Unravelling the Spectrum of von Willebrand Factor Variants in Quantitative Von Willebrand Disease: Results from a German Cohort Study.

INTRODUCTION: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF). OBJECTIVES: This large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations. PATIENTS/METHODS: Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70%). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments. RESULTS: Following ISTH-SSC VWF guidelines, 77 index patients characterized as type 1 VWD (VWF:Ag < 30%), 111 as type 1 VWD (VWF:Ag 30-50%), and as 33 type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30-50%, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70%) displayed VWF variants. CONCLUSION: Our data advances our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag <30%) and type 1 (VWF:Ag 30-50%), an area with limited prior investigation.

Patient perspective on living with mild hemophilia in Germany: results from a nationwide survey.

Introduction: The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. Aim: This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. Methods: An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. Results: A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0-15.0), and the median factor activity was 14.0% (IQR 12.0-25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Conclusion: Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients' QoL. Hemophilia centers satisfied the patients' needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.

Factors influencing the success and complications of intraosseous access in pediatric patients-a prospective nationwide surveillance study in Germany.

Background: Vascular access is essential for the efficient treatment of critically ill children, but it can be difficult to obtain. Our study was conducted to analyze the feasibility and short-term safety of intraosseous access (IO) use as well as factors influencing its success and the incidence of complications in pediatric emergencies and resuscitation. This dataset of systematically documented intraosseous access attempts constitutes one of the largest published in the literature. Methods: Two-year nationwide prospective surveillance study in Germany from July 2017 to June 2019. Pediatric hospitals anonymously reported the case data of all children aged 28 days to 18 years who arrived with or were treated with an intraosseous access to the German Pediatric Surveillance Unit (GPSU). The main outcomes were the occurrence of complications, overall success and success at the first attempt. The influence of individual factors on outcomes was evaluated using multivariate regression models. Results: A total of 417 patients underwent 549 intraosseous access attempts. The overall rates of success and success at the first attempt were 98.3% and 81.9%, respectively. Approximately 63.6% of patients were successfully punctured within 3 min from the time of indication. Approximately 47.7% of IO access attempts required patient resuscitation. Dislocation [OR 17.74 (5.32, 59.15)] and other complications [OR 9.29 (2.65, 32.55)] occurred more frequently in the prehospital environment. A total of 22.7% of patients experienced minor complications, while 2.5% of patients experienced potentially severe complications. Conclusion: We conclude that intraosseous access is a commonly used method for establishing emergency vascular access in children, being associated with a low (age-dependent) rate of severe complications and providing mostly reliable vascular access despite a relatively high rate of dislocation.

Teamwork and mental workload in postsurgical pediatric patient handovers: Prospective effect evaluation of an improvement intervention for OR-PICU patient transitions.

Postsurgical handover of pediatric patients from operating rooms (OR) to pediatric intensive care units (PICU) is a critical step. This transition is susceptible to errors and inefficiencies particularly if poor multidisciplinary teamwork occurs. Despite wide adoption of standardized handover interventions, comprehensive investigations into joint effects for patient care and provider outcomes are scarce. We aimed to improve OR-PICU handovers quality and sought to evaluate the intervention with particular attention to patient care effects and provider outcomes. A prospective, before-after-study design with an interrupted-series and a multi-source, mixed-methods evaluation approach was established. Drawing upon a participative plan-do-study-act approach, a standardized, checklist-based handover process was designed and implemented. For effect assessments, we observed OR-PICU handovers on site (pre implementation: n = 31, post: n = 30), respectively, with standardized expert observation and provider self-report tools (n = 111, n = 110). Setting was a tertiary Pediatric University Hospital. Supplementary qualitative, semi-structured interviews were conducted, and a general inductive content analysis approach was used to identify key facilitators and barriers on implementation. Improvement efforts focused on stepwise implementation of (1) standardized handover process and (2) a checklist for multi-professional OR-PICU handover communication. We observed significant increases in team and patient setup (pre: 79.3%, post: 98.6%, p < .01), enhanced team engagement (pre: 50%, post: 81.7%, p < .01), and comprehensive information transfer by the anesthesia sub-team (pre: 78.6%, post: 87.3%, p < .01). Expert-rated teamwork outcomes were consistently higher, yet self-reported teamwork did not change over time. Provider perceived stress and disruptions did not change, mental workload tended to decrease over time (pre: M = 3.2, post: 2.9, p = .08). Comprehensiveness of post-operative patient information reported by PICU physician increased significantly: pre: 65.9%, post: 76.2%, p < .05. After implementation, providers acknowledged the importance of standardized handover practices and associated benefits for facilitation of information transfer and comprehensiveness. Among reported barriers were obstacles during implementation as well as insufficient consideration of professionals' individual workflow after surgery. CONCLUSION:  A multidisciplinary intervention for postsurgical pediatric patient handovers was associated with improved expert-rated teamwork and fewer omissions of key patient information over time. Inconsistent results were obtained for provider-rated mental workload and teamwork outcomes. The findings contribute to a better understanding concerning the interplay of teamwork and provider cognitions in the course of establishing safe patient transitions in pediatric care. WHAT IS KNOWN: • Transfer of critically ill children conveys significant challenges for interprofessional communication and teamwork. Prospective research into interventions for safe and efficient handover practices of OR PICU patient transitions is necessary. • Checklists are assumed to facilitate cognitive load among providers in acute clinical environments. WHAT IS NEW: • A standardized, checklist-based handover intervention was associated with improvements in team set-up and information transfer. Provider outcomes such as mental workload and stress did not change over time. • The combination of teamwork and provider assessments allows a more nuanced understanding of implementation barriers and sustainable effects in course of OR-PICU handover interventions.

