Fernando F Corrales-Medina

The clinical focus of haemophilia has expanded beyond bleeding outcomes to encompass long-term comorbidities such as cardiovascular disease (CVD). However, it remains unclear when vascular changes begin in this population. Carotid intima-media thickness (cIMT), a validated, non-invasive marker of subclinical atherosclerosis, may help detect early vascular remodelling in youth with haemophilia, even in the absence of conventional CVD risk factors. This single-centre, cross-sectional study compared adolescent males (ages 10-21 years) with severe haemophilia (FVIII or IX <1%) to age-matched healthy controls. Bilateral carotid ultrasonography was performed, and right-sided cIMT was the prespecified primary endpoint. Conventional CVD clinical risk factors were also collected. Thirty-eight participants were enrolled, 22 with haemophilia and 16 controls. Median right cIMT was higher in the haemophilia group (0.40 mm, SD 0.08 range 0.35-0.47) versus the control group (0.38 mm, SD 0.06 range 0.32-0.39; p = 0.009). When referenced to age-and-height specific nomograms, cIMT percentiles were also elevated in the haemophilia group (6.5% vs. 1.6%; p = 0.026 and 12.9% vs. 1.7%; p = 0.018; respectively). HDL-cholesterol was significantly lower in the haemophilia group (48.9 SD 9.9 vs. 60.2 SD 14.9 mg/dL; p = 0.012). No correlations were found between cIMT and any CVD risk factors. Adolescent males with severe haemophilia show early arterial thickening, suggesting that vascular remodelling in this population may begin in adolescence. Incorporating cIMT and CVD risk assessment into routine haemophilia care may support timely interventions and reduce long-term cardiovascular complications.

Background and Significance: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder affecting up to 0.1-1% of the population, typically characterized by mucocutaneous bleeding. There is increased focus on prophylaxis for VWD with severe bleeding phenotypes, currently limited treatment options, and non-intravenous therapeutics are desired to tailor therapy for patient needs. Emicizumab is a monoclonal, bispecific antibody that demonstrates factor VIII-like activity enhancing thrombin generation, transforming prophylactic therapy for many with hemophilia A. Emicizumab can be administered subcutaneously at a frequency less than that of other currently available therapies for VWD, with a half-life of 27 days. Based on available literature emicizumab has been utilized successfully for VWD prophylaxis, and further investigation is warranted. Our objective is to evaluate the safety and efficacy of emicizumab for prophylaxis in severe VWD compared to the preceding 12-month bleed history. Study Design and Methods: We initiated a pilot multicenter, prospective open-label study (NCT05500807) to evaluate emicizumab prophylaxis in severe VWD type 3, or VWD with VWF antigen (VWF:Ag), VWF activity (VWF:RCo or VWF:GPIbM), or VWF collagen binding (VWF:CB) ≤20 IU/dl or variant VWD confirmed by genetic mutation or additional VWF activity assays (ie. VWF platelet binding, VWF:FVIII binding, VWF propeptide), or VWD with concomitant hemophilia A defined as VWF:Ag, VWF activity, or VWF:CB < 50 U/dl, and mild, moderate or severe hemophilia A based upon historical medical records, with indication for hemostatic prophylaxis. Targeted enrollment is 40 patients of any age (≥3 kg). Exclusion criteria include patients with non-severe VWD, other bleeding disorders, renal and/or hepatic impairment, emicizumab treatment in the previous 18 months, or previous treatment thromboembolic disease in the past 12 months. Pre-investigation annualized bleed rate and hemostatic therapies are determined by a one-year retrospective chart review, collected at the time of enrollment. Patients then receive Emicizumab, 3mg/kg weekly for 4 consecutive weeks, followed by once weekly dosing of 1.5mg/kg for 52 weeks total therapy. Dose up-titration to 3 mg/kg once weekly will be allowed if suboptimal efficacy. Treatment records are maintained along with bleeding event logs. Patients are closely monitored for safety and tolerability. Breakthrough bleeding events may be treated with the patients usual on-demand products per the investigator's discretion. Central clinical laboratory testing will be completed, in addition to genetic testing. Patient-reported outcomes (PROMIS-29 PROs, SF-36) will be gathered to gain understanding on the impact of treatment on patients. Analysis will be performed through descriptive statistics