Publications by authors named "Paul Monagle"

246 Publications

Baby steps in managing CVAD-related thrombosis.

Blood 2022 Jan;139(3):321-322

University of Melbourne.

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http://dx.doi.org/10.1182/blood.2021014615DOI Listing
January 2022

Anticoagulant Treatment for Pediatric Infection-Related Cerebral Venous Thrombosis.

Pediatr Neurol 2021 Dec 28;128:20-24. Epub 2021 Dec 28.

Bayer AG, Wuppertal, Germany.

Background: We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection.

Methods: In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive.

Results: Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision.

Conclusions: Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.12.011DOI Listing
December 2021

Platelet Phenotype and Function Changes With Increasing Duration of Extracorporeal Membrane Oxygenation.

Crit Care Med 2022 Jan 12. Epub 2022 Jan 12.

Haematology, Murdoch Children's Research Institute, Melbourne, VIC, Australia. Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia. Department of Clinical Haematology, The Royal Children's Hospital, Melbourne, VIC, Australia. Department of Cardiac Surgery, The Royal Children's Hospital, Melbourne, VIC, Australia. Department of Intensive Care, The Royal Children's Hospital, Melbourne, VIC, Australia. Paediatric Intensive Care Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia. Department of Cardiac Surgery, Children's National Heart Institute, Washington, DC. Cardiothoracic Intensive Care Unit, National University Health System, Singapore. School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.

Objectives: To investigate platelet pathophysiology associated with pediatric extracorporeal membrane oxygenation (ECMO).

Design: Prospective observational study of neonatal and pediatric ECMO patients from September 1, 2016, to December 31, 2019.

Setting: The PICU in a large tertiary referral pediatric ECMO center.

Patients: Eighty-seven neonates and children (< 18 yr) supported by ECMO.

Interventions: None.

Measurements And Main Results: Arterial blood samples were collected on days 1, 2, and 5 of ECMO and were analyzed by whole blood flow cytometry. Corresponding clinical data for each patient was also recorded. A total of 87 patients were recruited (median age, 65 d; interquartile range [IQR], 7 d to 4 yr). The median duration of ECMO was 5 days (IQR, 3-8 d) with a median length of stay in PICU and hospital of 18 days (IQR, 10-29 d) and 35 days (IQR, 19-75 d), respectively. Forty-two patients (48%) had at least one major bleed according to a priori determined definitions, and 12 patients (14%) had at least one thrombotic event during ECMO. Platelet fibrinogen receptor expression decreased (median fluorescence intensity [MFI], 29,256 vs 26,544; p = 0.0005), while von Willebrand Factor expression increased (MFI: 7,620 vs 8,829; p = 0.0459) from day 2 to day 5 of ECMO. Platelet response to agonist, Thrombin Receptor Activator Peptide 6, also decreased from day 2 to day 5 of ECMO, as measured by binding with anti-P-selectin, PAC-1 (binds activated GPIIb/IIIa), and anti-CD63 monoclonal antibodies (P-selectin area under the curve [AUC]: 63.46 vs 42.82, respectively, p = 0.0022; PAC-1 AUC: 93.75 vs 74.46, p = 0.0191; CD63 AUC: 55.69 vs 41.76, p = 0.0020).

Conclusions: The loss of platelet response over time may contribute to bleeding during ECMO. These novel insights may be useful in understanding mechanisms of bleeding in pediatric ECMO and monitoring platelet markers clinically could allow for prediction or early detection of bleeding and thrombosis.
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http://dx.doi.org/10.1097/CCM.0000000000005435DOI Listing
January 2022

Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary.

Pediatrics 2022 Jan;149(Supplement_1):S1-S12

Sections of Critical Care and Nephrology.

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.
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http://dx.doi.org/10.1542/peds.2021-052888BDOI Listing
January 2022

Coagulation Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

Pediatrics 2022 01;149(1 Suppl 1):S79-S83

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

Context: Previous criteria for coagulation dysfunction in critically ill children were based mainly on expert opinion.

