ORCID Profile
0000-0002-7777-6179
Current Organisation
University of the SunshineCoast
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Publisher: Wiley
Date: 05-03-2013
DOI: 10.1111/VOX.12032
Abstract: Transfusion of blood products in particular older products is associated with patient morbidity. Previously, we demonstrated a higher incidence of acute lung injury in lipopolysaccharide-treated sheep transfused with stored blood products. As transfusion following haemorrhage is more common, we aimed to determine whether a 'first hit' of isolated haemorrhage would precipitate similar detrimental effects following transfusion and also disrupt haemostasis. Anaesthetized sheep had 33% of their total blood volume collected into Leukotrap bags (Pall Medical), which were processed into packed red blood cells and cross-matched for transfusion into other sheep. After 30 mins, the sheep were resuscitated with either: fresh (<5 days old) or stored (35-42 days old) ovine blood followed by 4% albumin to replacement volume, albumin alone or normal saline alone and monitored for 4 h. The first hit of haemorrhage precipitated substantial decreases in mean arterial pressure however haemostasis was preserved. Transfusion of stored ovine blood induced (1) transient pulmonary arterial hypertension but no oedema and (2) reduced fibrinogen levels more than fresh blood, but neither induced coagulopathy. Thus, transfusion of stored blood affected pulmonary function even in the absence of overt organ injury. The fact that stored blood transfusions: (1) did not induce acute lung injury in contrast to previous lipopolysaccharide-primed animal models identifies the 'first hit' as an important determinant of the severity of transfusion-mediated injury (2) impaired pulmonary dynamics verifies the sensitivity and vulnerability of the pulmonary system to injury.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0891-Z
Abstract: Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline s ling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood s les were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. Four hundred eighty s les were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone ( P = 0.01), caspofungin ( P = 0.01) and thiopentone ( P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination ( R 2 = 0.88, P .001). Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.
Publisher: Wiley
Date: 02-09-2014
DOI: 10.1111/VOX.12076
Abstract: The growing awareness of transfusion-associated morbidity and mortality necessitates investigations into the underlying mechanisms. Small animals have been the dominant transfusion model but have associated limitations. This study aimed to develop a comprehensive large animal (ovine) model of transfusion encompassing: blood collection, processing and storage, compatibility testing right through to post-transfusion outcomes. Two units of blood were collected from each of 12 adult male Merino sheep and processed into 24 ovine-packed red blood cell (PRBC) units. Baseline haematological parameters of ovine blood and PRBC cells were analysed. Biochemical changes in ovine PRBCs were characterized during the 42-day storage period. Immunological compatibility of the blood was confirmed with sera from potential recipient sheep, using a saline and albumin agglutination cross-match. Following confirmation of compatibility, each recipient sheep (n = 12) was transfused with two units of ovine PRBC. Procedures for collecting, processing, cross-matching and transfusing ovine blood were established. Although ovine red blood cells are smaller and higher in number, their mean cell haemoglobin concentration is similar to human red blood cells. Ovine PRBC showed improved storage properties in saline-adenine-glucose-mannitol (SAG-M) compared with previous human PRBC studies. Seventy-six compatibility tests were performed and 17·1% were incompatible. Only cross-match compatible ovine PRBC were transfused and no adverse reactions were observed. These findings demonstrate the utility of the ovine model for future blood transfusion studies and highlight the importance of compatibility testing in animal models involving homologous transfusions.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/CC11679
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 12-03-2019
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.TMRV.2019.03.001
Abstract: Evidence-based patient blood management guidelines commonly recommend restrictive hemoglobin thresholds of 70 to 80 g/L for asymptomatic adults. However, most transfusion trials have enrolled adults across a broad age span, with few exclusive to older adults. Our recent meta-analysis of transfusion trials that focused on older adults paradoxically found lower mortality and fewer cardiac complications when these patients were managed using higher hemoglobin thresholds. We postulate that declining cardiac output with age contributes to deteriorating oxygen delivery capacity which impacts anemia-associated outcomes in older adults and propose a model to explain this age-related difference. We reviewed evidence concerning the pathophysiology of aging to explore the disparity in transfusion trial outcomes related to hemoglobin thresholds in different age groups. The literature was searched for normative cardiac output values at different ages in healthy adults. Using normative peak cardiac output data, we modeled oxygen delivery capacity in young, middle-aged, and older adults at a range of hemoglobin levels. Cardiovascular and pulmonary systems are impacted by age-related pathophysiological changes. Diminishing peak cardiac output associated with aging reduces the maximal oxygen delivery achievable under metabolic stress. Hence, at low hemoglobin levels, older adults are more susceptible to tissue hypoxia than younger adults. Our model predicts that an older adult with a hemoglobin of 100 g/L has a similar peak oxygen delivery capacity to a young adult with a hemoglobin of 70 g/L. Age-related pathophysiological changes provide some explanation as to why older adults have a lower tolerance for anemia than younger adults. This indicates the need for patient blood management hemoglobin thresholds specific to older as distinct from younger adults. The primary application of this model is in the consideration of patients rehabilitating to life outside hospital. It is important to note that pathophysiological changes associated with critical illness and major surgery are more complex than can be described in a simple model based on cardiac output and hemoglobin concentration. However, our review of oxygen transport and delivery in health and disease states allows the model to be considered in the context of treatment decisions for anemic adults in a range of hospital and community settings.
