Effects of primary and secondary prophylaxis on the clinical expression of joint damage in children with severe haemophilia A. Results of a multicenter non-concurrent cohort study.

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.

Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study.

BACKGROUND: The relative importance of previous diagnosis and hereditary prothrombotic risk factors for cerebral venous thrombosis (CVT) in children in determining risk of a second cerebral or systemic venous thrombosis (VT), compared with other clinical, neuroimaging, and treatment variables, is unknown. METHODS: We followed up the survivors of 396 consecutively enrolled patients with CVT, aged newborn to 18 years (median 5.2 years) for a median of 36 months (maximum 85 months). In accordance with international treatment guidelines, 250 children (65%) received acute anticoagulation with unfractionated heparin or low-molecular weight heparin, followed by secondary anticoagulation prophylaxis with low-molecular weight heparin or warfarin in 165 (43%). RESULTS: Of 396 children enrolled, 12 died immediately and 22 (6%) had recurrent VT (13 cerebral; 3%) at a median of 6 months (range 0.1-85). Repeat venous imaging was available in 266 children. Recurrent VT only occurred in children whose first CVT was diagnosed after age 2 years; the underlying medical condition had no effect. In Cox regression analyses, non-administration of anticoagulant before relapse (hazard ratio [HR] 11.2 95% CI 3.4-37.0; p<0.0001), persistent occlusion on repeat venous imaging (4.1, 1.1-14.8; p=0.032), and heterozygosity for the G20210A mutation in factor II (4.3, 1.1-16.2; p=0.034) were independently associated with recurrent VT. Among patients who had recurrent VT, 70% (15) occurred within the 6 months after onset. CONCLUSION: Age at CVT onset, non-administration of anticoagulation, persistent venous occlusion, and presence of G20210A mutation in factor II predict recurrent VT in children. Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with newly identified CVT and at high risk of recurrent VT. Factors that affect recanalisation need further research.

Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children--results of a multicenter studys.

The present multicenter cohort study of 107 pediatric PUPs was performed to determine whether the concomitant inheritance of the factor (F) V G1691A or the F II G20210A mutation influences the clinical expression of severe hemophilia A (HA). Carriers of the FV and FII mutations had a significantly lower annual bleeding frequency (ABF) than non-carriers (p=0.012). Joint damage (Pettersson score) was significantly less severe in patients with thrombophilia (p=0.022). A protective effect of thrombophilic risk factors was shown for ABF (OR [CIs]: 0.7[0.5-0.9]; p=0.02) and the severity of the hemophilic arthropathy (OR [CIs]: 0.06[0.01-0.3]; p=0.0009).

Familial elevated factor VIII in children with symptomatic venous thrombosis and post-thrombotic syndrome: results of a multicenter study.

OBJECTIVE: To evaluate the role of factor (F) VIII in children with non-cancer related venous thrombosis (DVT), post-thrombotic syndrome (PTS) or recurrent DVT. METHODS AND RESULTS: FVIII levels were measured in White patients and age- and gender-matched healthy controls. Heritability of factor VIII was estimated in 99 pedigrees by the variance component method implemented in SOLAR. The group of 103 patients showed higher median values of FVIII than 206 controls [FVIII:Ag, 115 versus 96 IU/dL, P<0.0001; FVIII:C, 119 versus 106 IU/dL, P=0.0009], and had a significantly increased odds ratio (OR) for fibrinogen-adjusted elevated FVIII levels [FVIII >90th percentile versus values below the cut-off: FVIII:Ag, OR 4.3, 95% confidence interval (CI) 1.5 to 12.1; FVIII:C, OR 5.5, CI 2.03 to 15.06]. PTS occurred in 19 of 59 children and persisted in 5 individuals. Recurrent DVT was seen in 8 patients. The heritable(h2)/household(c2) components were calculated for FVIII:Ag levels (h2, 0.48+/-0.15, P=0.0008; c2, 0.21), and FVIII:C (h2, 0.61+/-0.15, P<0.0001; c2, 0.41). When incorporating h2 and c2 in the estimate, the phenotypic variance for FVIII:Ag levels is predominantly explained by h2, whereas c2 stayed significant in the model for FVIII:C (P=0.00002). CONCLUSIONS: Elevated FVIII levels increase the DVT-risk in children.

