Haemophilia and thrombophilia. What do we learn about combined inheritance of both genetic variations?

UNLABELLED: For the study presented here 135 pediatric PUP patients with haemophilia consecutively admitted to German pediatric haemophilia treatment centers were investigated. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the factor II (FII) G20210A variant, methylenetetrahydrofolate reductase (MTHFR) T677T genotype, elevated lipoprotein a (Lp a), antithrombin, protein C, and protein S were investigated. 103 out of 122 HA patients (FVIII activity <1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe haemophilia A (HA) did not differ from previously reported data: FV GA 5.8%, FII GA 3.9%, MTHFR TT 10%, elevated Lp a 7%, protein C type I deficiency 1.1%. The first symptomatic bleeding leading to diagnosis of severe haemophilia occurred with a median age of 1.6 years (range: 0.5-7.1 years) in children carrying prothrombotic risk factors compared to non-carriers (0.9 years (0.1-4.0; p = 0.01). Two patients presenting with neonatal stroke due to elevated Lp a and the FII GA variant showed haemorrhagic stroke transformation triggered by severe haemophilia. In addition, when haemophilia A was corrected by administration of factor VIII concentrates eight out of 25 children with central lines in place developed catheter-related thrombosis. CONCLUSION: The data of this multicentre cohort study demonstrate that the clinical phenotype of severe haemophilia A in childhood is clearly influenced by the coinheritance of prothrombotic risk factors.

Foetal growth restriction in children with prothrombotic risk factors.

Placental infarction is frequently observed in low birth weight children. To evaluate whether low birth weight in healthy term neonates is associated with foetal inherited prothrombotic risk factors this retrospective study was conducted. Outcome measures were "birth weight in the lowest quartile" and "birth weight in the lowest decile" in singletons with a gestational age of > or =37 weeks. The analyses were based on 375 Caucasian children screened at the Monster childhood thrombophilia centre with complete data for all prothrombotic risk factors (factor V G1691A, prothrombin G20210A, elevated lipoprotein (a), protein C-, protein S-, antithrombin-deficiency). The proportion of children in the lowest birth weight quartile increased from 23.7% to 30.5% to 48.0% for children with no, only single heterozygous and multiple or homozygous defects respectively. The respective adjusted odds ratios (95% confidence intervals) of thrombophilia for birth weight in the lowest quartile (lowest decile) were 1.53 (0.76-3.08) in carriers of one prothrombotic risk factor and 4.01 (1.48-10.84) in subjects carrying multiple or homozygous defects. We identified foetal thrombophilia as an additional cause of low birth weight.

Thromboembolism in newborns, infants and children.

As in adults, acquired and inherited prothrombotic risk factors increase the risk of thrombosis in neonates, infants and children. Duplex sonography, venography, computed tomography and magnetic resonance imaging can be used to diagnose childhood thromboembolism, but venography is the recommended method to confirm vascular occlusion of the upper venous system. After suffering thrombosis, patients should be screened for factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes, deficiencies of protein C, protein S, and antithrombin, elevation of lipoprotein (a) and fasting homocysteine concentrations (3 to 6 months after thrombotic onset: plasma-based assays). Data interpretation is based on age-dependent reference ranges and the identification of causative gene mutations/polymorphisms with respect to the individual ethnic background. Paediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are hampered by the lack of appropriate clinical trials. Thus, recommendations from small-scale studies in paediatric patients and guidelines adapted from adult patient protocols may be helpful in the management of paediatric patients on an individual patient basis.

Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease.