Dilemmas on emicizumab in children with haemophilia A: A survey of strategies from PedNet centres.

INTRODUCTION: Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres. AIM: We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia. METHODS: An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors. RESULTS: All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol. CONCLUSION: Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI.

First detected geographical cluster of BoDV-1 encephalitis from same small village in two children: therapeutic considerations and epidemiological implications.

BACKGROUND: The Borna disease virus (BoDV-1) is an emerging zoonotic virus causing severe and mostly fatal encephalitis in humans. METHODS AND RESULTS: A local cluster of fatal BoDV-1 encephalitis cases was detected in the same village three years apart affecting two children. While the first case was diagnosed late in the course of disease, a very early diagnosis and treatment attempt facilitated by heightened awareness was achieved in the second case. Therapy started as early as day 12 of disease. Antiviral therapy encompassed favipiravir and ribavirin, and, after bioinformatic modelling, also remdesivir. As the disease is immunopathogenetically mediated, an intensified anti-inflammatory therapy was administered. Following initial impressive clinical improvement, the course was also fatal, although clearly prolonged. Viral RNA was detected by qPCR in tear fluid and saliva, constituting a possible transmission risk for health care professionals. Highest viral loads were found post mortem in the olfactory nerve and the limbic system, possibly reflecting the portal of entry for BoDV-1. Whole exome sequencing in both patients yielded no hint for underlying immunodeficiency. Full virus genomes belonging to the same cluster were obtained in both cases by next-generation sequencing. Sequences were not identical, indicating viral diversity in natural reservoirs. Specific transmission events or a common source of infection were not found by structured interviews. Patients lived 750m apart from each other and on the fringe of the settlement, a recently shown relevant risk factor. CONCLUSION: Our report highlights the urgent necessity of effective treatment strategies, heightened awareness and early diagnosis. Gaps of knowledge regarding risk factors, transmission events, and tailored prevention methods become apparent. Whether this case cluster reflects endemicity or a geographical hot spot needs further investigation.

[Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)]. / Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

Clinical experience of switching patients with severe hemophilia to rVIII-SingleChain or rIX-FP.

OBJECTIVE: Prophylaxis treatment is the current standard of care for patients with severe hemophilia. Factor concentrates with improved pharmacokinetics have offered more options for individualizing treatment. The treatment focus may be on increased protection, aiming for higher trough factor levels or longer dosing intervals to reduce the burden of hemophilia. Both aspects can have long-term effects on joint health. Products, such as rVIII­SingleChain and rIX-FP have been developed to reduce the treatment burden for patients with hemophilia and optimize prophylactic efficacy. The objective of this report is to provide a summary of the clinical experience of different Hemophilia Treatment Centers in managing the switch to rVIII-SingleChain or rIX-FP in patients with hemophilia. METHODS: This report summarizes a selection of patient cases presented at the 3rd Alliance for Coagulation Academy Meeting in October 2020. The cases from the participating centers provide examples of the clinical experience in managing patients' switch to rVIII-SingleChain and rIX­FP, including which types of patients are suitable for switching, and practical steps in managing a switch. RESULTS: It is important to take into consideration the physical and social fulfillment of the patient when deciding to switch to rVIII-SingleChain or rIX-FP. The physician plays an important role in the motivation of patients as they understand not only the patient's needs but the potential benefits of the new treatment. CONCLUSION: The selected patient cases reported here demonstrate that patients may wish to switch factor products for a variety of reasons; therefore, it is critical to understand why patients switch and what they expect from switching.

Pediatric intensive care unit admissions network-rationale, framework and method of operation of a nationwide collaborative pediatric intensive care research network in Germany.

