Dr Freda Passam

"As a haematologist I am struck by the high incidence of blood clots in the population. I believe that being at the leading edge of cardiovascular research will help an unquantifiable number of people."

Dr Freda Passam leads the Haematology Research Group at the Heart Research Institute/Charles Perkins Centre of the University of Sydney, focused on basic and translational research in thrombotic disease. She is a clinical academic haematologist in the Royal Prince Alfred Hospital, Sydney, with a special interest in thrombosis and haemostasis. Dr Passam received her medical degree and PhD in Greece. She trained in clinical and laboratory haematology, initially in Greece and then in Sydney, and did postdoctoral thrombosis research in the University of New South Wales and Harvard University. Dr Passam returned to Sydney in 2013 as a haematologist at St George Hospital and Senior Lecturer in Medicine at UNSW. She is a recipient of the 2017 Sydney Cardiovascular Fellowship, which brings her to the University of Sydney to develop her research program and to RPA Hospital to establish a Thrombosis Clinic dedicated to the management of patients with thrombotic disease. Dr Passam’s research has identified a group of clotting enzymes, named thiol isomerases, that have potential as novel antithrombotic targets. Her research group has detected post-translational modifications of clotting proteins as novel biomarkers of thrombotic disease. The Haematology Research Group also has a keen interest in the application of microfluidic devices for the diagnosis of thrombotic and bleeding tendency in patients. 

Current Appointments

Group Leader, Haematology Research Group

Heart Research Institute, Charles Perkins Centre, University of Sydney

Clinical Academic Haematologist

Royal Prince Alfred Hospital

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Research Project Opportunities
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Thiol isomerases as novel antithrombotic targets

An exciting recent discovery in the thrombosis field is that thiol isomerases form a new clotting pathway. Thiol isomerases are a group of enzymes that regulate the function of blood cell receptors and clotting proteins by reacting with their disulphide bonds. We have identified a thiol isomerase, named ERp5, which is released into the circulation from activated platelets and promotes clot formation in vivo.

In this project we will dissect the role of ERp5 in platelet function and clot formation by using mice with genetic deletion of ERp5 in their platelets. We will investigate how this thiol isomerase regulates the interaction of platelets with clotting proteins (fibrinogen, von Willebrand factor) and vascular cells (endothelial cells and neutrophils). We will explore the potential of ERp5 inhibitors to prevent thrombus formation and become candidate antithrombotic drugs.

Redox biomarkers in thrombotic disease 

The redox balance (balance of reduction and oxidation reactions in our blood) is essential for a healthy circulation. Redox imbalance causes alterations of protein function contributing to the development of thrombosis. The Haematology Group is focused on redox modification of disulphide bonds in two proteins critical for thrombus formation: the platelet receptor integrin a2bb3 and the plasma protein von Willebrand factor. We have found that reduced forms of a2bb3 and vWF have decreased thrombotic activity and may therefore protect from thrombotic disease, such as venous clots.

We have developed assays which measure the redox balance in blood including tests which measure the disulphide reducing activity of plasma and the production of reactive oxygen species by platelets. We will study the redox modifications of platelet a2bb3 and plasma vWF which occur in patients at high risk for thrombosis to identify those most likely to benefit from drugs which restore the normal redox balance.

Developing biochips for the evaluation of haemostasis and thrombosis

Many patients with bleeding and clotting disorders go undetected by routine laboratory tests in part because the available assays do not reflect the conditions in the circulation. The Haematology Group uses biochips in a microfluidic system that allows blood to flow through passages under controlled conditions. The passages are designed to mimic blood vessels and include features, eg, stenosis, that simulate the circulation in stenosed vessels. The flow of blood through these biochips generates thrombi that can be visualised by real-time microscopy and quantified.

This project will study blood cell adhesion and thrombus formation in microfluidic devices to assess for persisting thrombotic tendency in patients with a history of venous clots, who have completed treatment. Samples from patients with bleeding disorders, on treatment, will be assessed for haemostatic potential. Blood cells and proteins which participate in clot formation will be measured in the microfluidics system including platelets, fibrin, neutrophil extracellular traps and von Willebrand factor.

Featured Publication
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Mechano-redox control of integrin de-adhesion. Passam F, Chiu J, Ju L, Pijning A, Jahan Z, Mor-Cohen R, Yeheskel A, Kolšek K, Thärichen L, Aponte-Santamaría C, Gräter F, Hogg PJ.Elife. 2018 Jun 22;7. [Epub ahead of print]

How proteins harness mechanical force to control function is a significant biological question. Here we describe a human cell surface receptor that couples ligand binding and force to trigger a chemical event which controls the adhesive properties of the receptor. Our studies of the secreted platelet oxidoreductase, ERp5, have revealed that it mediates release of fibrinogen from activated platelet αIIbβ3 integrin. Protein chemical studies show that ligand binding to extended αIIbβ3 integrin renders the βI-domain Cys177-Cys184 disulfide bond cleavable by ERp5. Fluid shear and force spectroscopy assays indicate that disulfide cleavage is enhanced by mechanical force. Cell adhesion assays and molecular dynamics simulations demonstrate that cleavage of the disulfide induces long-range allosteric effects within the βI-domain, mainly affecting the metal-binding sites, that results in release of fibrinogen. This coupling of ligand binding, force and redox events to control cell adhesion may be employed to regulate other protein-protein interactions.

Awards for Research
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2017 Sydney Cardiovascular Fellowship, Charles Perkins Centre of the University of Sydney and Heart Research Institute, $1m

2016 Kanematsu Novo Nordisk Award, RCPA, $50,000

2015 UNSW Goldstar Award, $40,000

2013 St George Medical Research Foundation, New Investigator Award, $50,000

2015 Fellowship of the Royal Australasian College of Physicians

2015 Fellowship of the Royal College of Pathologists of Australasia

2007 Doctoral thesis “Role of angiogenesis in lymphomas”, Medical School, University of Crete

1997 Medical School of Athens, University of Athens, Athens, Greece