ORCID Profile
0000-0002-5548-5813
Current Organisations
Johns Hopkins All Children's Institute for Clinical and Translational Research
,
Murdoch Childrens Research Institute
,
University of Melbourne
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Plant Cell and Molecular Biology | Medical Biochemistry: Lipids | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry |
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Production of Biofuels (Biomass)
Publisher: Informa UK Limited
Date: 13-02-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2007
DOI: 10.1213/01.ANE.0000287645.26763.BE
Abstract: The hemostatic system of children changes with age and differs significantly from the hemostatic system of adults. Age-specific reference values are therefore required for most hemostatic variables. Thromboelastography (TEG) is a point-of-care coagulation test that may provide superior evaluation and management of coagulopathies after cardiac surgery, when large-dose unfractionated heparin is administered for cardiopulmonary bypass. In this study, we established reference values for kaolin-activated TEG in healthy children, to facilitate accurate interpretation of pediatric TEG results. Kaolin-activated TEG was performed on 100 healthy children undergoing elective day surgery and 25 healthy adult volunteers. The following TEG variables were recorded: reaction time, coagulation time, alpha angle, maximum litude, percentage lysis 30 min after maximum litude was reached, and the coagulation index. Differences between age-groups were evaluated using analysis of variance. Age-specific reference values for kaolin-activated TEG in healthy children between 1 mo and 16 yr of age are presented. No significant differences between children and adults were observed. TEG results, from a particular clinical setting, must be compared to age-specific, as well as analyzer- and activator-specific, reference values to allow for correct interpretation of the results. Reference values provided here will be of use in acute clinical situations where a practical monitor of hemostasis is required.
Publisher: Wiley
Date: 17-05-2010
DOI: 10.1111/J.1365-2141.2010.08163.X
Abstract: Low molecular weight heparins (LMWHs) are commonly used in paediatric tertiary institutions for primary prophylaxis and treatment of thromboembolic events. Despite this widespread use, the therapeutic and prophylactic guidelines for LMWH therapy in children are extrapolated from adult guidelines. In fact, there is very little information regarding the pharmacokinetics, clinical effectiveness, adverse event profile and optimal dose schedule for LMWH therapy in children. This study was designed to determine whether paediatric-specific dosage requirements for LMWH are justified, by investigating the doses required to achieve target therapeutic ranges. Patients who were treated with enoxaparin between October 2003 and July 2007 were identified for inclusion in this study. One hundred forty patients had an anti-activated factor X assay result with a total of 55 (39%) patients achieving therapeutic levels 4-6 h post dose. Children younger than 1 year required the highest dose of enoxaparin/kg and highest number of dose changes to achieve the target therapeutic range. Major bleeding occurred in one patient, equating to 0.7%, with complete clot resolution recorded in 16 (11%) patients. This study demonstrated a 2-3-fold variation in in idual dose requirements for LMWH in children <or=5 years of age, and further mandates the need for age-specific dosage requirements in children receiving enoxaparin.
Publisher: American Chemical Society (ACS)
Date: 21-10-2021
DOI: 10.1021/ACS.JPROTEOME.1C00657
Abstract: The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss ex les where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1111/JTH.12839
Publisher: American Physiological Society
Date: 03-2018
DOI: 10.1152/PHYSIOLGENOMICS.00046.2017
Abstract: Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection after heart transplantation but is costly and invasive. This study aims to distinguish no rejection (0R) from low-grade rejection (1R/2R) after heart transplantation in children by using global gene expression profiling in blood. A total of 106 blood s les with corresponding EMB from 18 children who underwent heart transplantation from 2011 to 2014 were analyzed (18 baseline retransplantation s les, 88 EMB s les). Corresponding rejection grades for each blood s le were 0R in 39% (34/88), 1R in 51% (45/88), and 2R in 10% (9/88). mRNA from each s le was sequenced. Differential expression analysis was performed at the gene level. A k-nearest neighbor (kNN) analysis was applied to the most differentially expressed (DE) genes to identify rejection after transplantation. Mean age at transplantation was 10.0 ± 5.4 yr. Expression of B cell and T cell receptor sequences was used to measure the effect of posttransplantation immunosuppression. Follow-up s les had lower levels of immunoglobulin gene families compared with pretransplantation ( P 3E-5) (lower numbers of activated B cells). T cell receptor alpha and beta gene families had decreased expression in 0R s les compared with pretransplantation ( P 4E-5) but recovered to near baseline levels in 1R/2R s les. kNN using the most DE gene (MKS1) and k = 9 nearest neighbors correctly identified 83% (73/88) of 1R/2R compared with 0R by leave-one-out cross validation. Using a genomic approach we can distinguish low-grade cellular allograft rejection (1R/2R) from no rejection (0R) after heart transplantation in children despite a wide age range.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.THROMRES.2008.07.009
Abstract: Unfractionated Heparin (UFH) is used widely in paediatrics. Paediatric specific recommendations for UFH therapy are few, with the majority of recommendations being extrapolated from adult practice. In vitro studies have shown that this practice may be suboptimal. This study aimed to improve the understanding of the impact of age upon UFH response in vivo. This prospective, observational study, conducted in the Paediatric Intensive Care Unit (PICU), included: patients 16 years or younger treated with UFH of at least 10 U/Kg/hr. Laboratory analysis included: Antithrombin, APTT, Anti-Xa, Anti-IIa and thrombin generation expressed as the Endogenous Thrombin Potential. Results were grouped according to patient age (i.e. <1, 1-5, 6-10 and 11-16 years). 85 patients received an equivalent mean UFH dose with a median duration of 3 days. Antithrombin levels were decreased compared to age-related norms in children up to 11 years of age. APTT results were comparable across the age-groups. The Anti-Xa results using two different assays showed a trend for lower values in younger children. All children less than one year old recorded Anti-Xa values outside the therapeutic range for heparin therapy, for both assays. There was a trend for decreased Anti-IIa activity in younger children. Endogenous Thrombin Potential showed a significant trend for increased inhibition in older children. In vitro Antithrombin supplementation did not change the Anti-Xa or thrombin generation. This study confirms that, in vivo, for the same dose of UFH, the anti Xa and anti IIa effect, as well as the inhibition of endogenous thrombin potential is age dependent and that these differences are not purely AT dependent. The implication is that the anticoagulant and antithrombotic effect of a given dose of UFH differs with age. Clinical outcome studies to determine the optimal dosing for each age group are warranted.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.THROMRES.2010.05.015
Abstract: Bleeding and thrombotic complications contribute to morbidity and mortality following paediatric orthotopic liver transplantation (OLT). However, the pathophysiology of haemostasis during paediatric OLT is not well understood. This report consists of two complimentary studies examining the frequency of haemostatic complications before and after the introduction of a post-operative thrombin inhibitor replacement therapy protocol at a single institution. A retrospective study of 40 patients who underwent 43 liver transplants between July 1992 and July 2002, identified bleeding to be the most frequent complication associated with OLT (30%), however thrombotic complications were also common (12.5%). In 2003, following a detailed analysis of haemostatic profiles of children undergoing OLT, a thrombin inhibitor replacement protocol was introduced. A prospective clinical outcome audit was undertaken from April 2003 to September 2008 to determine the effect of the new protocol on haemostasis. Commencement of the thrombin inhibitor replacement protocol significantly reduced the incidence of thrombosis (from 5 to 1, p<0.05), graft loss (from 4 to none, p<0.05), mortality due to thrombosis or bleeding (from 3 to none, p<0.05) and was associated with a 50% reduction in frequency of major bleeding. In conclusion, the introduction of a post-operative thrombin inhibitor replacement therapy protocol following paediatric OLT significantly improved haemostasis-related morbidity and mortality outcomes in children.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.THROMRES.2015.01.006
Abstract: While antithrombotics are usually administered intravenously, subcutaneously or orally, there are a number of publications reporting topical application of anticoagulation therapy. This paper aims to review the available literature regarding clinical conditions, the details of the topical antithrombotic treatment, as well as positive or adverse effects in an attempt to ascertain the safety and efficacy of this form of treatment. Published literature was searched to identify publications reporting the use of antithrombotic treatments administered via topical application between 1st January 1990 and 1st January 2013. There were 43 studies reported in 10 different clinical conditions. Majority of the studies were randomized controlled trials (51.2%), prospective studies (18.6%) or case reports (11.6%). The clinical conditions in which topical antithrombotics were administered included: microangiopathy, acute haemorrhoids, periodontitis, dermatitis, burns, ocular conditions and surgery, blunt force impact, scars, as well as clinical conditions associated with superficial venous thrombosis (SVT). The most commonly used topical antithrombotic was heparin (79.1% of studies). The respective dosage of different antithrombotics varied depending on specific clinical conditions. While most studies reported mean improvements or resolution of symptoms/condition in patients, the patient outcomes were variable. This review demonstrates that topical antithrombotic treatment is used according to a wide variety of protocols, with a subsequent variability in patient outcomes. Specific guidelines for the use of topical antithrombotics should be developed to standardize this form of treatment and ensure the best possible outcomes for patients.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2007
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.JPROT.2015.04.003
Abstract: Major age-related diseases such as cardiovascular disease and cancer are the primary causes of morbidity and mortality in Australia and worldwide. In our recent study characterising differences in the plasma proteome between healthy children and adults, a large number of proteins differentially expressed with age were found to be of platelet origin. This study aimed to characterise differences in the resting platelet proteome and the platelet releasate of healthy children compared to healthy adults. This study represents the setup of a procedure for the proteomic analysis of platelets from children. Differentially expressed platelet proteins were identified using Two-dimensional Differential In-Gel Electrophoresis and mass spectrometry. Significant differences in the expression of nine proteins (1.1%) in the resting platelet proteome were observed in children compared to adults. Serotransferrin, fibrinogen alpha chain, glyceraldehyde-3 phosphate dehydrogenase, serum albumin, transgelin-2, calponin-2/LIM and SH3 domain protein 1 and human chorionic gonadotropin 2039797 were up-regulated, whereas thrombospondin-1 was down-regulated in children. Eleven proteins (1.5%) were differentially expressed in the platelet releasate of children compared to adults, where transferrin was also upregulated and TSP-1 was down regulated. Identified proteins are involved in processes including tissue and organ development, cell proliferation regulation and angiogenesis. Our results provide novel insights into platelet physiology as well as growth, development and ageing in healthy in iduals. The incidence of major diseases such as cardiovascular disease (CVD) and cancer increase with increasing age and are the major causes of morbidity and mortality both in Australia and worldwide. As the aged population continues to increase dramatically, so too will the financial strains associated with the long term care of the elderly population. Compared to adults, children have a significantly lower incidence of major diseases such as thromboembolic disease. This suggests that children have a protective mechanism against the development of disease. Therefore, studies focussing on the molecular changes of proteins, the machinery of the cell, between children and adults are the key to determining the underlying mechanisms responsible for the onset of major diseases. A well-defined ex le of how protein expression can change with age is that of the plasma proteome. Significant differences in the expression of numerous plasma proteins between healthy children and adults have been recently demonstrated. Interestingly, a large number of differentially expressed proteins were found to be of platelet origin. This finding forms the basis for the current study, presenting as strong evidence for the age-specific differences of the platelet proteome.
