ORCID Profile
0000-0002-5383-6552
Current Organisation
University of South Australia
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Publisher: Georg Thieme Verlag KG
Date: 17-10-2018
Abstract: Background Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. Methods and Results Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and 90% reversal at 24 hours. Conclusion Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.JTCVS.2012.05.065
Abstract: To compare the potency, reversibility, and perioperative bleeding risk of Hepalean with those of PPC heparin. Because in vitro testing failed to detect differences in the potency or protamine reversibility of the 2 heparin preparations, we conducted a parallel group, single-center, double-blind, randomized, controlled trial to compare the anticoagulant effects of Hepalean to those of PPC heparin in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. From June 1, 2011, to June 30, 2011, we randomly assigned 11 patients to receive PPC heparin and 10 to receive Hepalean. Despite similar initial doses of heparin, the median initial activated clotting time was numerically lower in the PPC heparin group than in the Hepalean group (median, 516.0 seconds interquartile range, 481.0-633.0 vs median, 584.0 seconds, interquartile range, 520.0-629.0 P = .418). Those given PPC heparin required a greater total heparin dose (median, 46,000.0 U interquartile range, 39,500.0-60,000.0 vs median, 34,500.0 U interquartile range, 32,250.0-37,000.0 P = .011) and a greater dose of heparin per kilogram than those given Hepalean (median, 572.9 U/kg interquartile range, 443.0-659.7 vs median, 401.1 U/kg interquartile range, 400.0-419.4 P = .003). The key secondary results included an increased median total protamine dose (median, 600.0 mg interquartile range, 550.0-700.0 vs median, 500.0 mg interquartile range, 425.0-542.5 P = .026) and a trend toward increased chest tube output within 24 hours (median, 830.0 mL interquartile range, 425.0-1135.0 vs median, 702.5 mL interquartile range, 550.0-742.5 P = .324). PPC heparin use was associated with greater heparin and protamine dose requirements than Hepalean. These findings indicate that heparin preparations are not interchangeable and suggest that a direct comparison of the potency with the brand in use is needed if a change is made to ensure that the agents exert similar anticoagulant effects in vivo.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.THROMRES.2014.04.010
Abstract: There is minimal data on the influence of pre-analytical variables on the use of calibrated automated thrombography (CAT), to measure thrombin generation. To evaluate the impact of centrifugation methods, time after collection, and contact activation inhibition on the CAT assay performed using two commercial reagents. Six different methods of plasma separation were examined. Thrombin generation triggered by a 5 pM tissue factor reagent was not greatly affected by plasma separation method, with similar results obtained with all methods apart from single centrifugation and membrane filtration. Membrane filtration increased APTT and is not recommended. Extended double centrifugation at higher speed was required to minimise the impact of residual phospholipid with 1 pM tissue factor trigger, particularly with inhibition of contact activation. The effect of a delay of up to 24 hours in preparing plasma was assessed. No significant difference in results was observed among s les processed between 0.5 and 6 hours after blood collection into plastic Vacuette® tubes. The presence or absence of corn trypsin inhibitor had a significant impact on all parameters with 1 pM tissue factor trigger, with minor differences seen on Peak and ttPeak results using 5 pM tissue factor. The impact of pre-analytical variables on thrombin generation results is dependent on the concentration of tissue factor in the trigger reagent used. Results with 1 pM tissue factor are particularly sensitive to centrifugation method and contact activation, and standardisation is required to allow large collaborative studies to be performed.
