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Sepsis, a dysregulated host response to infection, has been difficult to accurately define in children. Despite a higher incidence, especially in neonates, a non-specific clinical presentation alongside a lack of verified biomarkers has prevented a common understanding of this condition. Platelets, traditionally regarded as mediators of haemostasis and thrombosis, are increasingly associated with functions in the immune system with involvement across the spectrum of innate and adaptive immunity. The large number of circulating platelets (approx. 150,000 cells per microlitre) mean they outnumber traditional immune cells and are often the first to encounter a pathogen at a site of injury. There are also well-described physiological differences between platelets in children and adults. The purpose of this review is to place into context the platelet and its role in immunology and examine the evidence where available for its role as an immune cell in childhood sepsis. It will examine how the platelet interacts with both humoral and cellular components of the immune system and finally discuss the role the platelet proteome, releasate and extracellular vesicles may play in childhood sepsis. This review also examines how platelet transfusions may interfere with the complex relationships between immune cells in infection. IMPACT: Platelets are increasingly being recognised as important "first responders" to immune threats. Differences in adult and paediatric platelets may contribute to differing immune response to infections. Adult platelet transfusions may affect infant immune responses to inflammatory/infectious stimuli.
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Plaquetas/metabolismo , Mediadores da Inflamação/metabolismo , Sepse/sangue , Plaquetas/imunologia , Proteínas Sanguíneas/metabolismo , Criança , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Recém-Nascido , Proteoma , Sepse/imunologia , Transdução de SinaisRESUMO
Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known: ⢠The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways. ⢠CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New: ⢠This review summarises the physiological differences in haemostasis between neonates and adults described using CAT. ⢠The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.
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Hemostáticos , Preparações Farmacêuticas , Testes de Coagulação Sanguínea , Hemorragia , Hemostasia , Humanos , Recém-NascidoRESUMO
Inborn errors of metabolism are an individually rare but collectively significant cause of mortality and morbidity in the neonatal period. They are identified by either newborn screening programmes or clinician-initiated targeted biochemical screening. This study examines the relative contribution of these two methods to the identification of inborn errors of metabolism and describes the incidence of these conditions in a large, tertiary, neonatal unit. We also examined which factors could impact the reliability of metabolic testing in this cohort. This is a retrospective, single-site study examining infants in whom a targeted metabolic investigation was performed from January 2018 to December 2020 inclusive. Data was also provided by the national newborn screening laboratory regarding newborn screening diagnoses. Two hundred and four newborns received a clinician-initiated metabolic screen during the time period examined with 5 newborns being diagnosed with an inborn error of metabolism (IEM) (2.4%). Of the 25,240 infants born in the hospital during the period examined, a further 11 newborns had an inborn error of metabolism diagnosed on newborn screening. This produced an incidence in our unit over the time described of 6.34 per 10,000 births. This number reflects a minimum estimate, given that the conditions diagnosed refer to early-onset disorders and distinctive categories of IEM only. Efficiency of the clinician-initiated metabolic screening process was also examined. The only statistically significant variable in requiring repeat metabolic screening was early day of life (z-score = - 2.58, p = 0.0098). A total of 28.4% was missing one of three key metabolic investigation parameters of blood glucose, ammonia or lactate concentration with ammonia the most common investigation missing. While hypoglycemia was the most common clinical rationale for a clinician-initiated metabolic test, it was a poor predictor of inborn error of metabolism with no newborns of 25 screened were diagnosed with a metabolic disorder. CONCLUSION: Clinician-targeted metabolic screening had a high diagnostic yield given the relatively low prevalence of inborn errors of metabolism in the general population. Thoughts should be given to the rationale behind each targeted metabolic test and what specific metabolic disease or category of inborn error of metabolism they are concerned along with commencing targeted testing. WHAT IS KNOWN: ⢠Inborn errors of metabolism are a rare but potentially treatable cause of newborn mortality and morbidity. ⢠A previous study conducted in a tertiary unit in an area with limited newborn screening demonstrated a diagnostic yield of 5.4%. WHAT IS NEW: ⢠Clinician-initiated targeted metabolic screening has a good diagnostic performance even with a more expanded newborn screening programme. ⢠Further optimisation could be achieved by examining the best timing and also the rationale of metabolic testing in the newborn period.
