VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion.

Previous studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF-ADAMTS13 axis dysfunction. In total, 180 children with a confirmed diagnosis of SCD (hemoglobin SS) on hydroxycarbamide (n = 96) or blood transfusion (n = 84) were included. Despite disease-modifying treatment, plasma VWF and VWF propeptide were elevated in a significant proportion of children with SCD (33% and 47%, respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared with the blood transfusion cohort (P < .05). Additionally, increased levels of other Weibel-Palade body-stored proteins, including factor VIII (FVIII), angiopoietin-2, and osteoprotegerin were observed, indicated ongoing endothelial cell activation. Children treated with hydroxycarbamide also had higher FVIII activity and enhanced thrombin generation compared with those in the blood transfusion cohort (P < .001). Finally, hemolysis markers strongly correlated with VWF levels (P < .001) and were significantly reduced in the blood transfusion cohort (P < .001). Cumulatively, to our knowledge, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF-ADAMTS13 axis is present in a significant subgroup of pediatric patients with SCD, especially those treated with hydroxycarbamide.

Sickle cell disease landscape and challenges in the EU: the ERN-EuroBloodNet perspective.

Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.

Adherence to hydroxyurea, health-related quality of life domains and attitudes towards a smartphone app among Irish adolescents and young adults with sickle cell disease.

INTRODUCTION: SCD patients experience declines in health-related quality of life (HRQOL) domains compared with healthy controls. Despite evidence supporting the benefits of hydroxyurea, medication non-adherence remains problematic, especially in adolescents and young adults (AYA). Adherence barriers include forgetfulness and lack of knowledge. Recently, increased interest in technology-based strategies to improve medication adherence has emerged. No data currently exists on hydroxyurea adherence, HRQOL or perceptions of technology-based tools in the Irish SCD population. METHODS: In order to interrogate these domains among Irish AYA SCD patients we administered an anonymous survey at two tertiary referral centres in Dublin, Ireland, in July 2019. RESULTS: Sixty-three patients participated; 63% female and 37% male, with a median and mean age of 17 and 19 years, respectively. Average monthly adherence was 76% using a visual analogue scale. Recall barriers were present in 62% while 26% omit hydroxyurea for reasons other than forgetting. Reviewing HRQOL; only 36.5% felt always physically able to engage in recreational activities, while 51% experienced disruption to school/college/work due to pain. Eighty-one percent reported that anxiety about health interferes with their lives and non-adherence correlated with worse HRQOL outcomes. Interest in a smartphone app was expressed by the majority, with daily medication reminders being the most popular feature. Sharing adherence data with doctors and discussion forums were less appealing. CONCLUSIONS: Representing over 10% of the Irish SCD population, our survey provides novel and valuable insights into medication adherence and HRQOL domains. Preferred app features may inform future technology-based interventions to improve medication adherence in SCD and other chronic health conditions.

HK1 haemolytic anaemia in association with a neurological phenotype and co-existing CEP290 Meckel-Gruber in a Romani family.

HK1 deficient Haemolytic Anaemia in association with a Neurological Phenotype & co-existing Meckel-Gruber due to CEP290 in a Romani family.

Newborn Screening for Sickle Cell Disease in Europe.

The history of newborn screening (NBS) for sickle cell disease (SCD) in Europe goes back almost 40 years. However, most European countries have not established it to date. The European screening map is surprisingly heterogenous. The first countries to introduce sickle cell screening on a national scale were France and England. The French West Indies started to screen their newborns for SCD as early as 1983/84. To this day, all countries of the United Kingdom of Great Britain and Northern Ireland have added SCD as a target disease to their NBS programs. The Netherlands, Spain and Malta also have national programs. Belgium screens regionally in the Brussels and Liège regions, Ireland has been running a pilot for many years that has become quasi-official. However, the Belgian and Irish programs are not publicly funded. Italy and Germany have completed several pilot studies but are still in the preparatory phase of national NBS programs for SCD, although both countries have well-established concepts for metabolic and endocrine disorders. This article will give a brief overview of the situation in Europe and put a focus on the programs of the two pioneers of the continent, England and France.

