Published online before print September 8, 2008, doi: 10.1161/CIRCULATIONAHA.108.789008
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(Circulation. 2008;118:1373-1382.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Impact of Inherited Thrombophilia on Venous Thromboembolism in Children
A Systematic Review and Meta-Analysis of Observational Studies
From the Division of Hematology/Oncology, Children’s Hospital Los Angeles, Los Angeles, Calif (G.Y.); Division of Hematology, University Children’s Hospital, Zurich, Switzerland (M.A.); Servicio de Hematolgía y Oncología, Hospital de Pediatría "Prof. Dr. J.P. Garrahan," Buenos Aires, Argentina (M.B.); Hospital for Sick Children, Toronto, Canada (L.B.); McMaster University, Hamilton, Canada (A.C.); Leibniz Institute for Arteriosclerosis Research, University of Münster, Münster, Germany (F.F.); Department of Pediatrics, Hematology/Oncology/BMT, University of Colorado and the Children’s Hospital, Denver (N.A.G., M.M.-J.); Massachusetts General Hospital, Harvard Medical School, Boston, Mass (E.G.); Department of Pediatric Hematology/Oncology, University Hospital Frankfurt, Frankfurt, Germany (C.H.); Department of Pediatrics, Children’s Medical Centre Dallas, University of Texas Southwestern Medical Center, Dallas (J.J.); Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel (G.K., A.L.); Department of Pediatric Hematology/Oncology, University Hospital Münster, Münster, Germany (A.K., U.N.-G.); Department of Pediatrics, University Hospital Munich, Munich, Germany (K.K.); Department for Pediatrics, Medical University, Vienna, Austria (C.M.); Department of Pediatrics, University of New Mexico, Albuquerque (P. Mathew); The Royal Children’s Hospital, Victoria, Australia (P. Monagle); Department of Pediatric Hematology, Emma Children’s Hospital AMC, Amsterdam, the Netherlands (H.v.O.); Department of Medical and Surgical Sciences, University of Padua, Padua, Italy (P. Simioni, D.T.); and Russian National Center of Pediatric Hematology/Oncology, Moscow State Medical University, Moscow, Russian Federation (P. Svirin).
Correspondence to Professor Dr U. Nowak-Göttl, Pediatric Hematology and Oncology, University Hospital of Münster, Albert-Schweitzer-Str 33, D-48149 Münster, Germany. E-mail leagottl{at}uni-muenster.de
Received January 3, 2008; accepted July 11, 2008.
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Abstract |
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Background— The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies.
Methods and Results— A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a).
Conclusions— The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.
Key Words: meta-analysis • pediatrics • recurrence • thrombosis
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Introduction |
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Venous thromboembolism (VTE) in children is a rare disease that is being increasingly diagnosed and recognized, usually as a secondary complication of primary underlying medical diseases such as sepsis, cancer, and congenital heart disease, as well as therapeutic interventions such as the use of central venous lines.1–6 Pediatric VTE is a severe condition for which long-term outcomes have included lack of thrombus resolution in 50% of cases and, excluding central line-associated thrombosis in children with malignancy, the development of postthrombotic syndrome in more than one third of patients.7–11 Within the entire childhood population, neonates are at the greatest risk of thromboembolism (5.1/100 000 live births per year in white children), with a second peak in incidence during puberty and adolescence.2 In prospective pediatric registries in North America and Europe, the annual incidence of venous events was estimated to be 0.7 to 1.4 per 100 000 children or 5.3 per 10 000 hospital admissions of children and 24 per 10 000 admissions of neonates to neonatal intensive care units.6,12–14
Clinical Perspective p 1382
The results of single studies of the risk of VTE onset and recurrence associated with inherited thrombophilia (IT) have been contradictory or inconclusive, mainly because of a lack of statistical power. Apart from acquired thrombophilic risk factors such as the presence of antiphospholipid antibodies,15–18 IT—particularly antithrombin, protein C, and protein S deficiency, variants of coagulation factor V (G1691A) and factor II (G20210A), and elevated lipoprotein(a)-have been established as risk factors for venous thromboembolic events in adults.19–29 The allele frequencies for the factor V G1691A or factor II G20210A variants differ among various ethnic groups.30–32 In children with idiopathic VTE and in pediatric populations in which thromboses were associated with underlying medical diseases, IT has been described as an additional prothrombotic risk factor.33–101 Follow-up data for VTE recurrence in children are available from several reports12,13,17,62,63,67,69,78–81,93,100 and suggest a recurrence rate of 
3% in neonates and 8% in older children. Unfortunately, the duration of follow-up is variable across studies. However, in the pediatric age group, it is unknown whether thrombus recurrence and other thrombotic outcomes in children are affected by IT; thus, it remains controversial whether children with thrombosis or offspring in thrombosis-prone families benefit from screening for IT.102–108 The aim of this systematic review and meta-analysis was to determine the impact of IT on VTE onset and recurrence in children as a prerequisite to the evaluation of primary and secondary treatment options through randomized controlled trials.