Publisher: Wiley
Date: 26-12-2022
DOI: 10.1111/TME.12845
Abstract: To investigate the blood supply contribution of older donors in five Asia Pacific regions. Older people are often the largest blood user group. Thus, as the population ages blood supply needs increase. Minimum and maximum donation age criteria potentially constrain the size of the donor pool. Haemoglobin values and demographic frequency analytics (sex, age and blood type) were analysed on blood donors aged 60 years or more, from Hong Kong, Indonesia, Japan, Singapore and South Korea over 12 months. Data on 434357 donations was analysed. ABO Rh(D) frequencies of older donors matched that of national frequencies. Older donors were a disproportionately smaller proportion of the total donor pool for each country. Indonesia was the only region with no maximum age limit. Median haemoglobin for older males ranged from 14.2 to 14.8 g/dl and for females 13.1 to 13.9 g/dl. The frequency of female donors was between 15% and 33% of older donors. Older donors had higher donation frequency and lower deferral rates. Older donors are loyal and regular donors but under‐represented in all regions studied. They could help meet future blood supply needs, especially post‐menopausal female donors. Studies including ferritin levels are needed to determine if upper age limits can be safely modified.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.TMRV.2016.06.006
Abstract: Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the health-related quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Springer Science and Business Media LLC
Date: 21-03-2013
Publisher: Wiley
Date: 09-07-2009
DOI: 10.1002/BIT.22433
Abstract: Dose-intensive chemotherapy results in an obligatory period of severe neutropenia during which patients are at high risk of infection. While patient support with donor neutrophils is possible, this option is restricted due to donor availability and logistic complications. To overcome these problems, we explored the possibility of large scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells (HPC). CD34+ HPC isolated from umbilical cord blood (UCB) and mobilized peripheral blood (mPB) were expanded in serum-free medium supplemented with stem cell factor, granulocyte colony stimulating factor, and a thrombopoietin peptide mimetic. After 15 days of cultivation a 5,800-fold expansion in cell number was achieved for UCB, and up to 4,000-fold for mPB, comprising 40% and 60% mature neutrophils respectively. Ex vivo expanded neutrophils exhibited respiratory burst activity similar to that for donor neutrophils, and were capable of killing Candida albicans in vitro. These yields correspond to a more than 10-fold improvement over current methods, and are sufficient for the production of multiple neutrophil transfusion doses per HPC donation. To enable clinical scale manufacture, we adapted our protocol for use in a wave-type bioreactor at a volume of 10 L. This is the first demonstration of a large scale bioprocess suitable for routine manufacture of a mature blood cell product from HPC, and could enable prophylactic neutrophil support for chemotherapy patients.
Publisher: Wiley
Date: 11-2014
DOI: 10.1111/TME.12087
Abstract: Oxidative stress from surgery or critically illness has been shown to adversely contribute to morbidity and mortality. Recent studies record that oxidative stress is heightened following packed red blood cell (PRBC) transfusions and that products of oxidative stress accumulate as the PRBC ages. However, there are no studies that investigate if transfusion of aged PRBC actually increases the recipient's oxidative stress profile more than fresh PRBC. To compare the effect of fresh vs aged PRBC transfusions on the recipient's oxidative stress using an ovine model. Male sheep were transfused with either fresh (n = 6) or aged (n = 6) ovine PRBC, and serial blood s les taken. Plasma s les were analysed for lipid peroxidation using the thiobarbituric acid reactive substances (TBARS) assay. This served as an indicator of oxidative injury. Antioxidant function and trace element levels were also measured. Like human PRBC, the ovine PRBC had negligible selenium levels. Irrespective of age, PRBC transfusion was associated with reduced selenium levels and antioxidant function, which correlated with increased markers of lipid peroxidation. Transfusion of selenium poor PRBC can dilute selenium levels and compromise glutathione peroxidase antioxidant activity and thereby allow lipid peroxidation. As there was no evidence that aged PRBC induced more severe oxidative injury this suggests that selenium dilution is a key underlying mechanism. Further studies are needed to assess the impact of transfusion-related oxidative stress in massive transfusions.
