title: Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion.
abstract: Thrombin generation (TG) is decreased in children. TG is determined by two underlying processes: the conversion of prothrombin to thrombin and the inactivation of thrombin. Therefore, lower TG capacity in children can either be caused by a reduction of prothrombin conversion, an increase of thrombin inactivation, or both. In 36 children and 8 adults, TG and the factors that determine thrombin inactivation (antithrombin, α2Macroglobulin (α2M) and fibrinogen) were measured. Prothrombin conversion, thrombin inhibitor complex formation, and the overall thrombin decay capacity were determined. In silico modelling was performed to determine the contribution prothrombin conversion and thrombin inactivation to deviant paediatric TG. Both the amount of prothrombin converted and the maximal prothrombin conversion rate are significantly reduced in children as compared to adults. This is partly due to the prothrombin levels being lower and partly to a lower prothrombin conversion rate. The overall thrombin decay capacity is not significantly different in children, but α2Macroglobulin plays a more important role than it does in adults. In silico experiments demonstrate that reduced prothrombin conversion and to a lesser extent elevated α2M levels provide an explanation for low TG in children. Young age has a dual effect on prothrombin conversion. Lower plasma prothrombin levels result in decreased prothrombin conversion but the rate of prothrombin conversion is also decreased, i. e. the development of prothrombinase is lower than in adults.
authors.affiliation: Romy Kremers, Oxfordlaan 70, 6229 EV, Maastricht, the Netherlands, Tel.: +31 43 388 5891, E-mail: r.kremers@thrombin.com.
authors.forename: Romy M W
authors.initials: RM
authors.lastname: Kremers
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Wagenvoord
authors.forename: H Bas
authors.initials: HB
authors.lastname: de Laat
authors.forename: Paul
authors.initials: P
authors.lastname: Monagle
authors.forename: H Coenraad
authors.initials: HC
authors.lastname: Hemker
authors.forename: Vera
authors.initials: V
authors.lastname: Ignjatovic
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D058833:Antithrombin Proteins / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D045384:Pregnancy-Associated alpha 2-Macroglobulins / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D058833:Antithrombin Proteins; D045384:Pregnancy-Associated alpha 2-Macroglobulins; D011516:Prothrombin; D005340:Fibrinogen; D013917:Thrombin
keywords: Developmental haemostasis; haemostatic balance; prothrombin conversion; thrombin generation; thrombin inactivation