BAY 81‐8973 prophylaxis and pharmacokinetics in haemophilia A: Interim results from the TAURUS study

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High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder

Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES) : comprehensive genetic analysis by next-generation sequencing of 480 patients

Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population

“Intervalo QT en recién nacidos de diferente origen étnico. Utilidad del cribado con ECG neonatal

La rentabilidad del cribado electrocardiográfico neonatal está en discusión. El objetivo es conocer los valores normales del intervalo QT en recién nacidos de diferentes orígenes étnicos. Durante 12 meses entre 2005 y 2006 se realizó un ECG a 1.305 neonatos a término en el Hospital del Mar (Barcelona), en las primeras 48 h de vida. El intervalo QTc medio fue 417,79 ± 28,47 ms. Se halló un QTc > 440 ms en 240 (18,33%) neonatos. Se encontró un 17,9% de QTc patológicos en neonatos autóctonos, frente a un 27,7% en el grupo de Magreb y Próximo Oriente (p = 0,016) y un 28,2% en el grupo de India-Pakistán (p = 0,033). El intervalo QTc puede ser diferente por causas genéticas. Sería recomendable hacer un ECG neonatal sólo en los grupos étnicos con QTc más largos, para evitar un posible mayor riesgo de muerte súbita del lactante.The cost-effectiveness of neonatal electrocardiographic (ECG) screening has been questioned. The objective of this study was to establish normal values for the QT interval in newborns of different ethnic origin. Between 2005 and 2006, ECGs were obtained during the first 48 h of life from 1305 at-term newborns at the Hospital del Mar in Barcelona, Spain. The mean corrected QT interval (QTc) was 417.79±28.47 ms. A QTc longer than 440 ms was observed in 240 newborns (18.33%). The frequency of a pathologic QTc in Spanish newborns was 17.9%, compared with 27.7% in those of Maghreb or Near Eastern origin (P=.016), and 28.2% in those of Indian or Pakistani origin (P=.033). The QTc may vary for genetic reasons. A routine neonatal ECG is advisable only in ethnic groups in which the QTc is lengthened, to help counter the greater risk of sudden death in these infants

"Intervalo QT en recién nacidos de diferente origen étnico. Utilidad del cribado con ECG neonatal

La rentabilidad del cribado electrocardiográfico neonatal está en discusión. El objetivo es conocer los valores normales del intervalo QT en recién nacidos de diferentes orígenes étnicos. Durante 12 meses entre 2005 y 2006 se realizó un ECG a 1.305 neonatos a término en el Hospital del Mar (Barcelona), en las primeras 48 h de vida. ElLa rentabilidad del cribado electrocardiográfico neonatal está en discusión. El objetivo es conocer los valores normales del intervalo QT en recién nacidos de diferentes orígenes étnicos. Durante 12 meses entre 2005 y 2006 se realizó un ECG a 1.305 neonatos a término en el Hospital del Mar (Barcelona), en las primeras 48 h de vida. El intervalo QTc medio fue 417,79 ± 28,47 ms. Se halló un QTc > 440 ms en 240 (18,33%) neonatos. Se encontró un 17,9% de QTc patológicos en neonatos autóctonos, frente a un 27,7% en el grupo de Magreb y Próximo Oriente (p = 0,016) y un 28,2% en el grupo de India-Pakistán (p = 0,033). El intervalo QTc puede ser diferente por causas genéticas. Sería recomendable hacer un ECG neonatal sólo en los grupos étnicos con QTc más largos, para evitar un posible mayor riesgo de muerte súbita del lactante.The cost-effectiveness of neonatal electrocardiographic (ECG) screening has been questioned. The objective of this study was to establish normal values for the QT interval in newborns of different ethnic origin. Between 2005 and 2006, ECGs were obtained during the first 48 h of life from 1305 at-term newborns at the Hospital del Mar in Barcelona, Spain. The mean corrected QT interval (QTc) was 417.79±28.47 ms. A QTc longer than 440 ms was observed in 240 newborns (18.33%). The frequency of a pathologic QTc in Spanish newborns was 17.9%, compared with 27.7% in those of Maghreb or Near Eastern origin (P=.016), and 28.2% in those of Indian or Pakistani origin (P=.033). The QTc may vary for genetic reasons. A routine neonatal ECG is advisable only in ethnic groups in which the QTc is lengthened, to help counter the greater risk of sudden death in these infants

BAY 81-8973 prophylaxis and pharmacokinetics in haemophilia A: Interim results from the TAURUS study

Objectives: To report interim data from TAURUS, a study assessing real-world prophylactic treatment with unmodified, full-length recombinant FVIII BAY 81-8973 (Kovaltry®; Bayer) indicated for haemophilia A. Methods: TAURUS (NCT02830477) is an international, open-label, prospective, non-interventional, single-arm study with a one-year observation period (target N = 350). Patients have moderate or severe haemophilia A (FVIII ≤5% or ≤1%) and ≥50 exposure days to any FVIII product. Clinician- and patient-reported outcomes are captured on previous product use, changes in prophylaxis dose and dosing frequency, FVIII consumption, reported bleeding rates, treatment satisfaction and adherence, pharmacokinetic (PK) data (if available) and safety data. Results: At cut-off, baseline data were available from 160 patients (89 had ≥6 months of follow-up data). Most patients had severe haemophilia A (85%), infused BAY 81-8973 ≥ 3×/wk (59%) and experienced a median number of total bleeds of 2.0 (non-annualised; 246 days median documentation period). Good levels of treatment satisfaction (Hemo-SATA,P) and adherence (VERITAS-Pro) were maintained. TAURUS demonstrated a favourable PK profile of BAY 81-8973 in comparison with other standard half-life rFVIIIs and supported the WAPPS PopPK model. No patients developed inhibitors. Conclusions: TAURUS data demonstrate effective prophylaxis with BAY 81-8973 in the real world without compromising patient satisfaction or adherence.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Spanish registry of hemoglobinopathies and rare anemias (REHem-AR) : demographics, complications, and management of patients with β-thalassemia

The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) β-thalassemia cohorts are described and analyzed. We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021. Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27). Our registry enabled us to describe the management of β thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases

Venous thromboembolism in pediatric patients with acute lymphoblastic leukemia under chemotherapy treatment. Risk factors and usefulness of thromboprophylaxis. Results of LAL-SEHOP-PETHEMA-2013.

Symptomatic venous thromboembolism (VTE) is diagnosed in 3%-14% of patients during pediatric acute lymphoblastic leukemia (ALL) therapy. There are well-known risk factors, but the role of others as inherited thrombophilia is still controversial. Prophylaxis with low molecular weight heparin (LMWH) has been described, but its use is not globally accepted. A retrospective multicentric study in ALL patients 1-18 years old following SEHOP-PETHEMA-2013 treatment guideline was performed to evaluate VTE rate, anticoagulant treatment, outcome, risk factors, and safety and usefulness of LMWH administration as primary thromboprophylaxis in children with inherited thrombophilia. A total of 652 patients were included in the study. VTE incidence was 8.7%. Most of the cases occurred during induction therapy associated with central venous catheter. Univariant analysis showed that family history of thrombosis, presence of mediastinal mass, high-risk treatment group, and inherited thrombophilia were statistically significant risk factors. LMWH administration seemed to decrease VTE rate in patients with inherited thrombophilia and those with T-cell ALL phenotype. Most of the VTE cases occurred in patients without inherited thrombophilia, but when it is present, the VTE risk is higher. LMWH administration was useful to decrease VTE in these patients