01. PROTEIN S
Charactersation of miRNAs in Oestrogen-mediated Hypercoaguability During Pregnancy and Oral Contraceptive Use
Project summary
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 PS levels decline in response to increased circulating oestrogen levels during pregnancy, oral contraceptive use or oestrogen replacement therapy; leading to a higher risk of venous thrombosis. Molecular mechanisms, however, of oestrogen-mediated acquired PS deficiency are poorly understood. We discovered a novel involvement of microRNAs in coagulation pathways. The microRNAs identified are shown to participate in the regulation of oestrogen-responsive coagulation factors. Therefore, this study aims to identify additional oestrogen-responsive microRNAs, and decipher the role(s) of microRNAs in the regulation of haemostasis and thrombotic disorders.
Funded by: Kanematsu/Novo Nordisk Research Award, Hollywood Private Hospital Research Foundation, Perth Blood Institute.
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
Study Participant Recruitment Information:
Aim
Characterisation of miRNAs in oestrogen-mediated Protein S deficiency
Background
Protein S (PS) is an important anticoagulant (anti-blood clotting) factor and individuals with deficiencies in PS are at an increased risk of developing venous thrombosis (small blood clots in the vein). It is well documented in clinical studies that increased levels of the female hormone (oestrogen) during pregnancy are associated with acquired deficiencies in PS. However, how high oestrogen levels cause acquired PS deficiency is still poorly understood.
RNAs are present within all cells of the body. They are similar in structure to DNA which makes up our genes. RNAs are large molecules made up sequences of smaller units called nucleic acids. Larger RNAs produce all the proteins and other compounds needed for the structure and functioning of the body. The small RNA species, microRNAs, are short RNA sequences that do not get converted into proteins, but instead act to inhibit the production of target proteins.
Our research has found that high oestrogen concentrations similar to levels found in pregnant women cause changes to microRNA levels which been found to inhibit the production of PS. Building on our these, we want to investigate microRNA levels and PS between non-pregnant and pregnant women to find out if changes to specific levels of microRNA species the blood is associated with PS deficiency in conditions of high oestrogen levels, such as during pregnancy.
Patient Recruitment
As part of your involvement in this study we will need to collect a 40mL blood sample. This will be performed by a fully trained phlebotomist or a medical practitioner. Some individuals experience mild bruising around the site of the venipuncture that resolves within 1-3 days. No other complications are anticipated. Genetic material (DNA and RNA) from your blood will be tested as part of the study. Your samples may also be used in future research investigating factors causing clotting disorders and Protein S deficiency.
You will also be required to fill in a short questionnaire regarding medical and pregnancy history including details about previous miscarriages, hormone treatment / IVF and major surgery etc.
Number of Patients
100 pregnant and 100 non-pregnant women
Co-ordinating Centre and Central Laboratory
Western Australia Centre for Thrombosis and Haemophilia (WACTH), Murdoch University
Contacts
Prof. Ross Baker
Project summary
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 PS levels decline in response to increased circulating oestrogen levels during pregnancy, oral contraceptive use or oestrogen replacement therapy; leading to a higher risk of venous thrombosis. Molecular mechanisms, however, of oestrogen-mediated acquired PS deficiency are poorly understood. We discovered a novel involvement of microRNAs in coagulation pathways. The microRNAs identified are shown to participate in the regulation of oestrogen-responsive coagulation factors. Therefore, this study aims to identify additional oestrogen-responsive microRNAs, and decipher the role(s) of microRNAs in the regulation of haemostasis and thrombotic disorders.
Funded by: Kanematsu/Novo Nordisk Research Award, Hollywood Private Hospital Research Foundation, Perth Blood Institute.
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
Study Participant Recruitment Information:
Aim
Characterisation of miRNAs in oestrogen-mediated Protein S deficiency
Background
Protein S (PS) is an important anticoagulant (anti-blood clotting) factor and individuals with deficiencies in PS are at an increased risk of developing venous thrombosis (small blood clots in the vein). It is well documented in clinical studies that increased levels of the female hormone (oestrogen) during pregnancy are associated with acquired deficiencies in PS. However, how high oestrogen levels cause acquired PS deficiency is still poorly understood.
RNAs are present within all cells of the body. They are similar in structure to DNA which makes up our genes. RNAs are large molecules made up sequences of smaller units called nucleic acids. Larger RNAs produce all the proteins and other compounds needed for the structure and functioning of the body. The small RNA species, microRNAs, are short RNA sequences that do not get converted into proteins, but instead act to inhibit the production of target proteins.
