Many coagulation parameters, such as PT or aPTT, show age-dependency. In this study we investigated if the generation of thrombin, possibly better reflecting overall haemostasis, shows an age-dependency. Thrombin generation was measured in platelet poor plasma of 121 children and 86 adults at different ages by means of calibrated automated thrombography (CAT). Correlation analysis shows that endogenous thrombin potential (ETP) (r = 0.702), lag time (r = -0.266), peak (r = 0.533) and time to peak (r = -0.214) are significantly correlated with age (p < 0.01). 'Younger' (age limit 35 years) and 'older' adults were compared with groups of children and adolescent aged between 0.5 and 6 years, 7 and 11 years and 12 to 17 years by means of the Mann-Whitney-U-Test. ETP values of all children and adolescents were significantly lower than those of adults. In the group of the youngest children, additionally shorter lag times and times to peak and lower peak levels differed significantly from those of adults. In the group of 7- to 11-year-old children, lag times were significantly longer than those of both groups of adults, while lower peaks and longer times to peak differed only from the group of the 'older' adults. In the group of the 12- to 17-year-olds, the values of ETP were lower than those of adults. In addition, both adult groups differed significantly in all studied parameters. Our results show an age-dependency of thrombin generation even beyond the juvenile period. If thrombin generation measurement is to be used as a routine method, age has to be considered. Assuming that thrombin potential is an indicator for the risk of thrombosis, our findings are in accordance with the observation of an increased incidence of thrombembolic disease with higher age.

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Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed.AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells.Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins.HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

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