Haematology

• Developmental Haemostasis
• Anticoagulation
• Thrombosis and Bleeding
• Proteomics

DEVELOPMENTAL HAEMOSTASIS

Harmonising Age Pathology Parameters in (HAPPI) Kids
Age-specific reference ranges are essential for correct interpretation of laboratory tests. Only with accurate and relevant age-appropriate reference ranges can any test result be correctly assigned as being normal or abnormal. Reference ranges are expressed as the mean and boundary encompassing 95 per cent (between the 2.5th and 97.5th centiles) of the normal population. For all laboratory tests, reference ranges need to be established under identical conditions that a clinical test is to be performed. Frequently, age-appropriate references ranges are not available and the clinical laboratory relies on reference ranges established from different populations, using different analysis techniques, different reagents and analysers. The study aims to establish normative data for age appropriate reference intervals in haematology, immunology, and biochemistry for The Royal Children’s Hospital and laboratories throughout the state of Victoria. Blood samples will be collected from healthy newborns and children across five hospitals in Melbourne.

Platelet phenotype and function
Platelets are critical in thrombosis and inflammation, but have not been studied in children. The group has recently demonstrated for the first time increased circulating monocyte-platelet aggregates (MPAs) in children and increased responsiveness to platelet agonists. The preliminary data also shows age-specific changes in the platelet proteome and platelet proteins secreted following platelet activation.
This study aims to determine the age-specific differences in platelets responsible for differences in platelet function in children compared to adults.

ANTICOAGULATION

Anticoagulants and Antithrombotics (heparin, rivaroxaban, warfarin, aspirin)
Due to recent major advances in the surgical and medical management of children with complex diseases, many of these children are now surviving into adulthood. Despite these advances, many children require ongoing medication to prevent complications such as blood clots and stroke.
Anticoagulants, sometimes referred to as ‘blood thinners’, are used to prevent blood clots and stroke. The group’s research has shown that the blood clotting system in children is very different to that in adults. Due to these differences, the team has dedicated many years to investigating the effect of different anticoagulants in children. This research has become even more vital with the development of new anticoagulants. The team’s ongoing research in this area has become crucial in the effective and safe management of anticoagulants in children now and in the future.
Researchers will aim to determine the specific effects of anticoagulants in children and to improve current strategies for monitoring these drugs in children, by studying plasma samples from newborns to adults and
anticoagulants in unwell children at the Royal Children’s Hospital.

Heparin mimics
Synthetically produced anticoagulants have the potential to overcome the significant safety issues associated with heparin.
This study aims to develop bespoke polymers with suitable anticoagulant profiles for use as replacements for heparin.

Quality of Life of children receiving Warfarin
The need for the blood-thinning drug warfarin in childhood introduces challenges to patients and their families. These include the need for regular blood monitoring tests and the impact of modifying their lifestyle on social interactions and participation.
This study aims to discover if participation in a program supporting families to perform warfarin monitoring tests at home improves their quality of life, compared to having blood monitoring tests performed in a hospital or at a pathology service.

THROMBOSIS AND BLEEDING

Thrombosis – CVL
This study will for the first time document the natural history of asymptomatic centrale venous line (CVL)-related deep vein thrombosis (DVT) in sick children, allowing appropriate diagnostic and therapeutic strategies to be developed.
A CVL, or cental venous line, is a catheter placed into a large vein in the chest. The study will also identify and provide recommendations on the clinical value of routine ultrasound screening of all children with a CVL for the presence of a thrombosis by determining the incidence of clinically significant post thrombotic syndrome (PTS) a year later. This study will be conducted as a prospective cohort study of 200 children admitted to the Paediatric Intensive Care Unit (PICU), at the Royal Children’s Hospital, Melbourne. The unit admits approximately 1000 children a year. Of these, more than 40 per cent have a CVL placed due to heart surgery and a further 30 per cent require a CVL for medication support. This data indicates that recruitment of 200 children with CVLs in one year is feasible and practical in this setting.
 
Bleeding and clotting outcomes post Fontan surgery
The Fontan procedure is the last of a series of operations offered to children born with only one pumping heart chamber. Without this procedure these children would die, however, with the procedure comes with long term risks. Many patients have ongoing medical complications after the procedure including blood clots, stroke and bleeding. The team is currently investigating the long-term outcomes of the Australian and New Zealand (ANZ) Fontan population. This study aims to pinpoint the incidence and identify risk factors for blood clots, stroke and bleeding in the ANZ Fontan population and determine which medications are the best at preventing these complications.

Bleeding and thrombosis in children with liver disease
Children with liver disease can develop severe bleeding and thrombosis at the same time. These complications are associated with high mortality and morbidity and can be difficult to treat. Most coagulation proteins and anticoagulant proteins are synthesised in the liver and their levels are often reduced in advanced liver disease. Studies regarding pro- and anticoagulant mechanisms in liver disease have mainly been performed in adults. However, the coagulation system in children undergoes age-specific changes and the causes and pathogenesis of paediatric liver disease is different than in adults. Studies focusing on haemostasis in liver disease also need to be peformed in the paediatric setting and this study aims to predict an increased risk of bleeding and thrombosis in children with liver disease.

ECMO
Extracorporeal Membrane Oxygenation (ECMO) is a form of cardiopulmonary life support that uses a heart-lung machine to provide artificial oxygenation of blood and systematic perfusion in patients with severe heart and/or lung failure. Limitations of this therapy include significant complications with bleeding and clotting. This study aims to establish tailored therapy protocols to reduce bleeding and clotting complications for children on ECMO. 

PROTEOMICS

Age-mediated differences
Human blood plasma is a complex biological fluid that interacts with a wide array of bodily sytems. Changes in plasma protein expression, or the presence or absence of specific proteins are regularly used in a clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. Our research focuses on studying variations in protein expression across the age spectrum from neonates to adults.

OTHER: Thrombin generation
Thrombin generation (TG) is a global analysis of haemostasis that, in theory, could monitor thrombosis risk, anticoagulation management, and guide therapy in bleeding disorders. However, current TG methods care are inadequate because they are not able to specifically measure active and free thrombin, relying instead on extrapolation from algorithms. The team has patented a substrate to measure true active thrombin, which this study will analyse for the suitability of its use in patients.