Our research has found that high oestrogen concentrations similar to levels found in pregnant women cause changes to microRNA levels which been found to inhibit the production of PS. Building on our these, we want to investigate microRNA levels and PS between non-pregnant and pregnant women to find out if changes to specific levels of microRNA species the blood is associated with PS deficiency in conditions of high oestrogen levels, such as during pregnancy.
Patient Recruitment
As part of your involvement in this study we will need to collect a 40mL blood sample. This will be performed by a fully trained phlebotomist or a medical practitioner. Some individuals experience mild bruising around the site of the venipuncture that resolves within 1-3 days. No other complications are anticipated. Genetic material (DNA and RNA) from your blood will be tested as part of the study. Your samples may also be used in future research investigating factors causing clotting disorders and Protein S deficiency.
You will also be required to fill in a short questionnaire regarding medical and pregnancy history including details about previous miscarriages, hormone treatment / IVF and major surgery etc.
Number of Patients
100 pregnant and 100 non-pregnant women
Co-ordinating Centre and Central Laboratory
Western Australia Centre for Thrombosis and Haemophilia (WACTH), Murdoch University
Contacts
Prof. Ross Baker
02. ADAMTS13
Characterisation of ADAMTS13 Antibodies in Thrombotic Thrombocytopaenic Pupura (TTP)
Project summary
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 persist in the blood circulation leading 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 neutralising autoantibodies directed against ADAMTS13. There exist, however, individuals with high titres of ADAMTS13 autoantibodies that do not develop TTP, indicating that there are ADAMTS13 antibodies which are non-neutralising. Current ADAMTS13 autoantibody detection methods do not discriminate between the neutralising and non-neutralising forms, manifesting in high false-positives and a lack of specificity against targeted ADAMTS13 epitopes. This study aims to develop a method for screening patient samples for specific populations of ADAMTS13 autoantibodies and determining their role in thrombotic disorders including TTP onset and stroke.
Funded by: Australian Society for Thromboss and Haemostasis (ASTH)
Link: http://www.aptin.org and http://www.pbi.org.au
APMAT
Thrombotic thrombocytopenic purpure
Study participant recruitment information:
Aim
To establish a collaborative network of leading haematology centres in the Asian Pacific Region to study the pathophysiology, diagnosis and treatment of thrombotic thrombocytopenic purpura.
Background
Thrombotic Thrombocytopenic Purpura (TTP) is a rare disease (5-10 cases per million persons) characterised by occlusion of the microcirculation by platelet rich thrombi leading to neurological abnormalities, stroke, renal failure and death.
The diagnosis is difficult and despite early recognition and the institution of prompt standard care with plasmapheresis and plasma exchange, the mortality rate is still high and subsequent relapses after remission frequently occur. ADAMTS13 is a circulating protease that cleaves the prothrombotic ultra large multimers of von Willebrand factor (VWF) and severe deficiency has been described in a substantial proportion of patients with TTP.
There is, however, current uncertainty about the definition, diagnosis, the role and reliability of ADAMTS13 testing in a large prospective cohort of patients with the diagnosis of TTP. There is an unmet clinical need for standardised criteria including diagnostic testing for TTP to identify patients who may benefit from new therapies including recombinant ADAMTS13 therapy.
Patient Recruitment
Prospective Multicentre Study of consecutive patients fulfilling standardised clinical criteria for TTP. Thirty milliliter of venous blood will be collected at diagnosis for local and central laboratory testing and storage for ADAMTS13 activity and antibody level, other biomarkers for TTP and DNA/RNA extracted for genetic analysis. Ten milliliter of venous blood will be collected for further analysis if the platelet count returns to normal prior to day 30, at day 30 and day 90, 180 and day 360. Patients will then be followed for a period of 3 years for clinical and laboratory evidence of relapse.
Number of Patients
300 patients with TTP over a 5 year period (2015-2020).
Number of Centres
25 plus sites from Australia, New Zealand, Singapore, Malaysia, South Korea, Thailand, Hong Kong, India, Taiwan, Japan, Indonesia, and China.
Co-ordinating Centre and Central Laboratory
Western Australia Centre for Thrombosis and Haemophilia (WACTH), Murdoch University
Supporting Organisations
Australasian Society for Thrombosis and Haemostasis (ASTH), Asia Pacific Society on Thrombosis and Haemostasis (APSTH).
Contacts
Prof. Ross Baker
Dr. Jim Tiao
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
Recruitment update:
The APMAT study centres in Murdoch University, Hollywood Private Hospital, Malaysia, New Zealand, Thailand and China are currently collecting APAMT1 participant samples.
Please contact Dr. Jim Tiao if you wish to participate in the study.