Publisher: AME Publishing Company
Date: 04-2019
Publisher: Wiley
Date: 22-05-2003
DOI: 10.1046/J.1365-3148.2003.00435.X
Abstract: Human neutrophil antigen-4a (HNA-4a) is a high-frequency (99% in the USA) neutrophil antigen, which has recently been linked to a case of alloimmune neonatal neutropenia. We have devised a new polymerase chain reaction sequence-specific primer (PCR-SSP) method to assess HNA-4a genotype, and used it to determine the HNA-4a gene frequencies in an Australian population. The gene frequency was found to be 0.906, which is the same as in the American population. The PCR-SSP genotyping method perfectly correlates with serological phenotyping and is efficient for screening large numbers of s les.
Publisher: Wiley
Date: 23-08-2009
Publisher: Informa UK Limited
Date: 2020
DOI: 10.2147/JMDH.S232888
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
Publisher: Wiley
Date: 2006
DOI: 10.1111/J.1440-1754.2006.00774.X
Abstract: Abstract: The incidence of alloimmune neonatal neutropenia (ANN) is poorly defined. The reported incidence is less than or equal to 0.1%. This prospective study of unselected pregnancies found an incidence of 0.81% based on results of screening 247 ‘full term’ cord blood s les. Alloimmune neonatal neutropenia occurred more frequently in this population than expected from published historical data. Advances in techniques for antineutrophil antibody screening may have contributed to the higher incidence found in this study. The frequency of ANN supports increased surveillance and confirmatory serological testing in infants with unexplained neutropenia.
Publisher: Wiley
Date: 04-2005
DOI: 10.1111/J.0958-7578.2005.00565.X
Abstract: Pregnant women with autoimmune neutropenia (AIN) and circulating neutrophil-specific autoantibodies can deliver neutropenic neonates at risk of sepsis. We report the case of a woman who had two such pregnancies. The woman had been on prophylactic granulocyte colony-stimulating factor (G-CSF) treatment, but this was ceased prior to conception in both pregnancies. In the first pregnancy, there was no monitoring or interventions, and the neonate was neutropenic and required intensive care treatment. In the second pregnancy, the maternal neutrophil autoantibody level was monitored, and G-CSF treatment was introduced in the third trimester. The second infant had no neutropenia at delivery and an excellent Apgar score. We discuss the management strategy in the second pregnancy that included monitoring of serial titres of the maternal autoantibody and the introduction of G-CSF in the third trimester, which may have contributed to a more favourable clinical outcome. This may assist other clinicians faced with similar dilemmas in the future.
Publisher: Oxford University Press (OUP)
Date: 30-01-2014
DOI: 10.1093/EJCTS/EZT637
Abstract: There is an increased oxidative stress response in patients having cardiac surgery, haemodialysis or extracorporeal membrane oxygenation that is related to poorer outcomes and increased mortality. Exposure of the patients' blood to the artificial surfaces of these extracorporeal devices, coupled with inflammatory responses, hyperoxia and the pathophysiological aspects of the underlying illness itself, all contribute to this oxidative stress response. Oxidative stress occurs when there is a disruption of redox signalling and loss of control of redox balance. Ongoing oxidative stress occurring during extracorporeal circulation (ECC) results in damage to lipids, proteins and DNA and contributes to morbidity and mortality. This review discusses reactive species generation and the potential clinical consequences of oxidative stress during ECC as well as provides an overview of some current antioxidant compounds that are available to potentially mitigate the oxidative stress response.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.AUCC.2018.01.001
Abstract: Bleeding management in cardiac surgery is challenging. Many guidelines exist to support bleeding management however, literature demonstrates wide variation in practice. In 2012, a quality initiative was undertaken at The Prince Charles Hospital, Australia to improve bleeding management for cardiac surgery patients. The implementation of the quality initiative resulted in significant reductions in the incidence of blood transfusion, re-exploration for bleeding superficial leg and chest wound infections length of hospital stay, and cost. Given the success of the initiative, we sought to answer the question "How and why was the process of implementing a bleeding management quality initiative in the cardiac surgery unit successful, and sustainable?" A retrospective explanatory case study design was chosen to explore the quality initiative. Analysis of the evidence was reviewed through phases of the 'Knowledgeto Action' planned change model. Data was derived from: (1) document analysis, (2) direct observation of the local environment, (3) clinical narratives from interviews, and analysed with a triangulation approach. The study period extended from 10/2011 to 6/2013. Results demonstrated the complexity of changing practice, as well as the significant amount of dedicated time and effort required to support in idual, department and system wide change. Results suggest that while many clinicians were aware of the potential to apply improved practice, numerous barriers and challenges needed to be overcome to implement change across multiple disciplines and departments. The key successful components of the QI were revealed through the case study analysis as: (1) an appropriately skilled project manager to facilitate the implementation process (2) tools to support changes in workflow and decision making including a bleeding management treatment algorithm with POCCTs (3) strong clinical leadership from the multidisciplinary team and (4) the evolution of the project manager position into a perpetual clinical position to support sustainability.
