The Gardiner Group - Mechanisms of Thrombosis and Cancer

The Gardiner Group - Mechanisms of Thrombosis and Cancer relocated to the ACRF Department of Cancer Biology and Therapeutics in The John Curtin School of Medical Research at ANU in 2016. Circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events beyond the platelet’s traditional role in haemostasis and thrombosis. Emerging research shows that platelets orchestrate the complex interplay between haemostasis, thrombosis, inflammation, and cancer. These physiologically important processes during an inflammatory response can become pathologic and support transformation and cancer progression.

Since establishing her laboratory in JCSMR, ANU, Elizabeth has established the National Platelet Research and Referral Centre (NPRC) which seeks to improve our understanding of platelet disorders and identify the most effective treatment options through collaborative and targeted research approaches.

Platelets and the Hallmarks of Cancer: (Franco et al., Blood 2015)

  • Metastasis and evading immune surveillance
  • Resisting tumour cell apoptosis
  • Sustaining tumourigenesis
  • Inducing angiogenesis
  • Supporting cancer stem cells

The group investigates the molecular basis of processes coordinated by platelets across vascular biology. Primary areas of interest focus on the biochemical and molecular analysis of immune-based platelet disorders seen clinically in immunothrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT) and the group has expanded their core interest to focus on thrombosis associated with cancer.

Further, the group specialises in applying unique flow cytometry and platelet aggregometry tools to aid in the characterisation of platelet-based deficiencies underlying unexplained bleeding in people with healthy platelet counts and normal blood coagulation.

Important discoveries made by the Group

  • Identification of platelet receptor loss in people with early and late-stage leukaemia and the consequences of treatment with new and existing therapeutics on bleeding risk in these individuals
  • The identification and molecular characterisation of processes underlying ligand-dependent, metalloproteinase-mediated shedding of the primary adhesion/signalling receptors on platelets, glycoprotein (GP)VI and GPIba of the GPIb-IX-V complex.
  • The link between engagement of platelet Immunoreceptor Tyrosine-based Activation Motif (ITAM)-signalling and activation of A Disintegrin And Metalloproteinase (ADAM) family members.
  • A new role for active factor X (FXa) in triggering platelet receptor shedding, with bleeding implications for individuals with disseminated intravascular coagulation (DIC) and other coagulopathies.
  • The identification and quantification of rapid and acute changes in ADAMs metalloproteolytic activity upon brief exposure to elevated shear stress (10,000 s-1, 1 minute) and the implications that this pathway might have in patients with aortic stenosis, stroke and in people requiring mechano-circulatory support (LVADs, ECMO).
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Hearn, J.I. and E.E. Gardiner, Research and clinical approaches to assess platelet function in flowing blood. Arterioscler Thromb Vasc Biol, 2023. 43(10): p. 1775-1783.

Hearn, J.I. and E.E. Gardiner, Tumor Cell EnVoys advance the education of platelets. Circ Res, 2023. 132(11): p. 1462-1464.

Crispin, P.J., L.A. Coupland, and E.E. Gardiner, Achieving haemostasis in thrombocytopenia in remote settings: an in vitro comparison of frozen and lyophilized products. Blood Transfus, 2023. 21(4): p. 289-295.

Bhoopalan, V., E.E. Gardiner, and A. Kaur, An optimized method of collecting murine peripheral blood and dilution correction for accurate blood cell enumeration. Curr Protoc, 2023. 3(5): p. e765.

Crispin, P.J., P.Y. Choi, and E.E. Gardiner, SkM-ing information from traumatized tissue. J Thromb Haemost, 2022. 20(6): p. 1306-1308.

Crispin, P., et al., Cryoprecipitate as an alternative to platelet transfusion in thrombocytopenia. EJHaem, 2022. 3(1): p. 80-85.

Brysland, S.A., et al., Bleeding propensity in Waldenstrom Macroglobulinemia: potential causes and evaluation. Thromb Haemost, 2022. 122(11): p. 1843-1857.

Zheng, Y., et al., Label-free multimodal quantitative imaging flow assay for intrathrombus formation in vitro. Biophys J, 2021. 120(5): p. 791-804.

Hicks, S.M., et al., A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting. J Infect Dis, 2021. 223(1): p. 10-14.

Barrachina, M.N., et al., Phosphoproteomic analysis of platelets in severe obesity uncovers platelet reactivity and signaling pathways alterations. Arterioscler Thromb Vasc Biol, 2021. 41(1): p. 478-490.