Publisher: Wiley
Date: 20-07-2017
DOI: 10.1002/PBC.26725
Publisher: Georg Thieme Verlag KG
Date: 2010
DOI: 10.1160/TH09-10-0687
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.BLRE.2009.12.001
Abstract: Developmental Hemostasis refers to the age-related changes in the coagulation system that are most marked during neonatal life and childhood. An understanding of these changes is crucial to the accurate diagnosis of hemostatic abnormalities in neonates and children. This paper explains the current understanding of developmental hemostasis and describes the common pitfalls observed in clinical practice through failure to implement the principles into routine diagnostic work. Finally, there is a brief discussion as to a potential physiological rationale for developmental hemostasis and the implications of this for hemostatic interventions in neonates and children. There remains a need for further study to improve our understanding of the implications of developmental hemostasis in normal growth and development.
Publisher: Science Impact, Ltd.
Date: 31-12-2018
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
DOI: 10.1038/S41598-018-30868-X
Abstract: The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma s les taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of in idualized respiratory support approaches tailored to both the developmental and pathological state of the lung.
Publisher: Informa UK Limited
Date: 2000
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.TOXICON.2007.07.023
Abstract: The Snake Venom Detection Kit (SVDK) is of major medical importance in Australia, yet it has never been rigorously characterised in terms of its sensitivity and specificity, especially when it comes to reports of false-negative and false-positive results. This study investigates reactions and cross-reactions of five venoms the SVDK is directed against and a number of purified toxins. Snakes showing the closest evolutionary relationships demonstrated the lowest level of cross-reactivity between groups. This was, instead, far more evident between snakes that are extraordinarily evolutionary separated. These snakes: Pseudechis australis, Acanthophis antarcticus and Notechis scutatus, in fact displayed more false-positive results. Examination of in idual toxin groups showed that phospholipase A(2)s (PLA(2)s) tends to react strongly and display considerable cross-reactivity across groups while the three-finger toxins (3FTx) reacted poorly in all but the Acanthophis well. The hook effect was evident for all venoms, particularly Oxyuranus scutellatus. The results of this study show considerable variation in toxin detection, with implications in further development of venom detection, both in Australia and other countries.
Publisher: Wiley
Date: 04-09-2014
DOI: 10.1111/IJLH.12144
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-339-8_10
Abstract: Thrombin clotting time (TCT) is a coagulation assay used to diagnose congenital and acquired fibrinogen deficiency (Adcock et al., Coagulation handbook, Esoterix Coagulation, Austin, TX, 2002), as well as to identify contamination by heparin, prior to performing additional coagulation assays. This test is based on the principle that in citrated plasma, the addition of Thrombin allows for formation of a stable clot. The time required for the formation of a stable clot is recorded in seconds and represents the actual TCT result.
Publisher: Elsevier BV
Date: 10-2010
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000333262
Abstract: b i Background/Aims: /i /b Pre-ecl sia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality. PE is defined clinically as the onset of maternal hypertension and proteinuria following 20 weeks of gestation. It is associated with altered maternal uterine decidual spiral artery remodelling, which may lead to reduced blood flow and increased thrombosis within the uteroplacental vasculature. Proteoglycans (PGs) are macromolecules which have (in combination with glycosaminoglycans) important anticoagulant roles in vascular endothelial environments, including the uteroplacental circulation. The hypothesis under consideration in this study was that differential expression of placental PGs may be associated with PE. b i Methods: /i /b PE and control placental s les were collected with ethics approval and patient consent. RNA and protein were extracted and real-time PCR and Western immunoblotting were performed to determine the expression of the PGs in the s les. b i Results: /i /b Of the nine PGs investigated, none showed increased expression, whereas the mRNA and protein expression of five of them was significantly decreased in the placentae of pre-ecl tic women compared to gestation-matched controls. b i Conclusion: /i /b Therefore, the results of this study support the hypothesis that a placental PG deficiency may contribute to the placental thrombotic lesions characteristic of PE.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1111/J.1538-7836.2010.03847.X
Abstract: Clinically significant age-related differences in the anticoagulation effect of heparin have previously been established in vitro as well as in different clinical settings in vivo. These differences were hypothesized to be due to the age-specific differences in binding of heparin to plasma proteins. The aim of this project was to investigate global age-related differences in heparin binding to plasma proteins. Heparin-binding proteins were identified by incubating heparin-coated magnetic beads with plasma s les from neonates, children and adults, and purifying the proteins that were bound to the beads in this reaction system. These results provide the first preliminary evidence of age-related differences in the total number and concentration of proteins bound to heparin. The results also suggest, for the first time, that there are age-related differences of heparin binding to antithrombin and thrombin. The results of this study, although preliminary, support and contribute to the explanation of the mechanism of age-related differences in the effect of heparin observed previously in vitro and in vivo.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2014
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 06-07-2020
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1365-2141.2010.08302.X
Abstract: Paediatric recommendations for unfractionated heparin (UFH) management are extrapolated from adult trials, a practice that may contribute to the inferior UFH-related outcomes in children compared to adults. This is the first study to determine UFH concentration in a population of children and correlated UFH concentration with measures of UFH effect. Correlation coefficients between protamine titration (concentration) and activated partial thromboplastin time (APTT), anti- activated factor X (Xa) assay and thrombin clotting time (effect) were 0·59, 0·46 and 0·52 respectively. A protamine titration level of 0·2-0·4 iu/ml in children was not equivalent to an anti-Xa assay of 0·35-0·7 iu/ml but to an anti-Xa assay 0·17-0·85 iu/ml. In addition, use of the anti-Xa or protamine titration assays to establish an APTT therapeutic range resulted in upper limits of APTT ranges exceeding 200 s. Existing methods for determining therapeutic ranges for UFH in adult populations do not produce equivalent ranges in children. As a result, paediatric clinical guidelines that state a therapeutic range for UFH can be determined using a protamine titration assay of 0·2–0·4 iu/ml or an anti-Xa assay of 0·35-0·7 iu/ml are not based on appropriate evidence. There is an urgent need for change in our approach to the use of UFH in children.
Publisher: Mary Ann Liebert Inc
Date: 06-2019
Abstract: Mild traumatic brain injury (mTBI)-associated blood proteomics have become an emerging focus in the past decade, with the U.S. Food and Drug Administration recently approving the use of a blood test to determine the necessity of a computed tomography scan after adult mTBI. We now also know that the blood proteome of children is different from that of adults, and new evidence suggests that children may take longer to recover from an mTBI. Despite this, comparatively fewer studies have analyzed changes in blood protein expression after pediatric mTBI. Concussions, an mTBI subset, often go underreported, despite the potential for post-concussive symptoms to last more than one month in up to 30% of children. In the current study, we used a multiplex immunoassay to measure blood protein expression of Apolipoprotein, enolase 2, glial fibrillary acidic protein, interleukin (IL)-1B, IL-6, IL-8, IL-10, S100 calcium-binding protein B, tau and tumor necrosis factor alpha (TNFα) at admission, one to four days, two weeks, and three months post-pediatric concussion, comparing patients with normal recovery (
Publisher: Public Library of Science (PLoS)
Date: 18-02-2011
Publisher: Elsevier BV
Date: 09-2012
Publisher: Public Library of Science (PLoS)
Date: 31-03-2015
Publisher: Georg Thieme Verlag KG
Date: 19-12-2018
Abstract: Antiplatelet agents are used for the prevention and treatment of thromboembolic disease in an increasingly complex population of pediatric patients. Despite their importance for clinical outcome, there is no consensus on the most effective monitoring strategies. This review describes the current state of knowledge focusing on antiplatelet therapy monitoring in children. The authors searched five databases (PubMed-NCBI, MEDLINE-OVID, SCOPUS-Elsevier, ScienceDirect, and Cochrane) from January 2000 to October 2017 using keywords selected a priori. Identified articles were sorted according to the antiplatelet agents administered, methods of antiplatelet monitoring, and outcome measures. Twenty studies were included, with 14 cohort studies, 3 randomized controlled trials, and 3 cross-sectional studies. Eleven different antiplatelet monitoring tools were used, with the most common being Light Transmission Aggregometry, Urinary Thromboxane, Thromboelastography with Platelet Mapping, and VerifyNow. In the majority of studies, antiplatelet therapy monitoring was used to describe adequacy or responsiveness to treatment based on laboratory cut-off values, which were not uniform and sourced from adult studies or extrapolated from test manuals. Several studies evaluated monitoring related to clinical outcome or adjusted therapy to reach predefined therapeutic targets. There was no single laboratory method found to be distinctly better for monitoring antiplatelet treatment. Associations between laboratory assays and clinical outcomes or assays and gold standard measurements were highly inconsistent. The current literature lacks consensus on clinical benefits and measurable effects of monitoring antiplatelet therapy in pediatric patients. This review highlights important areas for research required to determine the value of antiplatelet therapy monitoring in children.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2011
DOI: 10.1007/S00246-011-0079-5
Abstract: This prospective, single-center study aimed to evaluate the platelet response during cardiopulmonary bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood s les were drawn at four time points: after induction of anesthesia, after initiation of the CPB, before protamine, and immediately after chest closure. The study recruited 60 children requiring CPB for surgical repair of congenital heart defects. The platelet count decreased throughout CPB surgery, but during the same period, platelet activity increased. The more pronounced decrease in platelet count observed in children younger than 1 year compared with that of children 1 to 6 years of age was not associated with an age-specific change in platelet activity. The overall increase in platelet function observed in this study could provide a mechanism that compensates for the decrease in platelet count. This study provides a new foundation for future studies investigating requirements of platelet supplementation in the setting of pediatric CPB surgery.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.PLACENTA.2014.05.009
Abstract: Fetal growth restriction (FGR) is a key cause of adverse pregnancy outcome where maternal and fetal factors are identified as contributing to this condition. Idiopathic FGR is associated with altered vascular endothelial cell functions. Decorin (DCN) has important roles in the regulation of endothelial cell functions in vascular environments. DCN expression is reduced in FGR. The objectives were to determine the functional consequences of reduced DCN in a human microvascular endothelial cell line model (HMVEC), and to determine downstream targets of DCN and their expression in primary placental microvascular endothelial cells (PLECs) from control and FGR-affected placentae. Short-interference RNA was used to reduce DCN expression in HMVECs and the effect on proliferation, angiogenesis and thrombin generation was determined. A Growth Factor PCR Array was used to identify downstream targets of DCN. The expression of target genes in control and FGR PLECs was performed. DCN reduction decreased proliferation and angiogenesis but increased thrombin generation with no effect on apoptosis. The array identified three targets of DCN: FGF17, IL18 and MSTN. Validation of target genes confirmed decreased expression of VEGFA, MMP9, EGFR1, IGFR1 and PLGF in HMVECs and PLECs from control and FGR pregnancies. Reduction of DCN in vascular endothelial cells leads to disrupted cell functions. The targets of DCN include genes that play important roles in angiogenesis and cellular growth. Therefore, differential expression of these may contribute to the pathogenesis of FGR and disease states in other microvascular circulations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2016
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.THROMRES.2018.05.009
Abstract: Extracorporeal Membrane Oxygenation (ECMO) is a form of Extracorporeal Life Support (ECLS) which is used frequently in the paediatric and neonatal setting to support either the pulmonary, or both the pulmonary and cardiac systems. Management of ECMO requires the use of systemic anticoagulation to prevent patient and circuit based thrombosis, which in turn increases the risk of haemorrhage. A number of coagulation tests, laboratory and point of care based, are used to monitor anticoagulation, however the evidence for correlation of the test results with level of anticoagulant and clinical outcomes in children remains poor.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.THROMRES.2008.02.001
Abstract: Major physiological differences in the coagulation system of children compared to that of adults are well documented. We have previously investigated the age-related differences in response to Unfractionated Heparin (UFH). However, the impact of developmental haemostasis on more recent anticoagulant drugs is unknown. A number of these drugs are approved for use in specific indications in adults and none are approved for use in children. This study aimed to determine whether age-related differences in effect and impact on monitoring tests exist in vitro for danaparoid, fondaparinux and lepirudin. Plasma s les were obtained from healthy children and pooled into age-specific pools, in order to obtain sufficient quantity of plasma required for the analysis of the three drugs. Each age-specific pool was spiked with different concentrations of danaparoid, fondaparinux and lepirudin and response was measured using standard techniques. All experiments were repeated using three separate plasma pools. The effect of each drug in children's plasma was compared to the effect in the respective adult plasma pool. Age-related differences in effect on thrombin potential and monitoring tests were observed only with the drug lepirudin. Specifically, APTT for children up to 5 years of age was increased compared to adults all children had lower ECT results compared to adults children up to 10 years of age had increased inhibition of ETP as compared to adults. This study confirms age-related differences in response to anticoagulants with predominant anti-IIa effect and highlights the need for further research into this area.
