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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.

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.

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-1 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

Background: Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events. Methods: Data were collected from 24 patients aged 4.5 to 23 years who had inflammatory bowel disease. Platelet count, antithrombin, fibrinogen, prothrombin fragment F1+2, soluble thrombomodulin, tissue plasminogen activator, D-dimer, and plasminogen activator inhibitor- 1 antigen were investigated. In addition the response to activated protein C, the factor V R506Q mutation, protein C, free protein S antigen, and lipoprotein (a) were analyzed. These data were compared with medical treatment, duration, and disease activity, estimated with the Pediatric Crohn's Disease Activity Index or the Clinical Colitis Activity Index. Results: Forty-five percent of our patients showed an increase in fibrinogen. 29% in prothrombin fragment F1+2, and 20% in platelet count, plasminogen activator inhibitor-1 antigen, and soluble thrombomodulin. Thrombomodulin was higher in active disease than in inactive disease and in Crohn's disease than in ulcerative colitis. Fibrinogen was also higher with Crohn's disease and tended to be higher in active disease than in ulcerative colitis and inactive disease. Plasminogen activator inhibitor-1 antigen was significantly higher in patients with Crohn's disease than in those with ulcerative colitis and was higher in the patient group treated with steroids. Conclusion: As has been shown in adults, young patients with active and inactive inflammatory bowel disease were found to have abnormal coagulation and fibrinolysis. The relevance as a thromboembolic risk factor is discussed.

SummaryTo determine to what extent the Arg506 to Gin mutation in the factor V gene influences the fibrinolytic response after 20 min venous occlusion (VO) we investigated a population of APC resistant children (n = 60) and a group of age-matched healthy controls (n = 25). After 20 min VO, symptomatic (n = 30) carriers of the common factor V mutation showed significantly reduced t-PA activities compared with asymptomatic (n = 30) carriers (p

Zusammenfassung:Thrombosen und Embolien sind im Kindesalter nicht zu unterschätzen. Typische Ursachen sind zentrale Katheter, Herzkatheteruntersuchungen mit Intervention, größere operative Eingriffe neben primären oder sekundären Mangelzuständen von Gerinnungsinhibitoren. Geschätzt wird eine Inzidenz von etwa 5 auf 10000 hospitalisierte Kinder mit einer Mortalität von 2%, einer Rezidivrate von 7-18% sowie der Entwicklung postthrombotischer Syndrome in 20% der Fälle. Die Erfahrungen mit thrombolytischen Therapieformen im Kindesalter sind begrenzt. In mehreren Studien gut dokumentiert sind Thrombolysen von akuten Verschlüssen der Femoralarterien nach Herzkatheruntersuchungen: In 10 Studien wurden 147 von 164 (90%) Patienten erfolgreich lysiert, lokale Blutungen traten bei 41 von 164 (25%) auf. Auf kleinere Studien begrenzt sind Therapien von Thrombosen in den Nierenvenen, den zentralvenösen Gefäßen sowie im rechten Atrium. Erfahrungen mit Lysen linksatrialer, linksventrikulärer oder aortaler Thrombosen sowie Lungenembolien im Kindesalter liegen bisher nur in Form von Kasuistiken vor.

Resistance to activated protein C (APCR), in the majority of cases due to the point mutation Arg 506 Gln of the factor V gene, has emerged as the most important hereditary cause of venous thromboembolism. Using an activated thromboplastin time (aPTT) based method in the presence of APC together with a DNA technique based on the polymerase chain reaction, we investigated 37 children with venous (V: n=19) or arterial (A: n=18) thromboembolism and 196 age-matched healthy controls for the presence of this mutation. In the control group 10 children were detected to be heterozygous for the factor V Leiden mutation, indicating a prevalence of 5.1%. 10/19 children (52%) with venous thrombosis and 7/18 (38%) patients with arterial thromboembolism showed the common factor V gene mutation. Additional inherited coagulation disorders were found in 1/10 (V:10%) and 2/7 (A:28%) APC-resistant patients. Inherited coagulation disorders without APCR were diagnosed in 3/9 (V: 33%) and 2/11 (A:18%) children. Furthermore, we diagnosed exogenous risk factors in 6/10 (V: 60%) and 2/7 (A: 28%) children with thrombosis and APCR. These data are evidence that APCR combined with exogenous reasons may play an important role in the early manifestation of thromboembolism during infancy and childhood.