Objective: To evaluate current evidence regarding coagulation tests associated with adverse outcomes in children to inform criteria for coagulation dysfunction during critical illness.

Data Sources: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 by using a combination of medical subject heading terms and text words to define concepts of coagulation dysfunction, pediatric critical illness, and outcomes of interest.

Study Selection: Studies were included if critically ill children with coagulation dysfunction were evaluated, if performance characteristics of assessment and/or scoring tools to screen for coagulation dysfunction were evaluated, and if outcomes related to mortality or functional status, organ-specific outcomes, or other patient-centered outcomes were assessed.

Data Extraction: Data were abstracted from each eligible study into a standard data extraction form, along with risk of bias assessment, by a task force member.

Results: The systematic review supports the presence of at least 2 of the following criteria reflecting coagulation dysfunction in the absence of liver dysfunction: platelet count <100 000 cells per μL, international normalized ratio >1.5, fibrinogen level <150 mg/dL, and D-dimer value above 10 times the upper limit of normal, or above the assay's upper limit of detection if this limit is below 10 times the upper limit of normal.

Limitations: The proposed criteria for coagulation dysfunction are limited by the available evidence and will require future validation.

Conclusions: Validation of the proposed criteria and identified scientific priorities will enhance our understanding of coagulation dysfunction in critically ill children.
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http://dx.doi.org/10.1542/peds.2021-052888LDOI Listing
January 2022

Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine, Victoria, Australia.

Vaccine 2021 11 30;39(48):7052-7057. Epub 2021 Oct 30.

Monash University, Wellington Rd, Clayton, Vic 3800, Australia.

Emerging evidence suggest a possible association between immune thrombocytopenia (ITP) and some formulations of COVID-19 vaccine. We conducted a retrospective case series of ITP following vaccination with Vaxzevria ChadOx1-S (AstraZeneca) and mRNA Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) vaccines and compare the incidence to expected background rates for Victoria during the first six months of the Australian COVID-19 vaccination roll-out in 2021. Cases were identified by reports to the Victorian state vaccine safety service, SAEFVIC, of individuals aged 18 years or older presenting with thrombocytopenia following COVID-19 vaccination without evidence of thrombosis. Twenty-one confirmed or probable cases of ITP were identified following receipt of AstraZeneca (n = 17) or Pfizer-BioNTech (n = 4) vaccines. This translates to an observed incidence of 8 per million doses for AstraZeneca vaccine, twice the expected background rate of 4.1 per million. The observed rate for Pfizer-BioNTech was consistent with the expected background rate. The median time to onset for the cases post AstraZeneca vaccination was 10 days (range 1-78) and median platelet nadir 5 × 10/L (range 0-67 × 10/L). Hospital presentations or admissions for management of symptoms such as bleeding occurred in 18 (86%) of the cases. The majority of cases (n = 11) required intervention with at least 2 therapy modalities. In conclusion, we observed a substantially higher than expected rate of ITP following AstraZeneca vaccination. ITP is the second haematological adverse event, distinct from that of thrombosis with thrombocytopenia syndrome (TTS), observed following AstraZeneca vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2021.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556135PMC
November 2021

Proteomics in Thrombosis and Hemostasis.

Thromb Haemost 2021 Nov 9. Epub 2021 Nov 9.

Department of Haematology, Murdoch Children's Research Institute, Melbourne, Australia.

Proteomics, the simultaneous study of all proteins in a given cell, tissue or organism, is an innovative approach used to identify novel markers for diagnosis, prognosis and the pathophysiological mechanisms associated with diseases. Proteomic methodologies have been used in a variety of contexts such as investigating changes in protein abundance that may occur with disease presence, the response to therapeutic treatments as well as the impacts of age on the plasma proteome.Over the last decade, significant technological advancements in proteomic techniques have resulted in an increase in the use of proteomics in thrombosis and hemostasis research, particularly in order to identify relevant and novel clinical markers associated with bleeding and thrombosis. This mini-review explores the use of proteomics in the setting of thrombosis and hemostasis from 2010-2020, across five main domains (platelets, blood clot composition, stroke, venous thromboembolism, and therapeutics), as well as provides insights into key considerations for conducting proteomic studies.
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http://dx.doi.org/10.1055/a-1690-8897DOI Listing
November 2021

Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure.