to determine proof of principle, with patient bleeding evaluated prior to and after emicizumab prophylaxis. End of study is expected to occur 18 months after the last patient's first dose of study drug, to include a 6-month post-emicizumab prophylaxis follow-up. The primary hypothesis is that emicizumab is safe and efficacious for prophylaxis in VWD. Secondary objectives include evaluation of treatment burden vs VWF concentrate prophylaxis, bleed rate and severity, VWF qualitative defects or genetic mutations that may have impact on emicizumab clinical response. Exploratory objectives include evaluation of health-related quality of life, impact on VWF concentrate use with bleeding events, surgeries, and heavy menstrual bleeding. Total length of the study is expected to be approximately 36 months. Six centers in the United States have currently been enrolling patients. Enrollment is currently ongoing. Conclusions: This ongoing pilot study is the first prospective investigation of emicizumab in patients with severe VWD. This study will shed light on feasibility, safety and potential efficacy of emicizumab prophylaxis in this patient population.

Background Long-term prophylaxis with von Willebrand factor (VWF) concentrate is recommended for patients with von Willebrand disease (VWD) who experience frequent and severe bleeding episodes. However, few cost-effectiveness or cost-comparison studies have evaluated prophylaxis versus on-demand (OD) treatment with VWF concentrates, and most rely on assumptions or literature-based inputs. This study presents a cost comparison of Wilate® prophylaxis versus OD treatment in patients with Type 3 VWD and a severe bleeding phenotype, using real-world prospective data from the WIL-29 and WIL-31 phase 3 studies. A unique feature of this analysis is the intrapatient comparison: the same individuals were treated with OD therapy in WIL-29 (6 months) and subsequently received prophylactic treatment in WIL-31 (12 months), enabling robust, patient-level comparative data. Methods A lifetime horizon cost model was developed from both a U.S. payer and societal perspective. Clinical inputs were derived directly from WIL-29 and WIL-31 studies, including observed Wilate® dosing, breakthrough bleeding rates, and treatment consumption. Healthcare resource utilization (HCRU) costs for minor and major bleeds were estimated from published literature. Societal costs were calculated using bleed duration data from the studies, to estimate productivity loss. Subgroup analyses were conducted for adults and adult women with Type 3 VWD. All costs were adjusted to 2025 U.S. dollars. Results In the overall Type 3 VWD population with a severe bleeding phenotype, prophylactic use of Wilate® was cost-saving, with an average annual cost of $293,851, compared to $304,240 for OD treatment, resulting in annual savings of $10,389 per patient. Even greater annual savings were observed among all adults ($52,720/year) and adult women ($124,737/year). Over a lifetime, prophylaxis was projected to yield cumulative savings of $298,504 for the overall population, $1,514,820 for adults, and $3,584,070 for adult women. Inclusion of productivity loss further increased the annual economic advantage of prophylaxis by an additional $43,002 per patient per year. These findings highlight the substantial clinical and economic burden of OD therapy and the value of long-term prophylactic treatment in this patient population. Conclusions This is the first cost comparison of prophylaxis versus OD treatment in Type 3 VWD based on prospective, intrapatient data, a design that enhances reliability by minimizing variability across treatment phases. The model's strength lies in its real-world clinical inputs, integration of societal costs considerations, and focus on patients with severe bleeding phenotypes. The results demonstrate that Wilate® prophylaxis delivers not only meaningful clinical benefits as demonstrated in the clinical trials, but also significant cost-savings, especially among adult women where the economic impact was most pronounced. These findings support the expanded use of VWF concentrate prophylaxis within comprehensive VWD management strategies. Future research incorporating broader direct/indirect costs, including those related to long-term health outcomes, e.g., joint deterioration, chronic anaemia, heavy menstrual bleeds, mental health and quality-adjusted life years (QALYs), may further strengthen the economic and therapeutic value of prophylactic treatment.