ZusammenfassungThrombosen im Kindes- und Jugendalter sind ernst zu nehmende Ereignisse und erfordern neben einer Ursachenklärung eine adäquate Therapie. Bei den heute üblichen Lysetherapien im Kindesalter haben Laboranalysen neben der Überwachung der Antikoagulanzientherapie die wesentliche Aufgabe der Therapiesteuerung. Die Laboranalyse besteht vor Thrombolysetherapie in der Bestimmung von Thrombozytenzahl, Hämoglobin, TPZ, aPTT, Fibrinogen, Antithrombin, Plasminogen und D-Dimer. Während der Lysetherapie sollen zur Therapiesteuerung, zur Erfassung von möglichen Nebenwirkungen und Begleitantikoagulation Thrombozyten, Hämoglobin, aPTT, Antithrombin, Plasminogen und D-Dimer bestimmt werden. Zur Verhinderung einer Reokklusion unter voller Antikoagulation nach Thrombolyse besteht die Laborkontrolle in der Akutphase in der Analyse von aPTT, Antithrombin und D-Dimer.

Summary Objective : resistance to activated protein C (APCR) has emerged as the most important hereditary cause of venous thromboembolism. To determine to what extent this relatively common gene mutation influences the overall haemostatic balance, coagulation and fibrinolysis were investigated in a population of APC resistant children (n=46) in comparison to an age-matched healthy control group (n=80). Results : compared to the sex- and age-matched healthy control thrombomodulin (TM), F1+2, D-Dimer formation, t-PA, u-PA, PAP and PAI 1 were significantly increased in the APCR children. In addition, TM, D-Dimer, t-PA, u-PA, PAI 1 and PAP showed a significantly positive correlation to the amount of thrombin generated. No difference was found between children and patients who had suffered from vascular insults before this study was conducted. Conclusions : children with APCR showed a combination of activated coagulation and fibrinolysis.

Summary Objective : circulating plasma thrombomodulin (TM), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) are endothelial cell markers which may reflect endothelial injury. To find out to what extent diagnostic cardiac percutaneous catheterisation irritates vascular endothelium we conducted a prospective study in 114 children. Results : compared to starting values TM, t-PA and u-PA concentrations show a clearly significant increase at the end of cardiac catheterisation. TM and u-PA returned to pretreatment values 24 hours later, t-PA remained elevated. Four of 114 children developed vascular occlusion near the puncture sites within 48 hours of cardiac catheterisation. Two patients Conclusions : data of this study indicate that increased TM, t-PA and u-PA concentrations after percutaneous cardiac catheterisation in children are signs of endothelial damage.

Ischaemic stroke is a rare event in childhood. In approximately one-fourth of cases an underlying cardiac disease can be detected. We investigated the importance of genetic risk factors of venous thromboembolism in childhood or stroke in adulthood as risk factors for ischaemic stroke in children in a multicentre survey focusing on patients with a cardiac disease. 38 of 162 white infants and children (neonate – 18 years) with ischaemic stroke were suffering from a cardiac disorder. An age-matched group of 100 children from the same geographic areas as the patients served as controls. Patients and controls were analysed for increased lipoprotein (a) levels >30 mg/dl, for the presence of the factor V (FV) G1691A mutation, the prothrombin (PT) G20210 A variant, and deficiencies of protein C, protein S, and antithrombin. The following frequencies (patients vs. controls), odds ratios (OR) and confidence intervals (CI) of single risk factors were found: Lp(a) >30 mg/dl (18.4% vs. 5%; OR/CI: 4.3/1.3–14.4; p = 0.03), FV G1691A (13.2% vs. 4%; OR/CI 3.63/0.92–14.3; p = 0.12) protein C type I deficiency (15.8% vs. 1%; OR/CI: 18.5/2.15–16.0; p = 0.0017), anticardiolipin antibodies (10.5% vs. 0%; p = 0.0051). No protein S or antithrombin deficiency was found. Combinations of haemostatic disorders were found in 10.5% of cases but in none of the controls (Fisher 0.005). Conclusion While FV G1691A and prothrombin G20210 A mutations show no significant data in our study, lipoprotein (a) levels >30 mg/dl protein C deficiency, anticardiolipin antibodies and combined prothrombotic disorders seem to be important risk factors for manifestation of ischaemic strokes in children with underlying cardiac disorders.

Zur Einschatzung der moglichen pathoatiologischen Bedeutung von Hamostasedefekten [8,18,23] werden im Rahmen einer ESPED-Studie [7] seit Oktober 1996 bei ischamischen Infarkten im Kindesalter folgende Parameter erfragt: Patientendaten, Lokalisation des Insults, nichthamostaseologische Grunderkrankungen and Triggerereignisse, die fur den Schlaganfall (mit-)ursachlich sein konnten, and hamostaseologische Parameter [APC-Resistenz, Faktor-V-Leiden-Mutation, Protein S, Protein C, Antithrombin, Faktor V and XII, Prothrombin and Prothrombin- 2021oA-Mutation, Plasminogen, PAI and PAI-Polymorphismus (4G/4G), Lipoprotein (a), Homozystein, Antiphospholipid-Antikorper] [4,5,9,14,18].

