ALBERT

Description: The present study was designed to evaluate prothrombotic risk profiles in 59 consecutively recruited white neonates with renal venous thrombosis (RVT). The rates of prothrombotic risk factors (PRs)—for example, the factor V (FV) 1691G〉 A mutation, the factor II (FII) 20210G〉 A variant, antithrombin (AT), protein C (PC), protein S (PS), elevated lipoprotein(a) (Lp(a)), total fasting plasma homocysteine (tHcy) levels, and anticardiolipin antibodies (ACAs)—were compared with those of 118 healthy control children. At onset, 32 (54.2%) of the 59 neonates showed underlying clinical conditions; 40 (67.8%) of them and 23 (85.2%) of the 27 infants with idiopathic RVT showed at least one PR. Univariate analysis revealed significantly elevated odds ratios/95% confidence intervals (ORs/95% CIs) for FV and Lp(a). Additionally, PC/AT deficiency and ACAs were found significantly more often in the patient group (P = .04). Multivariate analysis calculated significant ORs/95% CIs only for FV (OR, 9.4; 95% CI, 3.3-26.6) and elevated Lp(a) (OR, 7.6; 95% CI, 2.4-23.8). Of the 59 neonates investigated, 53 revealed renal atrophy, and 13 children additionally suffered from severe arterial hypertension. In conclusion, the present study demonstrates the significance of genetic PR—especially the FV mutation and elevated Lp(a)—for the etiology of neonatal RVT.

Description: Ischemic stroke is a rare event in childhood. In approximately one third of cases no obvious underlying cause or disorder can be detected. We investigated the importance of genetic risk factors of venous thromboembolism in childhood or stroke in adulthood as risk factors for spontaneous ischemic stroke in children. One hundred forty-eight Caucasian infants and children (aged 0.5 to 16 years) with stroke and 296 age-matched controls from the same geographic areas as the patients were analyzed for increased lipoprotein (a) [Lp(a)] levels 〉30 mg/dL; for the presence of the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR); and deficiencies of protein C, protein S, and antithrombin. The following frequencies (patients v controls), odds ratios (ORs), and confidence intervals (CIs) of single risk factors were found: Lp(a) 〉30 mg/dL (26.4% v 4.7%; OR/CI, 7.2/3.8 to 13.8; P 〈 .0001), FV G1691A (20.2% v 4%; OR/CI, 6/2.97 to 12.1; P 〈 .0001), protein C deficiency (6% v 0.67%; OR/CI, 9.5/2 to 44.6; P = .001), PT G20210A (6% v 1.3%; OR/CI, 4.7/1.4 to 15.6; P = .01), and the MTHFR TT677 genotype (23.6% v 10.4%; OR/CI, 2.4/1.53 to 4.5; P 〈 .0001). A combination of the heterozygous FV G1691A mutation with increased Lp(a) (n = 11) or the MTHFR TT677 genotype (n = 5) was found in 10.8% of cases, but only 0.3% of controls (OR/CI, 35.75/4.7 to 272;P 〈 .0001). Increased Lp (a) levels, the FV G1691A mutation, protein C deficiency, the prothrombin G20210A variant, and the MTHFR TT677 are important risk factors for spontaneous ischemic stroke in childhood.

Description: Background: Inherited thrombophilia (IT) has been described as a risk factor for venous thromboembolism (VTE) in children. So far the majority of studies performed in the field were either retrospective or prospective on small numbers of patients. Thus, the results are contradictory or inconclusive mainly due to lack of statistical power. The aim of this study was to better estimate the impact of IT on early VTE onset and recurrence in children as a prerequisite to develop primary and secondary treatment options. Methods: A systematic search of publications listed in the electronic databases (Pubmed, Medline, EMBASE, Web of Science, The Cochrane Library) up to August 2007 using key words in combination both as MeSH terms and text words, was conducted. Citations were screened by two independent group members and those meeting the inclusion criteria were retained. Articles were included if published after 1990, when pediatric VTE was started to be systematically investigated. Findings: Twenty case-control and 17 cohort studies from 13 countries met the inclusion criteria. In these studies 〉 70% of patients had at least one clinical risk factor. The summary odds ratios (OR) and 95% confidence intervals (CI) of included studies under a fixed-effects and random-effects model showed statistically significant associations between the IT traits investigated and VTE onset (table). For the rare event of VTE recurrence, 1227 patients (eight studies) were evaluated: at the present state due to high heterogeneity, a trend towards association with recurrent VTE was found for ≥2 IT traits in the fixed-effects model (0R/CI: 2.8/1.6–4.8). Interpretation: The present meta-analysis gives evidence that the detection of inherited thrombophilia is clincially meaningful in children with VTE and underlines the importance of a pediatric thrombophilia screening program. Summary of Data Risk Factors OR/CI:fixed model OR/CI:random model patients/controls 2470/4119 N/A FV G1691A 3.5/2.9–4.2 3.2/2.3–4.4 FII G20210A 2.2/1.5–3.3 2.2/1.5–3.4 Protein C defiiciency 9.8/5.9–16 9.9/6.1–16.1 Protein S deficiency 7.1/3.9–13.2 6.8/3.7–12.7 Antithrombin deficiency 7.9/3.8–16.6 7.3/3.4–15.3 Lipoprotein(a) 4.4/3,2–5.9 4/2.4–6.6 ≥ 2 risk factors 12.6/7.3–21.8 11.6/6.2–20.2

