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.
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).
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.
Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a ...GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P < 10−5). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of P = 1.42 × 10−6/2.0 × 10−6 and P = 6.11 × 10−6/1.8 × 10−5, respectively. Rs2748331 was replicated (P = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined P = 7.88 × 10−7). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in SMAP1 and 3 in RIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: P = .08326, SMAP1; rs767118962: P = .08326, RIMS1; and rs41265501: P = .05778, RIMS1). In conjunction, our data provide compelling evidence for SMAP1, B3GAT2, and RIMS1 as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.
•Our study identified a region on chromosome 6 comprising the genes SMAP1, B3GAT2, and RIMS1 as novel susceptibility locus for pediatric VTE.•Nonsynonymous variants in SMAP1 and RIMS1 are predicted as deleterious and may influence vesicle processing in blood cells.
Objective:
Limited data are available on health‐related quality of life (HR‐QoL) in pediatric stroke survivors. The aim of the present study was to assess HR‐QoL by self‐assessment and ...parent/proxy‐assessment in children and adolescents who survived a first stroke episode.
Methods:
We investigated HR‐QoL in pediatric stroke survivors (71 preschool children G1 and 62 school children/adolescents G2) and in 169 healthy controls. HR‐QoL was assessed in patients and parents/proxies with the generic KINDL‐R questionnaire exploring overall well‐being and 6 well‐being subdimensions (physical, psychological, self‐esteem, family‐related, friend‐related, and school‐related). In pediatric stroke survivors the neurological long‐term outcome was measured with the standardized Pediatric Stroke Outcome Measure.
Results:
Of stroke survivors, 65% exhibited at least 1 neurologic disability. Pediatric stroke survivors reported lower overall well‐being compared with healthy controls. In G2 stroke patients, friend‐related well‐being respectively emotional well‐being was significantly reduced compared with healthy controls (73.0 vs 85.0 points; p < 0.001 respectively 80.2 vs 84.5 points; p = 0.049). Parents/proxies of both stroke survivors rated the overall well‐being and all subdimensions (except family‐related and school‐related well‐being in G1 and G2 stroke survivors and physical functioning in G2 stroke survivors) lower compared with parents/proxies of healthy children/adolescents. Overall well‐being was significantly reduced in children with moderate/severe neurological deficits compared with normal/mildly affected patients (75.5 vs 83.3 points, p = 0.01). Neonatal stroke survivors reported a significantly better neurological long‐term outcome compared to childhood stroke survivors (82.0 vs 75.0 points; p = 0.005).
Interpretation:
Pediatric stroke survivors compared with healthy controls are strongly affected regarding their overall well‐being and older children/adolescents regarding their well‐being with peers. Ann Neurol 2011;
Patients with severe haemophilia A (HA) can either be treated by regular FVIII infusions twice or three times per week (prophylaxis), or only in case of bleeding episodes (on-demand). Whereas ...prophylaxis reduces the number of bleeding episodes and may therefore prevent the development of haemophilic arthropathy, there is still a lot of controversy surrounding recommendations on age and dose at start of prophylactic regimens. The present database study was performed to investigate the role of primary versus secondary prophylaxis in HA children. The outcome variable was imaging-proven haemophilic joint damage. Forty-two children were initially treated with primary prophylaxis following the first bleeding episode, and were frequency-matched (year of birth, catchment area) to 67 patients receiving "on-demand" therapy with an early switch to "secondary prophylaxis". In multivariate analysis adjusted for the HA mutation type and the presence or absence of thrombophilia, the Pettersson score investigated at a median age of 12.5 years in joints with at least one documented bleeding episode was not significantly different between the two patient groups (p = 0.944), and no statistically significant differences were found in patients with target joints (p = 0.3), nor in children in whom synovitis had occurred (p = 0.77). No conclusion can be drawn from the data presented herein whether primary prophylaxis or an early start of secondary prophylaxis is superior with respect to joint outcome in children with severe HA.
Cerebral sinovenous thrombosis (CSVT) is a serious disease, that leads to longterm neurological sequaelae in the majority of survivors. There is uncertainty with regard to age specific individual ...risk factors, the impact of hereditary thrombophilia or underlying diseases on development of thrombosis or outcome. Previously published cohort studies have described epidemiology, treatment practices and outcomes, but those studies are limited due to small sample size or diversity of the populations included. Neonatal CSVT is seen as a disease entity different from cerebral thrombosis in older children with regard to etiology and outcome, evidence is lacking.