Publisher: Wiley
Date: 22-08-2023
DOI: 10.1111/VOX.13500
Abstract: Human neutrophil antigens (HNAs) are categorized into five systems: HNA‐1 to HNA‐5. Given the importance of neutrophils in immunity, we sought to create awareness of the role of HNA diagnostic services in managing immune neutropenia and transfusion‐related acute lung injury. To provide health communities all around the world with access to these services, we conducted a survey to create a directory of these HNA diagnostic services. An Excel table‐based survey was created to capture information on the laboratory's location and was emailed to 55 in iduals with known or possible HNA investigation activity. The collected data were then summarized and analysed. Of contacted laboratories, the surveys were returned from 23 (38.2%) laboratories 17 have already established HNA diagnostic (of them 12 were regular participants of the International Granulocyte Immunobiology Workshop [ISBT‐IGIW]), 4 laboratories were in the process of establishing their HNA investigation and the remaining 2 responder laboratories, did not conduct HNA investigations. In established laboratories, investigation for autoimmune neutropenia (infancies and adults) was the most frequently requested, and antibodies against HNA‐1a and HNA‐1b were the most commonly detected. The directory of survey respondents provides a resource for health professionals wanting to access HNA diagnostic services. The present study offers a comprehensive picture of HNA diagnostics (typing and serology), identifying weak points and areas for improvement for the first time. Identifying more laboratories involved in HNA diagnostics with limited access to international societies in the field will globally improve HNA diagnostics.
Publisher: Wiley
Date: 06-03-2018
DOI: 10.1111/VOXS.12423
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/468309
Abstract: Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, s ling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.
Publisher: Wiley
Date: 26-10-2021
DOI: 10.1111/VOX.13020
Publisher: Springer Science and Business Media LLC
Date: 29-07-2017
Publisher: Inderscience Publishers
Date: 2015
Publisher: Elsevier BV
Date: 10-2017
Publisher: Oxford University Press (OUP)
Date: 13-08-2015
DOI: 10.1093/EJCTS/EZV244
Abstract: Calcific aortic valve stenosis (CAVS) is an important clinical problem predominantly affecting elderly in iduals. Studies suggest that the progression of CAVS is actively regulated with valve endothelial injury leading to inflammation, fibrosis and calcification. The aim of this study was to delineate the possible regulatory role of osteopontin (OPN) on high-mobility group box 1 (HMGB1) function and the associated inflammatory and fibrotic response in CAVS. Aortic valve leaflets were collected from CAVS patients undergoing aortic valve replacement (n = 40), and control aortic valve leaflets were obtained from heart transplant recipients (n = 15). Valves and plasma were analysed by quantitative real-time polymerase chain reaction (PCR), immunohistochemical staining and Western blot. Recombinant OPN or neutralizing OPN antibody was added to cultured endothelial and valvular interstitial cells (VICs), and cell proliferation scores and HMGB1 expression were assessed. CAVS valves had a decreased total percentage of VICs but increased numbers of infiltrating macrophages relative to control valves. RT-PCR studies showed higher expression of OPN, the inflammatory cytokine tumour necrosis factor-alpha as well as markers of fibrosis, tissue inhibitor of matrix metalloproteinase 1 and matrix metalloproteinase 2 in CAVS valves. Elevated expression of OPN was also observed in plasma of CAVS patients compared with controls. HMGB1 was detected in the secretory granules of cultured valve endothelial and VICs derived from CAVS valves. The addition of exogenous OPN inhibited the proliferation of cultured endothelial and VICs from CAVS valves and was associated with the extracellular expression of HMGB1, whereas neutralizing OPN had the opposite effect. We conclude that altered OPN expression in CAVS affects cellular HMGB1 function inducing cytoplasmic translocation and secretion of HMGB1 in endothelial cells and VICs, thus indicating a regulatory role for OPN in the progression of CAVS through alteration of HMGB1 function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2012
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/CC11178
Publisher: Wiley
Date: 11-01-2011
DOI: 10.1111/J.1423-0410.2010.01381.X
Abstract: Even with the introduction of specific risk-reduction strategies, transfusion-related acute lung injury (TRALI) continues to be a leading cause of transfusion-related morbidity and mortality. Existing small animal models have not yet investigated TRALI resulting from the infusion of heat-treated supernatant from whole blood platelet concentrates. In this study, our objective was the development of a novel in vivo two-event model of TRALI in sheep. Lipopolysaccharide (LPS 15 μg/kg) as a first event, modelled clinical infection. Transfusion (estimated at 10% of total blood volume) of heat-treated pooled supernatant from date-of-expire human whole blood platelet concentrates (d5-PLT-S/N) was used as a second event. TRALI was defined by both hypoxaemia that developed either during the transfusion or within two hours of its completion and post-mortem histological evidence of pulmonary oedema. LPS infusion did not cause lung injury itself, but did result in decreased circulating levels of lymphocytes and neutrophils with evidence of the latter becoming sequestered in the lungs. Sheep that received LPS (first event) followed by d5-PLT-S/N (second event) displayed decreased pulmonary compliance, decreased end tidal CO(2) and increased arterial partial pressure of CO(2) relative to control sheep, and 80% of these sheep developed TRALI. This novel ovine two-event TRALI model presents a new tool for the investigation of TRALI pathogenesis. It represents the first description of an in vivo large animal model of TRALI and the first description of TRALI caused by transfusion with heat-treated pooled supernatant from human whole blood platelet concentrates.
