research

haematology research

summary

Our research team studies the blood flow system in neonates and children, its interaction with anticoagulation drugs which are now used more commonly to stop bleeding in children, as well as the differences in the blood clotting proteins during development and ageing.

Key research areas:       

  1. Developmental haemostasis: age-related differences in the haemostatic system.
  2. Interaction of the haemostatic system with clinically important anticoagulants.
  3. Differences in the plasma proteome in infants and children compared to adults.
  4. Changes in the plasma proteome during cardiac surgery (collaboration).
  5. Investigation of placental coagulation markers in fetal growth restriction (collaboration).

Research aims:

  1. To improve understanding and treatment of blood clotting disorders in children.
  2. To better understand, use and monitor anticoagulation therapy in children.
  3. To understand how age-related changes in the haemostatic system affect our growth and development.
  4. To understand how plasma proteome changes with age and the implications of these changes in the development of diseases associated with the process of ageing.

group leader(s)

Vera Ignjatovic  Dr Vera Ignjatovic
  Haematology Research
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville Victoria 3052
 
  E vera.ignjatovic@mcri.edu.au

  group leader biography

current research projects

Project 1: Developmental Haemostasis

A child's coagulation system evolves with age, a concept known as Developmental Haemostasis. Developmental Haemostasis provides a protective mechanism for children, decreasing the risk for thromboembolic and/or haemorrhagic events. 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. We demonstrated 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 other haemostatic proteins.

Project 2: Anticoagulant Therapy in Children

There remain significant unanswered questions about the optimal use of all anticoagulant medications in children. Currently, the majority of evidence regarding anticoagulant management in paediatrics is extrapolated from adult-based studies. As such, the clinical safety, efficacy and impact upon quality of life of these therapies in children remain unclear. 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 are ideally positioned to lead clinical research into optimising anticoagulant therapies in paediatric practice. Our translational research program in this field is a major contributor to advancing international evidence in the safety, efficacy and quality-of-life impact of heparin, low molecular weight heparin and warfarin in paediatrics.

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. We have for the first time characterised the age-related differences in the plasma proteome of the healthy population. This 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 study is providing 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.

team members

  • Chantal Attard - Research Assistant
  • Chris Barnes - RESEARCH ASSOCIATE
  • Michele Hepponstall - PhD Student (UoM Paeds)
  • Vera Ignjatovic - Senior Research Fellow
  • Sophie Jones - Research Assistant
  • Vicky Karlaftis - RESEARCH ASSISTANT
  • Eliza Mertyn - VISITOR & VOLUNTEERS
  • Fiona Newall - HONORARY FELLOW
  • Anita Pratt - Work Experience Student
  • Robyn Summerhayes - Research Assistant
  • Christina Yip - PhD Student (RMIT MedLabSci)