Project summary
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 persist in the blood circulation leading 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 neutralising autoantibodies directed against ADAMTS13. There exist, however, individuals with high titres of ADAMTS13 autoantibodies that do not develop TTP, indicating that there are ADAMTS13 antibodies which are non-neutralising. Current ADAMTS13 autoantibody detection methods do not discriminate between the neutralising and non-neutralising forms, manifesting in high false-positives and a lack of specificity against targeted ADAMTS13 epitopes. This study aims to develop a method for screening patient samples for specific populations of ADAMTS13 autoantibodies and determining their role in thrombotic disorders including TTP onset and stroke.
Funded by: Australian Society for Thromboss and Haemostasis (ASTH)
Link: http://www.aptin.org and http://www.pbi.org.au
APMAT
Thrombotic thrombocytopenic purpure
Study participant recruitment information:
Aim
To establish a collaborative network of leading haematology centres in the Asian Pacific Region to study the pathophysiology, diagnosis and treatment of thrombotic thrombocytopenic purpura.
Background
Thrombotic Thrombocytopenic Purpura (TTP) is a rare disease (5-10 cases per million persons) characterised by occlusion of the microcirculation by platelet rich thrombi leading to neurological abnormalities, stroke, renal failure and death.
The diagnosis is difficult and despite early recognition and the institution of prompt standard care with plasmapheresis and plasma exchange, the mortality rate is still high and subsequent relapses after remission frequently occur. ADAMTS13 is a circulating protease that cleaves the prothrombotic ultra large multimers of von Willebrand factor (VWF) and severe deficiency has been described in a substantial proportion of patients with TTP.
There is, however, current uncertainty about the definition, diagnosis, the role and reliability of ADAMTS13 testing in a large prospective cohort of patients with the diagnosis of TTP. There is an unmet clinical need for standardised criteria including diagnostic testing for TTP to identify patients who may benefit from new therapies including recombinant ADAMTS13 therapy.
Patient Recruitment
Prospective Multicentre Study of consecutive patients fulfilling standardised clinical criteria for TTP. Thirty milliliter of venous blood will be collected at diagnosis for local and central laboratory testing and storage for ADAMTS13 activity and antibody level, other biomarkers for TTP and DNA/RNA extracted for genetic analysis. Ten milliliter of venous blood will be collected for further analysis if the platelet count returns to normal prior to day 30, at day 30 and day 90, 180 and day 360. Patients will then be followed for a period of 3 years for clinical and laboratory evidence of relapse.
Number of Patients
300 patients with TTP over a 5 year period (2015-2020).
Number of Centres
25 plus sites from Australia, New Zealand, Singapore, Malaysia, South Korea, Thailand, Hong Kong, India, Taiwan, Japan, Indonesia, and China.
Co-ordinating Centre and Central Laboratory
Western Australia Centre for Thrombosis and Haemophilia (WACTH), Murdoch University
Supporting Organisations
Australasian Society for Thrombosis and Haemostasis (ASTH), Asia Pacific Society on Thrombosis and Haemostasis (APSTH).
Contacts
Prof. Ross Baker
Dr. Jim Tiao
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
Recruitment update:
The APMAT study centres in Murdoch University, Hollywood Private Hospital, Malaysia, New Zealand, Thailand and China are currently collecting APAMT1 participant samples.
Please contact Dr. Jim Tiao if you wish to participate in the study.
03. FOLATE RECEPTOR ALPHA
Characterisation of Folate Receptor alpha (FRα) Autoantibodies in Recurrent Miscarriage
Project summary
Folate deficiency is a known risk factor for recurrent miscarriage with a poorly understood aetiology. 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, suggesting impaired folate uptake as a mechanism of action. Recent studies have identified autoantibodies that block Folate Receptor alpha (FRα), a tissue specific folate transport protein, to inhibit folate transport. Embryonic folate transportation is highly dependent on FRα 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 FRα block folate binding to the receptor causing folate deficiency complications during pregnancy, leading to thrombotic miscarriage.
Funded by: Perth Blood Institute
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
Project summary
Folate deficiency is a known risk factor for recurrent miscarriage with a poorly understood aetiology. 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, suggesting impaired folate uptake as a mechanism of action. Recent studies have identified autoantibodies that block Folate Receptor alpha (FRα), a tissue specific folate transport protein, to inhibit folate transport. Embryonic folate transportation is highly dependent on FRα 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 FRα block folate binding to the receptor causing folate deficiency complications during pregnancy, leading to thrombotic miscarriage.
Funded by: Perth Blood Institute
News
We offer undergraduate, honours, masters and PhD research-based places through the School of Veterinary and Life Sciences, Murdoch University, Australia. Please email info@wacth.org for more information.
