the feasibil-
ity and diagnostic value of this method for the
diagnosis of acute pulmonary embolism were eval-
uated in 39 adult patients, showing sufficient
sensitivity and specificity, compared with MR
angiography and perfusion scanning, to allow the
diagnosis of acute central, lobar, and segmental
pulmonary embolism [45].
Echocardiography
Echocardiography may directly visualize thrombi in
the heart or central pulmonary arteries. Indirect
signs of pulmonary embolism are echocardiographic
abnormalities such as right ventricular dilatation
and hypokinesis, abnormal motion of the interven-
tricular septum, tricuspid valve regurgitation, and
lack of collapse of the inferior vena cava during
inspiration [46]. In adults, these indirect indices
have a sensitivity and specificity of about 50% and
90%, respectively [24]. Although echocardiography
is a safe and convenient imaging technique, it is not
suitable as a routine test to diagnose suspected
pulmonary embolism. Nevertheless, echocardiogra-
phy can be useful in differentiating between
massive pulmonary embolism and other causes of
cardiovascular instability in the critically ill patient.
In addition, studies performed in adults showed that
echocardiography can identify patients with pulmo-
nary embolism who may have a poor prognosis [47
51]. Prognostic indicators of a poor outcome after
pulmonary embolism are moderate or severe right
ventricular dysfunction, persistent pulmonary hy-
pertension, a patent foramen ovale and free-
floating right heart thrombi. These patients might
be candidates for more aggressive antithrombotic
therapy, such as thrombolysis and embolectomy.
Treatment
Generally, treatment of pediatric patients with
pulmonary embolism has to be guided by the risks
associated with the individual clinical condition of
the patient. Patients with stable hemodynamics
will receive anticoagulation to prevent extension of
the thrombus and the development of late compli-
cations, such as recurrences. In patients with
unstable hemodynamical condition, such as shock,
quick reduction of the thrombus mass by more
aggressive therapy, such as thrombolysis, might
improve right ventricular function.
In children, large clinical trials concerning
antithrombotic therapy are lacking. Therefore,
children are treated according to recommendations
based on small pediatric studies and clinical trials
in adult populations (Table 2).
Unfractionated heparin
The most frequently used anticoagulant for the
initial treatment of pediatric venous thromboem-
C.H. Van Ommen, M. Peters 18
bolic disease is unfractionated heparin [11,12].
Unfractionated heparin is a glycosaminoglycan
consisting of chains of alternating residues of D-
glucosamine and uronic acid, either glucuronic acid
or iduronic acid. Its molecular weight ranges from
about 3000 to 30,000 d, with a mean molecular
weight of 15,000 d (approximately 45 monosac-
charides chains) [52]. It functions as an antithrom-
botic agent by binding to and potentiating the
activity of antithrombin. A unique pentasaccharide
sequence, which is randomly distributed along the
heparin chains, is responsible for the interaction
with antithrombin. The heparinantithrombin
complex inactivates coagulation factors, especially
thrombin and factor Xa.
Disadvantages of unfractionated heparin are
caused by the charge-dependent binding properties
of heparin to plasma proteins, endothelial cells,
and macrophages. Binding to plasma proteins
reduces the anticoagulant activity of heparin and
makes the anticoagulant response to heparin
among patients unpredictable due to the variability
of plasma levels of heparin-binding proteins [52].
Therefore, careful laboratory monitoring of the
activated partial thromboplastin time (APTT) is
very important. The recommended therapeutic
range is an APTT that corresponds to a heparin
level by protamine titration of 0.2 to 0.4 U/mL, or
an anti-factor Xa level of 0.3 to 0.7 U/mL [53].
The most common complication of unfractio-
nated heparin is bleeding. A prospective study
reported bleeding complications in about 2% of
the pediatric patients [54]. However, many children
were treated sub optimally. In critically ill patients,
the incidence of bleeding appears to be higher: a
recent review reported the occurrence of bleeding
in 18% of mostly post operation cardiac patients
[55]. Heparin-induced thrombocytopenia (HIT) may
be a serious complication of unfractionated heparin
therapy, requiring frequent monitoring of platelets.
Binding of heparin to osteoblasts causes osteopenia
in patients with long-term administration of hepa-
rin. Although this complication is rarely reported in
children, it is recommended to avoid long-term
unfractionated heparin therapy when other antic-
oagulants are available [55].