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Methods |
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The present systematic review and meta-analysis was performed in accordance with the recently published guidelines from Strengthening the Reporting of Observational Studies in Epidemiology (STROBE),109 with adaptations as further described below.
Inclusion/Exclusion Criteria
Published studies of VTE in children <20 years of age from 1970 through August 2007 were evaluated for inclusion if the frequency of 
1 IT traits was individually investigated in a given VTE cohort (descriptive analysis) and if the frequency of IT traits was compared between VTE patients and control subjects without a history of VTE in a given study (meta-analysis). Pediatric VTEs of any location objectively confirmed by suitable imaging methods were included. In addition, to be included, publications must have reported the country of origin, study design, ethnicity, number of patients and controls, type of VTE, number of individuals tested for IT, screening tests performed, and laboratory methods (including criteria for normal/abnormal results). In addition, in children with recurrent events, data on the time to recurrence, VTE type and location of recurrence, associated clinical risk factors, and duration and type of anticoagulation110 were required. Case reports and case series/studies in which <50% of cases were systematically screened for IT, publications reporting asymptomatic thrombosis, and studies with unclear laboratory/analytical methodology to differentiate between inherited and acquired deficiency states of protein C, protein S, or antithrombin were not included (except in instances when this distinction was subsequently clarified in personal communication with the responsible authors; only cases with inherited deficiency states were included in the analyses).
Search Strategy
A systematic search of publications listed in the electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) from 1970 to August 2007 was conducted using the following key words in combination as both MeSH terms and text words: ["deep vein thrombosis" or "thromboembolism" or "venous thromboembolism" or "pulmonary embolism" or "renal venous thrombosis" or "cerebral venous thrombosis" or "anticoagulation" OR "antithrombotic therapy"] and ["neonate" or "infant" or "children" or "child" or "childhood" or "adolescents" or "pediatric" or "pediatric" not "adult"] and ["thrombophilia" or "prothrombotic" or "procoagulant" or "protein C" or "protein S" or "antithrombin" or "factor V" or "activated protein C resistance" or "prothrombin" or "factor II" or "lipoprotein (a)"]. The terms "catheter-related," "central-line-related," and "recurrence" or "recurrent" also were included in the search strategy. In addition, reference lists of journal articles identified through the aforementioned search were searched manually to locate additional studies. The search strategy had no language restrictions. Citations were screened and classified into cohort/case-control, case series, or registry data by 2 independent group members (L.B. and H.v.O.). Those meeting the inclusion criteria were retained. The decision to include or exclude studies was hierarchical, made initially on the basis of the study title, followed by the abstract, and finally the complete body text. In the event of conflicting opinions, resolution was achieved though discussion (L.B., F.F., N.G., J.J., G.K., A.K., M.M.-J., U.N.G., H.v.O., and P.S.).