OBJECTIVE: Recently, an association between the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in infants with congenital neural tube defects or congenital oral clefts has been shown. However, no data are available so far with respect to the MTHFR 677TT genotype in children with underlying structural congenital heart disease (CHD). METHODS: We investigated the MTHFR genotype in 114 Caucasian CHD patients aged newborn to 16 years (median 0.6 years; 53% male) and in 228 age- and sex-matched healthy controls. RESULTS: In childhood patients with CHD the homozygous MTHFR 677TT genotype was found in 21 out of 114 subjects (18.4%) compared with 21 out of 228 controls (9.2%; odds ratio (OR) 2.2, 95%-confidence interval (CI) 1.2-4.3; P=0.027). In patients with pulmonary valve stenosis, hypoplastic left heart syndrome, coarctation of the aorta, aortic valve stenosis or subaortic stenosis the frequency of the TT genotype varied between 38 and 67% with corresponding ORs from 6.1 (CI, 1.4-27.5; P=0.034) to 20.4 (CI, 1.8-235.0; P=0.025), whereas in other structural CHD the frequency of this genotype was not significantly different from the controls. CONCLUSIONS: With the present study we can show for the first time that the embryonal MTHFR 677TT genotype is significantly associated with the development of structural congenital heart malformations during early pregnancy. It remains to be clarified, whether this genotype is at least a risk marker or a risk factor for structural congenital heart malformations.

Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.

After a first episode of spontaneous venous thromboembolism (VTE), the risk of recurrence persists for many years. However, comprehensive data about the risk of recurrence in pediatric patients have hitherto not been reported. Thus, this study evaluated the risk of recurrent VTE among children in relation to the presence of single or combined-inherited and/or acquired causes of thrombophilia. A total of 301 patients aged neonate to 18 years (median, 6 years) who were referred for an objectively confirmed first episode of spontaneous VTE were followed prospectively for a median time of 7 years (range, 6 months to 15 years) after withdrawal of anticoagulation. All patients were studied for established acquired and inherited causes of thromboembolism. With reference to all 301 patients, one single prothrombotic risk factor was found in 176 subjects (58.5%), whereas combined defects were found in 20.6% (n = 62). Recurrent VTE occurred in 64 patients (21.3%) within a median time of 3.5 years (range, 7 weeks to 15 years) after withdrawal of anticoagulation, with a significantly shorter cumulative thrombosis-free survival in children carrying combined defects (P <.0001; chi-square, 42.2). The factor V G1691A mutation was present in the majority of patients with recurrent VTE. Including genetic defects, gender, and acquired risk factors, multivariate analysis showed that only the presence of prothrombotic defects increases the risk of recurrent VTE (single defect: odds ratio [OR], 4.6; 95% confidence interval [CI], 2.3-9.0; P <.0001; combined defect: OR, 24.0; 95% CI: 5.3-108.7; P <.0001). As a consequence of the data presented here, it is suggested that screening for genetic risk factors be done among pediatric patients with VTE.

The plasminogen activator inhibitor (PAI)-1 promoter 4G/4G genotype is not associated with ischemic stroke in a population of German children. Childhood Stroke Study Group.

OBJECTIVES: To investigate the relationship between an insertion/deletion (4G/5G) polymorphism of the plasminogen activator inhibitor (PAI)-1 gene and childhood patients with a past history of ischemic stroke. METHODS: The PAI-1 4G/4G genotype and the coinheritance with lipoprotein (Lp) (a) levels, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the methylene-tetrahydrofolate reductase (MTHFR) T677T genotype were studied in 198 Caucasian children with stroke and 951 controls (same age, sex and ethnical distribution). In a randomly selected subgroup of patients/controls (n=60) PAI-I activities have been investigated. RESULTS: The distribution of the 4G/5G genotypes was no different in childhood stroke patients and controls, with a 4G allele frequency of 55.8% in patients compared with 53.8% in control subjects (P=0.49). The 4G/4G genotype compared with the remaining genotypes was present in 43 cases and 167 (17.6% vs. 21.7%; OR/CI: 1.30/0.89-1.98; P=0.3). PAI-1 activity was significantly elevated (P < 0.001) in the patient group. CONCLUSIONS: Data presented here suggest that the 4G/4G genotype is not a major risk factor in the aetiology of childhood ischemic stroke.