Publisher: Wiley
Date: 02-05-2016
DOI: 10.1111/BCP.12930
Publisher: Elsevier BV
Date: 12-2018
Publisher: Informa UK Limited
Date: 06-01-2020
DOI: 10.1080/09537104.2019.1709630
Abstract: Flow cytometry is a valuable tool in determining the phenotype and function of platelets accurately. The emergence of platelet flow cytometry in recent years provides an attractive alternative to other platelet analytical techniques, with advantages such as requiring small volumes and being highly sensitive to minimal changes in receptor function and expression. Here we present a methodical approach encompassing the stages in the development and optimization of platelet flow cytometry panels based on our extensive experience in this area.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
Publisher: Cold Spring Harbor Laboratory
Date: 26-07-2019
DOI: 10.1101/716563
Abstract: The proteomic analyses of human blood and blood-derived products (e.g. plasma) offers an attractive avenue to translate research progress from the laboratory into the clinic. However, due to its unique protein composition, performing proteomics assays with plasma is challenging. Plasma proteomics has regained interest due to recent technological advances, but challenges imposed by both complications inherent to studying human biology (e.g. inter-in idual variability), analysis of biospecimen (e.g. s le variability), as well as technological limitations remain. As part of the Human Proteome Project (HPP), the Human Plasma Proteome Project (HPPP) brings together key aspects of the plasma proteomics pipeline. Here, we provide considerations and recommendations concerning study design, plasma collection, quality metrics, plasma processing workflows, mass spectrometry (MS) data acquisition, data processing and bioinformatic analysis. With exciting opportunities in studying human health and disease though this plasma proteomics pipeline, a more informed analysis of human plasma will accelerate interest whilst enhancing possibilities for the incorporation of proteomics-scaled assays into clinical practice.
Publisher: Mary Ann Liebert Inc
Date: 06-2022
Abstract: Soft gripping provides the potential for high performance in challenging tasks through morphological computing however, design explorations are limited by a combination of a difficulty in generating useful models and use of laborious fabrication techniques. We focus on a class of grippers based on granular jamming that are particularly difficult to model and introduce a "one shot" technique that exploits multimaterial three-dimensional (3D) printing to create entire grippers, including membrane and grains, in a single print run. This technique fully supports the de facto physical generate-and-test methodology used for this class of grippers, as entire design iterations can be fitted onto a single print bed and fabricated from Computer-Aided Design (CAD) files in a matter of hours. Initial results demonstrate the approach by rapidly prototyping
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NEUBIOREV.2018.02.006
Abstract: To summarize all current studies focusing on blood biomarkers in paediatric mild traumatic brain injury (mTBI) and to outline the possible use of blood biomarkers for diagnostic, prognostic and monitoring purposes within this setting. A systematic review following the PRISMA guidelines was conducted using the MEDLINE, PubMed and EMBASE databases. A total of 21 studies were included in the review, encompassing a total of 14 different biomarkers. Seventeen (81%) of these studies found a significant association between biomarker concentration and mTBI characteristics, however results from studies to date are erse and at times conflicting. GFAP appears to be a promising blood biomarker for the prognosis and monitoring of mTBI, whereas UCH-L1 appears more promising at mTBI diagnosis. Despite this, the overall heterogeneity in assessed biomarkers, study design and measurement tools has made drawing specific conclusions challenging. Future research will require more uniform study design and methodological approaches to allow for the comparison, corroboration and validation of blood biomarkers within the context of paediatric mTBI.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.THROMRES.2009.10.020
Abstract: Crotaline snake species, or pit vipers, are distributed throughout Asia and America. While much is known about the clinical effect of these snake venoms, there is a lack of evidence related to the various anti-venoms available and their effectiveness in reversing the effect of different venoms. This study aimed to determine the interaction of the venoms of the following species: Crotalus unicolor, Crotalus adamanteus, Crotalus vegrandis, Trimeresurus spp, Calloselasma rhodostoma, Bothriechis schlegelii and Agkistrodon and the following anti-venoms: Anticrotalico, Antivipmyn, Antibotropico, Antifidico and SAIMR by evaluating their effect on the thrombin clotting time in human plasma. The interactions of venoms and anti-venoms were evaluated using thrombin clotting time in human plasma. The results demonstrate that Anticrotalico anti-venom was most effective for the Crotalid species (Crotalus unicolor, Crotalus adamanteus, Crotalus vegrandis). Anticrotalico extended the time to clot formation 2.7 fold for Crotalus Unicolor, 3 fold for Crotalus Adamanteus and 4.6 fold for Crotalus Vegrandis. The anti-venoms most efficient in reversing the effect of the Trimeresurus spp venom, were Anticrotalico, Antivipmyn, Antibotropico and Antifidico anti-venoms, which all completely reversed the effect of clot formation as evident by no clot formation within the 999 seconds measurement limit. Bothriechis schlegelii venom was neutralized by all anti-venoms tested. Calloselasma rhodostoma venom was neutralized by Antifidico as well as Anticrotalico. The most efficient anti-venoms against the Agkistrodon venom were Anticrotalico and Antibotropico. In general, monovalent anti-venoms had improved efficiency for their corresponding snake species, depending highly on the composition of the snake venom. This study confirms the importance of considering the choice of anti-venom in a clinical setting, to reverse the effect of specific snake venoms. In addition, this study suggests that some anti-venoms can be considered for use against a variety of snake-venoms.
Publisher: Informa UK Limited
Date: 21-02-2022
DOI: 10.1080/10408363.2022.2038074
Abstract: Neonatal jaundice is one of the most common clinical conditions affecting newborns. For most newborns, jaundice is harmless, however, a proportion of newborns develops severe neonatal jaundice requiring therapeutic interventions, accentuating the need to have reliable and accurate screening tools for timely recognition across different health settings. The gold standard method in diagnosing jaundice involves a blood test and requires specialized hospital-based laboratory instruments. Despite technological advancements in point-of-care laboratory medicine, there is limited accessibility of the specialized devices and s le stability in geographically remote areas. Lack of suitable testing options leads to delays in timely diagnosis and treatment of clinically significant jaundice in developed and developing countries alike. There has been an ever-increasing need for a low-cost, simple to use screening technology to improve timely diagnosis and management of neonatal jaundice. Consequently, several point-of-care (POC) devices have been developed to address this concern. This paper aims to review the literature, focusing on emerging technologies in the screening and diagnosing of neonatal jaundice. We report on the challenges associated with the existing screening tools, followed by an overview of emerging sensors currently in pre-clinical development and the emerging POC devices in clinical trials to advance the screening of neonatal jaundice. The benefits offered by emerging POC devices include their ease of use, low cost, and the accessibility of rapid response test results. However, further clinical trials are required to overcome the current limitations of the emerging POC's before their implementation in clinical settings. Hence, the need for a simple to use, low-cost POC jaundice detection technology for newborns remains an unsolved challenge globally.
Publisher: MDPI AG
Date: 12-10-2020
DOI: 10.3390/JCM9103272
Abstract: The accumulation of blood proteins and cells on extracorporeal membrane oxygenation (ECMO) circuits has been proposed as a contributing factor to the coagulopathic state of many patients. This systematic review aims to summarize and discuss the existing knowledge of blood components binding to the ECMO circuits in human patients. A systematic review was conducted using the Medline, PubMed and Embase databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seven studies were included in this review. Three studies identified a leukocyte adhesion, three studies observed von Willebrand factor accumulation and four studies identified bound platelets on the surface of the circuits. Other identified components included fibrin, albumin, hemoglobin, erythrocytes, progenitor cells, fibronectin and IgG. This systematic review demonstrates the limited state of knowledge when it comes to adsorption to the ECMO circuits in humans. Most of the studies lacked insight or detail into the mechanisms of binding and the interactions between different components bound to the ECMO circuits. Further research is required to comprehensively characterize surface adsorption to ECMO circuits in humans and to define the specific mechanisms of binding, enabling improvements that increase biocompatibility between the blood-circuit interface in this important clinical setting.
