Infants and children have a lower incidence of bleeding and blood clotting events than adults. By understanding the balance between bleeding and clotting in healthy children we can improve the quality of care delivered to sick children and develop strategies for prevention of thrombosis in children and adults.
The Haematology group explores Developmental Haemostasis – how the blood’s clotting system matures with age. There are age-associated alterations in levels of coagulation proteins and their function. The group is the only team in Australia and one of three teams in the world performing this type of research. They established the only age-specific reference ranges for coagulation proteins in an Australian population. These have been adopted in patient care nationally and internationally.
The researchers’ novel approach has demonstrated:
- Differences in the concentration, structure and function of coagulation proteins with age,
- Differences in the platelet phenotype and function in children compared to adults,
- Differences in blood clot formation and structure in children compared to adults,
- The concept of “ageing of the plasma proteome”,
- The pharmacokinetics, pharmacodynamics and monitoring strategies for currently used and novel anticoagulants in children.
The Haematology group has led international clinical guidelines and eight position papers for the International Society for Thrombosis and 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.
Structural differences in Antithrombin
The group’s previous studies and preliminary data suggest that age-specific structural and functional differences for haemostatic proteins exist not only in the healthy population but also in seriously ill children.
This study aims to characterise the age-specific structural and functional differences in Antithrombin, which is the key naturally occurring anticoagulant and the main binding partner for the anticoagulant Heparin.
Researchers will utilise their competitive advantage in the field of Developmental Haemostasis, unique access to samples from healthy newborns, children and adults, as well as children in Paediatric Intensive Care Unit (PICU), established protein purification and characterisation techniques (e.g. Mass Spectrometry), as well as a technology called Surface Plasmon Resonance (SPR).
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.
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.
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 – 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.
Thrombosis – PE
This study aims to determine the distinguishing clinical features of teenagers with community-acquired pulmonary embolus as compared to other causes of chest pain in children presenting to the emergency department
Thrombosis – Arterial
Thea im of thise study is o determine the long term functional outcome of iatrogenic arterial occlusions in newborns and children
It will involve a case control study of children with known previous symptomatic iatrogenic arterial obstruction
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.
Epidemiology of thrombosis in children with cancer
Thrombosis is diagnosed with increasing frequency in children with cancer. A large amount of research has focused on the epidemiology of thrombosis in adults with cancer but little is known about thrombosis in child cancer patients. The team has recently published a detailed review on this topic and is now undertaking a study to identify critical areas for future studies in this field.
This study aims to determine the epidemiology, mechanisms, risk factors, prophylaxis and outcomes of thrombosis in children with cancer at the Royal Children’s Hospital, through a retrospective audit.
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.
Plasma proteomics (Diabetes)
Type 1 diabetes mellitus (T1DM) is a life-long disease that usually occurs in childhood and affects over 122,300 people in Australia. It is caused by the immune system mistakenly turning on itself and destroying insulin producing cells in the pancreas. Insulin allows the body to process sugar to create energy. Without insulin the body cannot process food and causes blood sugar levels to become dangerously high. Irregular blood sugar levels, such as those seen in diabetics, causes damage to organs which can lead to eye disease, nerve damage, kidney disease, heart disease and stroke. This damage is caused by the interaction of sugars with proteins in our bodies. Although this reaction occurs in all of us, in patients with T1DM, this reaction is sped up as their blood sugar levels tend to be less stable. This research will hopefully help in early detection of diabetic complications, which is crucial in preventing further disease and ensuring diabetic children enjoy a good quality of life, by comparing differences in plasma proteins in children with diabetes with health children.
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.