Front Immunol 2021 13;12:741639. Epub 2021 Oct 13.

Infection and Immunity Theme, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 T and CD4 T up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 T and CD4 T in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.
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http://dx.doi.org/10.3389/fimmu.2021.741639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548628PMC
November 2021

Direct Oral Anticoagulants: Overcoming the Challenges of Managing Venous Thromboembolism in Children.

J Pediatr 2022 Jan 21;240:14-23. Epub 2021 Oct 21.

Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.jpeds.2021.09.025DOI Listing
January 2022

Vaccine-induced immune thrombosis and thrombocytopenia syndrome following adenovirus-vectored severe acute respiratory syndrome coronavirus 2 vaccination: a novel hypothesis regarding mechanisms and implications for future vaccine development.

Immunol Cell Biol 2021 11 18;99(10):1006-1010. Epub 2021 Oct 18.

Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, VIC, Australia.

We hypothesize that thrombosis with thrombocytopenia syndrome recently described after administration of adenovirus-vectored vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs as a result of the unique properties of the adenovirus vectors, which can have widespread biodistribution throughout the body. The antigen is delivered to megakaryocyte cells, which act as part of the primary immune system and distribute the antigen within progeny platelets, also a key component of the immune system. The interaction of the antigen induces preformed antiplatelet factor 4 (PF4) antibodies to bind to PF4-heparan sulfate complexes in the absence of exogenous heparin, at sites where the heparan sulfate concentration in the vascular glycocalyx is optimal for complex formation, causing thrombosis and thrombocytopenia as observed clinically. This hypothesis is testable in cell culture and animal models, and potentially in vivo, and if proven correct has significant implications for vaccine development and our understanding of the links between the coagulation and immune systems.
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http://dx.doi.org/10.1111/imcb.12505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652900PMC
November 2021

How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines.

Blood Adv 2021 11;5(22):4721-4726

Michael G. DeGroote Cochrane Canada and McMaster GRADE Centres and.

Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation Centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: (1) title for guideline identification, (2) abstract, including a summary of key recommendations, (3) overview of all recommendations (executive summary), and (4) the main text, providing sufficient detail about the entire process, including objectives, background, and methodological decisions from panel selection and conflict-of-interest management to criteria for updating, as well as supporting information, such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify the preparation of an evidence-based guideline manuscript and facilitate its use.
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http://dx.doi.org/10.1182/bloodadvances.2020003577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759117PMC
November 2021

Recombinant Factor VIIa in Pediatric Cardiac Surgery.

J Cardiothorac Vasc Anesth 2021 Aug 8. Epub 2021 Aug 8.

Department of Anesthesia and Pain Management, The Royal Children's Hospital, Parkville, Australia. Electronic address:

Objectives: Recombinant activated factor VIIa (rVIIa) is used off-label for refractory bleeding after cardiac surgery. This study reviewed the indications, usage rates, and complications of rVIIa.

Design: A retrospective case-control observational study.

Setting: A single quaternary pediatric hospital.

Participants: All children undergoing cardiac surgery with cardiopulmonary bypass over a three-year period.

Interventions: Administration of rVIIa as rescue therapy for refractory bleeding after weaning from cardiopulmonary bypass.

