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View large Download slide View large Download slide OBJECTIVES The aim of this study is to determine whether recombinant activated factor VII (rVIIa) was associated with thrombus formation in neonates undergoing cardiac surgery. METHODS This is a retrospective study of neonates undergoing surgical repair of congenital cardiac lesions during a 9-year period. RESULTS In our study, 416 cardiac operations requiring cardiopulmonary bypass (CPB) were performed on 414 neonates. The overall intravascular thrombus (thrombus) frequency for all operations was 45 of 416 (11%). A thrombus developed in 17 of 287 (6%) operations when rVIIa was not given. rVIIa was administered in 129 of 416 (31%) operations. Thrombus formation occurred in 28 of 129 (22%) operations when rVIIa was administered. There was an association between rVIIa use and thrombus formation [odds ratio (OR) 4.4, 95% confidence interval (CI) 2.3–8.4; P  <   0.0001]. Patients with thrombus formation had an increased length of stay compared to those without thrombus. Neonates who underwent the Norwood procedures and received rVIIa and developed thrombus were more likely to be supported with extracorporeal membrane oxygenation (ECMO) and had a higher mortality compared to Norwood patients without thrombus. Logistic analysis adjusted for the paediatric index of mortality 2 score, the risk adjustment for congenital heart surgery and the use of ECMO demonstrated a strong association between rVIIa administration and thrombus formation (OR 3.5, 95% CI 1.7–6.9; P  = 0.0004). However, there was no effect of the risk adjustment for congenital heart surgery-1 category or the paediatric index of mortality 2 score on thrombus formation. CONCLUSIONS In neonates who underwent CPB surgery, administration of rVIIa was associated with an increased occurrence of intravascular thrombus formation compared to neonates not given rVIIa. In the Norwood population, thrombus formation was associated with a higher mortality. [ABSTRACT FROM AUTHOR]

Introduction: There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors' Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion.Main Recommendations: During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered.Changes in Management AsA Result Of This Statement: Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid. [ABSTRACT FROM AUTHOR]

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing ( NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family. [ABSTRACT FROM AUTHOR]

Background: Although it is widely appreciated that vigorous physical activity can increase the risk of bleeding episodes in children with haemophilia, the magnitude of the increase in risk is not known. Accurate risk estimates could inform decisions made by children with haemophilia and their parents about participation in physical activity and aid the development of optimal prophylactic schedules. The aim of this study is to provide an accurate estimate of the risks of bleeding associated with vigorous physical activity in children with haemophilia. Methods/Design: The study will be a case-crossover study nested within a prospective cohort study. Children with moderate or severe haemophilia A or B, recruited from two paediatric haematology departments in Australia, will participate in the study. The child, or the child's parent or guardian, will report bleeding episodes experienced over a 12-month period. Following a bleeding episode, the participant will be interviewed by telephone about exposures to physical activity in the case period (8 hours before the bleed) and 2 control periods (an 8 hour period at the same time on the day preceding the bleed and an 8 hour period two days preceding the bleed). Conditional logistic regression will be used to estimate the risk of participating in vigorous physical activity from measures of exposure to physical activity in the case and control periods. Discussion: This case-control study will provide estimates of the risk of participation in vigorous physical activity in children with haemophilia. [ABSTRACT FROM AUTHOR]

Background: Children with haemophilia have lower levels of fitness and strength than their healthy peers. We present the protocol of a study designed to determine whether an exercise intervention improves quality of life, aerobic fitness and strength in children with haemophilia. Methods/Design: The study will be a randomised, assessor-blinded, controlled trial of exercise treatment. Seventy children aged between 6 and 18 years with haemophilia or von Willebrand disease will be recruited from two paediatric haemophilia clinics in NSW. Each participant will be allocated to an exercise group or a control group using a concealed allocation procedure. The control group will receive usual medical care while the intervention group will receive usual medical care plus an exercise program for 12 weeks. Outcomes (VO2peak, knee extensor strength and quality of life) will be measured at baseline and on completion of the exercise program by a blinded assessor. The primary analysis will be conducted on an intention to treat basis. The effects of the exercise intervention on each of the three primary outcomes will be estimated from between-group differences in the mean outcome adjusted for baseline scores. Discussion: This study will be the first randomised controlled trial to examine the effects of a structured exercise program on fitness and quality of life in children with haemophilia. [ABSTRACT FROM AUTHOR]

Objective: To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells., Design and Setting: Ex-vivo culture and gene transfer procedures were performed at The Children's Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available., Patient: A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation., Procedure: CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human gamma c (the common gamma chain of several interleukin receptors; mutations affecting the gamma c gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 x 10(6) CD34+/gamma c+ cells/kg) were returned to the infant via a central line., Results: T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 x 10(9) CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy., Conclusions: This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant's NK+ phenotype may also have exerted an effect.