Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-04-1186.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2403-2405
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
The incidence of venous thromboembolism in thrombophilic
children: a prospective cohort study
Daniela Tormene,
Paolo Simioni,
Paolo Prandoni,
Francesca Franz,
Patrizia Zerbinati,
Giulio Tognin, and
Antonio Girolami
From the Department of Medical and Surgical Sciences,
2nd Chair of Internal Medicine, University of Padua Medical School,
Padua, Italy.
 |
Abstract |
Antithrombin and protein C and S defects, factor V Leiden mutation,
and G20210A prothrombin gene mutation are well-recognized risk factors
for venous thromboembolism (VTE) in adults, especially during
circumstantial situations such as trauma, immobilization, surgery, or
oral contraceptive treatment. The relevance of these defects in
predisposing children to VTE is still undefined. In a prospective
cohort study we assessed the incidence of spontaneous and risk
period-related VTE in asymptomatic children (aged 1-14 years), who
were family members of a proband with an objectively diagnosed venous
thromboembolic event and a documented single thrombophilic abnormality.
We enrolled 143 children from 63 families. Of them, 81 (56.6%) were
carriers of an inherited defect, whereas the remaining 62 were free
from known genetic or acquired causes of thrombophilia. The mean
observation period was 5 years (range, 1-8 years) in each group.
Thirty-one risk periods occurred in the carriers group and 20 in
noncarriers. Neither spontaneous nor risk period-related VTE occurred
in either group during 395 and 296 observation years, respectively.
However, circumstances where most of the pediatric thromboses occur
(insertion of central venous lines, cancer, and cardiovascular surgery)
were not encountered. In conclusion, the thrombotic risk in otherwise
healthy children with a single identified thrombophilic defect appears
to be very low. Common triggering conditions for VTE in thrombophilic
adults do not seem to increase the thrombotic risk in children carrying the same inherited defect. Accordingly, screening for thrombophilia in
otherwise healthy children younger than 15 years who belong to families
with inherited defects predisposing to thrombosis seems unjustified.
(Blood. 2002;100:2403-2405)
© 2002 by The American Society of Hematology.
| |
Introduction |
Venous thromboembolic disorders develop much less
frequently in children than in adults.1-6 According to
recent findings from a Canadian registry, the incidence of venous
thromboembolism (VTE) in childhood has been reported to be as
low as 0.07/10 000 individuals.3,6 Among children,
newborns exhibit the highest risk, with reported incidences of VTE
ranging between 0.24 and 0.51 per 10 000 subjects.4,5
Most episodes occur in association with underlying neoplasms,
congenital heart diseases, systemic lupus erythematosus, renal failure,
or infective diseases, or are triggered by central venous lines, major
trauma, or surgery.3,6-9
Unlike the situation in adults, the role played by congenital
prothrombotic abnormalities in the development of venous thromboembolic complications in pediatric patients still has to be clarified. In the
large majority of available family studies of thrombophilic patients,
members younger than 15 years were excluded from the evaluation.10-13 As a consequence, it is unclear whether
children who are family members of symptomatic probands with
thrombophilia have, in turn, an increased risk of spontaneous or risk
period-related VTE. Potential benefits coming from the early
identification of congenital prothrombotic abnormalities in
asymptomatic children depend on valid estimates of such a risk and on
whether identified carriers might benefit from some form of
thromboprophylaxis when exposed to triggering factors for VTE.
We carried out a prospective long-term follow-up of 143 consecutive children belonging to 63 families with prothrombotic
abnormalities, of whom 81 were carriers of the qualifying defect. We
assessed the incidence of both spontaneous and risk-related
thromboembolic complications during an average 5-year follow-up period.
| |
Patients and methods |
Patients
Consecutive patients referring to the Thrombosis Center of the
University of Padua with an episode of objectively proven deep vein
thrombosis (DVT) or pulmonary embolism (PE) between 1993 and 2001 were
screened for deficiencies of antithrombin and protein C or S, and the
presence of factor V Leiden mutation or G20210A prothrombin mutation.
All consenting family members of probands who were identified as
carriers of a thrombophilic state were eligible for this investigation
provided they were younger than 15 years and older than 1 year and had
not experienced previous episodes of VTE. Approval was obtained from
the Institutional Review Board of the University of Padua for
this study. Informed consent was provided according to the Declaration
of Helsinki.
