Platelet proteomic profiling in sitosterolemia suggests thrombocytopenia is driven by lipid disorder and not platelet aberrations.

Sitosterolemia is a rare autosomal-recessive genetic disorder in which patients develop hypercholesterolemia, and may exhibit abnormal hematologic and/or liver test results. In this disease, dysfunction of either ABCG5 or ABCG8 results in intestinal hyperabsorption of all sterols, including cholesterol and more specifically plant sterols or xenosterols, as well as in the impaired ability to excrete xenosterols into the bile. It remains unknown how and why some patients develop hematologic abnormalities. Only a few unrelated patients with hematologic abnormalities at the time of diagnosis have been reported. Here, we report on two unrelated pedigrees who were believed to have chronic immune thrombocytopenia as most prominent feature. Both consanguineous families showed recessive gene variants in ABCG5, that were associated with disease by in-silico protein structure analysis as well as clinical segregation. Hepatosplenomegaly was absent. Thrombopoietin levels and megakaryocyte numbers in bone marrow were normal. Metabolic analysis confirmed the presence of strongly elevated plasma levels of xenosterols. Potential platelet proteomic aberrations were longitudinally assessed following dietary restrictions combined with the administration of the sterol absorption inhibitor ezetimibe. No significant effects on platelet protein content before and after onset of treatment were demonstrated. Although we cannot exclude that lipotoxicity has a direct and platelet-specific impact in patients with sitosterolemia, our data suggest that the thrombocytopenia is neither caused by a lack of megakaryocytes nor driven by proteomic aberrations of the platelets themselves.

Organized Sports Activities Are Safe for Children With Sickle Cell Disease: A Pilot Intervention Study.

Historically, children with sickle cell disease (SCD) are advised to refrain from sports activities, based on the assumption that physical exercise can trigger vaso-occlusive episodes. This pilot intervention study examined the safety (ie, no vaso-occlusive episodes) of a 10-week organized sports program for children with SCD. Eight children with SCD (5 boys/3 girls), aged 7 to 12 years old, received 10 training sessions (each 90 min) once a week. Training sessions were performed by a professional soccer club under the supervision of a medical team from the Wilhelmina Children's Hospital. During the study period, one child experienced a vaso-occlusive crisis, which could not be directly related to the organized sports program. None of the other children experienced vaso-occlusive episodes. The results of this study indicate that children with SCD can participate safely in moderate-intensity organized sports activities when personalized medical background and practical training information is shared with the trainer beforehand. All children continued their sports participation after the study period.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related venous thrombosis.

BACKGROUND: In critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management. OBJECTIVES: To evaluate the efficacy and safety of the national guideline. METHODS: This prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding. RESULTS: Overall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration. CONCLUSION: The management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates.

[Increasing prevalence of G6PD deficiency in the Netherlands]. / Steeds meer mensen met G6PD-deficiëntie in Nederland.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme deficiency with a high prevalence in Sub-Saharan countries and countries in the Middle East. Due to increased migration in the past decennium, the prevalence of this disorder has increased in the Netherlands. Here we present three patients with acute haemolysis due to G6PD deficiency: a male neonate with severe hyperbilirubinaemia leading to kernicterus; a 3-year-old girl with a severe acute haemolysis due to an infection; and a 5-year-old boy with acute haemolysis with no clear cause. These cases serve to trigger the awareness of all caregivers of the increased prevalence of this disorder, and of the limited health literacy of many immigrants.

Are low-molecular-weight heparins safe and effective in children? A systematic review.

The incidence of venous thromboembolism (VTE) in children is rising. Hence, there is an increasing off-label use of low-molecular-weight heparin (LMWH). There is little data about therapeutic and prophylactic LWMH dosages, and their safety and efficacy. This systematic review provided an oversight of the therapeutic and prophylactic dosages of LMWH required to reach therapeutic and prophylactic target ranges. Furthermore, the safety and efficacy of LMWH, in terms of bleeding complications, achieving therapeutic and prophylactic anti-factor Xa levels, development of (recurrent) VTE and cloth resolution were reviewed. A total of 49 studies were included, encompassing 3101 patients. Initial weight-adjusted dosages to reach therapeutic or prophylactic target ranges decreased with age. In children with therapeutic use of LMWH, major bleeding complications occurred in 1.8% (95% CI: 1.1-2.5%) of the patients, a mean of 79.9% (95% CI: 77.5-82.3%) of the children achieved the target range with or without dosage adjustments, recurrent VTE occurred in 3.2% (95% CI: 2.1-4.3%) and thrombus resolution in 63.5% (96% CI: 60.2-66.8%) of the patients. In children with prophylactic LMWH, major bleedings occurred in 0.6% (95% CI: 0.2-1.0%) of the patients, a mean of 90.4% (95% CI: 84.6-96.2%) of the children achieved the target range, and 2.2% (95% CI: 1.3-3.1%) experienced a new VTE. In conclusion, a higher initial therapeutic dosage of LMWH was needed in comparison to advised dosages, to achieve target range, especially in neonates and children <5 years. LMWH appeared to be safe and effective for therapeutic and prophylactic treatment of VTE in children.