Publisher: Wiley
Date: 31-08-2012
DOI: 10.1111/J.1423-0410.2011.01532.X
Abstract: There is an international need for a large-scale human neutrophils antigen (HNA) antibody screening platform to minimize the risk of antibody-mediated transfusion-related acute lung injury. However, sourcing a substantial, reliable source of HNA, as well as the scarcity of well-characterized HNA antisera for validating new screening platforms, remain as major obstacles. This short communication presents an improved protocol for the effective use of HNA-expressing KY cells as a screening platform using eight well-characterized HNA antisera of a single defined specificity.
Publisher: American Society of Hematology
Date: 21-10-2010
DOI: 10.1182/BLOOD-2010-05-284570
Abstract: Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion and has been ranked as one of the leading causes of transfusion-related fatalities. Nonetheless, many details of the immunopathogenesis of TRALI, particularly with respect to recipient factors are unknown. We used a murine model of antibody-mediated TRALI in an attempt to understand the role that recipient lymphocytes might play in TRALI reactions. Intravenous injection of an IgG2a antimurine major histocompatibility complex class I antibody (34-1-2s) into BALB/c mice induced moderate hypothermia and pulmonary granulocyte accumulation but no pulmonary edema nor mortality. In contrast, 34-1-2s injections into mice with severe combined immunodeficiency caused severe hypothermia, severe pulmonary edema, and approximately 40% mortality indicating a critical role for T and B lymphocytes in suppressing TRALI reactions. Adoptive transfer of purified CD8+ T lymphocytes or CD4+ T cells but not CD19+ B cells into the severe combined immunodeficiency mice alleviated the antibody-induced hypothermia, lung damage, and mortality, suggesting that T lymphocytes were responsible for the protective effect. Taken together, these results suggest that recipient T lymphocytes play a significant role in suppressing antibody-mediated TRALI reactions. They identify a potentially new recipient mechanism that controls the severity of TRALI reactions.
Publisher: Wiley
Date: 07-09-2019
DOI: 10.1111/VOXS.12450
Publisher: Wiley
Date: 21-09-2011
DOI: 10.1111/J.1423-0410.2011.01511.X
Abstract: BACKGROUND AND OBJECTIVES Severe transfusion-related acute lung injury (TRALI) events have been linked to donor-derived neutrophil antibodies. The journey to developing mass donor neutrophil antibody screening platforms is challenged by the fragility of neutrophils and their unique-specific antigenic characteristics. MATERIAL AND METHODS This article critically evaluates the capabilities and potential of five emerging antibody screening platforms designed to detect neutrophil reactive antibodies relevant to TRALI. They are compared with established neutrophil serological methods. RESULTS Data from two recombinant antigen platforms and a method using human neutrophil antigens-expressing KY cells indicated high specificity. Two mixed cellular flow cytometric assays have the advantage of presenting native conformation of the human polymorphonuclear neutrophil antigenic epitopes. CONCLUSIONS To date, the number and specificity of test sera applied to each platform is small. This needs to be substantially increased and further rigorous serological evaluation is yet needed to compare the sensitivity and specificity limits of each new platform with classical methods. With a limited world supply of TRALI-relevant test sera, a collaborative effort of laboratories with neutrophil and TRALI investigation expertise is required.
