PBI’s active clinical research focuses on deep vein thrombosis, stroke, thrombophilia, thrombocytopenia, haemophilia A, recurrent miscarriage, Von Willebrand disease, leukaemia, lymphoma, myeloma, anaemia and iron overload. PBI’s research division, together with PBI’s clinical trials division, conducted early- and late-phase international clinical trials with new therapeutics developed through PBI’s clinical research.
The trials produced research publications in leading medical journals, including the Journal of Thrombosis and Haemostasis and the New England Journal of Medicine; and provided the basis for early access to new-targeted drugs for Australian patients.
PBI’s research team was the first to understand the complexity of microRNA's control on blood coagulation factors, leading to the discovery of a novel mechanism of oestrogen mediated thrombosis. MicroRNAs are a group of small RNA molecules involved in regulating gene expression, a process where information starting at a DNA level is ultimately used in making a functional product such as proteins.
This discovery has been in the works for several years. In 2013, PBI lead a study publishing the first evidence demonstrating microRNA-494 is involved in the mechanism of oestrogen-mediated reduction of Protein S (PS). Protein S is an important anti-coagulation factor. High oestrogen levels can lead to reduced PS and a deficiency of PS could lead to unexpected clotting events. Following this breakthrough, the research team posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner. In February 2021, the PBI research team published a study identifying microRNA-365a-3p as a tissue factor regulator. Tissue Factor is important in initiating clots when required.
These studies have provided crucial information on understanding microRNA's action and its link to coagulation processes. Moreover it is a powerful tool to have in developing personalised precision medicines.
This research has resulted in new miR-based related blood diagnostic tests and miR-based therapies currently being developed.
Thrombotic Thrombocytopenic Purpura (TTP) is a rare and fatal disease caused by a deficiency of the Von Willebrand factor cleaving enzyme, ADAMTS-13. ADAMTS-13 deficiency can be hereditary, but more often is an acquired disorder due to the production of inhibitory autoantibodies. It occurs in around 20 patients per year per million people. The PBI research division leads the Asia Pacific Microangiopathy Thrombocytopenia (APMAT) Network across 24 leading centres in the Asia Pacific (AP) to rapidly collect and bio-bank clinical material on a large number of patients with Thrombotic Microangiopathy. Our work has standardised diagnostic ADAMTS-13 testing in the AP region, and utilising the APMAT bio-bank we are exploring new diagnostic algorithms and developing new molecular testing.
Our understanding of the rare TTP disease has led to a proposal for further research on the disease and a global standardisation study of ADAMTS13 testing.
Bleeding is a common complication of advanced chronic lymphocytic leukaemia (CLL). PBI’s research discovered important cancer-related platelet dysfunctions, which could contribute to the exacerbated bleeding phenotype seen in CLL patients. This could be particularly significant in malignant CLL clone and/or therapeutic interventions, where further impaired platelet function could be at play. One study examined Bruton’s tyrosine kinase inhibitors (eg. ibrutinib, acalabrutinib) and their effect on blood samples collected from patients. These drugs are known to inhibit platelet aggregation mediated by glycoprotein VI (GPVI) and other platelet signalling pathways. Furthermore, the study examined the anti-platelet effects of BH3 mimetics (eg. venetoclax), a less well understood property of the drug. CLL is associated with a broad platelet functional defect, which persists despite the clinical benefits of ibrutinib or venetoclax treatment.
Results of the study showed that ibrutinib, not venetoclax, induces additive inhibition of platelet function in CLL patients, that is not related to altered GPVI cleavage. Additionally, it was shown that clinically-utilised whole blood platelet function assays are capable of quantifying the degree of functional impairment in CLL patients - a world first observation made by PBI scientists.