Publisher: Georg Thieme Verlag KG
Date: 2010
DOI: 10.1160/TH09-09-0624
Abstract: Previous studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75–100 IU/kg in children. Venous blood s les were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all s les. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration as-says, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in s les collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-339-8_9
Abstract: Prothrombin time (PT) and/or International Normalized Ratio (INR) is the most commonly used coagulation assay in health care, to diagnose the risk of bleeding and to monitor oral anticoagulation therapy. This test is based on the principle that in citrated plasma, the addition of a thromboplastin and CaCl2 allows for formation of a stable clot. The time required for the formation of a stable clot is recorded in seconds and represents the actual PT result. INR is calculated from the PT and allows for worldwide standardization of results.
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-339-8_8
Abstract: Activated partial thromboplastin time (APTT) is a commonly used coagulation assay that is easy to perform, is affordable, and is therefore performed in most coagulation laboratories, both clinical and research, worldwide. The APTT is based on the principle that in citrated plasma, the addition of a platelet substitute, factor XII activator, and CaCl2 allows for formation of a stable clot. The time required for the formation of a stable clot is recorded in seconds and represents the actual APTT result.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.TOXICON.2008.09.007
Abstract: Platelets play a vital role in the coagulation, yet the potential for differences in platelet function, between adults and children, remains underexplored. This is despite the age-related variation in haemostatic proteins, that is encompassed by the term Developmental Haemostasis. Hemotoxins found in the venoms of Australian snakes mimic human blood coagulation factors. The effects of Australian snake venoms on platelets, as well as the possible differential response in adults and children were subject of this study.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.THROMRES.2018.11.019
Abstract: Durable Ventricular Assist Devices (VADs) are increasingly used in children with end-stage heart failure. Major complications are bleeding and thromboembolism (TE). Our objective was to determine the timing, incidence and risk factors for bleeding and TE in children implanted with VADs. This was a retrospective cohort of 8 years experience for children implanted with HeartWare HVAD and Berlin Heart EXCOR VADs at the Royal Children's Hospital, Melbourne. 44 patients were implanted with Berlin Heart EXCOR or HeartWare HVAD devices. Major bleeding occurred in 17 patients (39%), 7 (16%) experienced thromboembolic strokes, 13 (30%) required device exchange for TE, and 4 (9%) experienced arterial thromboembolism. Twenty-seven patients (61%) were transplanted, three (7%) recovered, and six (14%) remain on device when censored. Eight patients (18%) died on VAD, with leading causes being thromboembolic stroke and intracranial bleeding. The majority of bleeding events and thromboembolic events occurred while patients were on unfractionated heparin (bleeding 66%, TE 40.5%) or transitioning between heparin and warfarin (bleeding 22%, TE 38%). Majority of patients were on more than one antiplatelet agent at the time of a major bleeding (87%) or thromboembolic (89%) event. The majority of bleeding and TE events occurring in children supported with durable VADs occur when they are on unfractionated heparin or transitioning to warfarin. Modifications to anticoagulation and monitoring in the early post-operative periods should be a research focus.
Publisher: Elsevier BV
Date: 2012
Publisher: Public Library of Science (PLoS)
Date: 24-06-2013
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.THROMRES.2018.11.016
Abstract: Positive family history is known to be an independent risk factor for venous thromboembolic (VTE) that may or may not reflect an underlying hereditary disorder. However, there is no clear standardized definition of what constitutes a positive family history for VTE in children. We aimed to assess the current published definitions of positive family history as a risk factor for VTE in children and ascertain if any consensus exists. We conducted a literature review through two major databases PUBMED and EMBASE (1969-June 2018). Three different search statements were used for each database to maximize the number of relevant results, giving rise to 1050 non-duplicated papers. Of the 1050 papers, 32 articles demonstrated 18 separate definitions on what constitutes a positive family history in paediatric studies. Variations in definitions were related to the closeness of kinship (first or second-degree relatives), whether thrombosis was provoked or unprovoked, the age of presentation of thrombosis in the kinship, and clinical vs. laboratory definition of positive family history. Of the definitions, 1st degree relative/s developing VTE at any age whether provoked or unprovoked was most commonly described. According to this literature review, the definition of a positive family history in paediatric populations is non-standardized amongst current published papers. To enable accurate comparisons across studies and improve clinical risk assessment, we therefore propose the need for a standardized definition of what constitutes a positive family history.
Publisher: Elsevier BV
Date: 02-2012
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 03-2011
Publisher: Wiley
Date: 19-04-2012
DOI: 10.1111/J.1440-1754.2012.02451.X
Abstract: The aim of this study was to investigate the clinical use of antithrombin concentrate (ATC) in children and specifically to determine the current practice of ATC administration, including dosing and indications for administration. A clinical audit was performed of patients treated with ATC during two 12-month periods: 1 June 1999-1 June 2000 and 1 June 2009-1 June 2010. Thirty-seven patients whose age ranged from 1 day to 13.5 years (median 30 days) received a median of two doses (range 1-15) with a median dose of 40 units/kg (range 1-200 units). The majority (90%) of patients were located in the intensive care unit, and the major indication (76%) for use of the ATC was in the setting of unfractionated heparin (UFH) resistance. Post-ATC administration, 32% of the doses given resulted in antithrombin levels reaching age-specific normative levels. Of the patients administered ATC with the aim of optimising UFH therapy, 28% of patients had their UFH dose reduced without any measurement of UFH effect. This data provides the basis for future investigations of the specific biochemical changes accompanying ATC administration and the development of paediatric-specific evidence-based guidelines for ATC use.
Publisher: Wiley
Date: 29-08-2002
Publisher: Informa UK Limited
Date: 03-09-2021
Publisher: Springer Science and Business Media LLC
Date: 23-05-2020
Publisher: Wiley
Date: 30-09-2014
DOI: 10.1111/BJH.13153
Abstract: Platelets are crucial subcellular elements of haemostasis at sites of vascular injury and are also known to be immune mediators in pathological thrombosis. Despite the integral role of platelets in many disease processes, there is very little information available on platelet function and response to agonists in healthy children. We recently reported important differences in the interaction of platelets with monocytes in the circulation, including increased formation of monocyte-platelet aggregates (MPAs) without concomitant increase in P-selectin expression. Our current study investigates parameters of platelet activation (PAC-1 binding and P-selectin expression) and MPA formation in response to a range of physiologically relevant platelet agonists in healthy children compared to healthy adults. All parameters were significantly higher in children in response to sub-maximal concentrations of thrombin receptor activator peptide and adenosine diphosphate, reflecting an age-specific difference in agonist-stimulated platelet reactivity in children. The results of our study challenge the general assumption that platelet reactivity in children is similar to adults. This finding is fundamental to investigating the role of platelets in diseases of childhood and pathogenesis of adult-based diseases that have their origins in childhood. Our findings underscore the need for age-specific reference ranges for platelet function in children rather than extrapolation from adult data.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
DOI: 10.1161/ATVBAHA.117.309422
Abstract: Biglycan (BGN) has reduced expression in placentae from pregnancies complicated by fetal growth restriction (FGR). We used first trimester placental s les from pregnancies with later small for gestational age (SGA) infants as a surrogate for FGR. The functional consequences of reduced BGN and the downstream targets of BGN were determined. Furthermore, the expression of targets was validated in primary placental endothelial cells isolated from FGR or control pregnancies. BGN expression was determined using real-time polymerase chain reaction in placental tissues collected during chorionic villous s ling performed at 10 to 12 weeks’ gestation from pregnancies that had known clinical outcomes, including SGA. Short-interference RNA reduced BGN expression in telomerase-immortalized microvascular endothelial cells, and the effect on proliferation, angiogenesis, and thrombin generation was determined. An angiogenesis array identified downstream targets of BGN, and their expression in control and FGR primary placental endothelial cells was validated using real-time polymerase chain reaction. Reduced BGN expression was observed in SGA placental tissues. BGN reduction decreased network formation of telomerase-immortalized microvascular endothelial cells but did not affect thrombin generation or cellular proliferation. The array identified target genes, which were further validated: angiopoetin 4 ( ANGPT4 ), platelet-derived growth factor receptor α ( PDGFRA ), tumor necrosis factor superfamily member 15 ( TNFSF15 ), angiogenin ( ANG ), serpin family C member 1 ( SERPIN1 ), angiopoietin 2 ( ANGPT2 ), and CXC motif chemokine 12 ( CXCL12 ) in telomerase-immortalized microvascular endothelial cells and primary placental endothelial cells obtained from control and FGR pregnancies. This study reports a temporal relationship between altered placental BGN expression and subsequent development of SGA. Reduction of BGN in vascular endothelial cells leads to disrupted network formation and alterations in the expression of genes involved in angiogenesis. Therefore, differential expression of these may contribute to aberrant angiogenesis in SGA pregnancies.
Publisher: Wiley
Date: 2015
Publisher: Elsevier BV
Date: 06-2008
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1111/JTH.12597
Abstract: Antithrombin, a hemostatic protein and naturally occurring anticoagulant, is a major thrombin inhibitor. The capacity of antithrombin to inhibit thrombin is known to increase a 1000-fold whilst in the presence of unfractionated heparin. β-antithrombin is an isoform of antithrombin with a high affinity for unfractionated heparin. This study aimed to determine the differences in the anticoagulant activity of the β-antithrombin isoform in children compared with adults. Plasma s les were obtained from 105 healthy in iduals from the following age groups: neonates (day 1 and day 3), 28 days to 1 year, 1-5 years, 6-10 years, 11-16 years and adults. The method utilized to measure the activity of β-antithrombin in plasma is a modified version of the total antithrombin assay routinely used in diagnostic laboratories. The modified version of this assay allows for the specific quantification of the β-antithrombin glycoform anticoagulant activity alone, as the β-antithrombin molecule is activated under a high salt concentration, which in turn does not allow activation of other antithrombin isoforms. This study demonstrated that there are no age-specific differences in the activity of β-antithrombin. However, considering that the total AT activity is significantly reduced in neonates, our results suggest that in this population β-antithrombin activity is a major contributor to the overall activity of AT.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2012
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 02-05-2022
DOI: 10.1038/S41467-022-29951-9
Abstract: COVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.THROMRES.2018.04.011
Abstract: The Fontan procedure has transformed the lives of children born with single-ventricle physiology, previously deemed inoperable. Worldwide, there are an increasing number of children with Fontan circulation, with the potential for survival into adulthood. Due to the abnormal circulation, Fontan patients have an increased risk of thromboembolic (TE) events, with up to 25% of events leading to death. Despite the importance of preventing TE events in this patient population, there is currently no clinical consensus on the optimal monitoring, thromboprophylaxis therapies, and treatment of these events. This paper reviews the available literature regarding anticoagulation in the pediatric and adult Fontan population, including the mechanisms for thrombosis and current antithrombotic therapies.