Description: Background The present study was performed to assess the association of prothrombotic risk factors and underlying conditions, e.g. smoking and obesity, with unexplained recurrent miscarriage (uRM) in white women. Methods and Results From 1998 to 2003, 133 Caucasian women aged 18–42 years (median 28 years) suffering from uRM were consecutively enrolled. In patients and 133 age-matched healthy controls prothrombotic risk factors (factor V (FV) G1691A, factor II (FII) G20210A, MTHFR T677T, 4G/5G plasminogen activator inhibitor (PAI)-1, lipoprotein (Lp) (a), protein C (PC), protein S (PS), antithrombin (AT), antiphospholipid/anticardiolipin (APA/ACA) antibodies) as well as associated environmental conditions were investigated. 70 (52.6%) of the patients had at least one prothrombotic risk factor compared with 26 control women (19.5%; p 30 mg/dL, increased APA/ACA and BMI 〉 25 kg/m2 in combination with a prothrombotic risk factor were found to be significantly associated with uRM. Associations of the heterozygous FII variant, MTHFR or 4G/4G PAI-1 genotypes, deficiency states of PC, PS and AT, as well as the combination of smoking with at least one prothrombotic risk factor did not reach statistical significance. In multivariate analysis, increased Lp(a) (odds ratio (OR): 4.7/95% confidence interval (CI): 2.0–10.7), the FV mutation (OR:3.8/CI:1.4–10.7), and increased APA/ACA (OR: 4.5/CI: 1.1–17,7) had independent associations with uRM. Conclusion In Caucasian women uRM is associated with the presence of elevated Lp(a) or further prothrombotic risk factors.

Description: It has been recently shown that the first bleeding onset in children with severe hemophilia A (HA) carrying prothrombotic risk factors is significantly later in life than in non-carriers.1 The present multicenter study was performed to determine whether the factor (F) V G1691A or the F II G20210A are associated with decreased annual bleeding episodes (ABE) in 106 pediatric PUP patients with severe HA (Intron 22 58.6%) consecutively admitted to German pediatric hemophilia treatment centers. Treatment was initiated according to the frequency of bleedings, and most patients received on demand therapy with a switch over to prophylactic therapy 3x/week (40–60 IU/kgKG factor VIIII concentrate) when more than three bleedings (range 2–6) had occurred into the same joint (n=49). Prospective median(range) patient follow-up was 14(4–35) years. Heterozygosity of the FV mutation was found in 8 subjects, homozygosity in one, and 5 children carried the FII mutation once combined with protein C-deficiency. Carriers of the FV and FII mutations had significantly fewer ABE than non-carriers (p=0.004). 66 of 106 PUP patients developed at least one target joint with a median(range) Pettersson score of 1(0–12) available in 57 patients clearly dependent on age (p=0.039) as well as ABE (p=0.037). The “Nuss” joint score available in 33 subjects highly correlated with the Pettersson score (p=0.007). Data presented here give evidence that the clinical expression of severe HA in children is influenced by the co-expression of the FV and FII mutation.