Eligible patients underwent the blood determination of
prothrombotic abnormalities and the bilateral compression ultrasound of
the proximal vein system. Carriers of combined prothrombotic disorders
were excluded from further investigation, as were subjects with vein
incompressibility of either leg.
Study design
A follow-up visit was performed every 6 months. At each visit,
attention was paid to risk periods for VTE (such as prolonged immobilization, recent trauma or surgery, hormonal therapy, the insertion of a central venous line, or infectious diseases). In addition, a bilateral compression ultrasound test of the leg venous system was performed to check the occurrence of asymptomatic
thrombotic episodes.
Parents of children presenting with clinical signs or symptoms of
thromboembolic events were encouraged to address our center, where
proper objective tests (either compression ultrasonography or ascending
phlebography in subjects with suspected DVT, either ventilation-perfusion lung scan or spiral computed tomographic scanning
in case of suspected PE) were performed to confirm or rule out the
clinical suspicion.
The systematic use of antithrombotic drugs was vigorously discouraged.
The decision to administer thromboprophylactic drugs during periods at
risk for venous thrombosis was left to the discretion of treating physicians.
Children left the study when they reached the age of 15 years.
Laboratory assays
Laboratory tests for antithrombin and protein C and S were
performed according to methods previously described.13 The
following reference values were used: antithrombin antigen
concentration, 70% to 120%; antithrombin activity, 70% to 120%;
protein C antigen concentration, 65% to 130%; protein C activity,
65% to 130%; total protein S concentration, 60% to 120%; and free
protein S concentration, 60% to 108%. Those subjects who were found
to be deficient on 3 consecutive determinations and had at least one of
the investigated relatives with the same defect were labeled as
carriers of a prothrombotic state.
The DNA analysis for factor V Leiden mutation and G20210A
prothrombin variant was performed using previously described
methods.13,14
Outcomes
The primary outcome was the occurrence of an objectively
documented thromboembolic event. Thrombotic events were categorized as
spontaneous if occurring without a predisposing risk period and
secondary if occurring during or within 3 months after a risk period.
Analysis
The incidence of thromboembolic events and its 95% CI was
calculated in carrier and noncarrier groups. The relative risk (RR) for
the development of both spontaneous and risk period-related VTE was
calculated by dividing the incidence rate in carriers by the incidence
in noncarrier family members.
| |
Results |
Patients
All 143 eligible children, who were family members of 63 probands
with a single recognized prothrombotic disorder, were enrolled in the
current investigation. Eighty-one (56.6%) were carriers of inherited
defects: 9 heterozygous carriers of antithrombin deficiency, 13 of
protein C deficiency, 3 of protein S deficiency, 41 of factor V Leiden
mutation (of whom 38 were heterozygous and 3 homozygous), and 15 of
G20210A prothrombin mutation (of whom 2 were homozygous). The remaining
62 children were free from thrombophilia. The main characteristics of
included children are shown in Table 1.
Follow-up
There were 395 observation-years in carriers and 296 observation-years in noncarriers. The mean observation time in each
group was 5 years (range, 1-8 years), and at least 1 year of follow-up was available in all children (Table 1).
Risk periods
Of the 81 carriers of a thrombophilic state, 21 experienced one or
more risk periods of thrombosis (overall, 31 risk periods): 3 operations, 21 traumas (15 with plaster cast for 20-30 days, 6 with
immobilization for more than 10 days), and 7 periods of immobilization
for infections. Twenty risk periods occurred in 15 of the 62 control
subjects: 4 operations, 15 traumas (13 with plaster cast for 30 days, 2 with immobilization for more than 7 days), and 1 immobilization for
infection (Table 2).
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Table 2.
Type and number of risk periods experienced by the children
during follow-up according to their deficiency status
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Antithrombotic prophylaxis with low-molecular-weight heparin was used
during 3 risk periods (traumas with plaster cast) in the carriers
group: 1 in a protein C-deficient carrier, and 2 in carriers of factor
V Leiden.