Measurements And Main Results: Onethousand, five hundred fifteen cardiopulmonary bypass procedures were reviewed. Patients receiving rVIIa were each matched to two control patients by age, procedure type, and bypass time. Data collected included weight, crossclamp time, anticoagulant and antifibrinolytic dose, return to the operating room for bleeding, thrombotic events, and extracorporeal membrane oxygenation (ECMO) circuit interventions. Forty-two patients received rVIIa (2.8%). Major systemic thrombotic complications were observed in 19% (controls 12.5%) of patients; 80% of recombinant factor VIIa patients requiring postoperative ECMO had interventions for circuit thrombosis (controls 31.25%); 4.76% of rVIIa recipients required reexploration for intractable bleeding (controls 1.39%).

Conclusions: This study added to understanding regarding the use of recombinant factor VIIa in pediatric cardiac surgery and reported increased thrombotic complications, especially for children who progress to ECMO. Prospective studies to better understand the pathophysiology of coagulopathy and hemorrhage in pediatric cardiac surgery and the role of hemostatic agents, such as rVIIa, are required.
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http://dx.doi.org/10.1053/j.jvca.2021.08.002DOI Listing
August 2021

Influence of serum iron test results on the diagnosis of iron deficiency in children: a retrospective observational study.

BMJ Open 2021 07 5;11(7):e046865. Epub 2021 Jul 5.

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.

Background And Objective: Serum iron results are not indicative of iron deficiency yet may be incorrectly used to diagnose iron deficiency instead of serum ferritin results. Our objective was to determine the association between serum iron test results and iron-deficiency diagnosis in children by general practitioners.

Design, Setting, Patients And Main Outcome Measures: A retrospective observational study of 14 187 children aged 1-18 years with serum ferritin and serum iron test results from 137 general practices in Victoria, Australia, between 2008 and 2018. Generalised estimating equation models calculating ORs were used to determine the association between serum iron test results (main exposure measure) and iron-deficiency diagnosis (outcome measure) in the following two population groups: (1) iron-deplete population, defined as having a serum ferritin <12 µg/L if aged <5 years and <15 µg/L if aged ≥5 years and (2) iron-replete population, defined as having a serum ferritin >30 µg/L.

Results: 3484 tests were iron deplete and 15 528 were iron replete. Iron-deplete children were less likely to be diagnosed with iron deficiency if they had normal serum iron levels (adjusted OR (AOR): 0.73; 95% CI 0.57 to 0.96). Iron-replete children had greater odds of an iron-deficiency diagnosis if they had low serum iron results (AOR: 2.59; 95% CI 1.72 to 3.89). Other contributors to an iron-deficiency diagnosis were female sex and having anaemia.

Conclusion: Serum ferritin alone remains the best means of diagnosing iron deficiency. Reliance on serum iron test results by general practitioners is leading to significant overdiagnosis and underdiagnosis of iron deficiency in children.
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http://dx.doi.org/10.1136/bmjopen-2020-046865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258555PMC
July 2021

Fatigue Following Pediatric Arterial Ischemic Stroke: Prevalence and Associated Factors.

Stroke 2021 10 28;52(10):3286-3295. Epub 2021 Jun 28.

Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Australia (M.G., A.C., S.H., R.W.H., M.T.M., P.M., V.A.).

Background And Purpose: The aims of this study were to assess the prevalence of multidimensional fatigue symptoms 5 years after pediatric arterial ischemic stroke and identify factors associated with fatigue.

Methods: Thirty-one children (19 males) with pediatric arterial ischemic stroke, participating in a larger prospective, longitudinal study, were recruited to this study at 5 years poststroke. Parent- and self-rated PedsQL Multidimensional Fatigue Scale scores were compared with published normative data. Associations between parent-rated PedsQL Multidimensional Fatigue Scale, demographics, stroke characteristics, and concurrent outcomes were examined.

Results: Parent-rated total, general and cognitive fatigue were significantly poorer than population norms, with more than half of all parents reporting fatigue symptoms in their children. One-third of children also reported experiencing fatigue symptoms, but their ratings did not differ significantly from normative expectations, as such, all further analyses were on parent ratings of fatigue. Older age at stroke and larger lesion size predicted greater general fatigue; older age, female sex, and higher social risk predicted more sleep/rest fatigue. No significant predictors of cognitive fatigue were identified and only older age at stroke predicted total fatigue. Greater fatigue was associated with poorer adaptive functioning, motor skills, participation, quality of life, and behavior problems but not attention.