Publisher: Springer Science and Business Media LLC
Date: 02-10-2011
DOI: 10.1007/S00246-011-0122-6
Abstract: This prospective, single-centre cohort study aimed to evaluate plasmin generation and fibrinolysis during and after cardiopulmonary bypass (CPB) surgery in a cohort of children up to 6 years of age. Blood s les were drawn at eight time points: after induction of anesthesia, before unfractionated heparin (UFH), after UFH, after initiation of bypass, before protamine, after protamine, after chest closure, and 6 h after chest closure. The study identified an increase in fibrinolysis during CPB and particularly up to 6 h afterward in children. This could be the mechanism for the significant bleeding events observed in this young population after CPB. This study establishes the foundation for future studies in this area, particularly those focusing on clinical outcomes after CPB surgery.
Publisher: Public Library of Science (PLoS)
Date: 05-11-2012
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.AJPATH.2011.10.023
Abstract: Pregnancy represents a hypercoagulable state characterized by increased thrombin generation. However, placentas from fetal growth restriction (FGR) pregnancies are characterized by increased fibrin deposition and thrombi in the vasculature, indicative of a further increase in thrombin activation and a disturbance in coagulation in this clinical setting. The cause of the coagulation disturbance observed in FGR pregnancies is currently unknown. Anticoagulant mechanisms are crucial in the regulation of thrombin activity, and current evidence suggests that syndecans are the principal placental anticoagulant proteoglycans. The aim of this study was to determine the localization, distribution, and expression of syndecans 1 to 4 in placentas complicated by idiopathic FGR compared with gestation-matched controls. Immunohistochemistry results revealed that all of the syndecans were localized to cells located closely to the maternal and fetal circulation. The mRNA and protein expression levels of both syndecan 1 and syndecan 2 were significantly decreased in FGR s les compared with controls. This is the first study to demonstrate the differential expression of syndecans 1 to 4 in idiopathic FGR placentas compared with controls. Reduced levels of syndecan expression may result in increased placental thrombosis in the uteroplacental circulation and may therefore contribute to the pathogenesis of FGR.
Publisher: Elsevier BV
Date: 05-2017
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.THROMRES.2015.12.005
Abstract: Current clinical decision rules for pulmonary embolism are based on adult populations and have not been validated in children. The objective was to identify and evaluate clinical features for a first lifetime episode of pulmonary embolism in children presenting to the emergency department. We present a case-control study of children (≤18years) presenting to the emergency department of the Royal Children's Hospital, Melbourne between November 2007 and February 2015. Children with radiologically proven pulmonary embolism formed the case group, whilst children in whom there was a clinical suspicion of pulmonary embolism but negative diagnostic imaging formed the control group. Charts, electronic medical and imaging records of both cases and controls were reviewed and analysed. There were a total of 50 patients in this study (11 cases and 39 controls). Current or recent (within three months) use of the oral contraceptive pill was the most significant risk factor in our study (odds ratio 14.667, 95% confidence interval 3.001-71.678, P<0.001). Most other features failed to discriminate between cases and controls, although there was a trend towards increased heart rate in cases. Pulmonary embolism is perhaps the most common presenting spontaneous venous thromboembolism in the community and teenage girls on the oral contraceptive pill are most at-risk amongst children. The clinical signs and symptoms are often non-specific. Additional larger studies are required to determine the significance and magnitude of potential clinical predictors identified in this study. This may lead to derivation of a paediatric-specific pre-test probability tool.
Publisher: Field Robotics Publication Society
Date: 10-03-2022
DOI: 10.55417/FR.2022047
Abstract: This paper presents and discusses algorithms, hardware, and software architecture developed by the TEAM CoSTAR (Collaborative SubTerranean Autonomous Robots), competing in the DARPA Subterranean Challenge. Specifically, it presents the techniques utilized within the Tunnel (2019) and Urban (2020) competitions, where CoSTAR achieved second and first place, respectively. We also discuss CoSTAR’s demonstrations in Martian-analog surface and subsurface (lava tubes) exploration. The paper introduces our autonomy solution, referred to as NeBula (Networked Belief-aware Perceptual Autonomy). NeBula is an uncertainty-aware framework that aims at enabling resilient and modular autonomy solutions by performing reasoning and decision making in the belief space (space of probability distributions over the robot and world states). We discuss various components of the NeBula framework, including (i) geometric and semantic environment mapping, (ii) a multi-modal positioning system, (iii) traversability analysis and local planning, (iv) global motion planning and exploration behavior, (v) risk-aware mission planning, (vi) networking and decentralized reasoning, and (vii) learning-enabled adaptation. We discuss the performance of NeBula on several robot types (e.g., wheeled, legged, flying), in various environments. We discuss the specific results and lessons learned from fielding this solution in the challenging courses of the DARPA Subterranean Challenge competition.
Publisher: BMJ
Date: 2016
Publisher: Georg Thieme Verlag KG
Date: 2009
DOI: 10.1160/TH09-01-0056
Abstract: Point-of-care (POC) monitoring of oral anticoagulation has been widely adopted in both paediatric and adult patients. A new POC system, the CoaguChek XS® has recently been developed to measure the international normalised ratio (INR) and may offer significant advantages. The CoaguChek XS® utilises a new method of electrochemical clot detection based on thrombin generation. This system has not been previously evaluated in children with reference to the laboratory gold standard, the prothrombin time using reference thromboplastin. It was the objective to compare values obtained by the CoaguChek XS® system with both the venous INR and the gold standard for anticoagulant monitoring, prothrombin time with reference thromboplastin (rTF/95).To evaluate the impact of testing using the Coagu-Chek XS® on clinical anticoagulant dosing decisions. Fifty paired venous INR and capillary CoaguChek XS® results were obtained from 31 children (aged up to 16 years).The laboratory gold standard, a manual prothrombin time with reference thromboplastin (rTF/95) was additionally performed on 26 s les. Correlation between the CoaguChek XS® result and the venous INR was r= 0.810. Agreement between the CoaguChek XS result and the reference INR was shown to be higher (r=0.95), in the subset analysed by this method. Correlation between the venous INR and reference INR was r=0.90. Despite changes to the methodology of testing with the CoaguChek XS® POC monitoring system, the accuracy of this method when compared with both the venous INR and gold standard reference INR was satisfactory. This resulted in infrequent changes to clinical decision making regarding anticoagulation
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1111/JTH.12641
Abstract: Enoxaparin is a frequently used anticoagulant in children. Unlike in adults, consensus guidelines recommend therapeutic monitoring to a target anti-factor Xa level of 0.5-1 U mL(-1) . Therapeutic ranges are not well correlated with clinical outcomes (e.g. thrombosis or hemorrhage), and assays are not standardized. Owing to limited reagent supplies, our clinical laboratory conducted a validation process and switched anti-FXa assays. Although the assays correlated well with each other, anti-FXa values were, on average, 33% higher with the new assay. The target anti-FXa range was not altered. We evaluated how this change in anti-FXa assays influenced enoxaparin dosing (mg kg(-1) ). Enoxaparin dosing and anti-FXa values for all patients started on enoxaparin for the 6 months before and after assay change were retrospectively compiled and analyzed with a Student's t-test. One hundred and nine children were started on enoxaparin before assay change, and 104 after assay change. The mean therapeutic enoxaparin dose (mg kg(-1) ) was significantly lower in subjects aged < 3 months (P = 0.01) and 3 months to 2 years (P 2 years (P = 0.18), after assay change. The median number of enoxaparin dose changes required to achieve the target range was significantly reduced after assay change, from 1 to 0 (P = 0.004). The current pediatric practice of dose adjustment to achieve and maintain a target anti-FXa range is vulnerable to assay determination, which may provide false reassurance of efficacy and safety and represent misappropriation of time and resources. These data support a pediatric randomized controlled clinical trial comparing the safety and efficacy of enoxaparin weight-based dosing with or without dose titration based on anti-FXa.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 03-2011
DOI: 10.1007/S00246-011-9929-4
Abstract: This prospective, single-center cohort study aimed to evaluate the hemostatic response during and after Cardiopulmonary Bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood s les were drawn at eight time points: post-induction of anesthesia, pre-unfractionated heparin (UFH), post-UFH, post-initiation of bypass, pre-protamine, post-protamine, post-chest-closure, and 6 h post-chest-closure. As expected, all measures of the UFH effect increased significantly post-UFH bolus and decreased post-protamine administration. However, thrombin generation remained inhibited compared to baseline values despite the post-UFH reversal by protamine. We also demonstrate that residual UFH effect is not responsible for the ongoing inhibition of thrombin observed post-protamine administration. The significant increase in both free and total tissue factor pathway inhibitor levels during the CPB surgery might contribute to the persistent thrombin generation/endogenous thrombin potential inhibition post-protamine administration. This study makes a significant and novel contribution by investigating the physiological mechanisms behind the degree of thrombin inhibition by UFH and the residual levels of thrombin inhibition that continue despite protamine reversal and provides a new foundation for future interventional studies in the setting of paediatric CPB surgery.
Publisher: Informa UK Limited
Date: 07-1999
Publisher: Wiley
Date: 10-2017
Abstract: Protein quantification using data-independent acquisition methods such as SWATH-MS most commonly relies on spectral matching to a reference MS/MS assay library. To enable deep proteome coverage and efficient use of existing data, in silico approaches have been described to use archived or publicly available large reference spectral libraries for spectral matching. Since implicit in the use of larger libraries is the increasing likelihood of false-discoveries, new workflows are needed to ensure high confidence in protein matching under these conditions. We present a workflow which introduces a range of filters and thresholds aimed at increasing confidence that the resulting proteins are reliably detected and their quantitation is consistent and reproducible. We demonstrated the workflow using extended libraries with SWATH data from human plasma s les and yeast-spiked human K562 cell lysate digest.