Description: The recurrence rate of thrombosis in children following a first thrombotic event ranges from 3% in neonates to 8% in older children. The relative importance of the factor II and factor FV mutations is unknown. We present a multicentre cohort study to assess the rate of symptomatic VTE recurrence per 1000 person-years in children heterozgous for the FII and FV mutations following a first VTE. Data were pooled to increase power for the secondary aims, e.g. time to recurrence, and predictors of recurrence. Between January 1994 and December 2006, 251 consecutively enrolled VTE patients aged newborn to ≤18 years (median 5.2 years: male n=141) carrying the FII (n=61) or FV mutation (n=190) were followed for a median of 58 (max 156) months. 128 of 251 VTE patients (51%) had at least one underlying medical condition at VTE onset, and 15 were heterozygous for both mutations. Children received acute anticoagulation (AC) with unfractionated heparin or low-molecular weight heparin, followed by AC with LMWH or warfarin for a three to 6 month period in 70% of cases. Of the 251 patients enrolled, 24 (9.5%: recurrence rate of 19.3 per 1000 person-years, 95% confidence interval (CI): 12.9–28.8) had recurrent VTE at a median (min-max) of 3.5 (0.1–120) months. Not including combined defects, the recurrence rate per 1000 person-years was 41.4 (95%CI: 22.3–77) for patients with the FII mutation, and 14 (95%CI: 8.3–23.6) for carriers of the FV mutation. Median (min-max) age at recurrence was 13.4 (0.1–17) years, 12 of 24 patients were male (50%), and in 21 of 24 children (87.5%) recurrence occurred after withdrawal of AC. When comparing FII with FV subjects, Cox regression analysis showed that the factor II mutation (HR/95%CI: 2.5/1.1–5.9; p=0.031) was associated more frequently with a second VTE. In addition, older age (〉 2 years) at first VTE onset (HR/95%CI: 1.1/1.01–1.14; p=0.025) independently influences the second VTE event [3.5 years (non-recurrence) vs. 12.7 years (recurrence); p〈 0.0001]. Among patients suffering from recurrent VTE, 58% occurred within the first six months following VTE onset. Time to recurrence (FII vs. FII and age at onset 〉/〈 2 ears) is shown in the Kaplan Meier analyses. The overall VTE recurrence rate of 9.5% is within the range recently reported in children. However, when comparing FII and FV carriers, the factor II G20210A variant is more often associated with a recurrent VTE. In addition, independently from the underlying gene mutation age 〉 2 years at first VTE increase the risk of a second symptomatic venous thrombosis. Figure Figure

Description: Objective To determine the importance of antithrombin [AT] deficiency as risk factor or predictor for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. Methods In the present cohort of 874 consecutively enrolled pediatric patients with VTE aged newborn to

Description: Abstract 3169 Background: Adapted from the adult definition, pediatric antiphospholipid syndrome [APS] has been defined as one or more arterial or venous thrombosis associated with persistent antiphospholipid antibodies, i.e. IgM or IgG anticardiolipin antibodies [ACL: cut-off 〉 99th age-dependent percentile] or the presence of lupus anticoagulants confirmed in at least one follow-up visit more than 8 to 12 weeks apart. Antiphospholipid antibodies play an important role in the development of pediatric thromboembolism [TE] with arterial TE or stroke being more often associated with primary APS compared to deep venous thrombosis [DVT], which is observed predominantly in children with secondary APS. However, results of single studies on the risk thromboembolism onset associated with APS have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of APS on risk of childhood arterial and venous TE via meta-analysis of published observational studies. Methods: A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2010 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, laboratory methodologies, country of origin, number of patients/controls, ethnicity, type and location of TE were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models. Results: Eight of 319 (DVT) and seven out of 185 (arterial TE) references found met inclusion criteria: In total 1403 patients and 1904 population-based controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. In addition, regression analysis did not reveal statistical significant differences between locations of TE, age at first disease onset, study country, or publication year. Thus, data from arterial and venous TE were analyzed together. A statistically significant association with a first TE onset was demonstrated with a cumulative summary ORs/CIs (fixed-effects model) of 5.9/3.6-9.7. Conclusions: The present meta-analysis indicates that APS serves as a clinical meaningful risk factor for a first symptomatic TE in children. However, the impact of APS upon outcome and recurrence risk needs to be further investigated. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3154 Poster Board III-91 Background. The development of alloantibodies that inhibit the coagulant activity of factor VIII (FVIII) is currently the most challenging complication of treatment in persons with hemophilia. Among other factors known to influence inhibitor development, several reports in the literature claimed for a different rate of inhibitor development in hemophilia A (HA) patients after plasma derived (pd-) or recombinant (r-) FVIII administration. Aim of this study was to compare the incident rate of inhibitors in HA patients treated with pd- or r-FVIII through systematic appraisal of the literature. Methods Studies reporting data about inhibitor rate in previously untreated patients (PUPs) with severe (〈 0.01 UI/mL) or severe-moderate HA were searched in the following electronic databases: Medline, EMBASE, OVID, Web of Science, The Cochrane Library. Details about study and patient characteristics were abstracted. To avoid double counting of patients included in more than one report of the same authors/working groups, patient recruitment periods and catchment areas were evaluated and authors were contacted for clarification if needed. If any of the required data could not be found in the published report, the corresponding author was contacted to provide the missing data of interest. High responder (HR) inhibitors were defined as 〉=5 BU/mL. Inhibitors were defined as transient when spontaneously disappearing within 6 months without the need to change treatment regimen. Firstly, the incident rate of inhibitor was recalculated for each study as the number of new inhibitor cases during the observation period divided by the number of HA patients initially inhibitor-free. Secondly, the recalculated rates were pooled for pd- and r- treated cohorts with the random effect model of Laird and Mosteller for single-cohort studies. Thirdly, a summary rate ratio (RR) was calculated for the subset of studies reporting parallel cohorts of patients treated with pd- or r-FVIII concentrates using fixed-effects and random-effects models. Sensitivity analysis, meta-regression and multivariate ANOVA were used to investigate the effect of covariates. Heterogeneity across studies and publication bias were evaluated. Results Twenty-four trials were included (19 prospective), 21 of which reporting details on HR inhibitors for a total of 2113 patients (1170 treated exclusively with pd-, 943 with r-FVIII; 1143 were severe), median age at enrolment was 9.6 months. The total number of inhibitors was 389 of which 135 in patients treated with pd- and 254 in patients treated with r-FVIII. HR inhibitors were 256 (103 for pd- and 153 for r-FVIII). Non-transient inhibitors were 162 (59 for pd- and 103 for r-FVIII). Inhibitor testing was from every 5 exposure days to every 2 year. Pooled incident rate (95% CI) was in all trials 14.7 (10.7 to 19.9) for pd- and 26.6 (22.6 to 31.0) for r-; for prospective trials 9.5 (5.7 to 15.3) for pd- and 22.4 (17.1 to 28.3) for r-; for HR inhibitors 8.5 (4.8 to 14.6) for pd- and 15.4 (12.2 to 19.3) for r-; for non-transient inhibitors 12.7 (7.3 to 21.1) for pd- and 18.9 (14.3 to 24.6) for r-. Six non concurrent cohort studies including 1259 HA patients met the inclusion criteria for RR calculation. Compared to pd-FVIII a statistically significant association with inhibitor development was demonstrated for r-FVIII, with summary RR ranging (95% CI) for HR inhibitors of 1.7 (C.I. 1.3 to 2.7), p〈 0.001, I2 = 0%, Harbord-Egger bias indicator p=0.07, fixed effect model; for all inhibitor patients of 2.0 (1.5 to 2.6), p〈 0.001, I2 = 41.6%, Harbord-Egger bias indicator p=0.06, random effect model. In the complete study set, testing frequency and study period correlated with rate of inhibitors development at meta-regression. At multivariate ANOVA testing frequency and study period were the strongest determinants of inhibitor development, and type of concentrate lost its statistical significance in the complete model. Conclusions This systematic review suggests that a lower inhibitor rate is found in patients with severe HA with the use of pd-FVIII, but also underscores the critical role of study related characteristics in the evaluation of the true effect of source of factor VIII. Future randomized and prospective follow-up studies are warranted. Disclosures No relevant conflicts of interest to declare.