Conclusions: Fatigue is a common problem following pediatric arterial ischemic stroke and is associated with the functional difficulties often seen in this population. This study highlights the importance of long-term monitoring following pediatric arterial ischemic stroke and the need for effective interventions to treat fatigue in children.
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http://dx.doi.org/10.1161/STROKEAHA.120.033000DOI Listing
October 2021

Severe COVID-19 and coagulopathy: A systematic review and meta-analysis.

Ann Acad Med Singap 2021 04;50(4):325-335

Cardiothoracic Intensive Care Unit, National University Heart Centre, National University Hospital, Singapore.

Introduction: Coronavirus disease 2019 (COVID-19)-induced coagulopathy (CIC) has been widely reported in the literature. However, the spectrum of abnormalities associated with CIC has been highly variable.

Methods: We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach.

Results: Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109/L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5-1.1), prothrombin time (0.4 second, 95% CI 0.2-0.6) and fibrinogen level (0.6g/L, 95% CI 0.3-0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease.

Conclusion: Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management.
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April 2021

Cross-sectional assessment of haemostatic profile and hepatic dysfunction in Fontan patients.

Open Heart 2021 05;8(1)

Heamatology Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.

Background: Fontan-associated liver disease is accompanied by a hypercoagulable state. While hepatic dysfunction in Fontan patients is common, its relationship with haemostatic changes and clinical outcomes in this patient population remains unclear.

Objective: To correlate liver dysfunction and haemostatic profiles with clinical outcomes in the Fontan population.

Patients/methods: Patients were enrolled in a multicentre, cross-sectional study in Australia and New Zealand. Hepatic structure and function were assessed using serum-based calculations (Fibrotest and model for end-stage liver disease excluding international normalised ratio scores). Haemostatic profiles were assessed by Thrombin Generation. Platelet function was assessed via Platelet Factor 4 (PF4) and P-selectin (P-SEL). Clinical outcomes were obtained from the Australian and New Zealand Fontan Registry.

Results: Seventy-three patients participated in the study (mean age 18.9±8.5 years with a mean of 13.5±6.9 years post-Fontan). The Endogenous Thrombin Potential (ETP) for patients who suffered thrombotic events (TE) (1366.4±66.2 nM/min) was higher compared with patients with major bleeding events (1011.1±138.4 nM/min) (p=0.03). Except for a negative correlation between Fibrotest-score and PF4 (p=0.045), PF4 and P-SEL concentrations did not correlate with markers of hepatic dysfunction or structural abnormality.

Conclusions: Increased ETP is associated with TE during clinical follow-up after Fontan. This study reinforces that hepatic dysfunction may contribute to the derangement of coagulation factors, impacting the individual risk of haemostatic complications for the Fontan population.
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http://dx.doi.org/10.1136/openhrt-2020-001460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112412PMC
May 2021

Paediatric Code Stroke.

J Paediatr Child Health 2021 Apr 19. Epub 2021 Apr 19.

Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15509DOI Listing
April 2021

The use of proteomics for blood biomarker research in premature infants: a scoping review.

Clin Proteomics 2021 Apr 14;18(1):13. Epub 2021 Apr 14.

Haematology Research Laboratory, Murdoch Children's Research Institute, Parkville, Australia.