Symptomatic ischemic stroke in full-term neonates : role of acquired and genetic prothrombotic risk factors.

BACKGROUND AND PURPOSE: The present multicenter case-control study was prospectively designed to assess the extent to which single and combined clotting factor abnormalities influence the onset of symptomatic ischemic stroke in full-term neonates. METHODS: Lipoprotein (Lp)(a); the factor V (FV) G1691A mutation; the prothrombin (PT) G20210A variant; the methylenetetrahydrofolate reductase (MTHFR) T677T genotype; antithrombin; protein C; protein S; and anticardiolipin antibodies (ACAs) were investigated in 91 consecutively recruited neonatal stroke patients and 182 age- and sex-matched healthy controls. RESULTS: Sixty-two of 91 stroke patients (68.1%) had at least 1 prothrombotic risk factor compared with 44 control subjects (24.2%) (odds ratio [OR]/95% confidence interval [CI], 6.70/3.84 to 11.67). An increased Lp(a) level (>30 mg/dL) was found in 20 patients and 10 controls (OR/95% CI, 4.84/2. 16 to 10.86); FV G1691A was present in 17 patients and 10 controls (OR/95% CI, 3.95/1.72 to 9.0); the PT G20210A variant was detected in 4 patients and 4 controls (OR/95% CI, 2.04/0.49 to 8.3); the MTHFR TT677 genotype was found in 15 patients and 20 controls (OR/95% CI, 1.59/0.77 to 3.29); and protein C type I deficiency was found in 6 neonates. Neither antithrombin deficiency nor protein S deficiency was found in the neonatal patients studied. Acquired IgG ACAs were found in 3 cases. Additional triggering factors, ie, asphyxia, septicemia, maternal diabetes, and perinatally acquired renal venous thrombosis, were reported in 54.0% of patients. CONCLUSIONS: Besides acquired triggering factors, the data presented here suggest that genetic prothrombotic risk factors play a role in symptomatic neonatal stroke.

Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study.

The present study was designed to assess to what extent single and combined clotting abnormalities influence spontaneous vascular accidents in pediatric patients, and how the children affected differ in their prothrombotic risk profiles from their biological first-degree family members. In addition, this study was performed to investigate if relatively mild thrombophilic polymorphisms not leading to thrombosis in the parents cause severe clinical expression when coinherited with an established prothrombotic risk factor. The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, the plasminogen activator inhibitor (PAI)-1 promoter polymorphism, lipoprotein (Lp)(a), antithrombin, protein C, and protein S were investigated in 48 childhood patients aged neonate to <18 years (median 0.5 years) with spontaneous venous thromboembolism (SVT) compared with the carrier status of their first-degree family members. In 19 of the 48 patients (39.6%), one prothrombotic risk factor was diagnosed, and in 27 of the 48 subjects (56.3%) at least two prothrombotic defects/alleles. In the majority of cases with SVT, the FV G1691A mutation was involved either with a second mutated allele or combined with elevated Lp(a), the 4G/4G genotype of the PAI -1 promoter polymorphism, and the T677T MTHFR genotype. The rate of combined prothrombotic risk factors was significantly higher in childhood patients compared with their parents. In conclusion, based on the data presented here we suggest that early-onset SVT in childhood patients is mainly caused by combinations of at least two prothrombotic risk factors.

[Thrombocytic alpha-delta-storage-pool-disease: shortening of bleeding time after infusion of 1-desamino-8-D-arginine vasopressin]. / Alpha-delta-storage-pool-disease der Thrombozyten: Verkürzung der Blutungszeit durch Gabe von 1-Desamino-8-D-Arginin-Vasopressin (DDAVP).