Data Extraction
To avoid possible double counting of patients included in >1 report by the same authors/working groups, the patient recruitment periods and catchment areas were evaluated, and authors were contacted for clarification. If the required data could not be located in the published report, the corresponding author was asked to provide the missing data of interest. Data extractions were checked for accuracy by multiple reviewers (M.A., L.B., F.F., J.J., G.K., M.M.-J., H.v.O., P.S., and G.Y.).
Study Design Classification
In this meta-analysis, studies were classified as having a cohort design when subjects with and without a factor being investigated were followed up for development of the outcome of interest. Studies were classified as having a case-control design when individuals grouped by outcome (ie, cases having the outcome/disease of interest and controls without the outcome/disease) were compared for the presence of a risk factor of interest. A case report or case series was defined as 1 case or a group of cases of a particular outcome of interest with no control group. Studies were classified as having a registry design when consisting of a multicenter population-based (ascertainment of >90% of cases available) case series using predefined standardized data collection criteria.111
Missing Data
Studies in which symptomatic pediatric VTE patients were not screened for ITs and studies in which the thrombophilia screening was done in <50% of cases or was performed only sporadically were not included in the present meta-analysis. When the percentage of patients screened for IT was not clear from the article, authors were asked for clarification.
Statistical Analyses
Data analyses were performed with STATA version 9 update and StatsDirect version 2.6.6 update (Altrincham, Trafford, UK: WWW. STATSDIRECT.COM). Continuous data are presented as median (minimum and maximum) values. For meta-analysis, summary odds ratios (ORs) and 95% CIs were calculated from the effect estimates of the individual studies weighted by SE using both a fixed-effects model (weighting each estimate by its SE via the Mantel-Haenszel method) and a random-effects model (estimating between-study variance in effect measures according to DerSimonian and Laird);112 the latter approach was used to control for heterogeneity according to Higgins et al.113 For both the factor V and factor II variants, the AA and GA alleles (ie, homozygosity and heterozygosity for A alleles) were analyzed together and compared with the absence of these genotypes as the reference category. A value of P<0.05 was considered statistically significant. In addition, we assessed heterogeneity among studies using I2 statistics. When P<0.05, the presence of heterogeneity was considered statistically significant, and when I2>50%, the magnitude of heterogeneity was considered substantial. Funnel plots of effect size against SE and a modified linear regression test were used to describe the presence of publication bias.114 In study design classification, the degree of agreement beyond chance between first and second raters was measured by 
statistic.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Descriptive Analyses
From 331 potentially relevant citations ascertained from electronic databases and search of reference lists, 50 cohort/case-control studies or case series/registries from 16 countries finally met the inclusion criteria for descriptive analysis (Figure 1 and Tables Ia, Ib, and II of the online Data Supplement). Apart from Reference 63, which reported the follow-up of high-risk children with idiopathic VTE, in these studies, >70% of patients with VTE had at least 1 clinical risk factor. In neonates and infants, these risk factors were predominantly medical diseases such as systemic sepsis, dehydration, congenital heart disease, or short-term central venous lines; in older children and adolescents, cancer and polychemotherapy, immobilization after surgery or plaster casts, obesity, rheumatic diseases, local infections, and the use of oral contraceptives pills (adolescent girls) were the leading exogenous triggers. Measurement of interrater reliability in study design classification showed a substantial agreement (92.68%) beyond that expected by chance alone (22.78%) in the analysis of VTE onset (
=0.90; Z=11.08; P<0.001), and in the analysis of VTE recurrence, the agreement beyond chance (24.8%) was 81.82% (=0.76; Z=4.91; P<0.001).
