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.
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.
- A review of commercially available thrombin generation assays. 2018
- Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues. 2018
- Anticoagulation during ECMO in neonatal and paediatric patients. 2018
- Antiplatelet Therapy Monitoring in Neonates and Children. 2018
- Antithrombotic therapies in children on durable Ventricular Assist Devices: A literature review. 2018
- Bleeding and thrombotic events occur early in children on durable ventricular assist devices. 2018
- Clinical presentation and therapeutic management of venous thrombosis in young children: a retrospective analysis. 2018
- Differentiating arterial ischaemic stroke from migraine in the paediatric emergency department. 2018
- Family history of venous thromboembolism in the paediatric population: The need for a standardized definition. 2018
- Heparin mimetics with anticoagulant activity. 2018
- Identifying low-grade cellular rejection after heart transplantation in children by using gene expression profiling. 2018
- Interdisciplinary medication decision making by pharmacists in pediatric hospital settings: An ethnographic study. 2018
- Medication error trends and effects of person-related, environment-related and communication-related factors on medication errors in a paediatric hospital. 2018
- Motor function daily living skills 5 years after paediatric arterial ischaemic stroke: a prospective longitudinal study. 2018
- Pathophysiology of thrombosis and anticoagulation post Fontan surgery. 2018
- Plasma proteomics reveals gestational age-specific responses to mechanical ventilation and identifies the mechanistic pathways that initiate preterm lung injury. 2018
- Plasma TNF alpha is a predictor of persisting symptoms post-concussion in children. 2018
- Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. 2018
- Slow progress. How do we shift the paradigm of thinking in pediatric thrombosis and anticoagulation? 2018
- Social functioning following pediatric stroke: contribution of neurobehavioral impairment. 2018
- The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children. 2018
- The Pediatric Stroke Outcome Measure: A predictor of outcome following arterial ischemic stroke. 2018
- Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial. 2018
- Anti-activated factor II assay for monitoring unfractionated heparin in children: results of the HEARTCAT study. 2017
- Antiangiogenic effects of decorin restored by unfractionated, low molecular weight, and nonanticoagulant heparins. 2017
- Anticoagulation therapy in neonates, children and adolescents. 2017
- Barriers to Addressing Social Determinants of Health in Pediatric Nursing Practice: An Integrative Review. 2017
- Characterization of the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt. 2017
- Disseminated intravascular coagulation in paediatrics. 2017
- Expression of Biglycan in First Trimester Chorionic Villous Sampling Placental Samples and Altered Function in Telomerase-Immortalized Microvascular Endothelial Cells. 2017
- Improving Protein Detection Confidence Using SWATH-Mass Spectrometry with Large Peptide Reference Libraries. 2017
- Medication communication between nurses and doctors for paediatric acute care: An ethnographic study. 2017
- Prehospital Emergency Care in Childhood Arterial Ischemic Stroke. 2017
- Principles and theory guiding development and delivery of patient education in disorders of thrombosis and hemostasis: Reviewing the current literature. 2017
- Providing opportunistic immunisations for at-risk inpatients in a tertiary paediatric hospital. 2017
- Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults. 2017
- Six Weeks Versus 3 Months of Anticoagulant Treatment for Pediatric Central Venous Catheter-related Venous Thromboembolism. 2017
- Trajectories of Motor Recovery in the First Year After Pediatric Arterial Ischemic Stroke. 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-factor Xa 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
- Factors Associated with Thrombotic Complications in the First 2 Years after the Fontan Procedure: A Multicentre Prospective Study 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
- Royal Children’s Hospital Foundation
- National Health and Medical Research Council
- University of Melbourne
- Murdoch Children's Research Institute
- Commercial sponsor: Bayer HealthCare
International
- Maastricht University, Maastricht, The Netherlands: A/Prof Bas de Laat, Prof Coen Hemker
- McMaster Children’s Hospital, Hamilton, Canada: Prof Anthony Chan (Patent)
- 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
National
- Department of Cardiac Surgery, Royal Children’s Hospital: Prof Yves d’Udekem
- Department of Gastroenterology and Clinical Nutrition: A/Prof Winita Hardikar
- Commonwealth Scientific and Industrial Research Organisation (CSIRO): Dr John Tsanaktsidis
- The University of Queensland: A/Prof Vito Ferro
- The University of Western Australia: A/Prof Matthew Linden
Industry collaborations: Diagnostica Stago, Bayer, Bristol Myers Squibb, Roche Diagnostics