Identifying Children with HEreditary Coagulation disorders (iCHEC): a protocol for a prospective cohort study.

INTRODUCTION: It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder. METHODS AND ANALYSIS: This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed. ETHICS AND DISSEMINATION: The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related thrombosis.

BACKGROUND: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014. METHODS: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC-thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome. DISCUSSION: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC-thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed. TRIAL REGISTRATION: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013.

Coagulopathy in Zellweger spectrum disorders: a role for vitamin K.

INTRODUCTION: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD. METHODS: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined. RESULTS: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation. CONCLUSION: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.

[Haemoglobinopathy in the 21st century: incidence, diagnosis and heel prick screening]. / Hemoglobinopathie in de 21e eeuw: incidentie, diagnose en hielprikscreening.

OBJECTIVE: To determine the incidence of severe haemoglobinopathy, to evaluate the effect of heel prick screening, and to identify those children who do not benefit from this early diagnosis. DESIGN: Prospective descriptive study. METHOD: Registration of all symptomatic and asymptomatic children who between 2003-2009 were newly diagnosed with the a severe form of a hereditary disorder concerning the formation of the alpha haemoglobin chain (HbH disease), or the beta haemoglobin chain (sickle cell disease or beta thalassaemia major) in the Netherlands. Registration was done by collecting anonymised reports from the Dutch Paediatric Surveillance Unit and TNO, and by additional questionnaires. RESULTS: During the study period, 48 children (range: 36-76) per year were diagnosed with severe haemoglobinopathy. The overall incidence was 2.5 per 10,000 live births. The incidence of sickle cell disease diagnosed by heel prick screening was 2.1 per 10,000 live births and of thalassaemia major 0.6 per 10,000 live births. In 7% of the children with sickle cell disease who were diagnosed without any form of screening, the diagnosis was made on (a life threatening) infection. Twenty-two percent of the children with a severe form of haemoglobinopathy were not born in the Netherlands. The parents of almost half of the children with sickle cell disease originally came from West- or Central Africa. The parents of children with thalassaemia major were mainly from Morocco or various Asiatic countries. CONCLUSION: The number of children with severe haemoglobinopathy in the Netherlands has trebled since 1992. In order for all children to benefit from early diagnosis and preventive treatment, it is advisable that children who originate from risk areas should be tested for haemoglobinopathy when they first arrive in the Netherlands.

Persistent sinus venosus valve requiring surgery in children.

OBJECTIVE: To review our experience with cardiac surgery due to remnants of the sinus venosus valve. DESIGN: We performed a retrospective evaluation of patients records during the period from 1980 to 2007. RESULTS: Three patients underwent surgical removal of the redundancy of the right sinus venosus valve. CONCLUSION: Remnants of the embryologic sinus venosus valve may present by various entities. Cardiac surgery should be performed only in patients with continuing symptoms attributed to a persistent sinus venosus valve.

Reliability and accuracy of techniques for surface area measurements of wounds and scars.

The applicability of simple methods to measure the size of pathological skin lesions for management and research has been poorly studied to date. The interobserver reliability and accuracy (validity) was established for planimetry by photography and planimetry by tracing on a transparent sheet in this study. Drawings of 25, 50, and 75 cm(2) were created on 3 locations with increasing curvature (back, thigh, and forearm) in 20 healthy volunteers. Three investigators evaluated the drawings by both planimetry techniques. Both techniques showed a good reliability (r >or= 0.82, intraclass correlation) for 25 cm(2) areas. Planimetry by photography was more reliable than planimetry by tracings for the 50 -and 75-cm(2) areas and was more accurate than planimetry by tracing for all areas except for the area with the greatest curvature, the forearm. The study permits the conclusion that planimetry by photography is more suitable for surface area measurements than planimetry by tracing except for extremely curved body parts, where it is likely that effects of distortion supervene.