BACKGROUND: The synthetic vasopressin derivate desmopressin (1-desamino-8-D-arginine vasopressin) has been reported to shorten the bleeding time in patients with hemophilia A, von Willebrand's disease and several functional platelet disorders. In addition to substitution of platelets, vasopressin is therefore used to prevent bleeding complications. CASE: We report the case of a 14-year-old female patient with prolonged bleeding time due to the rare thrombocytic alpha-delta-storage-pool-disease. When normal donor platelet substitution alone was ineffective, bleeding time was normalised after infusion of desmopressin and elective wisdom-tooth extraction was performed without significant postoperative bleeding. DISCUSSION: Infusion of desmopressin appears to be effective in shortening bleeding time in thrombocytic storage-pool-disease. Its use could prevent bleeding complications after trauma and surgical interventions and may possibly help to spare the need for platelet concentrates.

Role of genetic prothrombotic risk factors in childhood caval vein thrombosis.

UNLABELLED: Childhood caval vein thrombosis has a high incidence especially in the first year of life. Besides deficiencies of protein C, protein S, antithrombin and plasminogen, the factor (F) V G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydro-folate reductase (MTHFR) TT677 genotype, or increased lipoprotein (Lp) (a) > 30 mg/dl have emerged as important prothrombotic risk factors in childhood vascular accidents. 27 consecutive childhood patients with inferior caval vein thrombosis and 100 healthy age-matched controls were investigated for the presence of these prothrombotic risk factors with respect to the first thrombotic onset. In 19 out of 27, patients thrombosis occurred during infancy; the remaining vascular accidents were diagnosed during puberty. In 13 out of the 19 infants, vascular occlusion occurred spontaneously, five times associated with renal venous thrombosis. 68.4% of patients in the first year of life (n = 13) showed at least one prothrombotic risk factor. The FV mutation (heterozygous n = 4, homozygous n = 1). Lp (a) > 30 mg/dl and kringle 4 repeats < 28 (n = 4), MTH FR TT677 with mild hyperhomocysteinaemia (> 95th age-dependent percentile, i.e. 8.5 micromol/l: n = 3) and antithrombin deficiency type II (n = 1) were diagnosed with an overall odds ratio/95% confidence interval of 9.2/3.1-27.4. In the adolescent group, genetic risk factors were found in 50% of patients investigated (FV mutation (n = 1), PT variant (n = 3); odds ratio/95% confidence interval: 4.2/0.97-18.6). CONCLUSION: Data presented here suggest that genetic prothrombotic risk factors play an important role in childhood caval vein thrombosis. Remarkably, during puberty and adolescence the predominant defect diagnosed was the PT G20210A variant, whereas the FV G1691A mutation had a higher incidence during infancy.

[Assessment of independence in daily life in pediatric oncology by FMH-questionnaire]. / Quantifizierung von Krankheitsfolgen in der pädiatrischen Onkologie--klinische Erfahrungen mit der Fertigkeitenskala Münster/Heidelberg.

Therapy-related late effects are important for therapeutic decisions in pediatric oncology. We quantified the degree of impairment of independence in daily life in children with cancer. The German questionnaire "Fertigkeitenskala Münster/Heidelberg (FMH)" is a standardized tool for measurement of motoric and verbal functioning. A point-score leads to an age-related percentile ranking similar to typical percentiles in pediatrics. We used the FMH in 215 cancer patients (mean age 10.3 years, range 0.5-23.5 years, 56.3% male). Diagnoses were leukaemia (n = 91), bone tumors (n = 33), nephro- and neuroblastoma (n = 21), brain tumors (n = 18), lymphoma (n = 23), rhabdomyosarcoma (n = 11) and others (n = 18). The average time to answer the questionnaire was 4.5 min. Patients with brain and bone tumors showed significant lower percentile scores compared to patients with other diagnoses (p < 0.05). The FMH-scores increased with time since diagnosis (n = 215). This trend was confirmed in a longitudinal study over one year (n = 29). Quantitative assessment of independence and functioning in patients with cancer--especially in multicenter-studies--is possible. Because of therapy-related late effects this seems to be of special importance in brain and bone tumor patients.