Search

Phenotypic characterization of congenital platelet defects (CPDs) could help physicians recognize CPD subtypes and can inform on prognostic implications. We report the analyses of the bleeding phenotype and diagnostic characteristics of a large cohort of adult patients with a confirmed CPD. A total of 96 patients were analyzed and they were classified as Glanzmann thrombasthenia, Bernard-Soulier syndrome, dense granule deficiency, defects in the ADP or thromboxane A2 (TxA2) pathway, isolated thrombocytopenia or complex abnormalities. The median ISTH-BAT bleeding score was nine (IQR 5-13). Heavy menstrual bleeding (HMB) (80%), post-partum hemorrhage (74%), post-operative bleeds (64%) and post-dental extraction bleeds (57%) occurred most frequently. Rare bleeding symptoms were bleeds from the urinary tract (4%) and central nervous system (CNS) bleeds (2%). Domains with a large proportion of severe bleeds were CNS bleeding, HMB and post-dental extraction bleeding. Glanzmann thrombasthenia and female sex were associated with a more severe bleeding phenotype., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: δ-storage pool disease (δ-SPD) is a bleeding disorder characterized by a reduced number of platelet-dense granules. The diagnosis of δ-SPD depends on the measurement of platelet ADP content, but this test is time consuming and requires a relatively large blood volume. Flow cytometric analysis of platelet mepacrine uptake is a potential alternative, but this approach lacks validation, which precludes its use in a diagnostic setting., Objectives: To evaluate the performance of platelet mepacrine uptake as a diagnostic test for δ-SPD., Patients/methods: Mepacrine fluorescence was determined with flow cytometry before and after platelet activation in 156 patients with a suspected platelet function disorder and compared with platelet ADP content as a reference test. Performance was analyzed with a receiver operating characteristic (ROC) curve., Results: Eleven of 156 patients had δ-SPD based on platelet ADP content. Mepacrine fluorescence was inferior to platelet ADP content in identifying patients with δ-SPD, but both mepacrine uptake (area under the ROC curve [AUC] 0.87) and mepacrine release after platelet activation (AUC 0.80) had good discriminative ability. In our tertiary reference center, mepacrine uptake showed high negative predicitive value (97%) with low positive predictive value (35%). Combined with a negative likelihood ratio of 0.1, these data indicate that mepacrine uptake can be used to exclude δ-SPD in patients with a bleeding tendency., Conclusion: Mepacrine fluorescence can be used as a screening tool to exclude δ-SPD in a large number of patients with a suspected platelet function disorder., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Patients with congenital blood platelet disorders (CPDs) demonstrate a predominantly mucocutaneous bleeding tendency. Repeated bleeds throughout life can have a significant impact on health status-related quality of life (HR-QoL), but few studies have investigated HR-QoL in patients with CPDs., Objectives: To determine HR-QoL in patients with suspected or confirmed CPDs as compared with the general Dutch population and to assess the association between bleeding phenotype and HR-QoL., Methods: Data were derived from the Thrombocytopathy in the Netherlands (TiN) study, a cross-sectional study of individuals suspected for a congenital platelet defect. TiN patients with an increased ISTH Bleeding Assessment Tool (ISTH-BAT) score (>3 in men and > 5 in women) were included for analysis. HR-QoL was assessed with the Short Form (SF)-36 survey. Bleeding symptoms were evaluated with the ISTH-BAT, resulting in a bleeding score., Results: One hundred fifty-six patients were analyzed, of whom 126 (81%) were women. Sixty-two patients (40%) had a confirmed CPD. Compared to the general Dutch population, patients with a suspected or confirmed CPD reported decreased physical functioning, limitations in daily activities due to physical health problems, limitations in social activities, decreased energy levels and fatigue, pain, and lower general health status. HR-QoL was not correlated with the ISTH-BAT score and was similar in patients with a confirmed CPD and those in whom a CPD could not be diagnosed., Conclusion: A bleeding tendency in patients with a suspected or confirmed CPD significantly impacts HR-QoL, independent of a confirmed explanatory diagnosis., (© 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Sickle cell disease is an autosomal recessive, multisystem disorder, characterised by chronic haemolytic anaemia, painful episodes of vaso-occlusion, progressive organ failure and a reduced life expectancy. Sickle cell disease is the most common monogenetic disease, with millions affected worldwide. In well-resourced countries, comprehensive care programs have increased life expectancy of sickle cell disease patients, with almost all infants surviving into adulthood. Therapeutic options for sickle cell disease patients are however, still scarce. Predictors of sickle cell disease severity and a better understanding of pathophysiology and (epi)genetic modifiers are warranted and could lead to more precise management and treatment. This review provides an extensive summary of the pathophysiology and management of sickle cell disease and encompasses the characteristics, complications and current and future treatment options of the disease., (Copyright © 2019. Published by Elsevier Ltd.)

Congenital thrombocytopenia can easily be misdiagnosed as immune thrombocytopenic purpura, as is illustrated by this case of a woman and her two children. Doubts arose when steroid/IVIG therapy failed in the mother and the thrombocytopenia in the children persisted. By means of next-generation sequencing, two missense variants in cis in the ACTN1 gene of the affected family members were identified, both of unknown significance. We conclude, after further analysis of these mutations with, among others, in silico prediction tools, that the thrombocytopenia has a genetic cause, in particular the ACTN1 mutations, and is not immune mediated., (© 2018 Wiley Periodicals, Inc.)

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype., (Copyright© 2018 Ferrata Storti Foundation.)

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%., Summary: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 10 9 /L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 10 9 /L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 10 9 /L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563., (© 2018 by The American Society of Hematology.)

Introduction: Diamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries., Objectives: To create an overview of the pediatric DBA population in the Netherlands., Methods: Forty-three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records., Results: Congenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment-independent spontaneously., Conclusion: In agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients., Summary: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year., (© 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Hereditary spherocytosis (HS) is a heterogeneous hemolytic anemia treated with splenectomy in patients suffering from severe or moderate disease. Total splenectomy, however, renders patients vulnerable to overwhelming postsplenectomy infection despite preventive measures. Although subtotal splenectomy has been advocated as an alternative to total splenectomy, long-term follow-up data are scarce. We investigated how often hematologic recurrences requiring secondary total splenectomy occurred., Procedure: With a follow-up of at least 5 years, we analyzed the data of 12 patients, aged 11 years maximum (median 6.5 years), who had undergone intended subtotal splenectomy, and 9 patients (median age 11.9 years), who had undergone total splenectomy. We compared their hematologic results and searched for factors associated with secondary spleen surgery., Results: Hemolysis was reduced after subtotal splenectomy and absent after total splenectomy. Subtotal splenectomy was not successful in three children because no functional splenic remnant remained after 6 months (one conversion at surgery; one necrosis of splenic remnant; one early secondary splenectomy). Four children required secondary splenectomy after a median of 5 years for hematologic recurrence. In the remaining five patients, a functional splenic remnant was present for at least 5.5 years. The median time to secondary total splenectomy after intended subtotal splenectomy was 5.2 years. In all patients requiring secondary total splenectomy, increased reticulocyte levels within 2 years indicated hematologic recurrence., Conclusions: Subtotal splenectomy can be an alternative for total splenectomy in young patients with HS. It allows for hematologic improvement and may preserve splenic immune function for as many as 5 years., (© 2017 Wiley Periodicals, Inc.)

FAS-dependent apoptosis in V δ 1 T cells makes the latter possible culprits for the lymphadenopathy observed in patients with FAS mutations.Rapamycin and methylprednisolone resistance should prompt clinicians to look for V δ 1 T cell proliferation in ALPS-FAS patients., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.