Venous Malformations and Blood Coagulation in Children.

INTRODUCTION: Venous malformations (VMs) are congenital low-flow lesions with a wide spectrum of clinical manifestations. An increasing number of studies link VMs to coagulation abnormalities, especially to elevated D-dimer and decreased fibrinogen. This condition, termed localized intravascular coagulopathy (LIC), may pose a risk for hemostatic complications. However, detailed data on the laboratory variables for coagulation and fibrinolytic activity in VM patients are limited. We addressed this question by systematically analyzing the coagulation parameters in pediatric VM patients. METHODS: We included 62 patients (median age 11.9 years) with detailed laboratory tests for coagulation and fibrinolytic activity at a clinically steady phase. We assessed clinical and imaging features of VMs and their correlations with coagulation and fibrinolysis variables using patient records and MRI. RESULTS: D-dimer was elevated in 39% and FXIII decreased in 20% of the patients, as a sign of LIC. Elevated D-dimer and decreased FXIII were associated with large size, deep location, and diffuse and multifocal VMs. FVIII was elevated in 17% of the patients and was associated with small VM size, superficial and confined location, discrete morphology, and less pain. Surprisingly, antithrombin was elevated in 55% of the patients but without associations with clinical or other laboratory variables. CONCLUSIONS: LIC was common in pediatric patients with VMs. Our results provide a basis for when evaluating the risks of hemostatic complications in children with VMs. Further research is warranted to explore the mechanisms behind coagulation disturbances and their relation to clinical complications.

Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds.

The optimal mode of delivery for a pregnant hemophilia carrier is still a matter of debate. The aim of the study was to determine the incidence of intracranial hemorrhage and other major bleeds in neonates with moderate and severe hemophilia in relationship to mode of delivery and known family history. A total of 926 neonates, 786 with severe and 140 with moderate hemophilia were included in this PedNet multicenter study. Vaginal delivery was performed in 68.3% (n=633) and Cesarean section in 31.6% (n=293). Twenty intracranial hemorrhages (2.2%) and 44 other major bleeds (4.8%) occurred. Intracranial hemorrhages occurred in 2.4% of neonates following vaginal delivery compared to 1.7% after Cesarean section (P=not significant); other major bleeds occurred in 4.2% born by vaginal delivery and in 5.8% after Cesarean section (P=not significant). Further analysis of subgroups (n=813) identified vaginal delivery with instruments being a significant risk factor for both intracranial hemorrhages and major bleeds (Relative Risk: 4.78-7.39; P<0.01); no other significant differences were found between vaginal delivery without instruments, Cesarean section prior to and during labor. There was no significant difference in frequency for intracranial hemorrhages and major bleeds between a planned Cesarean section and a planned vaginal delivery. Children with a family history of hemophilia (n=466) were more likely to be born by Cesarean section (35.8% vs 27.6%), but no difference in the rate of intracranial hemorrhages or major bleeds was found. In summary, vaginal delivery and Cesarean section carry similar risks of intracranial hemorrhages and major bleeds. The 'PedNet Registry' is registered at clinicaltrials.gov identifier: 02979119.

Haematopoietic Stem Cell Transplantation in Children Shifts the Coagulation System towards a Pro-Coagulant State.

Coagulation system is disturbed by several mechanisms after allogeneic haematopoietic stem cell transplantation (HSCT). We evaluated the effect of HSCT on coagulation system by various conventional and investigational methods in 30 children and adolescents who received HSCT due to haematological malignancies. Pro-thrombin fragment 1 + 2, a specific measure of thrombin generation, and von Willebrand factor, a measure of endothelial activation, increased after conditioning treatment, and remained elevated until 3 months after HSCT (p < 0.05 for all comparisons to pre-conditioning treatment). D-dimer, a measure of fibrin turnover, was elevated from the second week onwards until 4 weeks after HSCT (p < 0.05). Endogenous thrombin potential was increased after conditioning, and at 2 weeks after HSCT (p < 0.05). Furthermore, the activities of acute phase reactants fibrinogen and coagulation factor VIII were increased (p < 0.05 for all comparisons to pre-conditioning treatment) from the first week onwards up to 3 weeks and 3 months after HSCT, respectively. Taken together, paediatric patients receiving HSCT demonstrate distinct and prolonged variations in the coagulation system towards a pro-coagulant state. This shift is of importance when estimating the risk of haemostatic and thrombotic complications in these children.

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors.

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0­6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8­28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5­10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

Growth impairment and gonadal axis abnormalities are common in survivors of paediatric brain tumours.