Publisher: Wiley
Date: 22-02-2010
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.THROMRES.2015.10.011
Abstract: Off label use of anticoagulants is common. The association between fibrin deposition in the lungs and primary lung disease, injury or prematurity affords a strong theoretical basis for the potential benefit of antithrombotic therapies administered directly to the lung tissue. This review offers a critical appraisal of current evidence related to the inhalational administration of antithrombotic therapy in humans. An interrogation of 2 databases across a 13 year period of time was undertaken using key words selected a priori. Identified publications were categorized according to the following themes: 1. Inhaled antithrombotic therapy in healthy subjects 2. Inhaled antithrombotic therapy for vascular thromboprophylaxis 3. Inhaled antithrombotic therapy in smoke inhalation and lung injury 4. Inhaled antithrombotic therapy in asthma or allergy 5. Inhaled antithrombotic therapy for plastic bronchitis post-Fontan surgery 6. Inhaled antithrombotic therapy for other indications. 33 articles were identified consistent with the inclusion criteria developed for this review. Unfractionated heparin, LMWH, activated protein C and thrombolytic agents have been administered via the respiratory track, with asthma and smoke inhalation/lung injury being the most frequently investigated clinical scenarios described. All studies reported had significant methodological limitations. The safety and clinical utility of inhaled antithrombotic therapies have not been adequately investigated to support the generation of any firm evidence. This review highlights where inhaled antithrombotic therapies have shown promise and importantly, the further research required to confirm mechanism of action and a definitive risk: benefit profile.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1002/RTH2.12048
Publisher: American Society of Hematology
Date: 03-07-2017
DOI: 10.1182/BLOODADVANCES.2017004333
Abstract: UFH, LMWH, and NAC restored angiogenesis in decorin-reduced endothelial cells. NAC treatment was similar to, or better than, UFH or LMWH at improving endothelial angiogenesis without increasing anticoagulant activity.
Publisher: Informa UK Limited
Date: 17-02-2017
DOI: 10.1080/08880018.2017.1313919
Abstract: Chronic liver disease causes a disruption of procoagulant and anticoagulant factors, resulting in a fragile state, prone to increased rates of both bleeding and thrombosis. Currently, there is limited literature describing the changes observed in pediatric liver disease and extrahepatic portal vein obstruction or shunt. This study aimed to describe the changes that occur in children with chronic liver disease and extrahepatic portal vein obstruction or shunt. We measured the concentration and activity of key procoagulant and anticoagulant factors in children with liver disease, children with extrahepatic portal vein obstruction or shunt, and healthy children. Children with severe liver disease had coagulopathic changes, including either decreased concentration or activity of factor II, factor V, and factor VII. Nineteen percent (8/42) of the cohort had significant bleeding. Thrombophilic changes were also observed, including decreased concentration or activity of protein C, protein S, and antithrombin and increased concentration and activity of factor VIII and Von Willebrand factor. Similar coagulation factor changes were observed in children with extrahepatic portal vein obstruction or shunt. There was a trend toward greater changes in coagulation factor activity compared to concentration. This study provides a detailed description of the changes in both the concentration and activity of coagulation factors in pediatric liver disease and extrahepatic portal vein obstruction or shunt. Interestingly, procoagulant and anticoagulant factors were deranged in portal vein obstruction or shunt to a similar degree as in liver disease. An improved understanding of the coagulation profile in the pediatric setting will contribute to the improved management of liver disease and extrahepatic portal obstruction or shunt. PELD: pediatric end-stage liver disease score MELD: model for end-stage liver disease score ELISA: enzyme-linked immunosorbent assay MCRI: Murdoch Childrens Research Institute FII: factor II FV: factor V FVII: factor VII FVIII: factor VIII AT: antithrombin III A2M: alpha-2-macroglobulin vWF: Von Willebrand factor PC: protein C PS: protein S ISTH-BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1111/JTH.12372
Abstract: Developmental hemostasis recognizes the physiologic differences between the hemostatic system of neonates and children and that of adults. As compared with the knowledge of hemostatic system physiology in adults, our understanding in neonates and children remains inadequate. Routine clinical coagulation testing most commonly measures functional parameters of the hemostatic system. Very few studies have measured age-specific levels of hemostatic proteins. An understanding of the normal fluctuations in the levels of hemostatic proteins is vital in the prevention, diagnosis and treatment of hemostatic problems during infancy and childhood. This study was designed as the first comprehensive study of the age-specific changes in the levels of important hemostatic proteins in healthy neonates, children, and adults. Plasma s les were obtained from 120 healthy in iduals from the following age groups: neonates (day 1 and day 3), 28 days to 1 year, 1-5 years, 6-10 years, 11-16 years, and adults. Factor II, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, plasminogen, protein C and total and free protein S were quantified with commercially available ELISA kits. The levels of 10 proteins were significantly different between neonates and adults, and these differences persisted throughout childhood for most of these proteins. The results of this study confirm that the levels of the majority of coagulation proteins vary significantly with age. Future studies should investigate how hemostatic protein level relates to functional changes with age.
Publisher: Elsevier BV
Date: 05-2006
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.PLACENTA.2010.05.009
Abstract: Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. The majority of FGR cases are idiopathic and are associated with placental insufficiency, which can result from placental thrombosis. Evidence suggests that Dermatan Sulfate (DS) is an important anti-coagulant in placentae of uncomplicated pregnancies. This study hypothesised that the expression of biglycan proteoglycan, a source of DS, is decreased in idiopathic FGR placentae compared with placentae from uncomplicated pregnancies. This study aimed to determine biglycan mRNA, protein expression and spatial distribution in idiopathic FGR placentae compared with the placentae from gestation-matched controls. Biglycan mRNA expression, protein expression and spatial distribution was determined in 26 idiopathic FGR-affected placentae and 27 placentae from gestation-matched controls (27-40 weeks gestation) using real-time PCR, immunoblotting and immunohistochemistry, respectively. Mean biglycan mRNA expression was significantly decreased in FGR placentae compared with control placentae (2.87 +/- 0.55, (n = 26) vs. 4.48 +/- 0.85, (n = 27) t-test p = 0.01). FGR placentae demonstrated a trend towards decrease in mean biglycan protein expression compared with control placentae (0.86 +/- 0.22 (n = 9, FGR) vs, 1.9 +/- 0.56 (n = 7, control) p = 0.07). Biglycan immunoreactivity was detected in endothelial cells and sub-endothelial cells of the perivascular region of fetal capillaries. Semi-quantitative analyses demonstrated a significant decrease in immunoreactive biglycan in FGR placentae compared with control placentae (51.1 +/- 19.3 vs, 500.7 +/- 223, n = 6, p < 0.001). This is the first study to demonstrate decreased biglycan expression in idiopathic FGR placentae compared to gestation-matched controls. Reduced biglycan expression may contribute to placental thrombosis within the fetal vasculature, and may contribute to the pathogenesis of idiopathic FGR.
Publisher: Wiley
Date: 07-1999
DOI: 10.1080/713803473
Abstract: C57BL/6J obese (ob/ob) and lean mice fed ad libitum on a normal mouse chow diet (Normal), were compared with lean mice of the same age and strain fed ad libitum on a high-fat diet, consisting of the Normal diet with the addition of beef lard (Lard), from age 3 months for 34 days. The lard-fed mice were seen to have significantly higher (P<0.05) body weight in this 34-day period than that of the other two groups fed on the Normal diet. Epididymal fat depot and adipocyte cell size were significantly larger (P<0.05) in the Lard-fed lean mice and in the obese (ob/ob) mice than were those of the Normal-fed lean mice. Dietary Lard intake did not significantly affect concentrations of plasma triglyceride although those of plasma cholesterol were significantly increased (P<0.05). The development of obesity in these Lard-fed mice appeared to be accelerated and significant.
Publisher: SAGE Publications
Date: 06-01-2015
Abstract: Cardiopulmonary bypass (CPB) can be associated with deleterious clinical effects. However, the impact of CPB on inflammatory, immunological and other homeostatic pathways remains poorly understood. We investigated the impact of CPB on the plasma proteome in children undergoing tetralogy of Fallot repair. Blood s les were taken from 20 children prior to and at the end of CPB and 6h, 12h and 24h after CPB. Plasma was analysed by liquid chromatography-mass spectrometry (LC-MS) in a label-free, untargeted approach. Data were analysed using Genedata software to identify peptides that were differentially expressed (p .01 above a false discovery rate). Proteins were identified from peptides that demonstrated differential expression. The proteins that were found to be differentially expressed were haptoglobin isoform 1 preproprotein, isoform 2 of semaphorin-6C, vitamin D-binding protein, inter-alpha-trypsin inhibitor, ceruloplasmin, apolipoprotein B100 and fibrinogen alpha. CPB alters the plasma proteome with differences most apparent at 6h and 12h post CPB. There was a return to baseline with no proteins differentially regulated by 24h.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 12-2014
Publisher: Wiley
Date: 22-10-2009
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.THROMRES.2012.07.009
Abstract: Current anticoagulation therapy in children is less than ideal, requiring regular venous monitoring and dosing adjustments. Limitations associated with conventional anticoagulants have prompted the development of novel drugs that specifically target key proteins in the coagulation system. Rivaroxaban is the first oral, direct Factor Xa inhibitor available for the prevention of venous thromboembolism in adults. Its predictable pharmacokinetic profile, high oral bioavailability and once-daily dosing make rivaroxaban an optimal anticoagulant that warrants investigation in children. The aim of this study was to investigate the age-related anticoagulant effect of rivaroxaban in vitro. Age-specific plasma pools were created (i.e. 28 days-23 months, 2-6, 7-11, 12-16 years and adults) and spiked with increasing concentrations of rivaroxaban (0-500 ng/ml). Commercially available PT, APTT and anti-Factor Xa assays, as well as sub-s ling thrombin generation assays, were used to measure rivaroxaban effect. The results of this study indicate that there are no significant differences in rivaroxaban effect across the age groups in vitro. In vivo studies are required to confirm the consistency of dose-response across the paediatric age groups.