AIMS—To determine to what extent the Arg506 to Gln point mutation in the factor V gene and further genetic factors of thrombophilia affect the risk of porencephaly in neonates and infants. METHODS—The Arg506 to Gln mutation, factor V, protein C, protein S, antithrombin, antiphospholipid antibodies and lipoprotein (a) (Lp(a)) were retrospectively measured in neonates and children with porencephaly (n=24). RESULTS—Genetic risk factors for thrombophilia were diagnosed in 16 of these 24 patients: heterozygous factor V Leiden (n=3); protein C deficiency type I (n=6); increased Lp (a) (n=3); and protein S type I deficiency (n=1). Three of the 16 infants had two genetic risk factors of thrombophilia: factor V Leiden mutation combined with increased familial Lp (a) was found in two, and factor V Leiden mutation with protein S deficiency type I in one. CONCLUSIONS—The findings indicate that deficiencies in the protein C anticoagulant pathway have an important role in the aetiology of congenital porencephaly.

Objective: To determine the association between catheter-related thromboses and hereditary causes of thrombophilia, including the factor V Leiden mutation, deficiencies of protein C or protein S, or increased lipoprotein (a). Study design: To evaluate the incidence of genetic risk factors for familial thrombophilia in catheter-related thrombosis, 163 consecutively admitted infants and children (cardiac disease and catheter placement [C] n = 140; Broviac catheter [B] n = 23) were prospectively investigated. In addition, an age-matched, healthy control group undergoing elective surgery (S: n = 155) was investigated. Results: Heterozygous factor V Leiden mutation was diagnosed in 20 of the 318 study subjects (C: n = 5; B: n = 4; S: n = 11), homozygous factor V Leiden mutation was found in two subjects (C: n = 1; S: n = 1), protein C deficiency type I was diagnosed in nine subjects (C: n = 4; B: n = 1; S: n = 4), and five subjects showed increased lipoprotein (a) (C: n = 3; S: n = 2). The frequency of thrombosis (C: n = 13; B: n = 5) in patients with familial thrombophilia was significantly higher ( p < 0.0001; chi square: 27.79) in the catheter groups (15 of 17 subjects) than in control subjects after minor elective surgery (none of 18). Fifteen of the 18 infants with thrombosis had congenital thrombophilia; two children with congenital thrombophilia did not have documented thrombosis, and three infants with vascular occlusion had no inherited predisposition to thrombophilia. Conclusions: Genetic risk factors for familial thrombophilia play an important role in the manifestation of catheter-related thromboembolism in children. (J Pediatr 1997;131:608-12)

Few studies of activated protein C resistance (APCR) and thromboembolism in childhood have been published. In the majority of childhood thromboses reported, the factor V Leiden mutation was associated with venous thromboses; however, one case report and three studies described arterial thromboembolism in infants and children due to the common mutation in the factor V gene. In one neonate purpura fulminans occurred, and heparin-induced thrombocytopenia type II was additionally documented. Two case reports and seven of nine studies reported associated clinical conditions together with inherited coagulation disorders. In three studies homozygous patients were mentioned. There are few studies describing the interaction between APCR and coagulation or the fibrinolytic system in symptomatic and nonsymptomatic infants. Compared with healthy brothers or sisters and a healthy age-matched control group, thrombin generation, D-dimer, PAI-1 activity, and t-PA antigen were found clearly elevated in children with APCR. In addition, infants and children with the Arg506-to-Gln mutation in the factor V gene showed significantly increased thrombomodulin concentrations along with normal protein C activities compared with relatives and healthy controls. No difference was recorded in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism. Until long-term data are available for the treatment of patients with APCR, such children should be treated in the same way as patients with deficiencies of protein C, protein S, or antithrombin.

This study was designed to prospectively evaluate haemostatic activation in 53 children undergoing cardiac catheterisation with intermittend flush heparin (10 IU/ml saline) and to relate these data to clinical findings and inherited risk factors for thrombophilia. In addition to flush heparin in infants < 6 months of age in whom additional arterial catheterisation was perfomed (n = 5) or patients with thrombophilia, heparin (300-400 IU/kg/d) was administered for a further 24 h. APTT was prolonged and anti Xa activity was significantly increased at the end of catheterisation and returned to normal 24 h later. Whereas thrombin generation (Fi + 2) showed a significant coagulation activation at the end of catheterisation, no concomitant fibrinolytic activation (D-Dimer) was observed. Three children showed resistance to APC: one of them in whom stroke had occurred before and one additional child heterzygous for APCR received further prophylactic heparin. Two neonates with APCR and flush heparin only suffered from thrombosis after catheterisation. No further thrombotic events occured. This study indicates that low-dose flush heparin during catheterisation may prevent long-term haemostatic activation in children without thrombophilia. Whether further heparin after cardiac catheterisation in children with APCR prevents vascular insults requires a more intensive study.