To evaluate the influence of transient risk factors and hereditary thrombophilia on clinical course, treatment practices and early outcome in a population based national cohort of children with CSVT. To study the influence of age (neonatal versus pediatric) on risk factors and outcome in CSVT.
We conducted a prospective nationwide surveillance study in pediatric patients <18 years through the hospital-based German Pediatric Surveillance Unit (ESPED). We included consecutive patients from 0-18 years of age admitted to hospitals in Germany with diagnosis of a first CSVT with an enrolment period between 2001-2010. Diagnosis was confirmed using MRI or CT imaging. Laboratory analysis of coagulation parameters have either been analyzed according to standardized thrombophilia screening protocols in the local hospitals or centrally in study center at the University of Muenster. We followed the course of disease over a period of 36 months. Follow up investigation included repetitive MRI or CT imaging and questionnaires on clinical outcome and recurrence.
A total of 599 patients, from birth to 18 years with a diagnosis of CSVT were enrolled in the study. We have observed a male predominance with 61%. 138 (23%) CSVT cases were diagnosed during the neonatal period, 461 (77%) patients were older than one month at time of diagnosis. In our cohort 40% of neonates and 20% of older infants/children developed thrombosis without identified underlying predisposing diseases. The majority of transient triggers associated with the development of thrombosis were local (mastoiditis, 18%) or systemic (sepsis, meningitis, 13%) infections or asparaginase administration during treatment for leukemia or lymphoma (12%). Outcome, dependent both on age at onset and existence of transient triggers was worse in children with spontaneous CSVT compared to triggered CSVT with regard to mortality rate (11 vs. 3%), patency of the veins and neurological impairment. Moreover, presenting symptoms as well as the clinical course differed between neonates and older infants/children.
In the pediatric population studied most of CSVT events were associated with infections as transient trigger. CSVT in neonates and children older than 1 months of age differed both with regard to underlying risk factors, treatment and outcome. Age specific, randomized controlled trials comparing treatment strategies are needed to optimize care in these patients.
No relevant conflicts of interest to declare.
Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and ...second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval CI, 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.
Summary
Deficiency of antithrombin (AT), protein C (PC) or protein S (PS) constitutes a major risk factor for venous thromboembolism (VTE). Individuals at high risk for recurrence who benefit from ...screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non‐central‐venous‐catheter‐associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event‐free‐survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46–17·2) and female gender (2·6/1·1–6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6–10) in AT‐deficient children, 1·3% (0·3–3·8) in patients with PC deficiency, 0·7% (0·08–2·4) in the PS‐deficient cohort and 0·9% (0·4–1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE.
To better understand self-reported health-related quality-of-life (HrQoL) in children and adults with chronic hemostatic conditions compared with healthy controls.
Group 1 consisted of 74 ...children/adolescents aged 8–18years with hereditary bleeding disorders (H-BD), 12 siblings and 34 peers. Group 2 consisted of 82 adult patients with hereditary/acquired bleeding disorders (H/A-BD), and group 3 of 198 patients with deep venous thrombosis (DVT) on anticoagulant therapy. Adult patients were compared to 1011 healthy blood donors. HrQoL was assessed with a ‘revised KINDer Lebensqualitaetsfragebogen’ (KINDL-R)-questionnaire adapted to adolescents and adults. No differences were found in multivariate analyses of self-reported HrQoL in children with H-BD. In contrast, apart from family and school-/work-related wellbeing in female patients with DVT the adult patients showed significantly lower HrQoL sub-dimensions compared to heathy control subjects. Furthermore, adults with H/A-BD disorders reported better friend-related HrQoL compared to patients with DVT, mainly due to a decreased HrQoL subscale in women on anticoagulation.
In children with H-BD, HrQoL was comparable to siblings and peers. In adults with H/A-BD HrQoL was comparable to patients with DVT while healthy blood donors showed better HrQoL. The friend-related HrQoL subscale was significantly reduced in female compared to male patients.
Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even ...though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed.
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