Thromboembolism in neonates and infants: impact of underlying diseases, prothrombotic risk factors and treatment modalities.
Explore the source record for details and available documents.
Anticoagulants↗
Biomedical subjects
U Nowak-Göttl
Publications and source records attributed to U Nowak-Göttl.
Isolated internal cerebral venous thrombosis in a neonate with increased lipoprotein (a) level: diagnostic and therapeutic considerations.
Background. Internal cerebral venous thrombosis is a life-threatening condition, which requires immediate therapy. Being infrequent in childhood, internal venous thrombosis is very rare in the neonate and has never been observed without concomitant occlusion of further dural sinuses. Case Description. We report a neonate born at term, who developed seizures on the third day of life after normal pregnancy and uneventful delivery. Ultrasound and CT disclosed bilateral intraventricular and intracerebral hemorrhage with an unusual distribution for germinal matrix hemorrhage. MRI disclosed thrombotic occlusion of the straight sinus and the internal cerebral veins with concomitant bleeding into the ventricles, the basal ganglia, thalamus and the periventricular hemispheres. The other sinuses were not affected. The clinical condition of the child improved after initiation of a low-dose heparin treatment with subsequent partial recanalization of the occluded vessels. The screening for risk factors disclosed an elevated lipoprotein (a) level, also present in both parents. Conclusion. Internal cerebral venous thrombosis may be encountered in neonates and must be included in the list of differential diagnosis of perinatal intraventricular and intracerebral bleeding. MRI allows the diagnosis even in the absence of widespread dural sinus occlusion. Low dose heparin may be a therapeutic option in these cases. This is the first report of neonatal internal venous thrombosis due to hereditary lipoprotein (a) level elevation, which must be included in the list of possible predisposing conditions.
Humans↗
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.
Blood Proteins↗
A common haplotype for the 677T thermolabile variant of the 5,10-methylenetetrahydrofolate reductase gene in thrombophilic patients and controls.
The common polymorphic transition 677C>T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene causes a thermolabile enzyme variant. This variant is associated with moderate hyperhomocysteinemia, a risk factor for vascular disease and thrombophilia. Up to now, it remained unclear if the thermolabile MTHFR variant either directly predisposes to vascular disease, or if 677T is only a genetic marker for another causative genetic alteration in cis. Aim of this study was to characterize the genetic background of 677T-alleles by haplotype analysis. We analyzed 25 individuals of German descent homozygous for 677T: nine young patients, who had suffered from thromboembolic events, and 16 healthy controls. The results of this study demonstrate that the 677T alleles are associated with a common haplotype most likely due to a founder effect and that the 677T haplotype was the same in the healthy and the thrombophilic German subjects.
Alleles↗
Association of the GPIa C807T and GPIIIa PlA1/A2 polymorphisms with premature myocardial infarction in men.
Aims Recent studies have reported an association between the platelet glycoprotein (GP) Ia C807T polymorphism and myocardial infarction, whereas other studies have reported contradictory results concerning the platelet GPIIIa PlA1/A2 polymorphism. In most of these studies the patients were older than 45 years. Thus we decided to examine both genotypes in 287 men who had their first myocardial infarction before age 45, and a group of 138 healthy controls. Methods and Results The frequency of T807 allele carriers was similar among myocardial infarction patients and among controls (54.6% vs 62.3%; odds ratio (OR) 0.73; 95% confidence interval (CI), 0.47-1.12). The frequency of PlA2 carriers was higher in cases than in controls (26.5% vs 15.2%; OR 1.65; CI, 1.09-2.54). After performing a logistic regression analysis, taking into account other cardiovascular risk factors, this difference did not remain significant. The combination of the risk alleles of both genotypes had no major effect on the myocardial infarction risk. Conclusions The GPIIIa PlA2 allele is not independently associated with the risk of premature myocardial infarction. The T807 allele of the GPIa gene alone or in combination with the PlA2 allele had no major effect on premature myocardial infarction risk.
Adult↗
Laboratory testing for thrombophilia in pediatric patients. On behalf of the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (ISTH).
Explore the source record for details and available documents.
Child↗
Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.
Explore the source record for details and available documents.
Child↗
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.
Adolescent↗
Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration.
Recently published data suggest that the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and elevated lipoprotein (a) concentrations were associated with venous thromboembolism in childhood patients treated according to the BFM protocol. To unravel the role of these prothrombotic risk factors and different treatment modalities, the present comparative study was performed in childhood leukemia patients of the same living population. Four hundred and twenty consecutively recruited leukemic children (BFM n=300; COALL n=120) were enrolled in this study with respect to the presence of prothrombotic risk factors and the occurrence of symptomatic venous thrombosis. No significant difference was found in the prevalence rates of thrombotic risk factors in the Caucasian populations studied. Symptomatic venous thromboembolism occurred in 11.6% of BFM patients compared with 2.5% in the COALL treatment group [odds ratio (OR)/95% confidence intervals (CI): 7.7/1.8-32.6; P=.005]. Including age, prothrombotic risk factors, central venous lines, treatment protocols, and anti-leukemic drugs in a logistic regression model, only the concomitant Escherichia coli asparaginase/prednisone administration in leukemic children suffering from a prothrombotic risk factor was found to increase the rate of thrombotic manifestations during leukemia treatment in patients of the same Caucasian origin (OR/95% CI: 34.5/4.39-271.42; P=.0008). Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases.
Adolescent↗
Interaction of fibrinolysis and prothrombotic risk factors in neonates, infants and children with and without thromboembolism and underlying cardiac disease. a prospective study.