Low-molecular-weight heparin
The low-molecular-weight heparins are derived
from heparin by chemical or enzymatic polymeri-
zation. They have a mean molecular weight of 4500
to 5000 d and saccharide chain lengths of 8 to 16
monosaccharide units. Like unfractionated heparin,
the anticoagulant activity of LMWHs results from
catalyzing the ability of antithrombin to inactivate
coagulation factors. The main difference between
LMWHs and unfractionated heparin is in the inhib-
itory activity against thrombin and factor Xa. To
inhibit thrombin, heparin has to have at least 18
monosaccharide units, which are not required for
its anti-Xa activity. As a consequence, whereas
heparin has equal activity against factor Xa and
thrombin, LMWHs have greater activity against
factor Xa [56]. Therefore, monitoring of LMWH
should be done by using the anti-factor Xa assay;
the therapeutic anti-factor Xa level is 0.51.0 U/
mL [53].
Table 2 Treatment of pulmonary embolism [53,108]
Drug Dosage Monitoring
Unfractionated heparin Loading dose: 75 U/kg in 10 min iv.
Maintenance: 28 U/kg/h iv (b1 year),
20 U/kg/h iv (N1 year)
APTT, platelets
LMWHs
Enoxaparin b2 months: 1.5 mg/kg/dose each 12 h sc Anti-factor Xa level, platelets
N2 months: 1.0 mg/kg/dose each 12 h sc
Reviparin b5 kg: 150 U/kg/dose each 12 h sc
N5 kg: 100 U/kg/dose each 12 h sc
Vitamin K antagonists
Warfarin Loading dose: 0.2 mg/kg. Maintenance:
individual dosage adjusted to INR 2.03.0
INR
Acenocoumarol
Phenprocoumon
Thrombolytic therapy
tPA 0.10.6 mg/kg/h iv for 6 h Fibrinogen, plasminogen, D-dimer,
platelets, APTT, PT
Abbreviations: APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, LMWH low-
molecular-weight heparin, iv intravenously, sc subcutaneously.
Acute pulmonary embolism in childhood 19
Compared to unfractionated heparin, LMWHs
have a reduced capacity to bind to plasma proteins,
endothelial cells and macrophages. Therefore, they
have a greater bioavailability, a more predictable
anticoagulant response, and longer half-life.
Hence, LMWHs can be given subcutaneously, once
or twice daily, with limited laboratory monitoring,
which allows outpatient management. Further-
more, as result of reduced binding to platelet
factor 4 or osteoblasts, the risk of HIT and
osteopenia is decreased.
In adults, large clinical trials proved that LMWHs
are at least as safe and effective as unfractionated
heparin for the initial therapy of deep-vein throm-
bosis and pulmonary embolism [57,58]. In children,
only one randomized controlled trial (REVIVE) was
performed to assess the efficacy and safety of
LMWH (reviparin) compared to heparin and couma-
din for the treatment of venous thromboembolic
disease [59]. At 6 months, the risk of recurrent
venous thrombosis was 12.5%, identical to the risk
of major bleeding for heparin/coumadin, compared
to 5.6% for recurrent thrombosis and 5.6% major
bleeding for LMWH. This study, however, was
underpowered as result of premature closure.
Based on small case series, evaluating the efficacy
and safety of enoxaparin, reviparin, nadroparin and
dalteparin in children, LMWH seems to be an
efficient and safe anticoagulant for treatment as
well as prophylaxis of venous thromboembolic
disease in children [60,61]. A study investigating
efficacy in terms of clot resolution showed com-
plete thrombus resolution in the venous system in
48% of the children treated with LMWH, similar to
the rate reported in adults [62].
Bleeding is the most common complication of
LMWHs. In children treated with LMWHs, major
bleedings occurred in 0% to 5.6% [59,63,64]. Very
recently, the first pediatric patient was published
with acute venous thrombosis as a result of HIT
after prolonged LMWH therapy [65]. One case
report showed that total bone mineral density
decreased during therapeutic doses of LMWH for 6
months in a child of 11 years of age. Bone mineral
density returned to normal during the subsequent
years of prophylactic LMWH therapy [66].
Vitamin K antagonists
Vitamin K antagonists function by blocking the
regeneration of vitamin K from its epoxide. Vitamin
K is necessary for the addition of g-carboxyglutamic
acid residues to the coagulation factors II, VII, IX,
and X. As a consequence, plasma concentrations of
these factors are reduced in patients treated with
vitamin K antagonists [67].
Monitoring of vitamin K antagonists in children is
difficult and should be done frequently because of
diet, medication, and primary underlying clinical
conditions [68]. Breastfed babies are very sensitive
to vitamin K antagonists, as they ingest low
concentrations of vitamin K in breast milk. In
contrast, other children are relatively resistant to
vitamin K antagonists as a result of impaired
absorption, total parenteral nutrition, or formula
containing high concentrations of vitamin K [69].
Many children with venous thromboembolic disease
have underlying clinical conditions and use medi-
cation that may influence the dose requirements of
vitamin K antagonists. Furthermore, monitoring
can be difficult because of poor venous access,
especially in neonates. Whole-blood prothrombin
time/International Normalized Ratio (INR) monitors
appeared to be acceptable and reliable in the
outpatient laboratory and home settings [70,71].