Over the last decade, the use of proteomics in the setting of prematurity has increased and has enabled researchers to successfully identify biomarkers for an array of associated morbidities. The objective of this scoping review was to identify the existing literature, as well as any knowledge gaps related to proteomic biomarker discoveries in the setting of prematurity. A scoping review was conducted using PubMed, Embase and Medline databases following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The study selection process yielded a total of 700 records, of which 13 studies were included in this review. Most studies used a tandem Mass Spectrometry (MS/MS) proteomics approach to identify key biomarkers. The corresponding studies identified proteins associated with retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), late onset sepsis (LOS) and gestational age. This scoping review demonstrates the limited use of proteomics to identify biomarkers associated with severe complications of prematurity. Further research is warranted to identify biomarkers of other important morbidities associated with prematurity, such as intraventricular haemorrhage (IVH) and cerebral palsy, and to investigate the mechanisms associated with these outcomes.
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http://dx.doi.org/10.1186/s12014-021-09316-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048323PMC
April 2021

Social Cognitive Dysfunction Following Pediatric Arterial Ischemic Stroke: Evidence From a Prospective Cohort Study.

Stroke 2021 05 8;52(5):1609-1617. Epub 2021 Apr 8.

Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Australia (N.P.R., M.G., L.C., A.C, L.C., R.W.H., P.M., M.T.M., V.A.).

Background And Purpose: Childhood and adolescence coincide with rapid maturation of distributed brain networks supporting social cognition; however, little is known about the impact of early ischemic brain insult on the acquisition of these skills. This study aimed to examine the influence of arterial ischemic stroke (AIS) on facial emotion recognition and theory of mind (ToM) abilities of children and adolescents initially recruited to a single-center, prospective longitudinal study of recovery following AIS.

Methods: The study involved 67 participants, including 30 children with AIS (mean time since stroke=5 years) and 37 age-matched typically developing controls who were assessed on measures of cognitive ToM, facial emotion recognition, and affective ToM. Acute clinical magnetic resonance imaging, including diffusion-weighted imaging sequences, were used to evaluate prospective structure-function relationships between acute lesion characteristics (size, location, and arterial territories affected) and long-term social cognitive abilities.

Results: Relative to age-matched typically developing controls, children with AIS showed significantly worse performance on measures of basic facial emotion processing, cognitive ToM, and affective ToM. In univariate models, poorer ToM was associated with larger infarcts, combined cortical-subcortical pathology, and involvement of multiple arterial territories. In multivariate analyses, larger lesions and multiterritory infants were predictive of ToM processing but not facial emotion recognition. Poorer cognitive ToM predicted less frequent prosocial behavior and increased peer problems.

Conclusions: Social cognitive skills appear vulnerable to disruption from early ischemic brain insult. In the first study to examine social cognition in a prospective cohort of children with AIS, our findings suggest that acute magnetic resonance imaging-based lesion characteristics may have predictive value for long-term social cognitive outcomes and may assist to identify children at elevated risk for social cognitive dysfunction.
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http://dx.doi.org/10.1161/STROKEAHA.120.032955DOI Listing
May 2021

International pediatric thrombosis network to advance pediatric thrombosis research: Communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis.

J Thromb Haemost 2021 04;19(4):1123-1129

Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm-PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high-quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.
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http://dx.doi.org/10.1111/jth.15260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252713PMC
April 2021

Continuous reference intervals for leukocyte telomere length in children: the method matters.

Clin Chem Lab Med 2021 06 15;59(7):1279-1288. Epub 2021 Mar 15.

Murdoch Children's Research Institute, Parkville, Australia.

Objectives: Children with very short telomeres commonly develop bone marrow failure and other severe diseases. Identifying the individuals with short telomeres can improve outcome of bone marrow transplantation, with accurate diagnosis requiring the use of age-matched reference intervals (RIs). This study aimed to establish RIs for telomere length (TL) in children using three commonly used methods for TL measurement.

Methods: Healthy children aged 30 days to 18 years were recruited for assessment using age as a continuous variable. Venous blood samples were collected and leukocyte TL was measured using terminal restriction fragment (TRF) analysis, quantitative PCR (QPCR) and flow cytometry with fluorescence hybridization (Flow-FISH). Fractional polynomial model and quantile regression were performed to generate continuous RIs. Factors that might contribute to variation in TL, such as gender, were also examined.

