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Investigates the relationship between an insertion of polymorphism of the plasminogen activator inhibitor gene of ischemic stroke. Risk factors of thromboembolic events in adults; Development of cardiovascular disease; Focus of the acute phase of stroke onset.

The diagnosis and treatment of inflammatory rheumatic diseases can be delayed by a long waiting period for an appointment with a rheumatologist. This study investigated whether preselection of patients in an early arthritis clinic is a suitable tool to improve this situation. In 2006 an early arthritis clinic was founded by the Collaborating Center of Rheumatology in Halle (Saale). General practitioners refer patients by using a special registration form that helps to identify patients with an early joint swelling or inflammatory back pain. Patients are then allocated to a pool of participating rheumatologists and are seen by one of them within 2 weeks. For our scientific evaluation the data of 248 patients from the early arthritis clinic and data of 187 regular patients were gathered by means of an additional questionnaire for rheumatologists and patients. In the early arthritis clinic 40.3 % of patients received the diagnosis of an inflammatory rheumatic disease compared with 19.3 % in the control group. In the latter group 51 % were diagnosed as having degenerative joint or spine disorders compared with 22 % in patients from the early arthritis clinic; however, 61 % of patients who were referred to the early arthritis clinic did not fulfill the criteria of the registration form. On the other hand, patients in this group fulfilling these criteria had an inflammatory rheumatic disease in 68.1 % of the cases. The mean duration of symptoms at the time of first rheumatological consultation was significantly shorter in the early arthritis clinic than in the control group (6 vs. 39 months). Our data demonstrate that the preselection of patients can serve as a useful instrument to guide the referral of patients to rheumatologists. The high percentage of patients who did not fulfil the criteria of the registration form indicates that a further improvement of this form is necessary and stresses the need for intensive communication between rheumatologists and general practitioners. Early arthritis clinics may be an alternative to the current efforts of the legislative authorities to improve specialist care by centralized distribution of specialist appointments.

Cardiovascular diseases are the most common disorder in the developed countries. Invasive cardiological and cardiosurgical techniques are known therapies. Yet, patients with severe hereditary haemorrhagical diseases (haemophilia, rare deficiencies of coagulation factors) have an increased bleeding risk by the use of anticoagulants. Therefore, the treatment of these patients requires a concomitant therapy. This article shows eight patients with a severe bleeding diathesis and cardiosurgical interventions in the years 2006 to 2011. This case report shall demonstrate that an adequate therapy can be accomplished with the help of a good cooperation between haemostaseologists and colleagues of the cardioinvasive/cardiosurgical disciplines.

The von Willebrand-Jürgens syndrome (VWJS) type 1 is a common hereditary bleeding disorder with a bleeding tendency located especially in the mucous membranes. Women suffering from VWJS type 1 show menorrhagia and prolonged postoperative bleedings. During pregnancy the clinical presentation varies by the increase of the von Willebrand factors. In this article the laboratory findings and the clinical presentation of patients with VWJS during pregnancy was examined. The necessity of interventions during pregnancy and at the time of delivery was under consideration.

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.

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.

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.

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.

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., (Copyright 2006 S. Karger AG, Basel)

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.

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.

Thromboembolic events in neonates are very rare. They are often associated with severe disease affecting the newborn or are secondary to central venous lines or arterial catheters. Most of the described cases of thromboses of the iliac or femoral arteries are associated with cardiac catheterisation or femoral invasive blood pressure monitoring. The relationship between single umbilical arteries and an increased incidence of structural and chromosomal anomalies is well known, but a higher rate of thromboembolic disease in infants with single umbilical arteries has not been described. Rt-PA (recombinant tissue plasminogen activator) has been successfully used in small studies and numerous case reports. To date controlled clinical trials giving guidelines for antithrombotic therapy using rt-PA are still lacking. We report the clinical course of a 700 g premature male, who was born by Caesarean section at 29 + 6 gestational weeks. On the fifth day the baby suffered from arterial thrombosis of the right pelvis axis. Antenatally a single umbilical artery was identified. Iliac arteries on the involved site appeared hypoplastic. Additionally, the prothrombin G20210A mutation was found. The patient was treated successfully using recombinant tissue plasminogen activator. In the case of a high risk of limb or organ loss due to arterial thrombosis, thrombolysis using rt-PA is justified. Appropriate rt-PA treatment has been studied for the adult but not the paediatric population. Hence, well-designed clinical trials are necessary to determine the pharmacokinetics and dynamics of thrombolytic agents in children.

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.