Long-term safety and efficacy data on childhood venous thrombosis treated with a low molecular weight heparin: an open-label pilot study of once-daily versus twice-daily enoxaparin administration.

In this open label pilot safety study 80 children over 3 months old with deep venous thrombosis were treated with enoxaparin with a target 4 h anti-factor Xa activity between 0.5-0.8 IU/mL. The children were stratified to receive once daily or twice daily doses. The study end-points were post-thrombotic syndrome, re-thrombosis, bleeding, and therapy-related death. The median duration of treatment was 5 months and the median follow-up was 24 months. No significant differences were found between the two groups of patients. No bleeding or therapy-related deaths occurred. These safety and efficacy data may serve as a basis to initiate an international multicenter study on enoxaparin treatment.

Cerebral venous thrombosis in children: a multifactorial origin.

BACKGROUND: The present study was performed to assess the association of prothrombotic risk factors and underlying conditions (infections, vascular trauma, immobilization, malignancies, autoimmune diseases, renal diseases, metabolic disorders, obesity, birth asphyxia, cardiac malformations, and use of prothrombotic drugs) with cerebral venous thrombosis (CVT) in children. METHODS AND RESULTS: From 1995 to 2002, 149 pediatric patients aged newborn to <18 years (median 6 years) with CVT were consecutively enrolled. In patients and in 149 age- and gender-matched children with similar underlying clinical conditions but without CVT, the factor V G1691A mutation, the factor II G20210A variant, lipoprotein(a) [Lp(a)], protein C, protein S, antithrombin, and antiphospholipid antibodies, as well as associated clinical conditions, were investigated. Eighty-four (56.4%) of the patients had at least 1 prothrombotic risk factor compared with 31 control children (20.8%; P<0.0001). In addition, 105 (70.5%) of 149 patients with CVT presented with an underlying predisposing condition. On univariate analysis, factor V, protein C, protein S, and elevated Lp(a) were found to be significantly associated with CVT. However, in multivariate analysis, only the combination of a prothrombotic risk factor with an underlying condition (OR 3.9, 95% CI 1.8 to 8.6), increased Lp(a) (OR 4.1, 95% CI 2.0 to 8.7), and protein C deficiency (OR 11.1, 95% CI 1.2 to 104.4) had independent associations with CVT in the children investigated. CONCLUSIONS: CVT in children is a multifactorial disease that, in the majority of cases, results from a combination of prothrombotic risk factors and/or underlying clinical condition.

Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study.

BACKGROUND AND PURPOSE: The present study was performed to evaluate the rate of recurrent symptomatic thromboembolism with respect to prothrombotic risk factors and underlying clinical conditions. METHODS: In a series of 215 consecutively enrolled neonates with arterial ischemic stroke (AIS), the factor V G1691A mutation, factor II G20210A variant, methylenetetrahydrofolate reductase (MTHFR) T677T genotype, lipoprotein (Lp) (a), antithrombin, protein C, protein S, and anticardiolipin antibodies (ACA) were investigated. Patient median follow-up was 3.5 years (range, 1 to 8 years). RESULTS: During follow-up, 7 infants and children (3.3%) showed recurrent symptomatic thromboembolism (AIS, n=4; venous sinus thrombosis, n=2; deep vein thrombosis of the leg, n=1). The factor V mutation, factor II variant, elevated Lp(a) >30 mg/dL, protein C deficiency, and protein S or antithrombin deficiency were associated with first stroke onset. In 5 of 7 cases (71.4%), prothrombotic risk factors [MTHFR T677T, elevated Lp(a), hyperhomocysteinemia, protein C deficiency] were involved at the time of recurrence. Furthermore, a second thromboembolic event was triggered additionally by underlying diseases (71%), eg, cardiac malformation and immobilization, diarrhea, mastoiditis, and moyamoya syndrome. CONCLUSIONS: Data shown here give evidence that symptomatic recurrent thromboembolism is not common in children with neonatal AIS. The risk of a second event, however, is increased when underlying diseases occur and prothrombotic risk factors are involved.

