To cite this article: Appel IM, Grimminck B, Geerts J, Stigter R, Cnossen MH, Beishuizen A. Age dependency of coagulation parameters during childhood and puberty. J Thromb Haemost 2012; 10: 2254-63.Summary. Background: Use of age-adjusted reference values is crucial for correct diagnosis and management of thrombotic and hemorrhagic disease in children. They vary with utilized reagents and analyzers. Objectives: We established reference values with the Sysmex CA-1500 System and in parallel with the Behring BCS System using reagents from Siemens Healthcare Diagnostics Products GmbH. Methods: After informed consent, blood samples were obtained from 218 healthy children and 52 healthy adults, grouped as 1-6 months (n = 29), 7-12 months (n = 25), 1-5 years (n = 57), 6-10 years (n = 57), 11-18 years (n = 50) and > 19 years (n = 52). Results: Most coagulation parameters demonstrate good comparability between analyzers with the exception of PT and APTT. Single coagulation factors fibrinogen, factor (F) II, FIX, FXI and XII were significantly decreased in the youngest children; the strongest age dependency was found for coagulation inhibitors Protein C and S, both significantly decreased in infancy and young childhood. We confirmed that high levels of von Willebrand factor are found in the youngest children without increased levels of FVIII followed by decreased von Willebrand levels in the subsequent age group. In children with blood group O a less distinct increase in time was found, compared with individuals with one of the other blood groups. Conclusions: The correlation between the CA-1500 and the BCS system was remarkable. Differences were most pronounced between children < 12 months and older children and adults, confirming the phenomenon of developmental hemostasis. The rationale for age-related changes in the hemostatic system remains unraveled. Our results underline the need for age-specific reference ranges.

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HRQOLHealth RESULTS Significant risk factors at presentation for a poor neurological outcome were young age, infarction in the right middle cerebral artery territory, and fever at presentation. Fifty-four % of children had severe neurological impairments at 12 months after PAIS, and at last follow-up more than half needed remedial teaching, special education, or institutionalization. Health-related quality of life (HRQOL) questionnaires showed a significantly lower HRQOL in all age groups. Children with a longer follow-up had a lower HRQOL in the cognitive functioning domain.INTERPRETATION Our study shows significant morbidity and mortality and a reduced HRQOL after PAIS depending on age, fever at presentation, and infarction in the right middle cerebral artery territory.Paediatric arterial ischaemic stroke (PAIS) is relatively rare, with an estimated incidence of 3 to 8 per 100 000 for children older than 1 month. 1 Many risk factors leading to PAIS have been identified. 1-3 The long-term outcome in children with PAIS is frequently poor, and a wide spectrum of impairments influencing physical and cognitive abilities as well as quality of life (QOL) has been reported. [4][5][6] Most studies focus on neurological impairments after PAIS, 7 and only a few studies have systematically addressed functional outcome. 4,[6][7][8] According to the World Health Organization's International Classification of Impairments, Disabilities and Handicaps, in clinical research functional outcome can be assessed on the following levels: disease process and impairment (the general effect of the disease on the child), disability (the restriction of the ability to perform tasks within the physical and social environment), handicap (the social consequences of these impairments and disabilities in the domains of relationships, school, and leisure activities), and QOL (the sense of the child's well-being and life satisfaction in physical, social, and emotional domains). 9 The first two levels are physician-oriented outcomes, whereas those at the third and fourth levels consist mainly of patient-based outcomes. The fourth level also contains information from the patient's or parent's perspective. Neurological impairments after PAIS may affect up to 90% of children and include hemiparesis, epilepsy, visual deficits, and language, educational, cognitive, and behavioural problems. 7,10-14 The percentage of disabilities after PAIS can be as high as 60%. 14 Most restrictions are found in the domains of education, motor function, self-care skills, communication, and socialisation. 8,12 When measured on the modified Rankin Scale (mRS), 12 ⁄ 100 of children have no disability, 63% have mild disabilities, and 25 ⁄ 100 have severe disabilities. 7,15 Handicaps in children with childhood stroke include a necessity for higher levels of educational support and special education, psychiatric symptoms and disorders, sleeping problems, fatigue, emotional lability, and aggressive outbursts and social problems. 7,11,12,16 The QOL in this patient group is sig...

L-asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is thought to result from depletion of asparagine in serum and cells. We investigated the clinical response in vivo of 1000 IU/m 2 pegylated (PEG)-asparaginase and its pharmacokinetic, pharmacodynamic and intracellular effects in children with newly diagnosed ALL before start of combination chemotherapy. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common/pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (P ¼ 0.01) and BCRABL-positive ALL (P ¼ 0.04). A poor in vivo clinical window response was related to in vitro resistance to L-asparaginase (P ¼ 0.02) and both were prognostic factors for long-term event-free survival (hazard ratio 6.4, P ¼ 0.004; hazard ratio 3.7, P ¼ 0.01). After administration of one in vivo dose of PEG-asparaginase no changes in apoptotic parameters or in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. One additional dose of PEG-asparaginase upfront ALL treatment did not lead to other severe toxicities.