Bleeding is the main complication of vitamin K
antagonists. In a prospective study of 319 consec-
utive children requiring warfarin, major bleedings
occurred in 2 children with target INR range 2.0 to
3.0, resulting in an incidence of 1% per patient year
in that group [69].
Treatment with vitamin K antagonists can be
initiated together with unfractionated heparin or
LMWH. The duration of initial therapy with heparin
is a minimum of 5 days. For extensive pulmonary
embolism, heparin should be administered for 7 to
10 days. Vitamin K antagonists should overlap with
heparin for at least 5 days. The target INR range is
2.0 to 3.0. Heparin can be discontinued if the INR is
in the therapeutic range for 2 consecutive days.
Little is known about the optimal duration of
antithrombotic treatment. In the individual patient,
the risk of bleeding should be balanced against the
risk of recurrence. Antithrombotic treatment should
be continued for at least 3 months, and longer in
extensive pulmonary embolism. In patients with a
first episode of idiopathic pulmonary embolism, the
total antithrombotic treatment should be continued
for a minimum of 6 months. Long-term antithrom-
botic treatment should be considered in some
patients, such as patients with recurrent venous
thromboembolism, patients carrying combined het-
erozygous prothrombotic risk factors with idiopath-
ic thrombosis [72], symptomatic patients with
homozygous protein S or protein C deficiency and
patients with antiphospholipid syndrome.
New anticoagulant therapy
Fondaparinux is a synthetic pentasaccharide, an
analogue of the unique pentasaccharide sequence
of heparin [73]. It exclusively targets activated
C.H. Van Ommen, M. Peters 20
factor X and lacks activity against thrombin. It is
given subcutaneously, once daily, and does not
need monitoring. The efficacy and safety of
fondaparinux in the initial anticoagulation of adult
patients with symptomatic pulmonary embolism
have been investigated in the MATISSE-PE study
[74]. In this study, patients were randomized to
fondaparinux and vitamin K antagonists or unfrac-
tionated heparin and vitamin K antagonists. Fonda-
parinux appeared to be as effective and safe as
unfractionated heparin in the initial treatment of
hemodynamically stable pulmonary embolism. Dis-
advantages of fondaparinux include the absence of
antidote and the higher costs than LMWH. If major
bleeding occurs, a procoagulant such as recombi-
nant Factor VIIa should be given [75].
Idraparinux is a long-acting synthetic pentasac-
charide with an expected half-life of approximately
4 days, which allows stable anticoagulation with
once-weekly subcutaneous injections. A phase II
trial in adult showed that after 5 to 7 days of
enoxaparin treatment, idraparinux dosed at 2.5 mg
appeared as effective as warfarin for secondary
prevention in patients with deep-vein thrombosis
and was not associated with major bleeding [76].
Ximelagatran is an orally administered direct
thrombin inhibitor. It has a plasma half-life of 3 to 4
h and is given twice daily. Advantages of ximelaga-
tran are rapid onset of action, and predictable
anticoagulant response. A recently published re-
port showed that ximelagatran was as effective as
enoxaparin and warfarin for treatment of deep-
vein thrombosis with or without pulmonary embo-
lism and had similar, low rates of bleeding in adults
[77]. A disadvantage of ximelagatran is an increase
in serum levels of alanine aminotransferase, which
takes place in 6% to 10% of the patients. It typically
occurs within the first 6 months, and returns to
baseline spontaneously or after stopping the drug
[7779]. However, in trials investigating the effi-
cacy of ximelagatran for prevention of stroke and
systemic embolism in adult patients with nonvalv-
ular atrial fibrillation, 3 of the 6948 participants
died with possible liver failure [80]. Hence, the
possibility of liver toxicity requires further evalu-
ation. Ximelagatran as well as both pentasacchar-
ides have not been used in children.
Thrombolytic therapy
Thrombolytic agents are plasminogen activators
and include urokinase, streptokinase and tissue
plasminogen activator (tPA). In most centers, tPA is
favoured over the other thrombolytic agents as
result of fibrin specificity and affinity, and low
immunogenecity [53,81].
Thrombolytic therapy causes faster resolution of
the embolus than heparin therapy [82]. Therefore,
it is a useful adjunct to heparin in patients who
have pulmonary embolism and are hemodynamical-
ly unstable. These patients are at serious risk of
death due to right ventricular failure within the
first hour of onset. Survival depends on rapid
recanalisation of the pulmonary arterial occlusion
and reduction of the right ventricular afterload. A
multicentre registry showed overall in-hospital
mortality rate ranging from 25% for adult patients
presenting with cardiogenic shock to 65% for
patients undergoing cardiopulmonary resuscitation
[83]. Rapid improvement of right ventricular func-
tion and pulmonary perfusion, accomplished with
thrombolytic therapy followed by heparin, may
lead to a lower rate of death and recurrent
pulmonary embolism.