Description: Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombin [ATD]-, protein C [PCD]- or protein S [PSD]-deficiency constitutes a major risk factor. Since screening for thrombophilia is controversial, individuals at high risk for recurrence who benefit from screening need to be identified. Primary study objective was to determinethe individual recurrence risk in children compared to adults with TE with respect to their thrombophilia status. Methods: In 142 consecutively enrolled TE patients (children n=85; adults n=57) with ATD, PCD or PSD after exclusion of six children with purpura fulminans due to homozygous PCD or PSD we calculated i) the cumulative recurrence rates (CRR) at 1, 5 and 10 year following the first TE onset and, ii) in addition, the absolute recurrence risk (ARR) per 100 patient years (%). Results: At first TE onset in univariate analysis a higher rate of unprovoked TE was found in children, whereas adults presented with a higher rate of a positive TE family history and a higher rate of recurrence: 40 out of 136 patients showed a second TE after withdrawal of anticoagulation (AC) or insufficient AC [n=6]. Two events in children were fatal [pulmonary embolism]. The overall CRR at 1, 5 and 10 years was 10.9%, 20.4% and 29.2% with total ARR [95% CIs] of 5.3 [3.4-7.8] in adults compared to 2.1 [1.0-5.3] in children [p=0.004]. Whereas the ARR was no different between adults and children in ATD patients [5.1 versus 4.7; p=0.85] and in symptomatic PCD subjects [3.9 versus 1.6; p=0.17], adults with PSD showed a higher ARR compared to children [6.3 versus 0.1; p=0.001]. Positive family TE history did not predict recurrence. Conclusion: Given the high ARR of 5.3% in adults and 2.1% in children we suggest screening for ATD, PCD and PSD in adult and pediatric TE patients. The high rate of ARR should be taken into account when initiating future therapeutic trials. Duration and intensity of AC should be carefully reevaluated in patients with ATD, PCD or PSD. Disclosures Young: Baxter, Grifols: Consultancy, Honoraria. Nowak-Gottl:Bayer, LFB: Membership on an entity's Board of Directors or advisory committees.