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In rare diseases, such as hemophilia A, the development of accurate population pharmacokinetic (PK) models is often hindered by the limited availability of data. Most PK models are specific to a single recombinant factor VIII (rFVIII) concentrate or measurement assay, and are generally unsuited for answering counterfactual ("what‐if") queries. Ideally, data from multiple hemophilia treatment centers are combined but this is generally difficult as patient data are kept private. In this work, we utilize causal inference techniques to produce a hybrid machine learning (ML) PK model that corrects for differences between rFVIII concentrates and measurement assays. Next, we augment this model with a generative model that can simulate realistic virtual patients as well as impute missing data. This model can be shared instead of actual patient data, resolving privacy issues. The hybrid ML‐PK model was trained on chromogenic assay data of lonoctocog alfa and predictive performance was then evaluated on an external data set of patients who received octocog alfa with FVIII levels measured using the one‐stage assay. The model presented higher accuracy compared with three previous PK models developed on data similar to the external data set (root mean squared error = 14.6 IU/dL vs. mean of 17.7 IU/dL). Finally, we show that the generative model can be used to accurately impute missing data (< 18% error). In conclusion, the proposed approach introduces interesting new possibilities for model development. In the context of rare disease, the introduction of generative models facilitates sharing of synthetic data, enabling the iterative improvement of population PK models. [ABSTRACT FROM AUTHOR]

Introduction: The severity of Von Willebrand disease (VWD) is currently based on laboratory phenotype. However, little is known about the severity of the patient's experience with the disease. The most recent VWD guidelines highlight the need for patient-reported outcomes (PROs) in VWD., Aim: The study aimed to investigate the patient-perspective on VWD severity and to identify key factors that determine the severity of disease experienced by patients., Materials and Methods: Patients participated in a nationwide cross-sectional study on VWD in the Netherlands (WiN-study). Patients filled in a questionnaire containing questions on the experienced severity of VWD (4-point scale), bleeding score (BS) and quality of life (QoL)., Results: We included 736 patients, median age of 41.0 years (IQR 23.0-55.0) and 59.5% were women. A total of 443 had type 1, 269 type 2 and 24 type 3 VWD. Self-reported severity of VWD was categorized as severe (n = 52), moderate (n = 171), mild (n = 393) or negligible (n = 120). Classification by historically lowest FVIII:C levels < 0.20 IU/mL as a proxy for severe VWD aligned with patient-reported severity classification with a 72% accuracy. Type 3 VWD (OR = 4.02, 95%CI: 1.72-9.45), higher BS (OR = 1.09, 95%CI: 1.06-1.11), female sex (OR = 1.36, 95%CI: 1.01-1.83), haemostatic treatment in the year preceding study inclusion (OR = 1.53, 95%CI: 1.10-2.13) and historically lowest VWF:Act levels (OR = 0.26, 95%CI: 0.07-1.00) were independent determinants of patient-reported severity., Conclusion: This study shows that patient-reported data provide novel insights into the determinants of experienced disease severity. Our findings highlight the need for studies on PROs with validated questionnaires to assess the burden of VWD., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Background: Postthrombotic syndrome (PTS) is a chronic condition following deep vein thrombosis (DVT) and is associated with pain, swelling, and restricted use of the affected limb. In pediatric age groups, its incidence and risk factors are not well-known., Methods: This observational cohort study of all consecutive children (≤18 years) with DVT treated at the Emma Children's Hospital Amsterdam between January 2001 and January 2021 was conducted to identify incidence and risk factors for PTS in neonates aged ≤2 months and children aged >2 months. PTS was diagnosed using the modified Villalta scale., Results: In total, 315 patients were included. The 20-year incidence of PTS was 20.0% in neonates and 40.0% in children. In neonates, involvement of ≥3 vessels (odds ratio [OR], 6.6; 95% CI, 1.6-26.4) and incomplete thrombus resolution (OR, 3.0; 95% CI, 1.1-8.0) were risk factors for PTS. In children, involvement of ≥3 vessels (OR, 6.2; 95% CI, 2.2-17.8), recurrent DVT (OR, 3.7; 95% CI, 1.3-10.3), and incomplete thrombus resolution (OR, 5.2; 95% CI, 1.6-17.0) were associated with PTS. Exercise ≥3 times/wk (OR, 0.4; 95% CI, 0.2-0.9), central venous catheter-related DVT (OR, 0.2; 95% CI, 0.1-0.5), and provoked DVT (OR, 0.4; 95% CI, 0.1-0.97) were protective factors for PTS., Conclusion: This study demonstrated a high incidence of pediatric PTS. Additionally, risk factors for PTS differed between neonates and children. These findings provide a basis for better prevention and management of PTS that may differ between neonates and children., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting 'normal,' making the most of available resources, and considering treatment affordability. Ultimately, all PwH-men and women, of all ages and severities, and worldwide-should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JB has received consultation and/or speaker’s fees from NovoNordisk, Roche, Sobi, Takeda, and CSL Behring. JA has received research grants from Sobi, CSL Behring, Takeda/Shire, and Bayer, and speaker’s fees and consultancy for Octapharma, Novo