Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion

Romy M. W. Kremers; Rob J. Wagenvoord; H. Bas de Laat; Paul Monagle; H. Coenraad Hemker; Vera Ignjatovic

doi:10.1160/TH15-09-0716

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(06): 1090-1100
DOI: 10.1160/TH15-09-0716

Coagulation and Fibrinolysis

Schattauer GmbH

Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion

Romy M. W. Kremers

¹Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

²Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

,

Rob J. Wagenvoord

¹Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

,

H. Bas de Laat

¹Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

²Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

,

Paul Monagle

³Murdoch Childrens Research Institute, Parkville, Victoria, Australia

⁴Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia

⁵Department of Clinical Hematology, Royal Children’s Hospital, Parkville, Victoria, Australia

,

H. Coenraad Hemker

¹Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

²Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands

,

Vera Ignjatovic

³Murdoch Childrens Research Institute, Parkville, Victoria, Australia

⁴Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia

› Author Affiliations

Abstract

Summary

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, α₂ Macroglobulin (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.

Keywords

Developmental haemostasis - haemostatic balance - prothrombin conversion - thrombin generation - thrombin inactivation

Full Text

References

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