Alterations in hemostasis leading to symptomatic thromboembolism have been observed in patients with acute lymphoblastic leukemia (ALL) receiving Escherichia coli asparaginase (CASP) combined with steroids. Moreover, hereditary prothrombotic risk factors are associated with an increased risk for venous thromboembolism in pediatric ALL patients treated according to the BFM 90/95 protocols (including CASP combined with prednisone during induction therapy). To assess whether the thromboembolic risk associated with established prothrombotic risk factors is modified by treatment modalities (prednisone or dexamethasone), the present analysis was performed. Three hundred thirty-six consecutively recruited leukemic children treated according to different BFM protocols (PRED group, n = 280, 60 mg/m(2) prednisone; DEXA group, n = 56, 10 mg/m(2) dexamethasone during induction therapy) were studied. Study end point was the onset of symptomatic vascular accidents during induction therapy. Cumulative thromboembolism-free survival was significantly reduced in children in the PRED group (thrombosis frequency, 10.4%) compared with children in the DEXA group (thrombosis frequency, 1.8%; P =.028). Although no significant difference was found in the overall prevalence of prothrombotic risk factors, 46.5% of patients in the PRED group who experienced thromboembolic events were carriers of a prothrombotic risk factor, whereas no carrier in the DEXA group had a thromboembolism. At the time of maximum CASP activity, fibrinogen and activities of antithrombin, plasminogen, and protein S were significantly reduced in the PRED group. No significant correlation could be found between CASP activity and levels of coagulation factors. In conclusion, the use of dexamethasone instead of prednisone, administered with CASP, significantly reduced the onset of venous thromboembolism.

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.

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 factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, together with fasting homocysteine (HCY) concentration, lipoprotein (Lp)(a), anti-thrombin (AT), protein C (PC), protein S (PS) and anti-cardiolipin antibodies were investigated in 65 consecutively recruited infants (neonate to < 12 months) with renal venous thrombosis (RVT; n = 31), portal vein thrombosis (PVT; n = 24) or hepatic vein thrombosis (HVT n = 10), and 100 age- and sex-matched healthy controls. FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only. PC type I deficiency was diagnosed in three patients (RVT n = 2; PVT n = 1) and AT deficiency in two patients (RVT n = 1; PVT n = 1). Three neonates with spontaneous thrombosis showed FV G1691A combined with Lp(a) and the FV G1691A was combined with the PT G20210A genotype in two infants. Additional triggering factors were reported in 27 patients (41.5%). The overall odds ratios (ORs) and 95% confidence intervals (CIs) with respect to the different thrombosis locations were: RVT (OR/CI: 10.9/3.85-31.1; P < 0.0001), PVT (5.47/1.7-17.6; P < 0.0007) and HVT (3.3/0.58-18.7; P = 0.18). The data presented here suggest that genetic prothrombotic risk factors also play an important role in abdominal venous thrombosis during infancy.

The reported incidence of thromboembolism in children with acute lymphoblastic leukemia (ALL) treated with L-asparaginase, vincristine, and prednisone varies from 2.4% to 11.5%. The present study was designed to prospectively evaluate the role of the TT677 methylenetetrahydrofolate reductase (MTHFR) genotype, the prothrombin G20210A mutation, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and increased lipoprotein (a) concentrations in leukemic children treated according to the ALL-Berlin-Frankfurt-Muenster (BFM) 90/95 study protocols with respect to the onset of vascular events. Three hundred and one consecutive leukemic children were enrolled in this study. Fifty-five of these 301 subjects investigated had one established single prothrombotic risk factor: 20 children showed the TT677 MTHFR genotype; 5 showed the heterozygous prothrombin G20210A variant; 11 were carriers of the factor V G1691A mutation (heterozygous, n = 10; homozygous, n = 1); 4 showed familial protein C, 4 protein S, and 2 antithrombin type I deficiency; 9 patients were suffering from familially increased lipoprotein (a) [Lp(a)] concentrations (>30 mg/dL). In addition, combined prothrombotic defects were found in a further 10 patients: the FV mutation was combined with the prothrombin G20210A variant (n = 1), increased Lp(a) (n = 3), protein C deficiency (n = 1), and homozygosity for the C677T MTHFR gene mutation (n = 1). Lp(a) was combined with protein C deficiency (n = 2) and the MTHFR TT 677 genotype (n = 2). Two hundred eighty-nine of the 301 patients were available for thrombosis-free survival analysis. In 32 (11%) of these 289 patients venous thromboembolism occurred. The overall thrombosis-free survival in patients with at least one prothrombotic defect was significantly reduced compared with patients without a prothrombotic defect within the hemostatic system (P <.0001). In addition, a clear-cut positive correlation (P <.0001) was found between thrombosis and the use of central lines. However, because the prothrombotic defects diagnosed in the total childhood population studied were all found within the prevalences reported for healthy Caucasian individuals, the interaction between prothrombotic risk factors, ALL treatment, and further environmental factors is likely to cause thrombotic manifestations.

In the period of 1.1.1988 to 1.5.1992 49 children, 28 boys and 21 girls, were treated with 219 MTX infusions. The acute hepatotoxicity was investigated from day--1 to day 5 of treatment duration. 30 patients suffered of a ALL, 6 of a relapse of a ALL, 3 of a ANLL and 10 of a NHL. We studied the MTX dosage and the infusion time. At all patients the determination of the activity of the liver enzymes ASAT, ALAT and GGTP in the serum took place according to the treatment protocol. The increase of enzymes activity correlated with the intensity and kind of hepatocellular damage. Partly the extreme increase of lesion parameters is not the expression of an irreversible cytonecrosis. Beside the ALAT also the GGPT is a sensitive predictor of hepatocellular lesion. The high enzyme activity before the MTX application is a indicator of a preexistent cell damage of the liver. The hepatotoxicity measured in the serum was highly correlated with the AUC.