There is an ongoing debate about the use of
thrombolysis in hemodynamically stable patients
with pulmonary embolism and right ventricular
dysfunction, a risk factor for poor outcome [84,85].
One study compared heparin and placebo to heparin
and tPA in adult patients with pulmonary embolism
and pulmonary hypertension or right ventricular
dysfunction but without arterial hypotension or
shock [86]. The combination of tPA and heparin
caused less clinical deterioration requiring an es-
calation of treatment (with open-label tPA, cate-
cholamine infusion, or mechanical ventilation).
There was, however, no significant difference in
mortality or recurrent pulmonary embolism betwe-
en the two treatment groups. The rates of bleeding
complications were very low in both groups.
Although several case reports and small case
series have reported successful thrombolysis in
children, large clinical trials assessing the efficacy
and safety of thrombolytic therapy in children are
lacking due to low number of children requiring
thrombolysis [87,88]. Two retrospective case series
of children with arterial and venous thrombosis
studied efficacy of thrombolysis with tPA in terms
of clot resolution and showed complete clot
resolution in 55% to 65% of children, partial in 5%
to 20%, and no effect in 15% to 40% [89,90]. The
major drawback of thrombolytic therapy as com-
pared to heparin is increased major bleeding
complications. The retrospective case series
revealed these complications to occur in up to
40% of the children treated with tPA.
The optimal dose and duration of thrombolytic
therapy in children is unknown. The recommended
dose of tPA is 0.1 to 0.6 mg/kg/h for 6 h [53].
However, lower doses of tPA appear to be effective
as well. In a recent study, complete clot resolution
was achieved in all 17 children with acute throm-
Acute pulmonary embolism in childhood 21
bosis and treated with low-dose infusions of tPA
(0.010.06 mg/kg/h) [91]. Major bleeding occurred
in 1 patient.
Embolectomy
Open surgical embolectomy or transvenous catheter
embolectomy can be beneficial in hemodynamically
unstable patients for whom thrombolysis is contra-
indicated or unsuccessful. Surgical embolectomy
has been reported as successful therapy in prema-
ture neonates and infants, usually following major
cardiac surgery [92]. There are several catheter
thrombectomy techniques: aspiration thrombect-
omy, fragmentation thrombectomy, and rheolytic
thrombectomy [93]. However, the commercial
devices used in these procedures are not widely
available, and these techniques should only be done
by an experienced interventionist. Effective me-
chanical fragmentation of pulmonary embolism has
been reported in children [94]. The technique
consists of fragmentation of central emboli and
dislocation of the fragments to the periphery,
resulting in a relative gain of non-obstructed,
cross-sectional artery area and in an enlarged
surface area of the fragments accessible for active
thrombolysis.
Outcome
In children, large studies investigating the outcome
of asymptomatic as well as symptomatic pulmonary
embolism have not been performed. Both the
Canadian and the Dutch registry of children with
venous thromboembolic disease reported a mortal-
ity rate of about 10%; in the Canadian registry 2 out
of 22 children with pulmonary embolism died as
result of embolism, and in the Dutch registry 1 out
of 10 children [11,12]. Few children in both
registries were investigated for the presence of
pulmonary embolism. In the Canadian Childhood
Thrombophilia Registry of catheter-related venous
thrombosis, 7 of the 39 children (18%) with
pulmonary embolism died as result of embolism
[18]. Furthermore, the recurrence rate for pulmo-
nary embolism is unknown in children and there is
no information about the long-term effects of
pulmonary embolism on pulmonary function.
Conclusions and future directions
Pulmonary embolism is an uncommon disorder in
childhood. However, the incidence rates are prob-
ably underestimated as pulmonary embolism fre-
quently is clinically silent or presents with
symptoms mimicking underlying disorders. Future
registry studies are needed to investigate the
hypothesis that the incidence of pulmonary embo-
lism is rising as a result of increased survival of
children with chronic diseases and increased num-
ber of pediatric patients with central venous
catheters. High incidences of pulmonary embolism
may have implications for the use of primary
antithrombotic prophylaxis in certain patient
groups. Furthermore, diagnostic as well as thera-
peutic strategies for pulmonary embolism in chil-
dren are mostly extrapolated from adult studies.
These strategies need to be validated in children.
Finally, outcome of pediatric pulmonary embolism,
including mortality, recurrent pulmonary embolism
and pulmonary function, is unknown. To improve
the care of children with pulmonary embolism,
multicenter and international prospective trials
will be essential.
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