AIM: Childhood brain tumour survivors have a high risk of endocrine morbidity. This study evaluated the growth, pubertal development and gonadal function in survivors of childhood brain tumours and identified factors associated with the problems we observed. METHODS: The 52 subjects (52% male) were diagnosed in 1983-1997 and treated for brain tumours at Tampere University Hospital, Finland. They were followed up at a mean age of 14.2 (3.8-28.7) years, a mean of 7.5 (1.5-15.1) years after diagnosis. RESULTS: We found that 30 (58%) participants had a lower height standard deviation score at follow-up than at diagnosis and short stature at follow-up was associated with tumour malignancy (p = 0.005), radiotherapy (p = 0.004), chemotherapy (p = 0.024), growth hormone deficiency (p < 0.001), hypogonadism (p = 0.044) and delayed puberty (p = 0.021). We found that five needed sex hormones to induce puberty, one had precocious puberty, 12 (23%) had growth hormone deficiency and eight (22%) of the 36 pubertal or postpubertal patients had hypogonadism. Testicular volume was low in 83% of late or postpubertal male survivors. CONCLUSION: Growth impairment, growth hormone deficiency and hypogonadism were common in childhood brain tumour survivors and low testicular volume was also common in male survivors. Lifelong annual follow-up checks are indicated for survivors.

Electroretinography and Visual Evoked Potentials in Childhood Brain Tumor Survivors.

This population-based cross-sectional study evaluates the clinical value of electroretinography and visual evoked potentials in childhood brain tumor survivors. A flash electroretinography and a checkerboard reversal pattern visual evoked potential (or alternatively a flash visual evoked potential) were done for 51 survivors (age 3.8-28.7 years) after a mean follow-up time of 7.6 (1.5-15.1) years. Abnormal electroretinography was obtained in 1 case, bilaterally delayed abnormal visual evoked potentials in 22/51 (43%) cases. Nine of 25 patients with infratentorial tumor location, and altogether 12 out of 31 (39%) patients who did not have tumors involving the visual pathways, had abnormal visual evoked potentials. Abnormal electroretinographies are rarely observed, but abnormal visual evoked potentials are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggest a general and possibly multifactorial toxic/adverse effect on the visual pathway. Electroretinography and visual evoked potential may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment.

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

[Transient hemorrhagic diathesis caused by prothrombin-binding antiphospholipid antibody in a child]. / Protrombiiniin sitoutuvan fosfolipidivasta- aineen aiheuttama lapsen ohimenevä verenvuototaipumus.

We describe three previously healthy children who developed acute extensive bruises about two weeks after a mild stomach bug. Coagulation tests revealed a shortened thromboplastin time (TT), long PT time, low level of coagulation factor II, and positive lupus anticoagulant among the antiphospholipid antibodies. In one patient the clinical symptoms disappeared during a one-week course of prednisolone, another one received a prothrombin complex preparation as substitution therapy. In the third patient the symptoms were milder and vanished without any specific treatment. The levels of coagulation factor increased in all patients and the lupus anticoagulant disappeared within a couple of months.

Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Children's Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Factor VIII products and inhibitor development in severe hemophilia A.

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

[Menorrhagia in adolescents: normal or a sign of underlying medical condition?]. / Nuoren runsaat kuukautiset- -normaalia vai merkki sairaudesta?

Variations in the length of menstrual cycle as well as duration of menstrual flow are broad and common during adolescence. They are mainly caused by the immaturity of the hypothalamic-pituitary-ovarian axis. Normalization of ovulation during the first postmenarcheal years will gradually regularize the menstrual cycle. Several medical conditions, endocrine disturbances or medical treatments may affect the hormonal balance and cause abnormal bleeding. If anemia exists, the possibility of bleeding disorder should be considered. After proper evaluation, most abnormal bleedings in adolescents can be managed hormonally, with the addition of hemostatic therapies when necessary. Oral contraceptives are most commonly used.

Neurological outcome of childhood brain tumor survivors.

We assessed neurological and neurocognitive outcome in childhood brain tumor survivors. Altogether, 75 out of 80 brain tumor survivors diagnosed below 17 years between 1983 and 1997; and treated in Tampere University Hospital, Finland, were invited to participate in this population-based cross-sectional study. Fifty-two (69%) participated [mean age 14.2 (3.8-28.7) years, mean follow-up 7.5 (1.5-15.1) years]. Neurological status was abnormal in 69% cases. All were ambulatory, but only 50% showed normal motor function. Twenty-nine percent showed clumsiness/mild asymmetry and 21% hemiparesis. One suffered from intractable epilepsy. According to structured interview, 87% coped normally in daily living. Median full-scale IQ was 85 (39-110) in 21 6-16 year olds (70%); in 29% IQ was <70. Thirty of the 44 school-aged subjects attended school with normal syllabus and 32% needed special education. Six of the 16 patients over 18 years of age were working. Regarding quality of life, 38% were active without disability, 33% active with mild disability, 21% were partially disabled, but capable of self-care, and 8% had severe disability, being incapable of self-care. Supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy were associated with neurological, cognitive and social disabilities. In conclusion, of the 52 survivors, neurological status was abnormal in 69%; 71% lived an active life with minor disabilities, 29% had major neurological, cognitive and social disabilities, and 8% of them were incapable of self-care. Predictors of these disabilities included supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy. Survivors need life-long, tailor-made multiprofessional support and follow-up.