Montague, S.J., et al., Imaging platelet processes and function-current and emerging approaches for imaging in vitro and in vivo. Front Immunol, 2020. 11: p. 78.

Montague, S.J., et al., Fibrin exposure triggers alphaIIbbeta3-independent platelet aggregate formation, ADAM10 activity and glycoprotein VI shedding in a charge-dependent manner. J Thromb Haemost, 2020. 18(6): p. 1447-1458.

Hicks, S.M., et al., The molecular basis of immune-based platelet disorders. Clin Sci (Lond), 2020. 134(21): p. 2807-2822.

Hicks, S.M. and E.E. Gardiner, Free reelin' along the platelet surface. Arterioscler Thromb Vasc Biol, 2020. 40(10): p. 2341-2343.

Hicks, S.M., et al., Novel scientific approaches and future research directions in understanding ITP. Platelets, 2020. 31(3): p. 315-321.

Crispin, P. and E.E. Gardiner, Platelets and cancer... the plot doesn't always thicken. J Thromb Haemost, 2020. 18(10): p. 2482-2485.

Kaur, A. and E.E. Gardiner, Parkin the bus to manage stress. EMBO Mol Med, 2019. 11(8): p. e10968.

Gardiner, E.E. and R.K. Andrews, Platelet Ubiquitylation-It's everywhere. Thromb Haemost, 2019. 119(1): p. 6-8.

Rivera, J. and E.E. Gardiner, An exit strategy for new platelets. Blood, 2018. 131(10): p. 1041-1042.

Qiao, J., et al., NLRP3 regulates platelet integrin alphaIIbbeta3 outside-in signaling, hemostasis and arterial thrombosis. Haematologica, 2018. 103(9): p. 1568-1576.

Qiao, J., et al., Regulation of platelet activation and thrombus formation by reactive oxygen species. Redox Biol, 2018. 14: p. 126-130.

Montague, S.J. and E.E. Gardiner, Matrix metalloproteinase-13 unlucky for the forming thrombus. Res Pract Thromb Haemost, 2018. 2(3): p. 525-528.

Montague, S.J., et al., Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI. Blood Adv, 2018. 2(3): p. 240-251.

Montague, S.J., R.K. Andrews, and E.E. Gardiner, Mechanisms of receptor shedding in platelets. Blood, 2018. 132(24): p. 2535-2545.

Li, Y., et al., High contrast imaging and flexible photomanipulation for quantitative in vivo multiphoton imaging with polygon scanning microscope. J Biophotonics, 2018. 11(7): p. e201700341.

Gardiner, E.E., Proteolytic processing of platelet receptors. Res Pract Thromb Haemost, 2018. 2(2): p. 240-250.

Flierl, U., et al., Targeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides: comment. J Thromb Haemost, 2018. 16(1): p. 181-185.

Casan, J., et al., Mechanisms of Platelet Dysfunction in Patients with Implantable Devices. Semin Thromb Hemost, 2018. 44(1): p. 12-19.

Andrews, R.K. and E.E. Gardiner, Monitoring the pulse of thrombus formation: Comment on "Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones" by A.V. Belyaev et al. Phys Life Rev, 2018. 26-27: p. 113-115.

Trevillyan, J.M., et al., Decreased levels of platelet-derived soluble glycoprotein VI detected prior to the first diagnosis of coronary artery disease in HIV-positive individuals. Platelets, 2017. 28(3): p. 301-304.

Stack, J.R., et al., Soluble glycoprotein VI, a specific marker of platelet activation is increased in the plasma of subjects with seropositive rheumatoid arthritis. PLoS One, 2017. 12(11): p. e0188027.

Rabbolini, D.J., et al., Anti-glycoprotein VI mediated immune thrombocytopenia: An under-recognized and significant entity? Res Pract Thromb Haemost, 2017. 1(2): p. 291-295.

Qiao, J., et al., An absence of platelet activation following thalidomide treatment in vitro or in vivo. Oncotarget, 2017. 8(22): p. 35776-35782.

Poulter, N.S., et al., Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets. J Thromb Haemost, 2017. 15(3): p. 549-564.

Coupland, L.A., et al., The influence of platelet membranes on tumour cell behaviour. Cancer Metastasis Rev, 2017. 36(2): p. 215-224.

Andrews, R.K. and E.E. Gardiner, The cutting edge of platelets. Platelets, 2017. 28(4): p. 317-318.

Andrews, R.K. and E.E. Gardiner, Basic mechanisms of platelet receptor shedding. Platelets, 2017. 28(4): p. 319-324.