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Doenças Metabólicas , Erros Inatos do Metabolismo , Amônia , Glicemia , Humanos , Lactente , Recém-Nascido , Lactatos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Triagem Neonatal/métodos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: The prevalence of cow's-milk protein allergy (CMPA) is between 2% and 3% and symptoms vary depending on underlying immune mechanism at play. Breast milk is the optimal nutrition for premature infants and breast milk fortifiers (BMF) are commonly used to optimise growth and nutrition. BMF are typically derived from cow's milk and, as such, preterm infants are exposed to cow's milk in the first weeks of life. Previously, preterm infants were suspected to have a higher risk of allergen development because of early antigen exposure and increased gut permeability. The primary aim of the present study was to evaluate the prevalence of CMPA among very preterm (<32 weeks) and/or very low birth weight (VLBW) infants. The secondary aim was to describe feeding practices, specifically the breastfeeding rates and specialist, non-standard formula use in this cohort over the first 6 months of life. METHODS: This was a retrospective study performed in a large tertiary maternity hospital (8500 deliveries/year and 110 very preterm infants/year) in Dublin, Ireland over a 3-year period, 2017-2020. Infants born very preterm and/or VLBW who were followed in the outpatient clinic until 6 months corrected gestational age (CGA) were included. Hospital ethical approval was obtained. RESULTS: One hundred and forty-four infants were included with a median birth weight of 1338 g. No infant had a diagnosis of CMPA when leaving the neonatal intensive care unit (NICU) but, by 6 months CGA, this increased to 1.4% (n = 2). Upon discharge from the NICU, 88 infants (61%) were receiving at least some breast milk, decreasing to 13 (9.1%) at 6 months CGA. Those who were receiving exclusive breast milk at discharge were significantly more likely to still be receiving any breast milk at three (p ≤ 0.001) and 6 months ( p ≤ 0.001) CGA compared to those combined feeding or exclusively formula feeding. At 6 months CGA, 18.9% (n = 27) were attending a dietician and 31.5% (n = 45) were using specialist, non-standard infant formula. CONCLUSIONS: The prevalence of CMPA in this cohort was 1.4%, which is similar to the reported prevalence of CMPA in the general paediatric population. Infants who were discharged from NICU exclusively breastfeeding were more likely to be receiving any breast milk at outpatient follow-up. This highlights the importance of on going dietetic and lactation support in the outpatient setting for this vulnerable cohort.
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Hipersensibilidade a Leite , Alérgenos , Animais , Aleitamento Materno , Bovinos , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Hipersensibilidade a Leite/epidemiologia , Leite Humano , Gravidez , Prevalência , Estudos RetrospectivosRESUMO
Extracellular vesicles (EVs) are cell-derived membrane-bound particles, extensively investigated across many fields to improve the understanding of pathophysiological processes, as biomarkers of disease and as therapeutic targets for pharmacological intervention. We aim to describe the current knowledge of EVs detected in the body fluids of human neonates, both term and preterm, from birth to 4 weeks of age. To date, EVs have been described in several neonatal body fluids, including cerebrospinal fluid, umbilical cord blood, neonatal blood, tracheal aspirates and urine. These studies demonstrate some important roles of EVs in the neonatal population, particularly in haemostasis. Moreover, some studies have demonstrated the pathophysiological mechanisms and the identification of potential biomarkers of neonatal disease. We must continue to build on this knowledge, evaluating the role of EVs in neonatal pathology, particularly in prematurity and during the perinatal adaption period. Future studies should use larger numbers, robust EV characterisation techniques and always correlate the findings to clinical outcomes. IMPACT: This article summarises the current knowledge of the effect of EVs in neonates. It describes the potential compensatory role of EVs in neonatal haemostasis. It also describes the role of EVs as mediators of pathology and as potential biomarkers of perinatal and neonatal disease.
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Vesículas Extracelulares/patologia , Doenças do Recém-Nascido/patologia , Biomarcadores/metabolismo , Desenvolvimento Infantil , Vesículas Extracelulares/metabolismo , Hemostasia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Doenças do Recém-Nascido/fisiopatologiaAssuntos
Hipersensibilidade , Hipersensibilidade a Leite , Lactente , Humanos , Animais , Fórmulas Infantis , Irlanda , Leite , Proteínas do LeiteRESUMO
BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) post SARS-CoV-2 vaccination is characterized by thrombocytopenia and severe thrombosis. Platelet function during patient recovery in the medium-/long-term has not been investigated fully. Here, we undertook a 3-month study, assessing the recovery of a VITT patient and assessing platelet morphology, granule content and dense-granule release at two distinct time points during recovery. CASE PRESENTATION: A 61 year-old female was admitted to hospital 15 days post ChAdOx1 nCov-19 vaccination. Hematological parameters and peripheral blood smears were monitored over 3 months. Platelet morphology and granule populations were assessed using transmission electron microscopy (TEM) at two distinct time points during recovery, as was agonist-induced platelet dense-granule release. Upon admission, the patient had reduced platelet counts, increased D-dimer and high anti-PF4 antibodies with multiple sites of cerebral venous sinus thrombosis (CVST). Peripheral blood smears revealed the presence of large, hypergranular platelets. Following treatment, hematological parameters returned to normal ranges over the study period. Anti-PF4 antibodies remained persistently high up to 90 days post-admission. Two days after admission, VITT platelets contained more granules per-platelet when compared to day 72 and healthy platelets. Additionally, maximal ATP release (marker of dense-granule release) was increased on day 2 compared to day 72 and healthy control platelets. CONCLUSION: This study highlights a previously unreported observation of platelet hypergranularity in VITT which may contribute to the thrombotic risk associated with VITT. Optimal approaches to monitoring recovery from VITT over time remains to be determined but our findings may help inform therapeutic decisions relating to anticoagulation treatment in this novel pathology.