Nordisk, Pfizer, Bayer, Sobi, CSL Behring, Takeda/Shire, BioMarin, Uniqure, and Spark Therapeutics. CC has received payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events, and support for attending meetings and/or travel from Sobi, Bayer, Roche, and Novo Nordisk, and has also participated in data safety monitoring boards or advisory boards for Sobi, Bayer, Roche, and Novo Nordisk. GD has received consulting fees from Pfizer, Biomarin, CSL, Roche, and Sobi, and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Pfizer, Spark Therapeutics, CSL, Bayer, Takeda, Roche, Chugai, and Sobi. KF has received unrestricted research grants from CSL Behring, Sobi, and Novo Nordisk, as well as consultancy fees from Hoffman-La Roche, Sanofi, Sobi, and Novo Nordisk, with all fees paid to her institution. CH has received research funding from Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Shire/Takeda, and Sobi, as well as honoraria/speaker’s bureau fees from Bayer, CAF-DCF, CSL Behring, Hoffmann-La Roche, LFB, Novo Nordisk, Octapharma, Pfizer, Shire/Takeda, Sobi, and UniQure. KH has received grants for research or clinical studies (paid to her institution) from Bayer, CSL Behring, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Sobi, as well honoraria or consultancy fees from Bayer, Biomarin, Biotest, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda. VJ-Y has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, BioMarin, CSL Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma, and Pfizer. RK has received consultancy fees and honoraria for lectures and advisory boards from Bayer, Biomarin, CSL Behring, Novo Nordisk, Grifols, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda. ML has served on an advisory board for CSL Behring, as a consultant for Sobi, CSL Behring, Takeda, and Band Therapeutics, and has received research funding from Takeda and speaker fees from Sobi and Takeda. PJL has received research support to his institute from Sobi, Sanofi, BioMarin, and Roche. SL has acted as a paid consultant to Faust Pharmaceuticals Inc. MEM has acted as a paid speaker/consultant/advisor for Bayer, Biomarin, CSL Behring, Kedrion, LFB, Octapharma, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda. JM has received honoraria and/or educational support from Sobi, Roche, Bayer, and CSL. JSO’D declares no conflicts of interest beyond the support for this manuscript from Sobi. CK has received funding from BFSH, Bayer, CSL Behring, Florio, MSD, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, and Takeda for presentations and/or scientific advice, and his institution has received research funding from Bayer, Biotest, CSL Behring, Intersero, Novo Nordisk, Pfizer, Roche/Chugai, Sobi/Sanofi, and Takeda., (© The Author(s), 2024.)

Importance: Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown., Objective: To describe neonatal RBC transfusion practice in Europe., Design, Setting, and Participants: This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation., Exposure: Admission to the NICU., Main Outcomes and Measures: Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion., Results: A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration., Conclusions and Relevance: In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Background: To enable personalized treatment and shared decision-making in chronic care, relevant health information is collected. However, health information is often fragmented across hospital information systems, digital health apps, and questionnaire portals. This also pertains to hemophilia care, in which scattered information hampers integrated care. We intend to co-design a nationwide digital personal health record (PHR) for patients to help manage their health information. For this, user perspectives are crucial., Objective: This study aims to assess patients' and health care providers' perspectives regarding the use of a PHR in hemophilia care in the Netherlands, required functionalities, and expectations and concerns., Methods: In this semistructured interview study, 19 pediatric and adult persons with hemophilia, parents, and women with other inherited bleeding disorders, as well as 18 health care providers working within and outside of hemophilia treatment centers, participated. Perspectives of patients and providers were explored separately. To explore requirements, participants were asked to prioritize functionalities., Results: Participants expected a PHR would increase the transparency of health information, improve patients' understanding of their illness, and help the coordination of care between health care providers and institutions. Prioritized functionalities included the integration of relevant health information and patient-entered data. Formulated expectations and concerns focused on 4 themes: usability, safety, inclusiveness, and implementation. While patients expressed worries over medicalization (ie, more confrontational reminders of their illness), providers were concerned about an increased workload., Conclusions: People with hemophilia, their parents, and health care providers welcomed the development of a PHR, as they expected it would result in better coordinated care. Formulated expectations and concerns will contribute to the successful development of a PHR for persons with hemophilia, and ultimately, for all persons with a chronic condition., (©Martijn R Brands, Lotte Haverman, Jelmer J Muis, Mariëtte H E Driessens, Stephan Meijer, Felix J M van der Meer, Marianne de Jong, Johanna G van der Bom, Marjon H Cnossen, Karin Fijnvandraat, Samantha C Gouw. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 03.09.2024.)