Publisher: Wiley
Date: 03-07-2007
DOI: 10.1111/J.1365-2141.2007.06663.X
Abstract: Currently available chromogenic and fluorogenic substrates for endogenous thrombin potential (ETP) measurement are cleaved by both free (active) and alpha-2-macroglobulin-bound (inactive) thrombin, leading to an overestimation of ETP. Commercial methods for ETP measurement determine this using a mathematical algorithm, which assumes the contribution of alpha-2-macroglobulin to the ETP. This limits application of such methods to populations where variation in alpha-2-macroglobulin concentrations is observed, primarily children. This study examined the contribution of alpha-2-macroglobulin-bound thrombin to the ETP measurement in neonates, children and adults, to determine whether automated methods are appropriate for use in neonates and children.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 04-2005
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PLACENTA.2018.12.007
Abstract: Placental mediated fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Heparan sulphate proteoglycans (HSPG) are highly expressed in placentae and regulate haemostasis. We hypothesise that altered expression of HSPGs, glypicans (GPC) may contribute to the development of FGR and small-for-gestational-age (SGA). GPC expression was determined in first-trimester chorionic villous s les collected from women with later SGA pregnancies and in placentae from third-trimester FGR and gestation-matched uncomplicated pregnancies. The expression of both GPC1 and GPC3 were significantly reduced in first-trimester SGA as well as in the third-trimester FGR placentae compared to controls. This is the first study to report a relationship between altered placental GPC expression and subsequent development of SGA/FGR.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JPROT.2014.01.004
Abstract: For over a century, venom s les from wild snakes have been collected and stored around the world. However, the quality of storage conditions for "vintage" venoms has rarely been assessed. The goal of this study was to determine whether such historical venom s les are still biochemically and pharmacologically viable for research purposes, or if new s le efforts are needed. In total, 52 s les spanning 5 genera and 13 species with regional variants of some species (e.g., 14 different populations of Notechis scutatus) were analysed by a combined proteomic and pharmacological approach to determine protein structural stability and bioactivity. When venoms were not exposed to air during storage, the proteomic results were virtually indistinguishable from that of fresh venom and bioactivity was equivalent or only slightly reduced. By contrast, a s le of Acanthophis antarcticus venom that was exposed to air (due to a loss of integrity of the rubber stopper) suffered significant degradation as evidenced by the proteomics profile. Interestingly, the neurotoxicity of this s le was nearly the same as fresh venom, indicating that degradation may have occurred in the free N- or C-terminus chains of the proteins, rather than at the tips of loops where the functional residues are located. These results suggest that these and other vintage venom collections may be of continuing value in toxin research. This is particularly important as many snake species worldwide are declining due to habitat destruction or modification. For some venoms (such as N. scutatus from Babel Island, Flinders Island, King Island and St. Francis Island) these were the first analyses ever conducted and these vintage s les may represent the only venom ever collected from these unique island forms of tiger snakes. Such vintage venoms may therefore represent the last remaining stocks of some local populations and thus are precious resources. These venoms also have significant historical value as the Oxyuranus venoms analysed include s les from the first coastal taipan (Oxyuranus scutellatus) collected for antivenom production (the snake that killed the collector Kevin Budden), as well as s les from the first Oxyuranus microlepidotus specimen collected after the species' rediscovery in 1976. These results demonstrate that with proper storage techniques, venom s les can retain structural and pharmacological stability. This article is part of a Special Issue entitled: Proteomics of non-model organisms.
Publisher: Elsevier BV
Date: 10-2006
Publisher: Wiley
Date: 05-2003
DOI: 10.1046/J.1440-1754.2003.00139.X
Abstract: To audit the frequency of heparinoid (standard heparin and low molecular weight heparin) use in a tertiary paediatric hospital, and to determine the occurrence of heparin-induced thrombocytopenia (HIT). A 1-week cross-sectional audit of all heparinoids given to inpatients at a tertiary paediatric hospital was undertaken and a retrospective medical record review of all suspected HIT cases at the tertiary paediatric centre over a 2-year period was carried out. One hundred and sixteen patients received heparinoid medications over a 7-day period. An average of 29 children received heparin daily. The retrospective medical record review identified four patients with suspected HIT over a 2-year period. Two patients developed thrombotic complications, which were fatal in one patient. Heparin is used frequently in paediatric tertiary hospitals, yet the occurrence of HIT in children is much lower than that reported in adults. Improved laboratory techniques could facilitate improved screening and diagnosis of this serious adverse drug reaction.
Publisher: Wiley
Date: 29-09-2010
DOI: 10.1111/J.1365-2141.2010.08373.X
Abstract: The impact of age upon therapeutic response to unfractionated heparin (UFH) in children is proposed to reflect quantitative and potentially qualitative differences in coagulation proteins across childhood. This study explores the UFH-dependent tissue factor pathway inhibitor (TFPI) release in children compared to previously published data in adults. Children <16 years of age undergoing cardiac angiography formed the population for this prospective cohort study. TFPI release was measured prior to (baseline) and at 15, 30, 45 and 120 min post-UFH dose. This study demonstrated that, whilst the immediate release of TFPI post-UFH was similar in children compared to adults, TFPI release in children remained increased and consistent for a significantly longer period post-UFH administration compared to adults. Plasma TFPI levels in children did not demonstrate an UFH concentration -dependent reduction, as has been previously reported in adults. The prolonged TFPI-mediated anticoagulant levels observed in children administered UFH may contribute to the increased rate of major bleeding reported in children compared to adults. Furthermore, we postulate that this sustained UFH-dependent increase in TFPI levels in children may influence the binding of UFH to competitive plasma proteins, such as those involved in the immunological response to UFH associated with heparin-induced thrombocytopenia.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.THROMRES.2006.10.006
Abstract: Anti-Factor Xa (Anti-Xa) assays specifically determine the anticoagulant activity of UFH by measuring the ability of heparin-bound Antithrombin (AT) to inhibit a single enzyme, Factor Xa (FXa). Recent improvements in the automation, cost-effectiveness and accessibility of the assay to clinicians, have resulted in the Anti-Xa assay becoming a part of daily clinical practice in many institutions. We hypothesized that different Anti-Xa assays have different applicability for use in clinical settings, depending on the amount of UFH administered. This was investigated in a tertiary paediatric institution. S les were collected from children receiving Low-dose of UFH of at least 10 IU/kg/h, with or without a previous bolus of up to 25 IU/kg/h, within the previous 6 h in the PICU and HDU. High-dose UFH population consisted of children undergoing Cardiac Catheterization (CC), who received a bolus of UFH of 100 IU/kg body weight, 30 min prior to s ling. The Anti-Xa activity for a given dose of UFH was found to vary significantly based on the Anti-Xa assay and the population being monitored. Our study suggests that the MODIFIED COMATIC Anti-Xa assay provides the best physiological measure of the UFH effect in children, as it does not introduce sources of error, such as exogenous AT, which may increase the measured ant Factor Xa activity, nor Dextran Sulphate which can displace plasma protein bound heparin and once again leading to falsely elevated assay results. Further studies that include assessment of clinical outcomes are required to confirm the applicability of use of this particular assay in monitoring UFH therapy.
Publisher: Georg Thieme Verlag KG
Date: 10-2011
Abstract: The coagulation system in children is complex and ever changing, a fact encapsulated in the term developmental hemostasis. Studies confirm that there are quantitative and almost certainly qualitative differences in the coagulation system with age, and the control of these changes comes from something external to the liver. What remains uncertain is the magnitude of the qualitative changes and the implications of the changes for the growing child. At the very least, developmental hemostasis probably provides a protective mechanism for neonates and children and hence contributes to the decreased risk of thromboembolic and/or hemorrhagic events in these age groups. In addition, developmental hemostasis could also reflect the role that hemostatic proteins play in physiological development and hence the demand of other processes, such as angiogenesis. Finally, without doubt, developmental hemostasis affects the interactions of anticoagulant drugs with the coagulation system. This article will initially discuss the most recent evidence with respect to qualitative age-related changes in the coagulation system. Subsequently the article will discuss the coagulation system during childhood in light of the three aforementioned areas of clinical impact and suggest possible strategies to further understand this complex and exciting field of study.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.THROMRES.2005.11.004
Abstract: Major physiological differences in the coagulation system throughout childhood, compared to adults, are well documented. However, the impact of this on anticoagulant drugs is unknown. This study aimed to determine whether heparin therapeutic range determination is affected by the age of plasma donors and whether age-specific therapeutic ranges for heparin therapy may need to be considered in the clinical setting. Plasma s les were obtained from healthy children and adults, and pooled into age-specific pools. These were spiked with different concentrations of heparin and APTT Anti-Factor Xa and Anti-Factor IIa were measured using standard techniques. The experiments were repeated using three separate plasma pools, and results expressed as means with standard deviations. The results show clear age-related differences in APTT for the same Anti-Factor Xa heparin concentration. The differences were more pronounced in younger children, with higher APTT for same Anti-Factor Xa. The Anti-Factor IIa activity of heparin for a given Anti-Factor Xa activity also differed between age-specific plasma pools. This study suggests that when using heparin in children, basic assumptions about the drug mechanism of action and implications for therapeutic ranges need to be considered.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1111/JTH.12462
Publisher: Georg Thieme Verlag KG
Date: 2010
DOI: 10.1160/TH09-07-0476
Abstract: Protein S, protein C and antithrombin are important regulators of coagulation. While deficiencies of these proteins have been linked to adverse pregnancy outcomes, testing for these deficiencies during pregnancy is limited by the use of non-pregnant reference ranges and a limited understanding of the changes that occur during pregnancy. Although several small studies have previously reported on the activity of these proteins during pregnancy, potentially important changes have been overlooked by continuing to compare the activity during pregnancy with non-pregnant reference ranges. In the current study, we investigated the activity of protein S, protein C and antithrombin during the first half of pregnancy in 440 otherwise asymptomatic women who went on to have uncomplicated singleton pregnancies. Consistent with previous studies, we found that antithrombin activity remained unchanged, while protein S activity decreased significantly to a mean level of 46%. We did not observe a progressive decrease in protein S during the second trimester as several studies have suggested previously. In contrast, we observed a potentially biologically significant increase in protein C activity throughout the first 22 weeks of pregnancy. Given the physiological role of protein C, we postulate that this increase may play a role in maintaining early pregnancy through both an anticoagulant and an inflammatory regulation pathway.