Newborn screening for sickle cell disease in Europe: recommendations from a Pan-European Consensus Conference.

Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes.

Prevalence of left ventricular hypertrabeculation/noncompaction among children with sickle cell disease.

OBJECTIVES: Incidence of sickle cell disease (SCD) in Ireland has dramatically increased. Disease survival has also steadily improved however cardiovascular manifestations remain important causes of morbidity. These include reports of left ventricular hypertrabeculation (LVHT)/noncompaction. We sought to investigate the prevalence of LVHT among a large cohort of children with SCD. METHODS: We retrospectively reviewed the records of all patients with a diagnosis of SCD who had undergone surveillance echocardiography at Our Lady's Children's Hospital Crumlin (OLCHC) from 1998 to 2015. Demographics, hemoglobin phenotype and treatment information was recorded. LV systolic function, evidence of LVHT, and possible pulmonary arterial hypertension was assessed. RESULTS: Two hundred thirty-six patients had echocardiograms available for interpretation. One hundred twenty-one (51.3%) were female; mean age was 11.3 years (± 4.1 years). Twenty-six patients (11%) had features of LVHT on echocardiography. Eleven patients (4.7%) had borderline features of LVHT. Mean LVEDD across the whole cohort was 4.2 ± 0.69 cm, LVEDD z-score of 1.44 ± 1.9, and mean LVSF was 37.3% ±15.7%. There were no significant differences in terms of age, LVEDD, LVEDD z-score, or LVSF between patients with and those without LVHT. CONCLUSIONS: The prevalence of LVHT/noncompaction in children with SCD is lower than the adult population and LV systolic function is well preserved throughout our patient group. The mechanism behind the development of LVHT in this population remains speculative. Further work is required in this field. Sickle cell patients require longitudinal evaluation to ascertain changes in left ventricular function and the presence of LVHT/noncompaction.

A case of parvovirus B19-induced pure red cell aplasia in a child following heart transplant.

We describe a case of an 11-year-old boy who underwent orthotopic heart transplant for dilated cardiomyopathy. He developed a normocytic, normochromic anaemia with a low reticulocyte count 1 month after transplant. A bone marrow biopsy was performed, which showed a mildly hypocellular bone marrow with few red blood cell precursors with giant pro-erythroblasts indicative of a pure red cell aplasia. Parvovirus B19 polymerase chain reaction in the blood was positive 2 months after transplant. Intravenous immunoglobulin administration resulted in a resolution of the anaemia over several months. Unexplained pure red cell aplasia in immunosuppressed patients should alert one to the possibility of parvovirus B19 infection.

The molecular landscape of childhood myeloproliferative neoplasms.

The classical myeloproliferative neoplasms (MPN) are comparatively uncommon in children and display a degree of mutational naivety if considering the high frequency of known MPN driver events observed in the corresponding adult diseases. Whole exome sequencing has unravelled much of the underlying molecular complexity of MPN in adult patients yet less is known of the pathogenetic mechanisms when these diseases occur in childhood. It is proposed that such methodological approaches will contribute significant insights into the molecular landscape of childhood MPN that may in turn impact on understanding the pathophysiology of disease in their adult counterparts.

The correlation of ultrasonographic placental architecture with placental histology in the low-risk primigravid population.

AIM: To determine the association, if any, between placental architecture findings assessed ultrasonographically at 22 and 36 weeks and placental histology. METHODS: There was prospective recruitment of 1011 low-risk primigravids from the antenatal clinic at the Rotunda Hospital, Dublin, Ireland. Ultrasound of the placenta was performed at 22 and 36 weeks and histological assessment was made of the placenta of all participants. RESULTS: Complete data pertaining to ultrasound and placental histology was available for 810 women (80%). Placental calcification on ultrasound in the third trimester was associated with a higher incidence of placental infarction identified following placental histology (80.0% vs. 21.5%; P=0.009: r=0.115). The placental thickness on ultrasound in the second trimester was less in cases complicated by chorioamnionitis (2.62 cm vs. 3.07 cm; P=0.039: r=-0.176). Chronic villitis was associated with a statistically significant increased incidence of antenatal placental infarction identified on ultrasound in the third trimester (10.7% vs. 1.9%; P=0.020: r=0.113). Intervillous thrombi occurred more frequently in cases with reduced placental thickness on ultrasound in the second trimester (3.0 cm vs. 3.3 cm; P=0.035: r=-0.171). CONCLUSIONS: Antenatal ultrasound of the placenta may aid detection of placental disease, particularly in the identification of placental infarction.

