Thrombosis and Haemostasis
Generous funding received from: Kanematsu/Novo Nordisk Research Award, Hollywood Private Hospital Research Foundation, Perth Blood Institute, Australian Society for Thrombosis and Haemostasis (ASTH).
The Western Australian Centre for Thrombosis and Haemostasis (WACTH) group is led by Professor Ross Baker with major research interests in the study of thrombosis and bleeding disorders. Ongoing projects are focused on identifying and characterising autoantibodies and non-coding RNA species that act to deregulate coagulation factors leading to thrombophilic disorders. These include developing immunoassays to characterise inhibitory autoantibodies targeting the anti-coagulant protein, ADAMTS13, which will help to improve the detection and diagnosis of thrombotic thrombocytopaenic pupura, as well as the investigation of the role of Folate Receptor Alpha autoantibodies and folate deficiency in thrombosis and recurrent miscarriage. The group is also investigating microRNAs that are regulated by high levels of oestrogen during pregnancy and oral contraceptive use which downregulate coagulation factors leading to deficiencies in key haemostatic proteins and a high risk of venous thrombosis.
Characterisation of ADAMTS13 antibodies in thrombotic thrombocytopaenic pupura (TTP)
ADAMTS13 is an anti-coagulant protein that cleaves the von Willebrand Factor (vWF), a process that is important in the maintenance of haemostasis. When ADAMTS13 deficiencies occur, ultra large vWF multimers remained uncleaved within the circulation and leads to the formation of small blood clots (microthrombi) resulting in thrombotic thrombocytopaenic pupura (TTP), a condition that is fatal if left untreated. Deficiencies in ADAMTS13 can result from inactivating mutations in ADAMTS13 or from the presence of inhibitory autoantibodies directed against ADAMTS13. However, there are individuals with high titres of ADAMTS13 autoantibodies that do not develop TTP, indicating that there are ADAMTS13 antibodies which are not inhibitory. Current methods to detect ADAMTS13 autoantibodies do not discriminate between the inhibitory and non-inhibitory forms, and also do not identify the ADAMTS13 epitopes that are targeted. This study aims to develop a method for screening patient samples for identifying specific populations of ADAMTS13 autoantibodies and determining their role in thrombotic disorders including TTP onset and stroke.
Characterisation of folate receptor alpha (FR) autoantibodies in recurrent miscarriage
Folate deficiency is a known risk factor for recurrent miscarriage, however its aetiology is not fully understood. It has been proposed that miscarriage results from thrombus formation as a function of reduced folate-dependent DNA synthesis and repair. Interestingly, folate deficiency can occur within the embryo even when maternal folate levels are within normal range, indicating impaired folate uptake. Recent studies have identified autoantibodies that block the folate receptor alpha (FRa), a tissue specific folate transport protein, to inhibit folate transport. Embryonic folate transport is highly dependent on FRa and dysregulation of folate transport has been associated with neural tube defects and cerebral folate deficiency. Furthermore, it is well known that immunological responses and autoimmune diseases can have a substantive impact on embryonic development; therefore we propose that autoantibodies directed against FRa block folate binding to the receptor causing folate deficiency complications to the pregnancy leading to thrombotic miscarriage.
Charactersation of miRNAs in oestrogen-mediated hypercoaguability during pregnancy and oral contraceptive use
Protein S (PS) is an anti-coagulant factor naturally produced in the liver that functions to inhibit the formation of blood clots. It is well documented in clinical studies that levels of PS decline in response to increased circulating oestrogen levels during pregnancy, oral contraceptive use or oestrogen replacement therapy, leading to a high risk of venous thrombosis. However the molecular mechanism of oestrogen-mediated acquired PS deficiency are poorly understood. We identified that microRNAs are involved with the regulation of coagulation factors responsive to oestrogens and this study aims to identify oestrogen-responsive miRNAs, as well as the establish role of microRNAs in the regulation of haemostasis and thrombotic disorders.