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/AM18033
Abstract: Ticks and blood smears were collected from a reintroduced population of threatened tammar wallabies (Notamacropus eugenii eugenii). Ixodes hirsti was common during autumn/winter, and Amblyomma spp. in spring/summer, reflecting the seasonal density of questing A. triguttatum triguttatum. Red blood cell parasites were not detected in the 90 smears analysed.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2012
DOI: 10.1007/S11239-012-0857-9
Abstract: Compared with warfarin, dabigatran is associated with less intracranial hemorrhage, but an increased risk of myocardial infarction. To explore these phenomena, we compared their effects on thrombin generation. Thrombin generation in plasma from 10 patients taking therapeutic doses of warfarin (mean INR 2.6) was compared with that in plasma containing 250 ng/mL dabigatran. Although lag times were similar when thrombin generation was induced by recalcification or with a range of tissue factor concentrations, there was a greater reduction in peak thrombin generation and endogenous thrombin potential in plasma from warfarin-treated patients than in dabigatran-containing plasma. Similar results were obtained when thrombin generation was determined in plasma s les from 18 warfarin or 36 dabigatran treated patients entered into the RE-LY trial. Warfarin suppresses thrombin generation more efficiently than dabigatran. Greater suppression of normal hemostatic mechanisms in the brain and pathological thrombosis at sites of atherosclerotic plaque disruption may explain the higher rate of intracranial bleeding and lower rate of myocardial infarction with warfarin compared with dabigatran.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2023
DOI: 10.1038/S41598-023-36266-2
Abstract: Thrombosis is one of the cardinal manifestations of myeloproliferative neoplasms (MPN). The mechanisms leading to a prothrombotic state in MPN are complex and remain poorly understood. Platelet mitochondria play a role in platelet activation, but their number and function have not been extensively explored in MPN to date. We observed an increased number of mitochondria in platelets from MPN patients compared with healthy donors. MPN patients had an increased proportion of dysfunctional platelet mitochondria. The fraction of platelets with depolarized mitochondria at rest was increased in essential thrombocythemia (ET) patients and the mitochondria were hypersensitive to depolarization following thrombin agonist stimulation. Live microscopy showed a stochastic process in which a higher proportion of in idual ET platelets underwent mitochondrial depolarization and after a shorter agonist exposure compared to healthy donors. Depolarization was immediately followed by ballooning of the platelet membrane, which is a feature of procoagulant platelets. We also noted that the mitochondria of MPN patients were on average located nearer the platelet surface and we observed extrusion of mitochondria from the platelet surface as microparticles. These data implicate platelet mitochondria in a number of prothrombotic phenomena. Further studies are warranted to assess whether these findings correlate with clinical thrombotic events.
Publisher: Wiley
Date: 27-07-2018
DOI: 10.1111/EJH.13109
Abstract: An increased rate of platelet production is a possible cause of reduced antithrombotic response to once-daily aspirin. Markers of immature platelets (IPs), such as immature platelet count (IPC), immature platelet fraction (IPF), and mean platelet volume (MPV) might be useful for identifying patients who have an increase in their rate of platelet production. However, their potential as markers of platelet production has not been rigorously evaluated. We aimed to investigate the utility of the IPC, IPF, and MPV as surrogates for increased platelet production using coronary artery bypass grafting (CABG) as a model of enhanced thrombopoiesis. Daily changes in platelet count, IPC, IPF, and MPV were followed in 45 patients undergoing CABG. The rise in IP markers preceded that in the platelet count. IPC (16% per day increase from nadir) but not IPF or MPV showed a significant and sustained rise, which paralleled the pattern observed with platelet count (18% per day increase from nadir). Of the 3 markers, IPC was the most promising as surrogates for platelet production. Future studies should evaluate the utility of the IPC to identify patients with cardiovascular disease with reduced response to aspirin who might benefit from twice-daily aspirin.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2014
Publisher: Informa UK Limited
Date: 15-10-2015
DOI: 10.1586/14779072.2015.1096779