Preeclampsia (PE) affects up to seven per cent of pregnant women and is one of the leading causes of maternal mortality worldwide. For every maternal death due to PE, there are many more cases of maternal morbidity as well as perinatal morbidity and mortality. PE is unique to human pregnancy. It is characterised by new onset hypertension – high blood pressure - after 20 weeks gestation and is accompanied by a range of other effects and adverse pregnancy outcomes - placental abruption, fetal growth restriction, prematurity and stillbirth. A growing body of evidence shows significant long-term cardiovascular consequences in women who experience PE, together with a reduced life expectancy, compared to those without PE. The cause of this devastating condition remains unknown and treatments are elusive.
Researchers in this study will investigate whether targeted anticoagulants can alleviate a range of defects that may be contributing to PE.
Early detection of Heart transplant rejection in children
Paediatric patients require hospital admission and general anaesthesia to undergo invasive procedures like heart biopsy, which remains the gold standard for detection of rejection following heart transplantation. The average cost of each biopsy is approximately $7,000 and current protocols specify 10 heart biopsies for routine surveillance in the first year post-transplant alone. These biopsies not only represent considerable difficulty for the patients, but also significant cost and strain on resources for the Australian healthcare system. Furthermore, early detection and personalised modification of the patient’s immunosuppressive therapy would reduce complications and the need for hospital admission. This would in turn further reduce the burden on the healthcare system. It would therefore be beneficial to identify patients who are rejecting a transplanted organ using a simple blood test. Such a diagnostic tool would help to reduce or eliminate the need for invasive, expensive and potentially risky heart biopsies. This research aims to develop a simple blood test, based on gene expression, to detect rejection.
This study aims to identify factors that inhibit the early diagnosis of children who have had a stroke, determine the long term physical and social outcomes of child stroke patients and determine the relationship between imaging and functional outcomes in paediatric stroke.
- Anti-activated factor II assay for monitoring unfractionated heparin in children: results of the HEARTCAT study. 2017
- Providing opportunistic immunisations for at-risk inpatients in a tertiary paediatric hospital. 2017
- A conceptual and practical approach to haemostasis in paediatric liver disease. 2016
- Brain attacks and stroke in children. 2016
- Congenital Methemoglobinemia Type II-Clinical Improvement with Short-Term Methylene Blue Treatment. 2016
- Creating a journal club competition improves paediatric nurses' participation and engagement. 2016
- Development of a population pharmacokinetic-pharmacodynamic model of a single bolus dose of unfractionated heparin in paediatric patients. 2016
- Development of competence in the first year of graduate nursing practice: a longitudinal study. 2016
- Differentiating Childhood Stroke From Mimics in the Emergency Department. 2016
- Importance of post-translational modifications on the function of key haemostatic proteins. 2016
- Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion. 2016
- Oral anticoagulant therapy interruption in children: A single centre experience. 2016
- Performance of bedside stroke recognition tools in discriminating childhood stroke from mimics. 2016
- Protocol for a prospective, longitudinal, cohort study of postconcussive symptoms in children: the Take C.A.Re (Concussion Assessment and Recovery Research) study. 2016
- Risk factors and clinical features of acute pulmonary embolism in children from the community. 2016
- Rituximab and protection from vaccine preventable diseases: applying the evidence to pediatric patients. 2016
- Safety and Efficacy Outcomes of Home and Hospital Warfarin Management Within a Pediatric Anticoagulation Clinic. 2016
- Cardiopulmonary bypass changes the plasma proteome in children undergoing tetralogy of Fallot repair. 2015
- Children with cerebral palsy: why are they awake at night? A pilot study. 2015