Results: A total of 212 samples were analyzed. Continuous RIs are presented as functions of age. TRF analysis and QPCR showed significant negative correlation between TL and age (r=-0.28 and r=-0.38, p<0.001). In contrast, Flow-FISH showed no change in TL with age (r=-0.08, p=0.23). Gender did not have significant influence on TL in children.

Conclusions: This study provides three options to assess TL in children by establishing method-specific continuous RIs. Choosing which method to use will depend on several factors such as amount and type of sample available and required sensitivity to age-related change.
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http://dx.doi.org/10.1515/cclm-2021-0059DOI Listing
June 2021

GRADE notes: How to use GRADE when there is "no" evidence? A case study of the expert evidence approach.

J Clin Epidemiol 2021 09 3;137:231-235. Epub 2021 Mar 3.

Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St West, Hamilton, ON L8S 4L8, Canada.

Objectives: One essential requirement of trustworthy guidelines is that they should be based on systematic reviews of the best available evidence. The GRADE Working Group has provided guidance for evaluating the certainty of evidence based on several domains. However, for many clinical questions, published evidence may be limited, too indirect or simply not exist. In this brief report (GRADE notes), we describe our method of developing evidence-based recommendations when publisheddirect evidence was lacking.

Study Design And Setting: When direct published literature was absent, an expert evidence survey was administered to panel members about their unpublished observations and case series. Focus was on collecting data about cases and outcome, not panel opinions.

Results: Out of 26 questions prioritized by the panel for pediatric venous thromboembolism, 12 had no, very limited, or very low certainty of evidence to inform them. The panel survey was administered for these questions.

Conclusions: Areas of sparse evidence often reflect key questions that are critical to address in clinical practice guidelines due to the uncertainty among health care providers. The expert evidence approach used in this study is one method for panels totransparently deal with the lack of published evidence to directly inform recommendations.
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http://dx.doi.org/10.1016/j.jclinepi.2021.02.026DOI Listing
September 2021

Investigating potential protein markers of cardiovascular disease in children with type 1 diabetes mellitus.

Proteomics Clin Appl 2021 05 16;15(2-3):e2000060. Epub 2021 Apr 16.

Haematology Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.

Background: Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by dysglycaemia. Cardiovascular disease (CVD) is a major complication among T1DM patients and the leading cause of mortality later in life.

Methods: The study subjects consisted of T1DM children with poor glycemic control (HbA1c > 7.5%) and healthy age and gender matched controls. Venous blood samples were collected and tested by utilizing a novel immunoassay panel with 96 protein biomarkers. Data were analyzed using non-linear regression analysis and the expression of biomarkers was compared between T1DM and healthy control groups using an unpaired student's t-test. Dynamic principal component analysis (PCA) was operated based on the differentially expressed proteins.

Results: Ten T1DM children and 10 healthy controls were analyzed. Twelve CVD markers show significant differential expression between T1DM patients and healthy controls (p < 0.05). Dynamic PCA clustering based on differentially expressed proteins demonstrated an obvious clustering between the two populations.

Conclusions: This preliminary study reveals the feasibility of utilizing a novel immunoassay panel to investigate potential biomarkers for predicting incipient CVD in children with T1DM. In future, longitudinal studies are required to track the relationships between measurements of the selected protein markers and the development of CVD in T1DM patients.
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http://dx.doi.org/10.1002/prca.202000060DOI Listing
May 2021

Long-term outcomes of warfarin versus aspirin after Fontan surgery.

J Thorac Cardiovasc Surg 2021 10 5;162(4):1218-1228.e3. Epub 2021 Jan 5.

Murdoch Children's Research Institute, Parkville, Australia; The University of Melbourne, Parkville, Australia.

Objectives: Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin.

Methods: This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively.

Results: Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group.

Conclusions: Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies.
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http://dx.doi.org/10.1016/j.jtcvs.2020.12.102DOI Listing
October 2021

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Blood Adv 2020 12;4(24):6250-6258

Bayer AG, Wuppertal, Germany.