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BACKGROUND: Hypercoagulability and endothelial dysfunction are hallmarks of coronavirus disease 2019 (COVID-19) and appear to predict disease severity. A high incidence of thrombosis despite thromboprophylaxis is reported in patients with moderate to severe COVID-19. Recent randomized clinical trials suggest that therapeutic-intensity heparin confers a survival benefit in moderate-severity COVID-19 compared to standard-intensity heparin, potentially by harnessing heparin-mediated endothelial-stabilizing and anti-inflammatory effects. OBJECTIVE: We hypothesized that patients with moderate-severity COVID-19 exhibit enhanced hypercoagulability despite standard-intensity thromboprophylaxis with low molecular weight heparin (LMWH) compared to non-COVID-19 hospitalized patients. METHODS: Patients with moderate COVID-19 and a control group (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-negative hospitalized patients) receiving LMWH thromboprophylaxis were recruited. Markers of endothelial damage and plasma thrombin generation parameters were assessed. RESULTS: Tissue plasminogen activator levels were significantly increased in the COVID-19 group (8.3 ± 4.4 vs. 4.9 ± 2.4 ng/ml; P = .02) compared to non-COVID-19-hospitalized patients. Despite thromboprophylaxis, mean endogenous thrombin potential was significantly increased among COVID-19 patients (1929 ± 448 vs. 1528 ± 460.8 nM*min; P = .04) but lag time to thrombin generation was significantly prolonged (8.1 ± 1.8 vs. 6.2 ± 1.8 mins; P = .02). While tissue factor pathway inhibitor (TFPI) levels were similar in both groups, in the presence of an inhibitory anti-TFPI antibody, the difference in lag time between the groups was abrogated. CONCLUSIONS: Collectively, these data demonstrate that COVID-19 of moderate severity is associated with increased plasma thrombin generation and endothelial damage, and that hypercoagulability persists despite standard LMWH thromboprophylaxis. These findings may be of clinical interest given recent clinical trial data which suggest escalated heparin dosing in non-severe COVID-19 may be associated with improved clinical outcomes.
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COVID-19 , Trombofilia , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , SARS-CoV-2 , Trombofilia/diagnóstico , Trombofilia/tratamento farmacológico , Ativador de Plasminogênio Tecidual , Tromboembolia Venosa/epidemiologiaRESUMO
Ichthyosis prematurity syndrome (IPS) is a rare disorder of autosomal recessive inheritance. The cardinal features include prematurity, vernix like hyperkeratosis, eosinophilia and neonatal asphyxiation. This case report discusses the presentation and management of IPS. We aim to characterise the common features, the spectrum of disease within a single family and discuss a potential role for low-dose dexamethasone in the management of ventilator-dependent patients with IPS.
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Ictiose , Doenças do Prematuro , Ceratose , Dexametasona/uso terapêutico , Humanos , Recém-Nascido , Doenças do Prematuro/tratamento farmacológicoRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) infection during pregnancy has been associated with adverse perinatal outcomes. We aim to evaluate the neonatal outcomes including the incidence of preterm birth, admission to the neonatal unit and incidence of congenital anomalies in this cohort. We will also describe these outcomes in the context of the B.1.1.7. variant outbreak, the dominant variant in Ireland since January 2021, which has had a greater impact on pregnant patients. METHODS: This was a retrospective study of liveborn infants, delivered between 1st March 2020 and 1st March 2021, to women with a severe acute respiratory syndrome coronavirus 2 diagnosis during pregnancy, in a tertiary maternity hospital (8,500 deliveries/year). Clinical data were collected, and analyses were performed to evaluate the impact of maternal symptom status, time from diagnosis to delivery and the B.1.1.7. variant on neonatal outcome. RESULTS: In total 133 infants (1.6%) were born to women with severe acute respiratory syndrome coronavirus 2 identified during pregnancy. The median birth weight was 3.45 kg and gestational age at birth was 39.3 weeks. 14 infants (10.5%) were preterm. 22 infants (16.5%) required admission to the neonatal unit and 7 (5.3%) were small for gestational age. There was no difference in growth, preterm birth or neonatal unit admission based on maternal symptom status or infection after the outbreak of B.1.1.7. as the dominant strain. CONCLUSIONS: Following a COVID-19 infection in pregnancy, there was no increase in the incidence of preterm birth or neonatal intensive care unit admission compared with 5-year hospital data. Maternal symptom status did not influence neonatal outcomes. Further studies to evaluate the impact of COVID-19 in early pregnancy, the variants of concern, particularly the emerging Delta variant and COVID-19 placentitis are required.
