ORCID Profile
0000-0001-5712-124X
Current Organisation
John Curtin School of Medical Research
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Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2020
DOI: 10.1101/2020.09.09.20191031
Abstract: Estimates of seroprevalence of SARS-CoV-2 antibodies have been h ered by inadequate assay sensitivity and specificity. Using an ELISA-based approach to that combines data about IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, we show that near-optimal sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (0 to 0.72%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Publisher: Informa UK Limited
Date: 13-02-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-11-2021
DOI: 10.1161/ATVBAHA.120.314485
Abstract: Obesity is associated with a proinflammatory and prothrombotic state that supports atherosclerosis progression. The goal of this study was to gain insights into the phosphorylation events related to platelet reactivity in obesity and identify platelet biomarkers and altered activation pathways in this clinical condition. We performed a comparative phosphoproteomic analysis of resting platelets from obese patients and their age- and gender-matched lean controls. The phosphoproteomic data were validated by mechanistic, functional, and biochemical assays. We identified 220 differentially regulated phosphopeptides, from at least 175 proteins interestingly, all were up-regulated in obesity. Most of the altered phosphoproteins are involved in SFKs (Src-family kinases)-related signaling pathways, cytoskeleton reorganization, and vesicle transport, some of them validated by targeted mass spectrometry. To confirm platelet dysfunction, flow cytometry assays were performed in whole blood indicating higher surface levels of GP (glycoprotein) VI and CLEC (C-type lectin-like receptor) 2 in platelets from obese patients correlating positively with body mass index. Receiver operator characteristics curves analysis suggested a much higher sensitivity for GPVI to discriminate between obese and lean in iduals. Indeed, we also found that obese platelets displayed more adhesion to collagen-coated plates. In line with the above data, soluble GPVI levels—indicative of higher GPVI signaling activation—were almost double in plasma from obese patients. Our results provide novel information on platelet phosphorylation changes related to obesity, revealing the impact of this chronic pathology on platelet reactivity and pointing towards the main signaling pathways dysregulated.
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2022
DOI: 10.1101/2022.06.17.496569
Abstract: Heterogenous fluid shear stress is known to provide mechanical cues for cell adhesion and translocation. To assemble 3D microstructures using current fabrication methods in a single channel and recapitulate in vivo heterogenous fluid flow would require hours of fabrication and specialized equipment. Inspired by the traditional art form of inside painting, we developed a technique for 3D fabrication of micro-patterned flow channels and mixed in vivo fluid flow in a matter of minutes. We termed this technique Multiphoton Inner Laser Lithography (MILL). We further showed that when combined with adaptive optics, MILL is compatible with both flat and curved channel shapes. MILL recapitulated in vivo tissue topology and 3D fluid flow within tissue stroma (low fluid shear, 0 - 3.5 dynes/cm2) and blood vessel (high fluid shear, 0 - 80 dynes/cm2). We demonstrate fibroblast cell and platelets adhere and translocate differently between laminar flow patterns that are homogenous versus heterogeneous in real time. Parallel strips of MILL channels were assembled for simultaneous platelet function test to quantify the efficacy of an antithrombotic GPVI Fab (~2000 microthrombi per test). The MILL technique can be readily reproduced in vivo fluid flow in minutes and benefit preclinical screening of drug pharmacokinetics.
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1111/JTH.14797
Publisher: Portland Press Ltd.