Hypercalciuria in children with haemophilia suggests primary skeletal pathology.

Several factors can compromise optimal bone mass accrual during childhood and predispose to osteoporosis later in life. Patients with haemophilia are already at risk of low bone mass during childhood, partly due to reduced physical activity related to joint bleeds and haemarthrosis. The introduction of primary prophylaxis with regular infusions of the deficient coagulation factor has enabled reduction or prevention of haemophilic arthropathy. Finnish children with severe haemophilia start prophylaxis early and are encouraged to participate in physical activities. We hypothesized that prophylactic therapy would ensure normal childhood bone mass development and carried out a case-control study in 29 children with haemophilia (2 mild, 6 moderate, 21 severe) and 58 age-matched controls. Their bone health was determined by fracture history, blood and urine biochemistry, bone densitometry and spinal imaging. Bone mineral density was lower in children with haemophilia but there was no evidence for significantly increased fracture rate. The patients had significantly higher urinary calcium excretion and higher serum calcium concentration, and reduced bone resorption as compared with the controls. Our findings suggest primary skeletal pathology, resulting in increased urinary calcium loss and altered bone metabolism, which may over time contribute to the development of osteoporosis in patients with haemophilia.

Obesity and metabolic changes are common in young childhood brain tumor survivors.

BACKGROUND: A population based cross-sectional study was used to examine the prevalence of metabolic syndrome and its components in childhood brain tumor survivors. PROCEDURE: Fifty-two survivors were examined at a mean age of 14.4 years (range 3.8-28.7). Lipid and glucose metabolism, thyroid function, and plasma uric acid were evaluated. Fat mass and fat percentage were assessed by dual-energy X-ray absorptiometry (DXA). Metabolic syndrome was defined on International Diabetes Federation criteria. RESULTS: Ten (19%) patients were overweight and four (8%) were obese. According to DXA, 16/46 (35%) patients were obese. Central obesity was found in 11 (21%) patients. Cranial irradiation, hypothalamic/hypophyseal damage, growth hormone (GH) deficiency and impaired mobility were associated with overweight/obesity and central obesity. Thirteen (25%) subjects had hypercholesterolemia, 14 (27%) had raised low-density lipoprotein cholesterol (LDL-C), 12 (23%) had raised blood pressure, four (8%) had metabolic syndrome, two (4%) had hyperinsulinemia and five (10%) had hyperuricemia. Cranial irradiation was associated with hypercholesterolemia (P = 0.019), raised LDL-C (P = 0.028), raised blood pressure (P = 0.040), and metabolic syndrome (P = 0.018). Impaired mobility was associated with hypercholesterolemia (P = 0.034). Hypothalamic/hypophyseal damage was associated with metabolic syndrome (P = 0.003) and hyperuricemia (P = 0.011) as was GH deficiency (P = 0.034 and P = 0.008). GH supplementation alleviated adverse metabolic outcomes among brain tumor survivors with GH deficiency. CONCLUSIONS: Obesity/overweight, dyslipidemia, hypertension, metabolic syndrome, and hyperuricemia were common in young childhood brain tumor survivors. Cranial irradiation, hypothalamic/hypophyseal damage, growth hormone deficiency, and/or impaired mobility were associated with higher risk for obesity and metabolic changes among these patients.

Fetomaternal platelet immunization associated with maternal Bernard-Soulier syndrome.

Our objective was to describe the clinical outcome and the association of fetomaternal platelet immunization in pregnancies with maternal Bernard-Soulier syndrome. We conducted an observational study of two mothers, six pregnancies, and six neonates, with special emphasis on platelet antibodies and thrombocytopenia-associated complications. The first woman presented with platelet-associated autoantibodies and thrombocytopenia, but her three newborn infants showed normal platelet count and function. The other woman had three pregnancies, all of which were complicated by severe fetal and neonatal alloimmune-type thrombocytopenia, without demonstrable antibodies. We concluded that fetomaternal immunization with severe fetal and neonatal thrombocytopenia may be encountered even in the absence of demonstrable antibodies.