Background: Once-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited., Methods: We conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics., Results: A total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours., Conclusions: In children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To describe the incidence of major bleeds according to different platelet counts in very preterm infants, and to explore whether this association is influenced by other risk factors for bleeding., Design: Observational cohort study., Setting: A Dutch tertiary care neonatal intensive care unit., Patients: All consecutive infants with a gestational age at birth <32 weeks admitted between January 2004 and July 2022., Exposure: Infants were stratified into nine groups based on their nadir platelet count (×10 9 /L) during admission (<10, 10-24, 25-49, 50-99, 100-149, 150-199, 200-249, 250-299 and ≥300), measured before the diagnosis of a major bleed and before any platelet transfusion was administered., Main Outcome Measure: Incidence of major bleeds during admission. Logistic regression analysis was used to quantify the relationship between nadir platelet count and incidence of major bleeds., Results: Among 2772 included infants, 224 (8%) developed a major bleed. Of the infants with a major bleed, 92% (206/224) had a nadir platelet count ≥50×10 9 /L. The incidence of major bleeds was 8% among infants with and without severe thrombocytopenia (platelet count <50×10 9 /L), 18/231 (95% CI 5 to 12) and 206/2541 (95% CI 7 to 9), respectively. Similarly, after adjustment for measured confounders, there was no notable association between nadir platelet counts below versus above 50×10 9 /L and the occurrence of major bleeds (OR 1.09, 95% CI 0.61 to 1.94)., Conclusion: In very preterm infants, the vast majority of major bleeds occur in infants without severe thrombocytopenia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Factors influencing the activation of neutrophils in SCD and the potential neutrophil-mediated ameliorating effects of therapies in SCD., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a "nonsevere" phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition., Competing Interests: G.D. has received medical writing support for this manuscript from Sobi, consulting fees from Pfizer, BioMarin, CSL, Roche, and Sobi, and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Spark Therapeutics, CSL, Bayer, Takeda, Roche, Chugai, and Sobi.K.F. has received medical writing support for this manuscript from Sobi, grants from Novo Nordisk, CSL Behring, and Sobi, consulting fees from Roche and Sanofi, support for meeting attendance from Sobi, and has participated in data safety monitoring boards/advisory boards for Sanofi and Roche.P.J.L. has received medical writing support for this manuscript from Sobi, research grants to his institution from Pfizer, Roche, Sanofi, and Sobi, and participated in advisory board meetings for BioMarin, Sanofi, and Takeda.C.C. has received medical writing support for this manuscript from Sobi, as well as payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events, and support for attending meetings and/or travel, from Sobi, Bayer, Roche, and Novo Nordisk. C.C. has also participated in data safety monitoring boards or advisory boards for Sobi, Bayer, Roche, and Novo Nordisk.M.L. has received medical writing support for this manuscript from Sobi, research funding from Takeda, consulting fees from Sobi, CSL Behring, Band Therapeutics, and Takeda, payment/honoraria from Takeda, Sobi, and Pfizer, support for meeting attendance from Takeda, and has roles in the WFH, EAHAD, FIGO, and ISTH., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Abstract: Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (β = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy., Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B., Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance., Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction., Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible., (© 2024 The Authors.)

