Haematology Research

Selected projects

Project 1: Developmental Haemostasis

A child’s coagulation system evolves with age, a concept known as Developmental Haemostasis. The term was coined in the early 1990s and relates to the marked physiological differences in the concentration of most haemostatic proteins within different age-groups. We previously developed the first age-related normative data for a large number of coagulation proteins in Australian neonates and children. This reference data is used by many laboratories around the world, and has been translated into a number of languages.

Developmental Haemostasis provides a protective mechanism for children, decreasing the risk for thromboembolic and/or haemorrhagic events. For example, the bleeding phenotype of von Willebrand Disease in children is different to that in adults, such that bleeding rarely occurs in the first six-12 months of life. Similarly, the risk of thrombosis after orthopaedic surgery in children is a fraction of that observed for similar surgery in adults. Despite the increasing frequency of thromboembolic events in tertiary paediatric hospitals, it remains substantially reduced compared to the frequency of thrombosis in adult populations. The marked age-related differences in the coagulation system are thought to contribute significantly to the reduced risk of thrombosis in neonates and children compared to adults. In 2006, we performed pilot studies showing that fibrinogen isolated from neonatal and child plasma is qualitatively different to that isolated from adult plasma. Our current investigations are focusing on further characterising the age-related structural differences in haemostatic proteins.

Project 2: Anticoagulant Therapy in Children

Unfractionated heparin (UFH) is the most commonly used anticoagulant in children. Over 15% of all patients at the Royal Children's Hospital are exposed to UFH during their stay. The therapeutic ranges for UFH therapy in children are calculated using adult plasma and therefore extrapolation of these to children may be invalid.

There remain significant unanswered questions about the optimal use of heparin in children. Currently, the only data on the interactions of UFH with the developmental haemostatic system has come from experiments with heparin spiked in vitro. With a clinical thrombosis service which manages large numbers of children with thromboembolic events and the first age-related reference ranges for coagulation proteins in Australian children, we can now examine in vivo the interactions of these antithrombotic agents in newborns and children as the first step in determining age-specific treatment guidelines.

The aim of this project is to increase our understanding of the interactions between UFH and the developing haemostatic system of newborns and children. This will provide a rational basis for determining the optimal UFH therapy in these patients.

Project 3: Ageing of the human plasma proteome and implications for diseases associated with ageing

Proteomics has previously been used to study diseased versus healthy states, the effects of particular drugs and also the discovery of biomarkers. We are using sophisticated laboratory techniques to investigate the age-specific differences in the human plasma proteome. Characterisation of the age-related differences in the plasma proteome of the healthy population will provide new insights into normal growth and development and in our understanding of developmental biology. For example, if the age-related functional changes reported in the coagulation system proteins are related to changes in function secondary to post-translational modifications (as distinct from actual changes in protein concentration), then this has enormous implications for the way we currently view the development of the human haemostatic system, and potentially the way those proteins work within other physiological systems. Given that the incidence of the majority of diseases (i.e. diabetes, thrombosis, cardiovascular disease, cancer) increase with age, these results will provide the basis for understanding the age of onset, as well as identification of potential biomarkers and therapeutic targets. This has the potential to impact on high frequency, high importance disease of adults. Until the age-related proteome is understood, any studies of childhood diseases using proteomic techniques will be ineffective because of a lack of normal comparators. Hence this study will provide the platform for future studies into numerous childhood diseases.

Project 4: Placental Coagulation Markers

Fetal Growth Restriction (FGR) is a serious pregnancy complication in which the fetus fails to achieve its full growth potential in utero. This has important short and long term consequences (obesity, adult-onset diabetes and cardiovascular disease). While 30% of FGR cases have an identifiable cause, the remaining are idiopathic but are often associated with placental dysfunction and placental thrombosis. It is thought that this interferes with the transfer of nutrients and oxygen from the mother to the fetus. This is not normally observed in uncomplicated pregnancies. The mechanism that prevents the development of blood clots in the placentae of uncomplicated pregnancies and allows for clot formation in the placentae of patients with FGR is not known. Of the glycosaminoglycan (GAG) molecules found in humans, dermatan sulphate (DS) is the only natural circulating GAG with anticoagulant properties. DS and Heparin Cofactor II (HCII) were shown to be increased in plasma concentration in late normal pregnancy, likely originating from the placenta. They presumably have a physiological role in peripartum thrombin regulation. No studies have examined the potential physiological role GAG molecules and HCII in normal placental function. Our aim is to observe the differences in GAG activity in placentae from (fetal growth restricted) FGR pregnancies compared to gestation matched normal controls; as it is hypothesised that these differences are responsible for the dys-regulation of placental thrombin observed in FGR which contribute to the impaired fetal growth.