- Congenital abnormalities of the inferior vena cava presenting clinically in adolescent males. 2015
- Differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults. 2015
- Differences in the resting platelet proteome and platelet releasate between healthy children and adults. 2015
- Empirical evolution of a framework that supports the development of nursing competence. 2015
- Factors associated with six-month outcome of pediatric stroke. 2015
- Inhalational use of antithrombotics in humans: Review of the literature. 2015
- Monitoring Central Venous Catheter Resistance to Predict Imminent Occlusion: A Prospective Pilot Study. 2015
- Parents and end-of-life decision-making for their child: roles and responsibilities. 2015
- Recognising and responding to deterioration in paediatric nursing practice: broadening our perspective 2015
- Recommendations for the development of a dedicated pediatric anticoagulation service: communication from the SSC of the ISTH. 2015
- Recommendations for the development of new anticoagulant drugs for pediatric use: communication from the SSC of the ISTH. 2015
- Remote ischemic preconditioning (RIPC) modifies the plasma proteome in children undergoing repair of tetralogy of fallot: a randomized controlled trial. 2015
- Thrombophilia testing in a tertiary paediatric hospital: Indications, outcomes and appropriateness. 2015
- Topical use of antithrombotics: review of literature. 2015
- Altered decorin leads to disrupted endothelial cell function: a possible mechanism in the pathogenesis of fetal growth restriction? 2014
- Anticoagulation of cardiomyopathy in children. 2014
- Beta (ß)-antithrombin activity in children and adults: implications for heparin therapy in infants and children. 2014
- Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease. 2014
- Epidemiology of venous thrombosis in children with cancer. 2014
- Lack of anti-factorXa assay standardization results in significant low molecular weight heparin (enoxaparin) dose variation in neonates and children. 2014
- Quality of life: Outpatient versus inpatient IV antibiotic management for pediatric oncology patients with low risk febrile neutropenia: A randomised trial. 2014
- The in-vitro anticoagulant effect of rivaroxaban in neonates. 2014
- Vintage venoms: proteomic and pharmacological stability of snake venoms stored for up to eight decades. 2014
- What parents want from doctors in end-of-life decision-making for children. 2014
- Activated partial thromboplastin time. 2013
- Commencement of warfarin therapy in children following the Fontan procedure. 2013
- Development of a home international normalized ratio monitoring program: Strategic approach and evaluation. 2013
- Developmental hemostasis: age-specific differences in the levels of hemostatic proteins 2013
- Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary thromboprophylaxis for 2 years after the Fontan procedure. 2013
- First report of elevated monocyte-platelet aggregates in healthy children. 2013
- Hypertension at time of diagnosis and long-term outcome after childhood ischemic stroke. 2013
- Latent antithrombin levels in children and adults. 2013
- Long-term follow-up of homozygote protein C deficiency after multimodal therapy 2013
- Prothrombin time/international normalized ratio. 2013
- Quality of life assessment in children commencing home INR self-testing 2013
- The microparticle-specific procoagulant phospholipid activity changes with age 2013
- Thrombin clotting time. 2013
- 'I don't want to hurt him.' Parents' experiences of learning to administer clotting factor to their child. 2012
- A clinical audit of antithrombin concentrate use in a tertiary paediatric centre. 2012
- An adolescent patient with post-thrombotic syndrome achieves excellence in sport. 2012
- Anticoagulation in children. 2012
- Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 2012
- Developmental hemostasis: recommendations for laboratories reporting pediatric samples. 2012
- Diagnosis and management of deep venous thrombosis and pulmonary embolism in neonates and children. 2012
- Employing a clinical governance framework to engage nurses in research. 2012
- Heparin concentrations in neonates during cardiopulmonary bypass: a rebuttal. 2012