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Studies investigating IT at the onset of VTE are shown in the supplemental tables. Forty-one of the 50 studies reported inherited deficiency states of protein C, protein S, or antithrombin. In these studies, 2653 patients with a first VTE onset and 1979 control children were investigated (supplemental Table Ia). Beginning in 1996 and 1999, the factor V and factor II variants, respectively, were systematically investigated in childhood VTE (44 studies; supplemental Table Ib). For the rare event of VTE recurrence, patients derived from 6 to 13 studies met the inclusion criteria. The median follow-up time was 48 months (minimum, 12 months; maximum, 96 months). The median age at onset in studies reporting recurrent VTE was 7.2 years (minimum, 0.1 years; maximum, 14.0 years) with a median age at recurrence of 14 years (minimum, 3.6 years; maximum, 15.0 years). Data on anticoagulation at the time of recurrence were available for 127 children from 7 reports. In 25 of 127 patients (19.7%), recurrence presented during anticoagulation therapy, and in the majority of cases, ie, in 102 of the 127 patients (80.3%), the second VTE occurred after withdrawal of anticoagulation. Study characteristics and the rates of recurrent VTE are shown in supplemental Table II. The proportion of children developing recurrent VTE over the median follow-up period was 11.4%.
Of note, because of authors’ clarifications, individual numbers of patients and controls in the studies listed in supplemental Table I and Tables 1 and 2
may vary from the original study articles. In addition, subject numbers for the analyses differ in Table 2 and supplemental Table II relative to the prior tables because of the reliance on case-control studies in the estimation of risk of first VTE onset.
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Meta-Analyses
In 35 of 50 studies, eligible data on VTE children and population-based controls were reported. For the event of VTE onset, patients derived from 8 to 23 studies were available. Table 2 summarizes the genetic traits investigated, the number of studies and patients included in the meta-analysis, and summary ORs and 95% CIs under a fixed-effects and random-effects model. In addition, results of testing for heterogeneity and publication bias are shown. No significant heterogeneity or publication bias was discerned across studies. ORs were first calculated separately by age groups (neonate, infant, child, adolescent). Because no statistically significant difference in ORs was detected with age (data not shown), summary ORs were then calculated for the overall pediatric age range. A statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary ORs ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Forest plots under random-effects models show that pediatric carriers of the factor II variant (Figure 2A) and of 2 genetic traits (Figure 2b) had an increased risk of developing a first symptomatic VTE. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a), with summary ORs ranging from 1.88 (95% CI, 1.01 to 3.49) for the factor II variant to 3.76 (95% CI, 1.76 to 8.04) for protein S deficiency. Substantial heterogeneity across studies was ruled out. When analyzing the role of factor V G1691A and recurrence, we achieved higher homogeneity and the absence of major publication bias after exclusion of Reference 63, which reported solely the follow-up of selected high-risk pediatric patients with idiopathic VTE (Table 2). Again, funnel plots of effect size against SE were explored for each parameter investigated and were broadly symmetrical, which was consistent with the conclusion that there was no major publication bias (data of bias assessment plots are exemplarily shown for the factor II mutation [supplemental Figure IIIa] and combined genetic traits at recurrent VTE [supplemental Figure IIIb]). The absence of major publication bias was also underlined by the results of the linear regression method according to Harbord et al.114
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Discussion |
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VTE is far less common in children than in adults and often is associated with underlying medical conditions such as malignancy, autoimmune disease, and congenital heart disease or is caused by medical interventions such as central venous lines. Keeping in mind that not all children with these risk factors will develop VTE, it is apparent that genetic risk factors play an important role in which children will develop thrombosis.33–101,115,116 Apart from a recent systematic review of the role of thrombophilia in children with acute lymphoblastic leukemia and ischemic stroke,117,118 to the best of our knowledge, this is the first meta-analysis of observational studies investigating the association of genetic traits and VTE in children. Each of the traits investigated shows a significant association with first onset of pediatric VTE, with the highest ORs found for combined genetic traits and deficiencies of antithrombin, protein C, and protein S. Our findings are concordant with adult studies demonstrating that inherited deficiencies of the natural anticoagulants protein C, protein S, and antithrombin are present in <10% of patients with VTE but that patients with these deficiency states are considered at higher risk for a first VTE onset.119 In the white adult population, the factor V mutation increases the risk of a first episode of VTE by 3- to 7-fold, whereas the factor II variant increases the risk by 2- to 3-fold.120,121 In addition, it has been demonstrated in a recent meta-analysis that elevated lipoprotein(a) increases the risk of a first symptomatic VTE in adults nearly 2-fold.29