Long-term treatment of thrombosis with enoxaparin in pediatric and adolescent patients.

Thrombosis is a rare event in childhood and adolescence. Nevertheless, increasing numbers of invasive diagnostic and therapeutic procedures also result in increasing numbers of thromboses in pediatric cases, necessitating effective antithrombotic treatment regimens. In recent years, low-molecular-weight heparins (LMWH) in particular have been proved to be a safe and effective alternative to unfractioned heparins. However, the application of LMWH in pediatric patients has not been supported by a single controlled study so far. Furthermore, there is no official approval of these drugs for children. In this pilot study 27 children with deep venous thromboses (DVT) were treated with the LMWH enoxaparin at a dosage of 1.5 mg/kg body weight b.i.d. in neonates and infants and 1 mg/kg body weight b.i.d. in children. This dosage was lowered for prophylaxis if therapeutic success was achieved. The aim of the study was to investigate both, efficacy with respect to patency rates and safety during acute and long-term follow-up. Sufficient therapeutic success required a rapid production of anti-Xa target activity and was reached in 85% of the treated patients, who showed patency of the affected vessel at last follow-up. The mean duration of treatment with full dosage was 16.5 days, followed by prophylaxis over a mean duration of 9.8 months. Rethrombosis or adverse events including heparin-induced thrombocytopenia were not observed in any patient. In conclusion, enoxaparin provides an effective and safe alternative to unfractioned heparins in the treatment of thrombosis in infancy, childhood and adolescence.

Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up.

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.

Thrombosis in children with hematologic malignancies.

This review is based on pediatric reports (- January 2004) on the presence of symptomatic thrombosis in children with hematologic malignancies, mainly acute lymphoblastic leukemia, treated with different treatment protocols and associated with acquired and inherited prothrombotic risk factors (factor V G1691A, factor G20210A, MTHFR C677T genotypes, protein C, protein S, antithrombin, elevated levels of lipoprotein(a), and homocysteine). The interactions of treatment modalities, study designs, ethnical backgrounds and associated central lines are discussed. Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases. In addition, primary preventive anticoagulant/antithrombotic strategies are discussed.

Prospective assessment of risk factors for recurrent stroke during childhood--a 5-year follow-up study.

BACKGROUND: Risk factors for arterial stroke in children include congenital heart malformations, vasculopathies, infectious diseases, collagen tissue diseases, and metabolic disorders. Results of previous case-control studies have shown an association between ischaemic stroke and hereditary prothrombotic risk factors: factor V G1691A and factor II G20210A mutations, raised lipoprotein (a), and deficiencies in antithrombin, protein C, and protein S. The relevance of these factors to a second ischaemic stroke event is not known. METHODS: We assessed the risk of a second arterial ischaemic stroke associated with these prothrombotic risk factors, with underlying diseases or stroke comorbidities, and with stroke subtypes (cardiac, vascular, infectious, idiopathic). 167 boys and 134 girls aged between 6 months and 18 years of age (median 7 years) with a first episode of ischaemic stroke were followed-up prospectively for a median of 44 months (range 20-56). FINDINGS: Recurrent ischaemic stroke was diagnosed in 20 of 301 children who survived (6.6%) at a median of 5 months (range 1.5-36) after first stroke onset. The relative risk of having a second stroke was significantly increased in patients with raised lipoprotein (a) (relative risk 4.4, 95% CI 1.9-10.5) and in children with familial protein C deficiency (3.5, 1.1-10.9). Additionally, survival analysis showed that a first ischaemic stroke of vascular origin was significantly associated with having a second stroke (odds ratio 3.9, 95% CI 1.4-10.6). INTERPRETATION: Raised lipoprotein (a), protein C deficiency, and stroke of vascular origin are risk factors for recurrent arterial ischaemic stroke in childhood.