UNLABELLED: To evaluate the role of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) in children with an estimated risk of vascular occlusion reported to range from 7% to 16%, we conducted a prospective study in infants and children with underlying cardiac disease. One hundred and twenty-five children (neonate - 16 years) were investigated. In 9 infants out of the 125 children vascular occlusion occurred, closely related to cardiac catheterisation and arterial or venous lines during major cardiac surgery. Six of the nine neonates and infants with (n=6) and without (n=3) prothrombotic risk factors showed evidence of a basically impaired fibrinolytic system. Five of the nine infants showed increased PAI-1 clearly correlated to the 4G/4G genotype of the plasminogen activator-1 promoter polymorphism along with elevated t-PA concentration before the first diagnostic cardiac catheterisation was performed. One infant presented with increased t-PA concentration only. Five of the six children with reduced fibrinolytic capacity had further prothrombotic risk factors. CONCLUSION: Data of this study indicate that neonates and infants with underlying cardiac disease and basically increased PAI-1 due to the 4G/4G variant of the PAI-1 promoter polymorphism along with elevated t-PA levels in combination with further prothrombotic risk factors are at high risk of developing early thromboembolism during cardiac catheterisation.
3' Untranslated Regions↗
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.
Activated Protein C Resistance↗
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.
3' Untranslated Regions↗
Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study.
BACKGROUND AND PURPOSE: We sought to compare different antithrombotic secondary treatments (mainly medium-dose aspirin with low-dose low-molecular-weight heparin [LMWH]) in pediatric patients with a first ischemic stroke onset with regard to the risk of stroke recurrence. METHODS: The population comprised 135 consecutively recruited children aged >/=6 months to </=18 years with a first episode of ischemic stroke (idiopathic, n=79; cardiac, n=15; vascular, n=30; infectious, n=11). The stroke patients enrolled received prophylactic antithrombotic therapy (aspirin, n=49; LMWH, n=86) in a nonrandomized fashion and were prospectively followed up for a median (range) of 36 (8 to 48) months. The study end point was recurrent stroke. RESULTS: Recurrent ischemic stroke was diagnosed at a median (range) of 5 (2 to 13) months after the first stroke onset in 13 of the 135 children (9.6%) receiving antithrombotic therapy. In the majority of cases (84.6%) the same vascular territory was involved. No significant difference was found with respect to the antithrombotic medication used (P=0.76, Fisher's exact test). No major drug-related side effects were observed. CONCLUSIONS: This prospective multicenter follow-up study has provided evidence that low-dose LMWH is not superior to aspirin and vice versa in preventing recurrent stroke in white pediatric stroke patients. However, further adequately sized randomized trials are required to obtain reliable information on safety and efficacy with respect to the antithrombotic medications used.
Adolescent↗
Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors.
It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and antithrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.
Actuarial Analysis↗
Effects of diets containing olive oil, sunflower oil, or rapeseed oil on the hemostatic system.
Various studies have already shown that the fatty acid composition of dietary fat has different effects on hemostasis and platelet function. However, knowledge on this topic is incomplete. In the present study, fifty-eight healthy students received either a 4-week rapeseed oil [high content of monounsaturated fatty acids (MUFA) and high n-3/n-6 PUFA ratio], an olive oil (high content of MUFA, low n-3/n-6 PUFA ratio) or a sunflower oil (low content of MUFA, low n-3/n-6 PUFA ratio) diet. In each group, effects on hemostatic parameters were compared with a wash-in diet rich in saturated fatty acids with respect to intermediate-time effects on the hemostatic system and platelet function. With the olive oil diet, a reduction of coagulation factors VIIc, XIIc, XIIa, and Xc was found, whereas sunflower oil led to lower values of coagulation factors XIIc, XIIa, and IXc. In all study groups levels of plasmin-alpha2-antiplasmin were lower in week 4 than at baseline. Lower fibrinogen binding on platelets was found after the sunflower oil diet, whereas expression of CD62 and spontaneous platelet aggregation were slightly higher after the olive oil diet. However, given the major differences in the fatty acid compositions of the diets, the differences between the groups with respect to hemostasis tended to be small. Therefore, the clinical significance of the present findings remains to be evaluated.
Adult↗
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.
Anticoagulants↗
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.
3' Untranslated Regions↗
Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism.
Elevation of serum lipoprotein (a) (Lp[a]) is a known risk factor predisposing to cardiovascular and cerebrovascular disease. However, little is known about the role of increased Lp(a) in venous thromboembolism (VTE). This study evaluated the role of Lp(a) among a panel of established hereditary thrombogenic defects in patients with VTE. A total of 685 consecutive patients with at least one episode of VTE and 266 sex- and age-matched healthy controls were screened with regard to activated protein C resistance, protein C, protein S, and antithrombin deficiency, elevated serum levels of Lp(a), and the factor V G1691A, MTHFR C677T, and prothrombin G20210A mutations. Elevated Lp(a) levels above 30 mg/dL were found in 20% of all patients, as compared to 7% among healthy controls (P <.001, odds ratio [OR] 3.2, 95% confidence interval [CI], 1.9-5.3). The coexistence of FV G1691A and elevated Lp(a) was significantly more prevalent among patients with VTE than in the control group (7% versus 0.8%; P <.001, OR 9.8, 95% CI, 2.4-40.7). No other established prothrombotic risk factor was found to be significantly combined with increased Lp(a). These data suggest that Lp(a) concentrations greater than 30 mg/dL are a frequent and independent risk factor for VTE. Furthermore, elevated Lp(a) levels might contribute to the penetrance of thromboembolic disease in subjects being affected by other prothrombotic defects, such as FV G1691A mutation.
Adolescent↗