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/VOXS.12253
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-1151-Y
Abstract: Ex vivo experiments in extracorporeal membrane oxygenation (ECMO) circuits have identified octanol-water partition coefficient (logP, a marker of lipophilicity) and protein binding (PB) as key drug factors affecting pharmacokinetics (PK) during ECMO. Using ovine models, in this study we investigated whether these drug properties can be used to predict PK alterations of antimicrobial drugs during ECMO. Single-dose PK s ling was performed in healthy sheep (HS, n = 7), healthy sheep on ECMO (E24H, n = 7) and sheep with smoke inhalation acute lung injury on ECMO (SE24H, n = 6). The sheep received eight study antimicrobials (ceftriaxone, gentamicin, meropenem, vancomycin, doripenem, ciprofloxacin, fluconazole, caspofungin) that exhibit varying degrees of logP and PB. Plasma drug concentrations were determined using validated chromatographic techniques. PK data obtained from a non-compartmental analysis were used in a linear regression model to predict PK parameters based on logP and PB. We found statistically significant differences in pH, haemodynamics, fluid balance and plasma proteins between the E24H and SE24H groups ( p 0.001). logP had a strong positive linear relationship with steady-state volume of distribution (V ss ) in both the E24H and SE24H groups ( p 0.001) but not in the HS group ( p = 0.9) and no relationship with clearance (CL) in all study groups. Although we observed an increase in CL for highly PB drugs in ECMO sheep, PB exhibited a weaker negative linear relationship with both CL (HS, p = 0.01 E24H, p 0.001 SE24H, p 0.001) and V ss (HS, p = 0.01 E24H, p = 0.004 SE24H, p =0.05) in the final model. Lipophilic antimicrobials are likely to have an increased V ss and decreased CL during ECMO. Protein-bound antimicrobial agents are likely to have reductions both in CL and V ss during ECMO. The strong relationship between lipophilicity and V ss seen in both the E24H and SE24H groups indicates circuit sequestration of lipophilic drugs. These findings highlight the importance of drug factors in predicting antimicrobial drug PK during ECMO and should be a consideration when performing and interpreting population PK studies.
Publisher: American Physiological Society
Date: 12-2016
DOI: 10.1152/AJPLUNG.00296.2016
Abstract: Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1–2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.
Publisher: Wiley
Date: 2003
DOI: 10.1046/J.1365-3148.2003.00413.X
Abstract: This is a novel case report of alloimmune neonatal neutropenia (ANN) linked to the neutrophil antibody anti-HNA-4a (MART). Since its discovery, the HNA-4a antigen has never been associated with any clinical neutropenia. A first-born neonate with respiratory distress was found to be severely neutropenic, because of ANN. The broad reactivity of the antibody together with its capture by CD11b and CD18 in monoclonal antibody immobilization of granulocyte antigen test suggested HNA-4a specificity. DNA sequencing confirmed that the father is HNA-4a-positive and that the mother is HNA-4a-negative, supporting the diagnosis of ANN linked to MART.
Publisher: Wiley
Date: 18-03-2019
DOI: 10.1111/VOX.12760
Abstract: Immunoglobulin replacement therapy (IRT) is often used to support patients with primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID). Home-based subcutaneous immunoglobulin (SCIg) is reported to be a cheaper and more efficient option compared to hospital-based intravenous immunoglobulin (IVIg) for PID. In contrast, there is little information on the cost-effectiveness of IRT in SID. However, patients who develop hypogammaglobulinaemia secondary to other conditions (SID) have different clinical aetiology compared to PID. This study assesses whether SCIg provides a good value-for-money treatment option in patients with secondary immunodeficiency disease (SID). A Markov cohort simulation model with six health states was used to compare cost-effectiveness of IVIg with SCIg from a healthcare system perspective. The costs of treatment, infection and quality-adjusted life years (QALYs) for IVIg and SCIg treatment options were modelled with a time horizon of 10 years and weekly cycles. Deterministic and probabilistic sensitivity analyses were performed around key parameters. The cumulative cost for IVIg was A$151 511 and for SCIg A$144 296. The QALYs with IVIg were 3·07 and with SCIg 3·51. Based on the means, SCIg is the dominant strategy with better outcomes and at lower cost. The probabilistic sensitivity analysis shows that 88·3% of the 50 000 iterations fall below the nominated willingness to pay threshold of A$50 000 per QALY. Therefore, SCIg is a cost-effective treatment option. For SID patients in Queensland (Australia), the home-based SCIg treatment option provides better health outcomes and cost savings.