A history of thrombosis is a predictor for VTE recurrence in adults in 3% to 13% of consecutive patients after 1 year and in 12% to 28% after 5 years.119 In pediatric cohorts, the proportion of children developing recurrent VTE ranged from 3% in neonates to 8% in older children2,12–14 and as high as 21% in children reported with a first idiopathic VTE.63 The results of this meta-analysis show that 11.4% of children with nonidiopathic thrombosis overall (ie, regardless of IT status) developed a second VTE, which is consistent with the rate reported in large pediatric cohort studies not systematically investigating genetic traits.2,12,14,79 Second events, however, were observed mainly in adolescents and occurred in 80% of affected children after withdrawal of anticoagulant therapy. In the present meta-analysis, a significant association with recurrent VTE in children was found for protein C, protein S, and antithrombin deficiency; the factor II variant; and 2 genetic traits. Pediatric carriers of the factor V mutation or elevated lipoprotein(a) did not show an increased risk for recurrent VTE in the present analysis. The summary ORs determined in this meta-analysis for recurrent VTE in children are consistent with results obtained from adult cohort studies of patients not receiving long-term anticoagulation.119,122–124
The present meta-analysis has several limitations. First, the included studies were conducted over different time periods; therefore, it has to be taken into consideration that diagnosis and treatment modalities, including referral patterns, might have changed over time. Second, most of the studies included in our meta-analysis were undertaken in white children with VTE; thus, it is unknown whether our findings can be extrapolated to other ethnic groups. A third limitation is the possible presence of publication bias. Although formal testing did not show a publication bias, it cannot be completely ruled out, considering the rarity of the disease and the small number of studies available in the field of pediatric VTE. It should also be mentioned here that the pediatric age groups most affected, ie, newborns and adolescents, are underrepresented in the present analysis. The former may be due to the fact that apart from genetic testing, thrombophilia screening and its interpretation are difficult in small children and may therefore be postponed by the treating physicians, with the increasing risk of patients lost to follow-up. As a consequence, data obtained from this meta-analysis have to be interpreted with caution, especially for infants within the first year of life. A fourth limitation of the study, specifically with regard to the VTE recurrence analysis, is that data were not available for the duration of follow-up on a per-patient level, so recurrence risk may be biased by differences in duration of follow-up across studies.
These limitations notwithstanding, the finding of the present meta-analysis that IT is associated with VTE onset and its recurrence in children has important implications for future advances in the field. Decisions on extending anticoagulation therapy are individually based on the perceived risks of VTE recurrence and anticoagulation-related bleeding, and whether long-term continuation of anticoagulation treatment should be considered after a first VTE in carriers of a thrombophilic trait is still a matter of debate. Randomized controlled trials are lacking in children with a first VTE, and treatment guidelines are mainly adapted from adults.110,125 More than in the typical elderly adult with VTE, the prolonged use of anticoagulation treatment in a physically active pediatric group must be weighed against the risk of bleeding. The results of this meta-analysis suggest that future investigation of secondary prevention in pediatric VTE should include trials of prolonged anticoagulation treatment duration targeting high-risk IT groups, particularly children with VTE who have combined IT but do not presently meet the criteria (eg, severe anticoagulant deficiency) for indefinite anticoagulation.
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Acknowledgments |
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We thank Klaus Berger of help in epidemiological discussions and Sandra Bergs and Doris Kunkel for technical support.
Sources of Funding
The study was supported by grants from the Karl Bröcker Stiftung and the local university research project Innovative Medizinische Forschung in Münster. These study supporters had no role in the study design, data collection, data analysis, or data interpretation or in the writing of this report.
Disclosures
None.
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Apart from the first/senior author, authors are listed alphabetically and contributed equally.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.789008/DC1.
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