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Peso ao Nascer , COVID-19/complicações , Idade Gestacional , Complicações Infecciosas na Gravidez/virologia , Nascimento Prematuro , Adulto , COVID-19/genética , Feminino , Humanos , Recém-Nascido , Doenças Placentárias/virologia , Gravidez , Estudos Retrospectivos , SARS-CoV-2RESUMO
Pulmonary arterial hypertension is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in pulmonary arterial hypertension which may provide insights into the pathobiology of the disease and opportunities to explore new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle autocrine and paracrine signalling in pulmonary arterial hypertension, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, extracellular vesicles and coagulation pathways in the pathobiology of pulmonary arterial hypertension. We highlight important unanswered clinical questions and the implications of these observations for future research and pulmonary arterial hypertension-directed therapies.
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OBJECTIVE: The aim of this study was to evaluate infants, born to women with SARS-CoV-2 detected during pregnancy, for evidence of haematological abnormalities or hypercoagulability in umbilical cord blood. STUDY DESIGN: This was a prospective observational case-control study of infants born to women who had SARS-CoV-2 RNA detected by PCR at any time during their pregnancy (n = 15). The study was carried out in a Tertiary University Maternity Hospital (8,500 deliveries/year) in Ireland. This study was approved by the Hospital Research Ethics Committee and written consent was obtained. Umbilical cord blood samples were collected at delivery, full blood count and Calibrated Automated Thrombography were performed. Demographics and clinical outcomes were recorded. Healthy term infants, previously recruited as controls to a larger study prior to the outbreak of COVID-19, were the historical control population (n = 10). RESULTS: Infants born to women with SARS-CoV-2 had similar growth parameters (birth weight 3600 g v 3680 g, p = 0.83) and clinical outcomes to healthy controls, such as need for resuscitation at birth (2 (13.3%) v 1 (10%), p = 1.0) and NICU admission (1 (6.7%) v 2 (20%), p = 0.54). Haematological parameters (Haemoglobin, platelet, white cell and lymphocyte counts) in the COVID-19 group were all within normal neonatal reference ranges. Calibrated Automated Thrombography revealed no differences in any thrombin generation parameters (lag time (p = 0.92), endogenous thrombin potential (p = 0.24), peak thrombin (p = 0.44), time to peak thrombin (p = 0.94)) between the two groups. CONCLUSION: In this prospective study including eligible cases in a very large population of approximately 1500 women, there was no evidence of derangement of the haematological parameters or hypercoagulability in umbilical cord blood due to COVID-19. Further research is required to investigate the pathological placental changes, particularly COVID-19 placentitis and the impact of different strains of SARS-CoV-2 (particularly the B.1.1.7 and the emerging Delta variant) and the severity and timing of infection on the developing fetus.
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Transtornos da Coagulação Sanguínea , COVID-19 , Sangue Fetal , Complicações Infecciosas na Gravidez , Estudos de Casos e Controles , Feminino , Humanos , Placenta , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez , Estudos Prospectivos , RNA Viral , SARS-CoV-2RESUMO
Clinical measurement of pelvic floor muscle activity commonly involves techniques that are both physically and psychologically invasive. This study investigated transabdominal application of ultrasound to measure pelvic floor muscle action. The specific aims were to establish the face validity of ultrasound measures of displacement of the posterior bladder wall as a reflection of pelvic floor muscle contraction, and the reliability of measurement between raters and between testing occasions. Non-pregnant adult female subjects aged 24 to 57 years were tested in lying with a 3.5 MHz 35 mm curved array ultrasound transducer over the lower abdomen. Posterior bladder wall displacement was observed in both sagittal and transverse planes. Digital vaginal palpation and transabdominal ultrasound were undertaken simultaneously during pelvic floor muscle contractions to confirm that pelvic floor contractions were performed correctly and to grade pelvic floor muscle strength. Displacement (mm) was measured using electronic calipers on the ultrasound monitor screen. In all subjects, a correct pelvic floor muscle contraction was confirmed on digital palpation, and consistent anterior and cephalic movement was observed on screen. Digital strength grading did not correlate with ultrasound measures in either transverse or sagittal planes (r = 0.21 and -0.13). Average intra-class correlation coefficients for within session inter-rater reliability ranged between 0.86 and 0.88 (95% CI 0.68 to 0.97), and for inter session intra-rater reliability between 0.81 and 0.89 (95% CI 0.51 to 0.96). Transabdominal application of diagnostic ultrasound is a personally non-invasive method for imaging and assessing pelvic floor muscle activity and is both valid and reliable.