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial.

BACKGROUND: Children with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain. METHODS/DESIGN: This study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05. DISCUSSION: This clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20.

Composition and significance of splenic Gamna-Gandy bodies in sickle cell anemia.

Children with sickle cell anemia may undergo acute splenic sequestration. Splenectomy is performed in an attempt to reduce further events. Histologic studies of spleens have revealed the presence of granuloma-like nodules, known as Gamna-Gandy bodies with amorphous inclusions; however, their significance is unknown. The medical case records and histologic samples of consecutive children with sickle cell anemia treated with splenectomy between 2001 and 2007 at Our Lady's Children's Hospital, Dublin, were reviewed. Seventeen patients were identified. Gamna-Gandy bodies were studied by scanning electron microscopy and x-ray fluorescence spectroscopy. Gamna-Gandy bodies were identified in 7 (41%) patients, and amorphous inclusions were always seen. Patient age correlated significantly with Gamna-Gandy bodies (P = .002). Scanning electron microscopic analysis demonstrated the crystalline nature of Gamna-Gandy bodies and the chemical composition (C 47.1%; O(2) 29.7%; P 9.0%; K(+) 0.4%; Ca(2+) 6.4%; Fe(2+) 7.4%), whereas x-ray diffraction studied the structure (CaPO(4) ∙ FeOH). A crystal-formation gradient was observed, increasing from the red pulp to the white pulp. Our study shows that Gamna-Gandy bodies contain crystals and that their formation is age dependent. We also demonstrated the crystal structure and chemical composition and the relationship between Gamna-Gandy bodies and chest crises presplenectomy or postsplenectomy.

South-east Asian ovalocytosis and the cryohydrocytosis form of hereditary stomatocytosis show virtually indistinguishable cation permeability defects.

The hereditary stomatocytoses are a group of dominantly inherited conditions in which the osmotic stability of the red cell is compromised by abnormally high cation permeability. This report demonstrates the very marked similarities between the cryohydrocytosis form of hereditary stomatocytosis and the common tropical condition south-east Asian ovalocytosis (SAO). We report two patients, one showing a novel cryohydrocytosis variant (Ser762Arg in SLC4A1) and a case of SAO. Both cases showed a mild haemolytic state with some stomatocytes on the blood film, abnormal intracellular sodium and potassium levels which were made markedly abnormal by storage of blood at 0°C, increased cation 'leak' fluxes at 37°C and increased Na(+) K(+) pump activity. In both cases, the anion exchange function of the mutant band 3 was destroyed. Extensive electrophysiological studies comparing the cation leak and conductance in Xenopus laevis oocytes expressing the two mutant genes showed identical patterns of abnormality. These data are consistent with the cryohydrocytosis form of hereditary stomatocytosis and we conclude that the cation leak in SAO is indistinguishable from that in cryohydrocytosis, and that SAO should be considered to be an example of hereditary stomatocytosis.

The impact of positive acquired thrombophilia serology on ultrasound, obstetric outcome and the placenta in a low-risk primigravid population.

Our aim was to determine the prevalence and sequelae of positive acquired thrombophilia serology in the asymptomatic low-risk primigravid population. We undertook a prospective blinded study of 1011 primigravid patients screening for lupus anticoagulant, anticardiolipin antibody, anti-ß 2 glycoprotein-1 and antinuclear antibody assessment at booking and 36 weeks gestation. Serial ultrasounds of the fetus with uterine and umbilical Dopplers and placental evaluation were performed at 24 and 36 weeks gestation. Antenatal course, labour and delivery outcome and placental histology were reviewed. The incidence of positive acquired thrombophilia serology was 27.4%. Overall, there was no difference in rates of fetal loss or maternal disease between women with positive acquired thrombophilia serology and the control population. Routine testing for acquired thrombophilic traits is therefore not warranted.