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated., Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients., Methods: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL., Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL., Conclusion: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objectives: Anti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including non-neutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities., Methods: All persons with hemophilia A (mild (FVIII > 5-40 IU/dL)/moderate [FVIII 1-5 IU/dL)/severe (FVIII < 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA)., Results: In total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24-60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor., Conclusion: In this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIII-specific antibodies is associated with clinically relevant inhibitors., Competing Interests: IO was supported by an unrestricted research grant from SOBI, the EAHAD research grant, the Heimburger Award, and the Martin Villar research grant. MM received funding from the European Community H2020-MSCA-ITN-2019 project 859974 EDUC8. SG received unrestricted research funding from SOBI, EAHAD, CSL Behring Heimburger Award, Grifols Martin Villar Award, and the Netherlands Organization for Scientific Research NWO. KF has received unrestricted research grants from CSL Behring, SOBI, and Novo Nordisk and consultancy fees from SOBI, Novo Nordisk, and Roche all fees to the institution. FL has received grants/research funding from CSL Behring, UniQure, SOBI, and Takeda and consultancy fees from Biomarin, CSL Behring, Takeda, and Uniqure all fees to the institution. FL also served as a DSMB member for a study sponsored by Roche. JE received research funding from CSL Behring funds to the institution. MC has received financial support for research from Anthos, Bayer, CSL Behring, Novo Nordisk, and Roche, as well as an honoraria for lecturing or consultancy from Alexion, Bayer, CSL Behring, Daiichi Sankyo, Octapharma, Pfizer, SOBI, and Viatris. Nonfinancial conflict of interest: member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders EAHAD, member of the European Reference Network ERN EuroBloodNet, chair of the working group thrombosis and hemostasis of the Dutch Society of Vascular Medicine NVIVG, part of the Dutch Internist’s Society NIV. JV is listed as an inventor on a patent application on ADAMTS13 variants. SS has received a research grant from Bayer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oomen, Verhagen, Miranda, Allacher, Beckers, Blijlevens, Bom, Coppens, Driessens, Eikenboom, Fijnvandraat, Hassan, van Heerde, Hooimeijer, Jansen, Kaijen, Leebeek, Meijer, Paul, Rijpma, Rosendaal, Smit, van Vulpen, Voorberg, Schols and Gouw.)

Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data., Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling., Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01)., Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Children with sickle cell disease (SCD) face various healthcare choices to be made during the disease process that may impact their lives. Shared decision-making (SDM) could improve their health outcomes. We assessed if, and to what extent, paediatricians engage children with SCD and/or their parents in the decision-making process. In this observational cross-sectional study, paediatric SCD patients and their parents visiting the outpatient paediatrics clinic of a university hospital participated in a SDM baseline measurement. Two evaluators independently and objectively analysed the level of patient involvement in decision-making from the audio-recordings of the consultations using the OPTION-5 instrument, a 0-20-point scale from which scores are usually expressed as a percentage of ideal SDM. The level of SDM, as perceived by patients, parents and paediatricians, was appreciated using the SDM-Q-9 and SDM-Q-Doc questionnaires, respectively. Scores could range from 0% (no SDM) to 100% (exemplary SDM). Twenty-four consultations in which a decision needed to be made about SCD treatment were audiotaped and analysed; six were from each paediatrician. The group consisted of 17 male and 7 female patients from various cultural backgrounds between 2 and 17 years old, with a mean age of 9.4 years (SD 4.2). Median OPTION-5 scores were 25.0% [IQR] 20.0-40.0%; range 0-55%). Median SDM-Q-9 and SDM-Q-Doc scores were 56.7% (IQR 39.4-88.9%) and 68.9% (IQR 57.8-77.8%), respectively., Conclusion: Although subjective scores of SDM were fair, the objectively scored level of SDM among children suffering from SCD leaves room for improvement. This may be realized by increasing knowledge about the benefits of SDM, child-centred SDM interventions and SDM-training for paediatricians that takes into account the complexity of intercultural challenges and risk communication between stakeholders., What Is Known: • Children that suffer from sickle cell disease (SCD) are more vulnerable to factors that negatively impact the care that they receive as well as suboptimal health outcomes. • Shared decision-making (SDM) can help children participate in a collaborative decision-making process about their preferred treatment options and improve their health outcomes., What Is New: • The level of participation in the decision-making process for patients suffering from SCD and the families that they belong to leaves room for improvement. The impact of intercultural challenges and the quality and consistency of risk-communication between stakeholders in paediatric SDM needs further exploration. • Paediatricians are more confident about their ability to involve the child and parents compared to how children and their parents experience their level of involvement in a shared decision-making process., (© 2023. The Author(s).)