publications

  • Gilmore H., Newall F. The Experience of Parents and Children Where Children Have Been Supported with a Ventricular Assist Device as a Bridge to Heart Transplantation. PEDIATRIC CARDIOLOGY 32 (6) : 772 - 777(2011) PubMed
  • Hiremath M., Elder J., Newall F., Mitchell S., Dyas R., Monagle P. Heparin in the long-term management of ligneous conjunctivitis: A case report and review of literature. BLOOD COAGULATION & FIBRINOLYSIS 22 (7) : 606 - 609(2011) PubMed
  • Ignjatovic V., Chandramouli A., Than J., Summerhayes R., Newall F., Horton S., Cochrane A., Monagle P. Plasmin Generation and Fibrinolysis in Pediatric Patients Undergoing Cardiopulmonary Bypass Surgery. PEDIATRIC CARDIOLOGY (2011) PubMed
  • Ignjatovic V., Ilhan A., Monagle P. Evidence for age-related differences in human fibrinogen. BLOOD COAGULATION & FIBRINOLYSIS 22 (2) : 110 - 117(2011) PubMed
  • Ignjatovic V., Lai C., Summerhayes R., Mathesius U., Tawfilis S., Perugini MA., Monagle P. Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults. PLOS ONE 6 (2) (2011) PubMed
  • Ignjatovic V., Mertyn E., Monagle P. The coagulation system in children:developmental and pathophysiological considerations. Seminars in Thrombosis and Hemostasis 37 (7) : 723 - 729(2011) PubMed
  • Ignjatovic V., Than J., Summerhayes R., Newall F., Horton S., Cochrane A., Monagle P. Hemostatic Response in Paediatric Patients Undergoing Cardiopulmonary Bypass Surgery. PEDIATRIC CARDIOLOGY 32 (5) : 621 - 627(2011) PubMed
  • Ignjatovic V., Than J., Summerhayes R., Newall F., Horton S., Cochrane A., Monagle P. The Quantitative and Qualitative Responses of Platelets in Pediatric Patients Undergoing Cardiopulmonary Bypass Surgery. PEDIATRIC CARDIOLOGY 33 (1) : 55 - 59(2011) PubMed
  • Jones S., Mertyn E., Alhucema P., Monagle P., Newall F. HEEADSSS assessment for adolescents requiring anticoagulation therapy. ARCHIVES OF DISEASE IN CHILDHOOD (2011) PubMed
  • Monagle P., Cochrane A., Roberts R., Manlhiot C., Weintraub R., Szechtman B., Hughes M., Andrew M., McCrindle BW. A Multicenter, Randomized Trial Comparing Heparin/Warfarin and Acetylsalicylic Acid as Primary Thromboprophylaxis for 2 Years After the Fontan Procedure in Children. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 58 (6) : 645 - 651(2011) PubMed
  • Monagle P., Massicotte P. Developmental haemostasis: Secondary haemostasis. Seminars in Fetal and Neonatal Medicine 16 (6) : 294 - 300(2011) PubMed
  • Monagle P., Studdert DM., Newall F. Infant deaths due to heparin overdose: Time for a concerted action on prevention. JOURNAL OF PAEDIATRICS AND CHILD HEALTH (2011) PubMed
  • Peake LJ., Grover SR., Monagle PT., Kennedy AD. Effect of warfarin on menstruation and menstrual management of the adolescent on warfarin. JOURNAL OF PAEDIATRICS AND CHILD HEALTH (2011) PubMed
  • Peng C., Doan J., Monagle P., Newall F. Compliance of antithrombotic management at a tertiary paediatric hospital with international guidelines: A 100-Day audit. THROMBOSIS RESEARCH 128 (2) : 135 - 140(2011) PubMed
  • Peng C., Monagle P., Newall F. Clinical outcomes of management of CVAD occlusions. ARCHIVES OF DISEASE IN CHILDHOOD 96 (9) : 885 - 887(2011) PubMed
  • Sullivan J., Monagle P. Bereaved Parents' Perceptions of the Autopsy Examination of Their Child. PEDIATRICS 127 (4) (2011) PubMed
  • Summerhayes R., Chan M., Ignjatovic V., Prankerd R., Monagle P. Stability and sterility of diluted enoxaparin under three different storage conditions. JOURNAL OF PAEDIATRICS AND CHILD HEALTH 47 (5) : 299 - 301(2011) PubMed
  • Wong CS., Batchelor K., Bua J., Newall F. Safety and efficacy of warfarin in paediatric patients with prosthetic cardiac valves: A retrospective audit. THROMBOSIS RESEARCH 128 (4) : 331 - 334(2011) PubMed

competitive funding

National Health & Medical Research Council (NHMRC)

collaborations & affiliations

Department of Cardiac Surgery, Royal Children's Hospital Professor Igor Konstantinov
Pregnancy Research Centre, Royal Women's Hospital Dr Padma Murthi, Dr Joanne Said, Professor Shaun Brennecke
Commonwealth Scientific and Industrial Research Organisation (CSIRO) Dr John Tsanaktsidis, Dr Greg Coia
RMIT Health Innovations Research Institute Dr Matthew Linden
University of Santiago de Compostela, Spain Dr Angel Garcia Alonso
Stollery Children's Hospital
Edmonton, Canada
Professor Patti Massicotte
Assistant Professor Mary Bauman
Dr. Aisha Bruce