Publisher: ACM
Date: 29-11-2022
Publisher: Springer Science and Business Media LLC
Date: 16-11-2006
DOI: 10.1038/NATURE04328
Abstract: Among extant reptiles only two lineages are known to have evolved venom delivery systems, the advanced snakes and helodermatid lizards (Gila Monster and Beaded Lizard). Evolution of the venom system is thought to underlie the impressive radiation of the advanced snakes (2,500 of 3,000 snake species). In contrast, the lizard venom system is thought to be restricted to just two species and to have evolved independently from the snake venom system. Here we report the presence of venom toxins in two additional lizard lineages (Monitor Lizards and Iguania) and show that all lineages possessing toxin-secreting oral glands form a clade, demonstrating a single early origin of the venom system in lizards and snakes. Construction of gland complementary-DNA libraries and phylogenetic analysis of transcripts revealed that nine toxin types are shared between lizards and snakes. Toxinological analyses of venom components from the Lace Monitor Varanus varius showed potent effects on blood pressure and clotting ability, bioactivities associated with a rapid loss of consciousness and extensive bleeding in prey. The iguanian lizard Pogona barbata retains characteristics of the ancestral venom system, namely serial, lobular non-compound venom-secreting glands on both the upper and lower jaws, whereas the advanced snakes and anguimorph lizards (including Monitor Lizards, Gila Monster and Beaded Lizard) have more derived venom systems characterized by the loss of the mandibular (lower) or maxillary (upper) glands. Demonstration that the snakes, iguanians and anguimorphs form a single clade provides overwhelming support for a single, early origin of the venom system in lizards and snakes. These results provide new insights into the evolution of the venom system in squamate reptiles and open new avenues for biomedical research and drug design using hitherto unexplored venom proteins.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2021
Publisher: Wiley
Date: 15-02-2018
DOI: 10.1002/MED.21489
Abstract: Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well-publicized contamination scandal, into the development of alternative anticoagulants derived from non-animal and/or totally synthetic sources that mimic the structural features and properties of heparin. Such compounds, termed heparin mimetics, are also needed as anticoagulant materials for use in biomedical applications (e.g., stents, grafts, implants etc.). This review encompasses the development of heparin mimetics of various structural classes, including synthetic polymers and non-carbohydrate small molecules as well as sulfated oligo- and polysaccharides, and fondaparinux derivatives and conjugates, with a focus on developments in the past 10 years.
Publisher: Georg Thieme Verlag KG
Date: 2014
DOI: 10.1160/TH13-10-0827
Abstract: There has been an extensive body of research focusing on the epidemiology of thrombosis in adult cancer populations however, there is significantly less knowledge about thrombosis in paediatric cancer populations. Thrombosis is diagnosed with increasing frequency in children being treated for cancer, and there is an urgent need to increase our understanding of the epidemiology of thrombosis in this population. Currently, there are no guidelines for identification of high-risk groups, prophylaxis or management of thrombotic complications in paediatric cancer patients. We reviewed the available literature regarding the epidemiology, mechanisms, risk factors, prophylaxis and outcomes of thrombosis in children with cancer and identified areas that require further research. The reported incidence of symptomatic venous thromboembolism (VTE) in children with cancer ranges between 2.1% and 16%, while the incidence of asymptomatic events is approximately 40%. Approximately 30% of VTE in this population is associated with central venous lines (CVL). The most common location of VTE is upper and lower extremity deep venous thrombosis (43 to 50% of events, respectively), while 50% of events in ALL patients occur in the central nervous system. Key characteristics that increase the risk of thrombosis include the type of cancer, age of the patient, the presence of a CVL, presence of pulmonary/intra thoracic disease, as well as the type of chemotherapy. Outcomes for paediatric cancer patients with VTE include post-thrombotic syndrome, pulmonary embolism, recurrent thromboembolism, destruction of upper venous system and death. Prospective studies aimed at enabling risk stratification of patients are required to facilitate development of paediatric specific recommendations related to thromboprophylaxis in this population.
Publisher: Informa UK Limited
Date: 18-05-2016
Publisher: Wiley
Date: 21-10-2014
Abstract: The possibility to detect biomarkers of adult disease in early life and particularly in newborns holds enormous promise for early disease detection and prevention. Early detection of disease or potential for future disease would allow for prevention or amelioration of disease before overt symptoms develop, by lifestyle modifications, appropriate medication and monitoring. It is now increasingly important to develop the technologies that allow dried blood spots (DBS) to be utilized for protein-based studies. The use of DBS in proteome wide association studies (PWAS) may in turn allow for detection of major diseases of adulthood at the earliest possible time. This review focuses on the utility of DBS in proteomics, the main challenges, as well as the latest approaches for overcoming those, facilitating the use of DBS for detection of major diseases of adulthood at the earliest possible time.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1111/JTH.15730
Abstract: The ISTH Scientific and Standardization Committee (SSC) Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis convened a working group on medication adherence to begin to understand the current state of clinical practice to inform priority areas for efforts to improve adherence for children, and adolescents and young adults (AYA) prescribed anticoagulants. We sought to survey an international group of clinicians involved in anticoagulation management in children and/or AYA about perceptions of medication on health outcomes, clinical practice related to medication adherence, and barriers to assessing and improving medication adherence. Clinicians involved in anticoagulation management in children and/or AYA were surveyed via REDCap There were 200 participants, 90% of whom were pediatric hematology/oncology physicians. Based on the results, which demonstrate that clinicians are concerned about impact of poor medication adherence and have limited resources to identify and improve adherence, the working group has identified next steps to further understand impact of medication adherence on anticoagulation-related health outcomes, address the need for validated measures to assess medication adherence for all anticoagulants prescribed to this population, and develop an intervention and implementation research agenda to improve outcomes.
Publisher: Wiley
Date: 18-01-2011
DOI: 10.1111/J.1440-1754.2010.01949.X
Abstract: This study assessed whether enoxaparin sodium diluted to a concentration of 20 mg/mL for clinical use with 0.9% sodium chloride remained stable and sterile for up to 43 days under three different storage conditions. Enoxaparin dilutions in polypropylene syringes were stored under three different controlled conditions of temperature and light: (i) room temperature (22-26°C) under natural light (ii) room temperature (22-26°C) in the dark and (iii) controlled refrigeration (2-8°C) in the dark. A weekly assay of anti-Xa and anti-IIa activity was undertaken to determine if the diluted enoxaparin preparations retained anticoagulant activity, thus remaining suitable for clinical application. Our findings indicate that diluted enoxaparin, when stored under the tested varied conditions of light and temperature, retained greater than or equal to 90% of baseline anticoagulant activity for anti-Xa and anti-IIa effect for up to 43 days. The study results are significant for families, in that they suggest that at least a month's supply of enoxaparin could be dispensed at a time, reducing the frequency of patients/families returning for supply and providing a more convenient service for paediatric patients.
Publisher: American Academy of Pediatrics (AAP)
Date: 03-2009
Abstract: Unfractionated heparin is frequently used in tertiary pediatric centers for the prophylaxis and treatment of thromboembolic disease. Recent evidence suggests that the clinical outcomes of unfractionated heparin therapy in children are poor, as determined by target-range achievement and adverse-event rates. These reports of poor outcomes may be related to an age-dependent mechanism of action of unfractionated heparin. Furthermore, several published studies have indicated that unfractionated heparin–monitoring assays currently in clinical use have significant limitations that likely affect the safety and efficacy of anticoagulant management. This review summarizes the growing body of evidence suggesting that pediatric-specific recommendations for unfractionated heparin therapy management are required to improve clinical outcomes related to this commonly prescribed medication.
Publisher: BMJ
Date: 24-03-2016
DOI: 10.1136/ARCHDISCHILD-2015-309535
Abstract: Children with liver disease can develop severe bleeding episodes and thrombosis. Liver failure usually results in decreased levels of procoagulant and anticoagulant factors. Additional risk factors, including changes in vascular flow and endothelial function, are of importance for the development of bleeding or thrombosis in in idual vascular beds. Detailed studies of haemostatic disturbances in the setting of paediatric liver disease are sparse and extrapolation from adult studies is common. The spectrum of liver diseases and the haemostatic system differs between children and adults. Specific paediatric liver diseases are reported to have more distinctive effects on haemostasis and the risk of bleeding and/or thrombosis. Conclusion: we propose a model regarding haemostasis in paediatric liver disease, taking into account a number of specific variables and mechanisms, as well as the type of liver disease, which will provide a framework for clinical decision-making in these complex patients.
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/RD09240
Abstract: Fetal growth restriction (FGR) is a clinically significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. Most cases of FGR are idiopathic and are associated with placental thrombosis. Previous studies suggest that proteoglycans, such as decorin, that contain the glycosaminoglycan dermatan sulfate are the principal anticoagulants in the normal placenta. The present study investigated decorin expression in placentas from pregnancies complicated by idiopathic FGR (n = 26) and gestation-matched controls (n = 27). Real-time polymerase chain reaction demonstrated significantly reduced decorin mRNA expression in FGR compared with control (1.52 ± 0.14 v. 2.21 ± 0.22, respectively P 0.01). Immunoblotting revealed decreased decorin protein (40 kDa) expression in FGR compared with controls (420.8 ± 39.0 v. 690.1 ± 42.2, respectively n = 12 in each group P = 0.0007). Immunohistochemistry demonstrated the presence of immunoreactive decorin protein in the placental villous stroma surrounding the fetal capillaries and a significant decrease in decorin protein presence in FGR compared with control (1.75 ± 0.66 v. 2.98 ± 1.12, respectively n = 6 in each group P 0.01, t-test). This is the first study to demonstrate reduced decorin in idiopathic FGR, indicating a potentially significant role for decorin in the aetiology of placental thrombosis in idiopathic FGR.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1111/JTH.12745
Publisher: Georg Thieme Verlag KG
Date: 2004
DOI: 10.1160/TH04-02-0085
Abstract: This paper reports the outcome of a research protocol aimed at optimising warfarin monitoring in a tertiary pediatric centre. The Thrombotest™ INR was the standard monitoring test employed to manage oral anticoagulant therapy in children at the Royal Children’s Hospital (RCH), Melbourne. This study compares the results of this standard method to the novel CoaguChek® INR monitor and the “gold standard” technique of venous INR s ling. The objectives were to determine 1) if point-of-care techniques of measuring the INR (Thrombotest and CoaguChek) are accurate and reliable compared to INR results obtained from venous s ling, processed in an accredited laboratory, and 2) if INR results generated by POC devices can be safely used to manage oral anticoagulant therapy in children. 18 children (10 females and 8 males) participated in the study. Ages ranged from 9 months to 21 years (Mean 11.9 years SD 5.03 years). The agreement between CoaguChek and venous INR measurements (r = 0.885) was shown to be higher compared to Thrombotest and venous INR (r = 0.700). Compared to the venous INR, values obtained with Coaguchek and Thrombotest crossed into or out of the therapeutic range in 25% and 36% of cases respectively. In 88% of the CoaguChek cases and 57% Thrombotest cases, the difference from the venous result was less than 0.5. The CoaguChek method of INR monitoring is a more accurate and reliable method compared to Thrombotest, in the pediatric population tested, and can be safely used to manage oral anticoagulant therapy in children.
Publisher: Wiley
Date: 22-06-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Publisher: Elsevier BV
Date: 2013
Location: United States of America
Start Date: 2016
End Date: 12-2016
Amount: $500,000.00
Funder: Australian Research Council
View Funded Activity