The Pediatric Intensive Care Unit Admissions (PIA) network aims to establish a nationwide database in Germany to gather epidemiological, clinical, and outcome data on pediatric critical illness. The heterogeneity of pediatric patients in intensive care units (PICU) poses challenges in obtaining sufficient case numbers for reliable research. Multicentered approaches, such as patient registries, have proven effective in collecting large-scale data. However, Germany lacks a systematic registration system for pediatric intensive care admissions, hindering epidemiological and outcome assessments. The PIA network intends to address these gaps and provide a framework for clinical and epidemiological research in pediatric intensive care. The network will interconnect PICUs across Germany and collect structured data on diagnoses, treatment, clinical course, and short-term outcomes. It aims to identify areas for improvement in care, enable disease surveillance, and potentially serve as a quality control tool. The PIA network builds upon the existing infrastructure of the German Pediatric Surveillance Unit ESPED and utilizes digitalized data collection techniques. Participating units will complete surveys on their organizational structure and equipment. The study population includes patients aged ≥28 days admitted to participating PICUs, with a more detailed survey for cases meeting specific criteria. Data will be collected by local PIA investigators, anonymized, and entered into a central database. The data protection protocol complies with regulations and ensures patient privacy. Quarterly data checks and customized quality reports will be conducted to monitor data completeness and plausibility. The network will evaluate its performance, data collection feasibility, and data quality. Eligible investigators can submit proposals for data analyses, which will be reviewed and analyzed by trained statisticians or epidemiologists. The PIA network aims to improve pediatric intensive care medicine in Germany by providing a comprehensive understanding of critical illness, benchmarking treatment quality, and enabling disease surveillance.

[Arterial ischemic stroke in childhood and adolescence : Time-critical emergency in pediatrics]. / Arteriell ischämischer Schlaganfall im Kindes- und Jugendalter : Zeitkritischer Notfall in der Pädiatrie.

Childhood arterial ischemic stroke is one of the most time-critical pediatric emergencies but is often diagnosed with a prognostically relevant time delay. The reasons are low awareness, sometimes unspecific clinical presentation with a wide variety of critical differential diagnoses and less coordinated acute care structures. The revascularization strategies established for adults also show sometimes spectacular success in children. These should therefore also be made available for affected children if possible, although the evidence is nowhere near comparable. In the postacute phase the etiological work-up is complex due to the risk factors which need to be considered, but identification of the individual risk profile is essential as it defines secondary prevention, risk of recurrence and outcome. The long-term care in a multiprofessional, interdisciplinary team must take into account all bio-psycho-social aspects of the child in the current developmental phase.

Intraosseous access in neonates is feasible and safe - An analysis of a prospective nationwide surveillance study in Germany.

Background: This was a prospective surveillance study to investigate reports on the safety and frequency of use of intraosseous (IO) access in neonates. Methods: Over a two-year period, paediatric hospitals in Germany were asked to report all cases of IO access to the nationwide Surveillance Unit for Rare Paediatric Diseases (ESPED). Hospitals reporting a case submitted responses via an anonymised electronic questionnaire, providing details on indication, success rate, system used, location, duration to first successful IO access, complications, alternative access attempts and short-term outcome. We present a subset of data for IO use in infants of less than 28 days. Results: A total of 161 neonates (145 term and 16 preterm born infants) with 206 IO access attempts were reported. In 146 neonates (91%), IO access was successfully established, and success was achieved with the first attempt in 109 neonates (75%). There was no significant impact of gestational age or provider's educational level on success rates. In 71 infants with successful IO access (79%), the estimated duration of placement was less than 3 min. The proximal tibia was the predominant site used. A semiautomatic battery-driven device was used in 162 attempts (88%). The most often applied medications via IO access were crystalloid fluid and adrenaline. Potentially severe complications occurred in 9 patients (6%). Conclusion: Within this surveillance study, IO access in neonates was feasible and safe. IO access is an important alternative for vascular access in neonates.

Analysis of pooled real-world data from Germany, Italy, and the United States of rVIII-SingleChain compared with standard- and long-acting FVIII products for prophylaxis of hemophilia A.

