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Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 10 9 /l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs . eltrombopag ( P  = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs . 2.2%, P  < 0.001), and to previous splenectomy in younger patients (100% vs . 33%, P  = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.

Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product’s optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences.

Background: Eptacog beta is a novel recombinant activated factor VII (rFVIIa). Preclinical studies have shown the product has a similar profile to eptacog alfa. The PERSEPT 1 and PERSEPT 3 trials proved the efficacy and safety of eptacog beta for surgical prophylaxis and treatment of bleed in patients with haemophilia A or B with inhibitors. This led to approval of the product by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Recently, real-world data have been published on the use of eptacog beta on this population which has provided positive outcomes. Given the similar in vitro and in vivo profile of eptacog beta and eptacog alfa positive outcomes could be expected not only in patients with haemophilia and inhibitors, but also in other situations where eptacog alfa is a therapeutic option. Methods: We report on the use of this product for on-label and off-label populations in two Spanish hospitals. Results: We describe four cases in an on-label population (haemophilia A with inhibitors) and four cases in another population (one with acquired haemophilia and three with mild factor VII deficiency). Conclusions: Our experience provides further evidence of the efficacy and safety of eptacog beta for surgical prophylaxis and treatment of bleeding in patients with haemophilia A with inhibitors, but also in those with factor VII deficiency. To our knowledge, this is the first report to describe the use of eptacog beta for factor VII deficiency and acquired haemophilia.

Key Clinical Message Switching to rIX‐FP prophylaxis at dosing intervals of up to 14 days in a hemophilia B pediatric patient decreased treatment burden by reducing the number of administrations and hospital visits, without affecting efficacy or treatment adherence. This is particularly important in contexts of limited mobility and overloaded healthcare services.

Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10–400 IU/dL) (Fanhdi ® /Alphanate ® , Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients. Graphical abstract

IntroductionHaemophilia A is a rare bleeding disorder caused by defects in coagulation factor VIII (FVIII). Damoctocog alfa pegol (BAY 94–9027, Jivi, Bayer, Germany) is a site-specifically PEGylated, extended-half-life, recombinant FVIII, approved for use in previously treated patients (PTPs) aged ≥12 years with haemophilia A. However, a real-world evidence regarding routine clinical use of damoctocog alfa pegol is limited.Methods and analysisHEM-POWR is a multinational, multicentre, non-interventional, prospective, postmarketing cohort study evaluating the effectiveness and safety of real-world treatment with damoctocog alfa pegol. Estimated enrolment is ≥200 PTPs with haemophilia A, receiving damoctocog alfa pegol (on-demand, prophylaxis or intermittent prophylaxis (as per local label)), observed for 36 months. Primary outcomes are total bleeding events and annualised bleeding rate; secondary outcomes include long-term safety, joint health, pharmacokinetics, patient-reported outcomes (PROs) from validated questionnaires and perioperative haemostasis. Where applicable, reasons for switching to damoctocog alfa pegol, choice of treatment regimen and dose will also be captured. Exploratory and descriptive statistical analyses will be performed, and will be stratified by parameters including, but not limited to, prophylaxis regimen and haemophilia severity. Patients can record bleeds and consumption in electronic (e) Diaries, ePROs, and can access non-promotional study information (videos explaining study procedures) via an online patient portal. Optionally, patients can enrol in the LIFE-ACTIVE substudy designed to investigate the relationship between activity (measured by the ActiGraph CP Insight watch) and effectiveness parameters collected from HEM-POWR.Ethics and disseminationStudy approval was obtained by local independent ethics committees and authorities in participating study centres across Europe, the Americas and Asia. Informed consent from patients or their legal representative is a requirement for participation. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.Trial registration numbers NCT03932201, EUPAS26416.Protocol version and dateV.1.2, 27 September 2019.

Introduction Certain behavioral traits increase the risk of obesity at early ages. Exploring patterns of eating behavior in schoolchildren using tools like the Children's Eating Behavior Questionnaire (CEBQ) is crucial for obesity prevention and intervention. Before this study, the CEBQ had been validated in various languages, including Spanish, but only in preschool‐aged children, despite its previous use in various studies in the Spanish language and population. The objective is to assess the reliability and internal consistency of the CEBQ questionnaire applied to a sample of Spanish schoolchildren and to explore the association between eating behavior assessed through the CEBQ and nutritional status based on BMI. Methods Parents or guardians of 283 Spanish schoolchildren aged 6–16 years completed the Spanish version of the CEBQ questionnaire. Factor analyses were conducted on all CEBQ items, and differences between genders and age groups were examined. Correlations between children's BMI Z‐scores and eating behaviors were analyzed through linear regression. Results The factor analysis revealed that the CEBQ is suitable in its original structure of eight subscales translated into Spanish, demonstrating adequate reliability and acceptable correlations between subscales. Gender appears to have minimal influence on eating behavior. However, with increasing age, schoolchildren tend to eat more quickly and are less fussy about food (SE [slowness in eating] [p = 0.012] and FF [food fussiness] [p = 0.012] decrease). Positive associations were found between BMI Z‐scores and all pro‐eating dimension subscales, while negative associations were identified with all antieating dimension subscales (p < 0.05) except EUE (emotional undereating) (p = 0.106). Conclusions The CEBQ is a valid psychometric tool that can be reliably used to assess eating behavior characteristics in Spanish schoolchildren aged 6–16 years. This study evaluates the reliability of the Spanish version of the Children's Eating Behaviour Questionnaire (CEBQ) in children aged 6–16. Results show an association between pro‐eating behaviors and higher BMI, emphasising the CEBQ's role in identifying traits linked to obesity risk in pediatric populations.

Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required. Objectives and design: The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq®), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered. Methods and analysis: The primary endpoint is overall perioperative hemostatic efficacy (“success” or “failure”) of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries. Ethics: Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. Discussion: Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients. Trial Registration: CT EU 2022-502061-17-00; NCT05936580 Plain language summary Design of an international study (NuDIMENSION) to examine the use of a factor VIII therapy during surgery in female hemophilia A patients Hemophilia A is an inherited bleeding disorder caused by an abnormality in the F8 gene that leads to a reduction in clotting factor VIII (FVIII). Females who inherit the abnormal gene can pass on the gene to their children and are known as ‘carriers’. Some carriers have FVIII levels below 40% of normal levels and are classified as having hemophilia A. However, excessive bleeding can also occur in females with FVIII levels greater than 40% of normal. Excessive bleeding may only be evident after injury, during surgery or during childbirth, but can also cause heavy periods, for example. Replacement therapy with FVIII can be used to treat or prevent bleeds in people with hemophilia A. During surgery higher levels of FVIII may be needed to prevent excessive bleeding. However, information on the use of FVIII comes predominantly from trials in male patients with severe disease. Information on the treatment of carriers is limited, and treatment guidelines for surgical management of carriers are lacking. Simoctocog alfa (Nuwiq®), a FVIII therapy, is effective at preventing and treating bleeds, including during surgery, in males with severe hemophilia A. NuDIMENSION is a multicenter, international study that will evaluate simoctocog alfa in women and girls with hemophilia A who need major surgery. The study will include women/girls aged 12 years or older who have mild or moderate hemophilia A and who are planned to have a major surgery. The primary endpoint is overall hemostatic efficacy (“success” or “failure”), that is, how well bleeding is prevented/controlled. This will be assessed at the end of the surgery and at the end of the postoperative period. Up to 28 women and girls will take part in the study. Data from NuDIMENSION will provide important information to help decide how best to treat women/girls with hemophilia A who need surgery. Graphical abstract