OBJECTIVES: In the majority of cases, resistance to activated protein C is caused by the point mutation Arg 506 to Gln in the factor V gene and has emerged as the most important hereditary cause of thromboembolism. METHODS: To determine to what extent resistance to activated protein C was present in children with thromboembolism and underlying cardiac disease, its occurrence was retrospectively investigated. By using a method based on activated partial thromboplastin time, with DNA technique derived from the polymerase chain reaction, we investigated nine children with underlying cardiac disease in whom thromboembolism had previously occurred. RESULTS: Heterozygous Arg 506 -to-Gln mutation in the factor V gene was diagnosed in five of the nine children investigated. In addition, protein C type I deficiency w as found in three patients, and two of the nine children showed increased lipoprotein (a) plasma values. Risk factors were present in all children with symptoms. CONCLUSIONS: These data indicate that deficiencies in the protein C anticoagulant pathway are likely to play an important role in the early manifestation of thromboembolism in children with underlying cardiac disease. (J Pediatr 1996;129:677-9)

This study was designed to prospectively evaluate haemostatic activation in 75 children undergoing cardiac catheterisation with intermittent flush heparin (10 IU/ml saline) and to relate these data to clinical findings and inherited risk factors for thrombophilia. In addition to flush heparin in infants < 6 months of age in whom additional arterial catheterisation was performed (n = 5) or patients with thrombophilia, heparin (300-400 IU/kg/d) was administered for a further 24 h. APTT was prolonged and anti Xa activity was significantly increased at the end of catheterisation and returned to normal 24 hours later. Whereas thrombin generation (F1 + 2) showed a significant coagulation activation at the end of catheterisation, no concomitant fibrinolytic activation (D-Dimer) was observed. Four children showed resistance to APC: one of them in whom stroke had occurred before and one additional child heterozygous for APCR received further prophylactic heparin. Two neonates with APCR and flush heparin only suffered from thrombosis after catheterisation. No further thrombotic events occurred. This study indicates that low-dose flush heparin during catheterisation may prevent long-term haemostatic activation in children without thrombophilia. Whether further heparin after cardiac catheterisation in children with APCR prevents vascular insults requires a more intensive study.

Resistance to activated protein C (APCR) has emerged as the most important hereditary cause of venous thromboembolism. Using an aPTT-based method together with DNA technique we investigated 120 healthy neonates and infants12 months of age and 24 infants with septicaemia for the presence of this mutation. In addition, data of 11 neonates with vascular occlusion, heterozygous (+/-) for the Arg 506 Gln mutation were included. Results of an aPTT-based method (clotting time using the APC/CaCl2 solution obtained in an undiluted, 1:5 and 1:11 dilution with factor V deficient plasma divided by clotting time with CaCl2 in the same plasma dilution) are shown: Whereas 7 (5.5%) out of 120 healthy neonates were (+/-) carriers for the factor V Arg 506 Gln mutation, concordance with the aPTT-based method (cut-off defined as ratio2) was found only when using the 1:11 plasma dilution. Six (four) out of 24 infants with sepsis, not carrying the factor V mutation, would have been classified as APC resistant when using the 1:1 (1:5) plasma dilution. Four (two) out of 18 patients, (+/-) for the Arg 506 Gln mutation showed APC ratios2 in the 1:1(1:5) plasma dilution.

Purpose. Elevated lipoprotein (a) [LP (a)] concentrations are independent risk factors of coronary heart disease or stroke in young adults. To clarify its role in childhood thromboembolism, Lp (a) was measured in 72 children with thromboembolism. Methods. In addition to Lp (a), defects of the protein C anticoagulant system, antithrombin, and antiphospholipid antibodies were investigated in children with arterial (n = 36) or venous (n = 36) thrombosis. Results. Enhanced Lp (a) >50 mg/dL was diagnosed in 8 out of 36 children with arterial and 5 out of 36 patients with venous thrombosis. Of the 72 children, 25 showed the factor V Leiden mutation, 10 showed protein C deficiency, 2 showed antithrombin deficiency, and 4 showed primary antiphospholipid syndrome. Three children with increased Lp (a) were heterozygous for the factor V Leiden mutation, and 1 girl showed additional protein C deficiency. Conclusions. Data of this study indicate that increased concentrations of Lp (a) play an important role in childhood thrombosis. childhood thrombosis, lipoprotein (a), factor V Leiden, protein C.