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.
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http://dx.doi.org/10.1182/bloodadvances.2020003244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756994PMC
December 2020

Consensus-based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illness.

J Thromb Haemost 2020 11;18(11):3099-3105

Division of Cardiology, Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

Background: Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness has recently been initiated in the United States. To date, there remains a paucity of high-quality evidence to inform clinical practice world-wide. Therefore, the objective of this scientific statement is to provide consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses, and to identify priorities for future research.

Methods: We surveyed 20 pediatric hematologists and pediatric critical care physicians from several continents who were identified by Pediatric/Neonatal Hemostasis and Thrombosis Subcommittee leadership as having experience and expertise in the use of anticoagulant thromboprophylaxis and/or the management of COVID-19-related illness in children. A comprehensive review of the literature on COVID-19 in children was also performed.

Results: Response rate was 90%. Based on consensus of expert opinions, we suggest the administration of low-dose low molecular weight heparin subcutaneously twice-daily as anticoagulant thromboprophylaxis (in the absence of contraindications, and in combination with mechanical thromboprophylaxis with sequential compression devices, where feasible) in children hospitalized for COVID-19-related illness (including the multisystem inflammatory syndrome in children [MIS-C]) who have markedly elevated D-dimer levels or superimposed clinical risk factors for hospitalassociated VTE. For children who are clinically unstable or have severe renal impairment, we suggest the use of unfractionated heparin by continuous intravenous infusion as anticoagulant thromboprophylaxis. In addition, continued efforts to characterize VTE risk and risk factors in children with COVID-19, as well as to evaluate the safety and efficacy of anticoagulant thromboprophylaxis strategies in children hospitalized with COVID-19-related illness (including MIS-C) via cooperative multicenter trials, were identified among several key priorities for future research.

Conclusion: These consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses and priorities for future research will be updated as high-quality evidence emerges.
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http://dx.doi.org/10.1111/jth.15073DOI Listing
November 2020

Clinical thresholds for diagnosing iron deficiency: comparison of functional assessment of serum ferritin to population based centiles.

Sci Rep 2020 10 26;10(1):18233. Epub 2020 Oct 26.

Centre for Health Systems and Safety Research, Australian Institute of Health Innovation, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 6, 75 Talavera Road, Ryde, NSW, 2109, Australia.

Low serum ferritin is diagnostic of iron deficiency, yet its published lower cut-off values are highly variable, particularly for pediatric populations. Lower cut-off values are commonly reported as 2.5th percentiles, and is based on the variation of ferritin values in the population. Our objective was to determine whether a functional approach based on iron deficient erythropoiesis could provide a better alternative. Utilizing 64,443 ferritin test results from pediatric electronic health records, we conducted various statistical techniques to derive 2.5th percentiles, and also derived functional reference limits through the association between ferritin and erythrocyte parameters: hemoglobin, mean corpuscular volume, mean cell hemoglobin concentration, and red cell distribution width. We find that lower limits of reference intervals derived as centiles are too low for clinical interpretation. Functional limits indicate iron deficiency anemia starts to occur when ferritin levels reach 10 µg/L, and are largely similar between genders and age groups. In comparison, centiles (2.5%) presented with lower limits overall, with varying levels depending on age and gender. Functionally-derived limits better reflects the underlying physiology of a patient, and may provide a basis for deriving a threshold related to treatment of iron deficiency and any other biomarker with functional outcomes.
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http://dx.doi.org/10.1038/s41598-020-75435-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589482PMC
October 2020

Adsorption of Blood Components to Extracorporeal Membrane Oxygenation (ECMO) Surfaces in Humans: A Systematic Review.

J Clin Med 2020 Oct 12;9(10). Epub 2020 Oct 12.

Department of Haematology Research, Murdoch Children's Research Institute, MCRI, Parkville 3052, Australia.

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.
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http://dx.doi.org/10.3390/jcm9103272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601136PMC
October 2020
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