Date: 11-2020
DOI: 10.1042/CS20191101
Abstract: Platelets have a predominant role in haemostasis, the maintenance of blood volume and emerging roles as innate immune cells, in wound healing and in inflammatory responses. Platelets express receptors that are important for platelet adhesion, aggregation, participation in inflammatory responses, and for triggering degranulation and enhancing thrombin generation. They carry a cargo of granules bearing enzymes, adhesion molecules, growth factors and cytokines, and have the ability to generate reactive oxygen species. The platelet is at the frontline of a host of cellular responses to invading pathogens, injury, and infection. Perhaps because of this intrinsic responsibility of a platelet to rapidly respond to thrombotic, pathological and immunological factors as part of their infantry role platelets are susceptible to targeted attack by the adaptive immune system. Such attacks are often transitory but result in aberrant platelet activation as well as significant loss of platelet numbers and platelet function, paradoxically leading to elevated risks of both thrombosis and bleeding. Here, we discuss the main molecular events underlying immune-based platelet disorders with specific focus on events occurring at the platelet surface leading to activation and clearance.
Publisher: Wiley
Date: 08-12-2021
DOI: 10.1002/JHA2.358
Abstract: Platelet transfusions are not always available for bleeding in severe thrombocytopenia, as storage outside of major centers is limited by their short shelf‐life. Data are lacking to support alternative available blood products however, additional fibrinogen has been shown to enhance clot formation in vitro. To test the hypothesis that cryoprecipitate supplementation could improve clot formation in severe thrombocytopenia, eight hematological malignancy patients with platelet counts under 10 × 10 9 /L each had 10 units of apheresis cryoprecipitate transfused prior to planned prophylactic platelet transfusions. The primary endpoint of thromboelastometry litude at 20 min increased by a mean of 5.1 mm ( p 0.01) following cryoprecipitate transfusion despite persisting thrombocytopenia. Thromboelastometry clotting times reduced by a mean of 7.8 s ( p 0.05) and alpha angle increased by a mean of 10.6⁰ ( p 0.01). These results are consistent with cryoprecipitate enhancing the strength of the fibrin latelet meshwork within the forming thrombus. While platelet transfusion remains the standard of care, where platelet supplies are limited, these data provide a rationale for the use of cryoprecipitate to obtain hemostasis in bleeding thrombocytopenic patients.
Publisher: Oxford University Press (OUP)
Date: 03-10-2021
Abstract: Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been h ered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay–based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0–1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Publisher: American Society of Hematology
Date: 10-06-2022
DOI: 10.1182/BLOODADVANCES.2021006698
Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria) vaccine. The putative mechanism involves formation of pathological anti–platelet factor 4 (PF4) antibodies that activate platelets via the low-affinity immunoglobulin G receptor FcγRIIa to drive thrombosis and thrombocytopenia. Functional assays are important for VITT diagnosis, as not all detectable anti-PF4 antibodies are pathogenic, and immunoassays have varying sensitivity. Combination of ligand binding of G protein–coupled receptors (protease-activated receptor-1) and immunoreceptor tyrosine–based activation motif–linked receptors (FcγRIIa) synergistically induce procoagulant platelet formation, which supports thrombin generation. Here, we describe a flow cytometry–based procoagulant platelet assay using cell death marker GSAO and P-selectin to diagnose VITT by exposing donor whole blood to patient plasma in the presence of a protease-activated receptor-1 agonist. Consecutive patients triaged for confirmatory functional VITT testing after screening using PF4/heparin ELISA were evaluated. In a development cohort of 47 patients with suspected VITT, plasma from ELISA-positive patients (n = 23), but not healthy donors (n = 32) or in iduals exposed to the ChAdOx1 nCov-19 vaccine without VITT (n = 24), significantly increased the procoagulant platelet response. In a validation cohort of 99 VITT patients identified according to clinicopathologic adjudication, procoagulant flow cytometry identified 93% of VITT cases, including ELISA-negative and serotonin release assay–negative patients. The in vitro effect of intravenous immunoglobulin (IVIg) and fondaparinux trended with the clinical response seen in patients. Induction of FcγRIIa-dependent procoagulant response by patient plasma, suppressible by heparin and IVIg, is highly indicative of VITT, resulting in a sensitive and specific assay that has been adopted as part of a national diagnostic algorithm to identify vaccinated patients with platelet-activating antibodies.
No related grants have been discovered for Sarah Hicks.