Abstract: Four direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) have been shown to be at least as effective and safe as warfarin for the prevention of stroke in atrial fibrillation and the prevention and treatment of venous thromboembolism. Although they are administered in fixed doses without routine coagulation monitoring, measurement of anticoagulant effect or drug levels may be useful to determine if: anticoagulant effect is present in patients who are bleeding or require an urgent procedure or thrombolysis levels are within usual on-therapy range in patients with recurrent thromboembolism during treatment and levels are outside of the usual on-therapy range in patients with overdose or with extreme clinical characteristics. Traditional coagulation assays are widely available but lack sensitivity to detect clinically relevant anticoagulant effects, and lack accuracy in quantitating drug levels. Specific drug assays are less widely available but can accurately measure drug levels and should be preferred.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1111/JTH.12720
Abstract: Clinical situations occur where expedient assessment of the anticoagulant activity of the direct factor Xa (FXa) inhibitors is required. Although quantitative anti-FXa (FXa) assays can be used to measure plasma levels of apixaban or rivaroxaban, turnaround is often slow and many laboratories do not perform these assays. We compared the in vitro effects of apixaban and rivaroxaban on two readily available laboratory tests, the prothrombin time (PT) and activated partial thromboplastin time (APTT), performed with different reagents. We aimed to identify the most sensitive reagents. Rivaroxaban or apixaban was added to human plasma at a range of concentrations covering expected peak and trough levels, and concentrations were confirmed using calibrated anti-FXa assays. S les were assayed with six PT and seven APTT reagents using different coagulometers. TriniCLOT PT Excel S was the only reagent to demonstrate sensitivity to apixaban. All of the PT reagents were sensitive to rivaroxaban with TriniCLOT PT Excel S and HemosIL HS PLUS being the most sensitive. Sensitivity to rivaroxaban varied among APTT reagents four reagents exhibited the greatest responsiveness, and of these, Actin FSL was the most responsive. Commonly used coagulation tests may be useful for assessing the anticoagulant effect of rivaroxaban but not of apixaban. The reason for the different effects of apixaban and rivaroxaban on the PT and APTT is unknown.
Publisher: Wiley
Date: 22-10-2015
DOI: 10.1111/BJH.13810
Abstract: Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2021
DOI: 10.1186/S12885-021-08482-4
Abstract: The formation of blood vessels within solid tumors directly contributes to cancer growth and metastasis. Until recently, tumor vasculature was thought to occur exclusively via endothelial cell (EC) lined structures (i.e. angiogenesis), but a second source of tumor vasculature arises from the cancer cells themselves, a process known as vasculogenic mimicry (VM). While it is generally understood that the function of VM vessels is the same as that of EC-lined vessels (i.e. to supply oxygen and nutrients to the proliferating cancer cells), the molecular mechanisms underpinning VM are yet to be fully elucidated. Human VM-competent melanoma cell lines were examined for their VM potential using the in vitro angiogenesis assays (Matrigel), together with inhibition studies using small interfering RNA and blocking monoclonal antibodies. Invasion assays and adhesion assays were used to examine cancer cell function. Herein we demonstrate that CD36, a cell surface glycoprotein known to promote angiogenesis by ECs, also supports VM formation by human melanoma cancer cells. In silico analysis of CD36 expression within the melanoma cohort of The Cancer Genome Atlas suggests that melanoma patients with high expression of CD36 have a poorer clinical outcome. Using in vitro ‘angiogenesis’ assays and CD36-knockdown approaches, we reveal that CD36 supports VM formation by human melanoma cells as well as adhesion to, and invasion through, a cancer derived extracellular matrix substrate. Interestingly, thrombospondin-1 (TSP-1), a ligand for CD36 on ECs that inhibits angiogenesis, has no effect on VM formation. Further investigation revealed a role for laminin, but not collagen or fibronectin, as ligands for CD36 expressing melanoma cells. Taken together, this study suggests that CD36 is a novel regulator of VM by melanoma cancer cells that is facilitated, at least in part, via integrin-α 3 and laminin. Unlike angiogenesis, VM is not perturbed by the presence of TSP-1, thus providing new information on differences between these two processes of tumor vascularization which may be exploited to combat cancer progression.
No related grants have been discovered for Brian Dale.