Publisher: Wiley
Date: 27-09-2023
DOI: 10.1111/VOX.13530
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Wiley
Date: 11-05-2013
DOI: 10.1111/VOX.12041
Abstract: Since 2000, Quality Assurance (QA) exercises for the detection and identification of granulocyte antibodies and DNA typing for human neutrophil antigens (HNA) have been distributed within the International Granulocyte Immunobiology Workshops, which are linked to International Society of Blood Transfusion. The exercises were standardised at the outset to enable laboratory performance to be monitored. Between 2000 and 2012, nine exercises were distributed to 20 laboratories. Overall, 45 ex les of 42 unique s les containing defined granulocyte reactive antibodies were distributed for serological analysis together with 20 s les for HNA genotyping. The level of satisfactory serological performance was initially set at 50% and later increased to 70%, while the 'cut-off' for HNA genotyping was set at 100% after 2008. Failure to achieve the minimum score in the QA exercises in consecutive years resulted in temporary exclusion. In 2000, the 15 participating laboratories had a mean score of 56.1% for serological analysis and 13 laboratories attempted HNA-1a and -1b genotyping, while 11 attempted HNA-1c typing. Steady improvements in proficiency for serological testing and HNA typing occurred in subsequent exercises. In 2012, the mean score for serology was 88.5% and 12/13 laboratories scored 100% for HNA-1a, -1b, -1c, -3a, -3b, -4a, -4bw, -5a and -5bw genotyping. These QA exercises have provided an invaluable tool to monitor and improve the standard of granulocyte immunology investigations for participating laboratories, thereby enhancing performance for both clinical investigations and donor screening programmes to reduce the incidence of TRALI.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2016
Abstract: Post-operative atrial fibrillation (POAF) is a frequent complication of cardiac surgery. Oxidative stress and reduced antioxidant function have major roles in its development. Selenium is a key to normal antioxidant function, and levels are often low before cardiac surgery. This study investigated whether low preoperative selenium levels were associated with POAF in cardiac surgical patients. Using the Society of Thoracic Surgeons (STS) Mortality risk score, 50 patients having primary coronary artery bypass grafts (CABG) surgery were ided into two groups: (i) low-risk group (STS ⩽0.5% n=26) and (ii) intermediate-risk group (STS ⩾2.0% n=24). Plasma levels of selenium, glutathione peroxidase (GPx) and malondialdehyde (MDA) were measured in all patients at anaesthetic induction, after aortic cross-cl removal, 3 h post cardiopulmonary bypass and on post-operative days 1 and 5. Multiple logistic regression was used to assess whether selenium levels were associated with POAF development. Seventeen patients developed POAF (14 patients in the intermediate-risk group and 3 patients in the low-risk group). Preoperative selenium was lower in patients who developed POAF compared with those with normal sinus rhythm (0.73±0.16 vs 0.89±0.13 μmol/l, P=0.005), and this was independently associated with POAF (PR 0.32 95% confidence credible interval (95%cI) 0.06-0.85, P=0.016). Regardless of POAF, preoperative selenium was lower in the intermediate-risk patients than in the low-risk patients (0.77±0.15 vs 0.89±0.14 μmol/l P=0.004). Intermediate-risk patients with low preoperative selenium levels may be at a greater risk of developing POAF following CABG. This raises the question of whether selenium supplementation in select cardiac surgical patients may reduce their POAF risk.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2006
DOI: 10.1097/00043426-200606000-00014
Abstract: We describe transfusion-related acute lung injury (TRALI) in 2 acute leukemia cases to increase awareness of this under reported serious transfusion complication syndrome in multitransfused patients. There are a number of reports in multitransfused patients with nonmalignant disorders. However, reports of pediatric oncology patients are few, suggesting a lack of recognition or misdiagnosis of the syndrome. A disproportionately high number of fatalities in children is recorded in the literature. This highlights the need for increased awareness and appropriate treatment of this serious complication of transfusion. Although TRALI is initially a clinical diagnosis, the laboratory investigation is vital as it contributes to defining the pathogenesis of the syndrome and importantly facilitates the effective management of implicated donations and donors. An investigational strategy for suspected cases is presented and the results are discussed in the context of current proposed mechanisms for TRALI. As each transfused blood product is associated with a potential risk of TRALI, more frequent reports in patients receiving large volume or recurrent transfusion would be expected.
Publisher: Wiley
Date: 11-2018
DOI: 10.1111/IMJ.51_14077
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.THROMRES.2014.05.026
Abstract: Similarities in size, anatomy and physiology have supported the use of sheep to model a wide range of human diseases, including coagulopathy. However, coagulation studies involving sheep are limited by the absence of high quality data defining normal ovine coagulation and fibrinolysis. Full blood examination, routine and specialised coagulation tests, rotational thromboelastometry and whole blood platelet aggregometry was performed on 50 healthy Samm & Border Leicester Cross ewes and compared to corresponding human ranges. Intraspecies breed and gender variability was investigated by comparison to a smaller population of 13 healthy Merino wethers. Ovine coagulation was similar to human according to routine coagulation methods (PT, aPTT, TCT, Fib(C)) and some specialised coagulation tests (vWF, AT, Plasmin Inh). Despite these similarities, ovine secondary haemostasis demonstrated substantial differences to that of human. Rapid initiation of the contact activation pathway, high levels of FVIII, low Protein C, greater overall clot firmness and a reduced capacity for clot lysis was documented in sheep. In addition, ADP and collagen agonists precipitated a reduced primary haemostatic response in sheep relative to human. Intraspecies differences in whole blood platelet aggregometry between the cohorts of sheep indicate the need for breed-specific normal ranges. The application of a board spectrum of coagulation assays has enabled elucidation of the similarities as well as differences between ovine and human coagulation. The new knowledge generated from this study will guide the design of future translational coagulation studies in ovine models.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JCRC.2007.09.004
Abstract: To study the effects of systemic inflammatory response syndrome (SIRS) on polymorhonuclear neutrophil (PMN) function and phenotype by comparing neutrophils from critically ill patients with SIRS against those from healthy blood donors. Intensive care unit patients (n = 110) who met at least one SIRS criterion were recruited to the study. One hundred healthy blood donors were recruited as normal controls. Polymorphonuclear cells from critically ill patients with SIRS were more resistant to activation than PMNs from healthy donors, but when stimulated had an exaggerated microbicidal response. Buffer-treated PMNs from patients with SIRS had significantly higher CD43 surface expression that may inhibit heterotypic cellular contact or ligand stimulation of membrane receptors, had significantly lower expression of IgG receptor CD16, demonstrated resistance to shedding of L-selectin when primed by platelet-activating factor which could be pro-inflammatory, and had reduced respiratory burst when primed by platelet-activating factor than activated by formyl-Met-Leu-Phe. The phenotypic and functional changes observed in neutrophils in the critically ill indicate that they require a higher level of stimulus to become activated. This may represent an auto-protective mechanism where the neutrophils in the already inflamed host may, by this mechanism, avoid excessive inflammation reducing the risk of further host cell injury and death.