Venous thromboembolic events
During the study period, 2 children presented with clinical
symptoms suggestive of VTE, which was excluded in all. Therefore, no
thromboembolic events (either clinically symptomatic or asymptomatic) occurred in the 2 groups, leading to an overall annual incidence of VTE
of 0% (95% CI, 0.0-0.9) in the carriers group and 0% (95% C,
0.0-1.2) in noncarriers.
| |
Discussion |
In contrast with the increasing risk of thromboembolic
complications shown by adults who are carriers of a thrombophilic
state, little is known about this risk in childhood. This is the first prospective cohort study designed to make an estimate of the
age-related risk of both spontaneous and risk-related VTE in subjects
younger than 15 years who are family members of a thrombophilic
proband. During an average follow-up of 5 years, no episodes of
symptomatic or asymptomatic VTE could be recorded in any of the
recruited individuals. It should be noted that during the study period
one or more risk factors of thrombosis were experienced by 26% of children, and that in the majority of cases no prophylactic treatment was carried out. These findings did not differ from those observed in
nonthrombophilic children. Although the relatively small number of
considered children precludes definite conclusions, the results of our
investigation suggest that the incidence of thromboembolic complications in children who are carriers of a single prothrombotic abnormality is low enough to rule out the need for systematic thromboprophylaxis.
It is interesting to note that the absence of risk period-related
complications in our cohort contrasts with the incidence reported in
adults under the same circumstances.10-13 Thrombophilic adults carry a risk of venous thromboembolic events during
circumstantial risk periods (such as major trauma or surgery,
immobilization, hormonal therapy, pregnancy, or puerperium), which is
significantly higher than that observed in
noncarriers.10,11,13 This risk is particularly important
in carriers of antithrombin and protein C and S
defects,10,13 but is substantial also in subjects with factor V Leiden mutation.11 Accordingly, many clinicians
recommend the screening for thrombophilia in adults who are
asymptomatic family members of thrombophilic probands, at least in
women of fertile age and in those subjects who are candidates for major risk factors for venous thrombosis. Although the small number of risk
periods and the nonuniform approach concerning anticoagulant prophylaxis preclude definite conclusions, the lack of thromboembolic complications even in children who were not given prophylactic drugs
following a major trauma or a surgical intervention suggests that the
screening for thrombophilia might not be necessary in children who are
family members of thrombophilic probands with a single identified
thrombophilic defect until they are 15 years old.
We think that our results provide a reliable estimate of the
thromboembolic risk of otherwise healthy thrombophilic children. All
identified subjects were prospectively followed-up at the same study
center. All episodes of clinically suspected DVT or PE were
investigated with properly validated objective tests. Moreover,
confounding factors were minimized by programming the exclusion from
our investigation of children with a history of previous
thromboembolism. Our findings should, however, be interpreted with
caution. In recent years, thromboembolic events have been increasingly
recognized as a major cause of morbidity and mortality in tertiary care
pediatrics, especially in newborns and children with neoplastic
diseases, in those requiring the placement of central venous lines or
the administration of asparaginase or other chemotherapeutic drugs, and
in those with congenital heart disease.3,15-17 In
addition, recent case-control studies suggest that thrombophilic
children have a higher risk of stroke and other thromboembolic
complications than matched control subjects without thrombophilia.18-21 We had neither the opportunity of
following individuals with cancer nor of observing children receiving
central venous lines. Moreover, subjects younger than 1 year were
excluded from our investigation. Finally, the observation time (on
average, 5 years) might not have been long enough to detect the
development of ischemic stroke or other thromboembolic complications.
In conclusion, otherwise healthy thrombophilic children who are
carriers of a single identified thrombophilic abnormality and are
family members of a thrombophilic proband appear to be at a very low
risk of both spontaneous and risk-related thromboembolic complications
outside extreme circumstances such as cancer, the need for prolonged
immobilization, cardiovascular surgery, or the insertion of central
venous lines. Accordingly, the routine screening for thrombophilia
before the age of 15 years does not seem justified. For final decisions
to be made, however, a longer follow-up in a larger group of
thrombophilic children observed in a wider variety of clinical
situations is needed.
| |
Footnotes |
Submitted April 22, 2002; accepted May 23, 2002.
Prepublished online as
Blood First Edition Paper, June 7, 2002; DOI
10.1182/blood-2002-04-1186.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Paolo Prandoni, Department of Medical and Surgical
Sciences, 2nd Chair of Internal Medicine, Via Ospedale 105, 35100-Padua, Italy; e-mail: paoprand{at}tin.it.
| |
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Abstract
Introduction