- Letter to the Editor regarding 'effect of rivaroxaban, in contrast to heparin, is similar in neonatal and adult plasma'. 2012
- Placental syndecan expression is altered in human idiopathic fetal growth restriction. 2012
- Recommendations for developing uniform laboratory monitoring of heparinoid anticoagulants in children. 2012
- Recommendations for measuring health-related quality of life in children on anticoagulation. 2012
- The expression of placental proteoglycans in pre-eclampsia. 2012
- The impact of Cardiopulmonary bypass on Factor XIII levels in children. 2012
- The in vitro anticoagulant effect of rivaroxaban in children. 2012
- The PAI-1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women. 2012
- Updates in thrombosis in pediatrics: where are we after 20 years? 2012
- A Multicenter, Randomized Trial Comparing Heparin/Warfarin and Acetylsalicylic Acid as Primary Thromboprophylaxis for 2 Years After the Fontan Procedure in Children 2011
- Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults 2011
- Bereaved Parents' Perceptions of the Autopsy Examination of Their Child 2011
- Clinical outcomes of management of CVAD occlusions 2011
- Compliance of antithrombotic management at a tertiary paediatric hospital with international guidelines: A 100-Day audit 2011
- Developmental haemostasis: Secondary haemostasis 2011
- Effect of warfarin on menstruation and menstrual management of the adolescent on warfarin. 2011
- Evidence for age-related differences in human fibrinogen 2011
- HEEADSSS assessment for adolescents requiring anticoagulation therapy 2011
- Hemostatic Response in Paediatric Patients Undergoing Cardiopulmonary Bypass Surgery 2011
- Heparin in the long-term management of ligneous conjunctivitis: A case report and review of literature 2011
- Infant deaths due to heparin overdose: Time for a concerted action on prevention. 2011
- Plasmin Generation and Fibrinolysis in Pediatric Patients Undergoing Cardiopulmonary Bypass Surgery. 2011
- Safety and efficacy of warfarin in paediatric patients with prosthetic cardiac valves: A retrospective audit 2011
- Stability and sterility of diluted enoxaparin under three different storage conditions 2011
- The coagulation system in children:developmental and pathophysiological considerations. 2011
- The Experience of Parents and Children Where Children Have Been Supported with a Ventricular Assist Device as a Bridge to Heart Transplantation 2011
- The Quantitative and Qualitative Responses of Platelets in Pediatric Patients Undergoing Cardiopulmonary Bypass Surgery. 2011
- Maastricht University, Maastricht, The Netherlands: A/Prof Bas de Laat, Prof Coen Hemker
- University of Murcia, Murcia, Spain: Prof Javier Corral
- McMaster Children’s Hospital, Hamilton, Canada: Prof Anthony Chan (Patent)
- Leibniz-Institut für Analytische Wissenschaften, Germany: Prof Albert Sickmann, Dr Julia Burkhart
- Lake Forest Hospital, Chicago, USA: Dr Rukhmi Bhat
- Karolinska Institute, Stockholm, Sweden: Dr Maria Magnusson
- The University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada: Prof Patricia Massicotte, Dr Aisha Bruce
- Medical University of Vienna, Austria: Prof Christoph Male
- Hadassah Medical Centre, Jerusalem, Israel: Dr Shoshana Revel-Vilk
- The Children’s Hospital of Philadelphia, USA: A/Prof Leslie Raffini
- Central Manchester University Hospital, UK: Prof Robert Wynn
- School of Pharmacy, University of Otago, Dunedin, New Zealand: Hesham S Al-Sallami, Prof Stephen Duffull1
- Department of Cardiac Surgery, Royal Children’s Hospital: Prof Igor Konstantinov, Prof Yves d’Udekem
- Department of Gastroenterology and Clinical Nutrition: A/Prof Winita Hardikar
- Northwest Academic Centre, Sunshine Hospital: Dr Padma Murthi, A/Prof Joanne Said
- Commonwealth Scientific and Industrial Research Organisation (CSIRO): Dr John Tsanaktsidis, Dr Greg Coia
- The University of Queensland: A/Prof Vito Ferro
- The University of Western Australia: A/Prof Matthew Linden
- Department of Endocrinology and Diabetes, Royal Children’s Hospital: A/Prof Fergus Cameron
- Early Life Epigenetics Team, Murdoch Childrens Research Institute: A/Prof Jeff Craig
- Skeletal Biology and Disease, Murdoch Childrens Research Institute: Dr Zerina Lokmic and Prof Tony Penington
Industry collaborations: Diagnostica Stago, Bayer, Bristol Myers Squibb, Roche Diagnostics, Affinity Biologicals