Multiple transfusion medicine research projects
Fields:
- Immunology
- Transfusion medicine
Location: Australian Red Cross Lifeblood
Type of student: Both HDR and Extra-curricular
Type of work:
- Literature review
- Secondary data analysis
- Statistical analysis
- Systematic review
- Wet lab work
Brief synopsis:
Transfusion-related acute lung injury (TRALI) research
Blood transfusion is essential to modern medicine; however, while it is very safe, there are some potential risks. One such risk is transfusion-related acute lung injury (TRALI) where patients develop difficulty in breathing either during or within six hours of transfusion. Treatment is supportive and can include supplemental oxygen and mechanical ventilation. Despite treatment, mortality rates of 5-10% have been reported, although this may be higher in critically ill patients. TRALI is thought to be under-diagnosed and under-reported, with estimates of its incidence ranging from 1:100,000 to 1:1,000,000 components transfused.
One cause of TRALI is the transfusion of antibodies directed against either human leucocyte antigens (HLA) or human neutrophil antigens (HNA). These antibodies typically develop during pregnancy or as a result of transfusion. Thus, many blood services aim to reduce the risk of TRALI by limiting the clinical use of plasma from female donors. In Australia, clinical plasma and aphaeresis platelets are sourced only from male donors. However, cases of TRALI continue to occur due to antibodies present in red cell units and buffy coat pooled platelet units, and due to the other cause of TRALI, what are termed biological response modifiers (BRMs). This term refers to the proteins, lipids, and extracellular vesicles that accumulate in red cell and platelet units during their routine storage of 42 days and 7 days respectively.
Typically, TRALI develops via the transfused antibodies or BRMs reacting with the neutrophils and/or endothelial cells present in the patient's lungs. This results in neutrophil activation and the release of reactive oxygen species (ROS), enzymes and neutrophil extracellular traps (NETs) that damage the lungs allowing vascular leakage and the development of TRALI. Other cell types to be implicated in TRALI development include platelets, monocytes, macrophages, and dendritic cells.
Our laboratory has used laboratory and animal (sheep) models of TRALI to better understand how TRALI develops. We have several potential student projects assisting with our laboratory TRALI models. These projects would be suitable for either HDR students or for extracurricular students. In these models, we culture human lung microvascular endothelial cells, add isolated neutrophils, and then expose them to different blood components, antibodies or BRMs. We then use microscopy to determine the resultant cytotoxic effects on the endothelial cells. We manipulate the model to include other cell types to investigate their roles in TRALI development. We are also testing potential treatments for TRALI which include IL-10, ROS inhibitors and NET inhibitors.
Cryopreserved platelet concentrate research
Platelet concentrates (PCs) are transfused either "prophylactically" to patients at risk of bleeding or "therapeutically" to patients who are bleeding. PCs are stored routinely at room temperature for up to 7 days. This short shelf-life can make it difficult to maintain an inventory of PCs in remote and regional settings, and in military settings. Lifeblood has a long-standing collaboration with the Australian Defence Force to investigate alternative storage methods for PCs that would extend their shelf-life. One potential method is freezing or cryopreserving PCs at -80oC using a cryoprotectant such as DMSO. These cryo-PCs have a shelf-life of 1-2 years.
A phase I clinical trial has already demonstrated that cryo-PCs are safe to transfuse, and a phase III clinical trial is underway to assess whether cryo-PCs are as effective as standard PCs in treating bleeding. However, it has been observed that transfusion of cryo-PCs does not improve platelet counts in patients as well as standard PCs. Laboratory research has demonstrated that platelets in cryo-PCs are more activated than those present in standard PCs. So it is hypothesised that these activated platelets are more readily recruited to the site of bleeding and therefore do not remain in circulation to improve the platelet count. We aim to investigate this hypothesis using mouse models. We will fluorescently label either cryopreserved or standard platelets and then transfuse them into mice. We will then induce an injury in the mice and observe the recruitment of the transfused fluorescent platelets into the clot. This project would be suitable for a HDR student.
Website: https://www.lifeblood.com.au/our-research/program/meet-our-researchers/dr-john-paul-tung