Publisher: Wiley
Date: 30-04-2015
DOI: 10.1111/VOX.12279
Abstract: Excessive bleeding is a risk associated with cardiac surgery. Treatment invariably requires transfusion of blood products however, the transfusion itself may contribute to postoperative sequelae. Our objective was to analyse a quality initiative designed to provide an evidenced-based approach to bleeding management. A retrospective analysis compared blood product transfusion and patient outcomes 15 months before and after implementation of a bleeding management protocol. The protocol incorporated point-of-care coagulation testing (POCCT) with ROTEM and Multiplate to diagnose the cause of bleeding and monitor treatment. Use of the protocol led to decreases in the incidence of transfusion of PRBCs (47·3% vs. 32·4% P < 0·0001), FFP (26·9% vs. 7·3% P < 0·0001) and platelets (36·1% vs. 13·5% P < 0·0001). During the intra-operative period, the percentage of patients receiving cryoprecipitate increased (2·7% vs. 5·1% P = 0·002), as did the number of units transfused (248 vs. 692 P < 0·0001). The proportion of patients who received tranexamic acid increased (13·7% to 68·2% P < 0·0001). There were reductions in re-exploration for bleeding (5·6% vs. 3·4 P = 0·01), superficial chest wound (3·3% vs. 1·4% P = 0·002), leg wound infection (4·6% vs. 2·0% P < 0·0001) and a 12% reduction in mean length of stay from operation to discharge (95%: 9-16%, P < 0·0001). Acquisition cost of blood products decreased by $1 029 118 in the 15-month period with the protocol. The implementation of a bleeding management protocol supported by POCCT in a cardiac surgery programme was associated with significant reductions in the transfusion of allogeneic blood products, improved outcomes and reduced cost.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.JTEMB.2015.01.004
Abstract: The purpose of this study was to determine the effects of smoke induced acute lung injury (S-ALI), extracorporeal membrane oxygenation (ECMO) and transfusion on oxidative stress and plasma selenium levels. Forty ewes were ided into (i) healthy control (n=4), (ii) S-ALI control (n=7), (iii) ECMO control (n=7), (iv) S-ALI+ECMO (n=8) and (v) S-ALI+ECMO+packed red blood cell (PRBC) transfusion (n=14). Plasma thiobarbituric acid reactive substances (TBARS), selenium and glutathione peroxidase (GPx) activity were analysed at baseline, after smoke injury (or sham) and 0.25, 1, 2, 6, 7, 12 and 24h after initiation of ECMO. Peak TBARS levels were similar across all groups. Plasma selenium decreased by 54% in S-ALI sheep (1.36±0.20 to 0.63±0.27μmol/L, p<0.0001), and 72% in sheep with S-ALI+ECMO at 24h (1.36±0.20 to 0.38±0.19, p<0.0001). PRBC transfusion had no effect on TBARS, selenium levels or glutathione peroxidase activity in plasma. While ECMO independently increased TBARS in healthy sheep to levels which were similar to the S-ALI control, the addition of ECMO after S-ALI caused a negligible increase in TBARS. This suggests that the initial lung injury was the predominant feature in the TBARS response. In contrast, the addition of ECMO in S-ALI sheep exacerbated reductions in plasma selenium beyond that of S-ALI or ECMO alone. Clinical studies are needed to confirm the extent and duration of selenium loss associated with ECMO.
Publisher: Elsevier BV
Date: 04-2019
No related grants have been discovered for Yoke Lin Fung.