OBJECTIVE: To evaluate real-world annualized bleeding rates (ABRs), dosing frequency, and factor consumption of four recombinant FVIII (rFVIII) products using pooled data from centers in the US, Germany, and Italy. METHODS: De-identified patient medical chart data were collected from 48 hemophilia treatment centers in the US, Germany, and Italy. Patients included in this analysis had hemophilia A and were treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, or BAY 81-8973 for ≥12 weeks. Where possible, patient selection considered age and disease severity in order to balance patient groups across products. Summary statistics were presented descriptively by product for dosing frequency, consumption, ABR/annualized spontaneous bleeding rate (AsBR), and corresponding percentage of patients with zero bleeds. Logistic regression was performed for patients with zero bleeds or zero spontaneous bleeds (vs. patients with any such bleeds). Generalized linear model regression was performed for ABR, AsBR, and consumption. All regression models included the product variable for comparison as well as additional independent variables for adjustment (age, weight, severity, and country for the consumption model, with the addition of consumption for the bleeding outcomes models). RESULTS: Overall, 616 patients were included (rVIII-SingleChain, n = 129; rFVIIIFc, n = 159; octocog alfa, n = 181; BAY 81-8973, n = 147). Dosing frequency was ≤2 times a week for 65.9%, 75.5%, 25.4%, and 40.1% of patients treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. ABRs were not significantly different among products, with mean (median) values of 1.1 (0.0), 1.0 (0.0), 1.4 (1.0), and 1.9 (1.0) for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. The percentage of patients with zero bleeds was comparable between rVIII-SingleChain and rFVIIIFc (59.7% vs. 62.3%; p =.916) and significantly higher for rVIII-SingleChain compared with octocog alfa (p <.001) and BAY 81-8973 (p =.003). Comparison of mean weekly consumption showed: rVIII-SingleChain (83.0 IU/kg/week) vs. rFVIIIFc (96.9; p =.055) and significantly lower for rVIII-SingleChain vs. octocog alfa (108.6; p <.001) and BAY 81-8973 (104.3; p =.001). The median values for weekly consumption were 85.7, 90.1, 100.1, and 98.5 IU/kg/week for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 91-8973, respectively. Similar trends were observed for all outcomes when analyzing the subgroups of patients aged ≥12 years and patients with severe disease (all age and ≥12 years). CONCLUSIONS: rVIII-SingleChain prophylaxis may provide improved bleed protection, less frequent dosing, and lower consumption compared with standard-acting FVIII products, and comparable protection and consumption to the other long-acting FVIII product, in patients with hemophilia A.

Interventional Treatment Options in Children with Extracranial Vascular Malformations.

Extracranial vascular malformations vary greatly and belong to the complex field of orphan diseases and can involve all segments of the vascular tree: arteries, capillaries, and veins, and similarly the lymphatic system. The classification according to the International Society for the Study of Vascular Anomalies (ISSVA) represents an important guidance for selecting appropriate therapy. Although many of the principles of endovascular treatment, including image-guided sclerotherapy and embolization, are similar in adult and pediatric practice, there are some distinct differences regarding the treatment of vascular malformations of children. Thus, it is crucial to involve longer-term plan about managing these chronic diseases and their impact on a growing child. This review provides a detailed overview over the clinical presentation of venous, lymphatic, and arteriovenous malformations in children and emphasizes the specifics of their interventional treatment options, including distinct pediatric dose limitations and procedure-related side effects.

The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

Electronic diaries in the management of haemophilia gene therapy: Perspective of an expert group from the German, Austrian and Swiss Society on Thrombosis and Haemostasis (GTH).

INTRODUCTION: Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres. AIM: To explore the potential use of electronic tools to improve the delivery of GT under real-world conditions. METHODS: Considering the hub-and-spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients. RESULTS: Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow-up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered. CONCLUSION: Important information needs to be shared between patients and treatment centres in a real-world GT hub-and-spoke model. Collecting and sharing this information in well-organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries.

Recanalization strategies in childhood stroke in Germany.

Childhood arterial ischemic stroke (CAIS) is a rare event. Diverse etiologies, risk factors, symptoms and stroke mimics hamper obtaining a fast diagnosis and implementing immediate recanalization strategies. Over a period of 3 years (2015-2017), the data of 164 pediatric patients (> 28 days of life-18 years) with a first episode of AIS were submitted to a hospital-based nationwide surveillance system for rare disorders (ESPED). We report a subgroup analysis of patients who have undergone recanalization therapy and compare these data with those of the whole group. Twenty-eight patients (17%) with a median age of 12.2 years (range 3.3-16.9) received recanalization therapy. Hemiparesis, facial weakness and speech disturbance were the main presenting symptoms. The time from onset of symptoms to confirmation of diagnosis was significantly shorter in the intervention group (4.1 h vs. 20.4 h, p ≤ 0.0001). Only in one patient occurred a minor bleed. Cardiac disease as predisposing risk factor was more common in the recanalization group. Recanalization therapies are feasible and increasingly applied in children with AIS. High awareness, timely diagnosis and a large amount of expertise may improve time to treatment and make hyperacute therapy an option for more patients.