Introduction: Children are at increased risk for preventable anticoagulation-related adverse events due to variable pharmacokinetics, which require frequent dosing adjustments and regimen modifications. Anticoagulation stewardship programs (ASPs) aim to reduce medication-related errors and enhance patient safety. This single-institution quality improvement (QI) initiative aimed to improve adherence to institutional anticoagulation protocols and optimize dosing and monitoring strategies in hospitalized pediatric patients. Methods: A physician-and pharmacist-led pediatric ASP was implemented at Holtz Children's Hospital for inpatients under 22 years of age receiving anticoagulation. QI interventions were introduced in two phases: Phase 1 (1/2024-6/2024) focused on multidisciplinary protocol development, creation of a HIPAA-compliant automated dashboard to identify eligible patients, and a pilot program of weekly stewardship rounds with prospective audit and feedback on protocol adherance. Phase 2, beginning in October 2024, added targeted staff education and continuation of weekly rounds. Stewardship recommendations on anticoagulant dosing and monitoring were provided weekly to primary teams. An interim analysis from 1/2024-7/2025 was conducted. Data collected included demographics, anticoagulant type, dose, indication, co-morbidities, and if applicable, new thrombosis events (characteristics, treatment, and outcomes including bleeding events, length of stay (LOS), and follow-up). Recommendations were categorized by type and acceptance. Metrics were compared between phases using two-sided p-values (p<0.05 was considered significant). Results: A total of 537 anticoagulation-related encounters across 205 patient admissions were reviewed. Indications included inpatient thromboprophylaxis (36.7%, n=197), acute thrombosis (34.1%, n=183), secondary/long-term thromboprophylaxis (26.6%, n=143), and extracorporeal membrane oxygenation (ECMO) (2.1%, n=11). Commonly used anticoagulants were low molecular weight heparin (LMWH) (69.5%, n=373), direct oral anticoagulants (DOACs) (13.8%, n=74), unfractionated heparin (UFH) (9.9%, n=53), and direct thrombin inhibitors (DTIs) (3%, n=16). Most patients were admitted to the cardiovascular intensive care unit (CVICU) (19.7%, n=106), gastrointestinal transplant unit (17%, n=91), and hematology/oncology/bone marrow transplant service (15.1%, n=81). Protocol adherence improved from 86.4% in Phase 1 to 91.5% in Phase 2 (p=0.024). Stewardship recommendations were made in 33.9% (n=182) of encounters with 84.6% (n=154) accepted by primary teams. Common interventions included laboratory monitoring (40.6%, n=74), dose adjustments (39.1%, n=71), and anticoagulant changes (11.5%, n=21). A new in-hospital thrombosis occurred in 43 patients (21%), most of which were venous thromboembolism (79.1%, n=34), central line-associated (81.4%, n=35), non-occlusive (55.8%, n=24), and located in the upper extremity (55.8%, n=24). Associated comorbidities included ICU admission (55.8%, n=24), recent surgery (34.9%, n=15), and congenital heart disease (25.6%, n=11). Anticoagulation-related bleeding occurred in 6 patients with new thrombosis (14%), the majority (83.3%, n=5) being clinically relevant non-major bleeding. One ECMO patient experienced major bleeding. Bleeding rates did not differ between phases (11.1% vs. 16%, p=0.61). Although mean LOS remained similar between phases (89.7 days vs. 88.3 days, p=0.96), the time to therapeutic goal improved slightly from 48.6 hours to 45.1 hours (p=0.77). Hematology outpatient follow-up for patients with new thromboses improved from 55.6% to 66.7% (p=0.46). Conclusions: This single-institution experience reinforces the role of ASPs in ensuring appropriate anticoagulant dosing and monitoring for hospitalized pediatric patients. Implementation of the program improved adherence to protocols and was associated with high acceptance of stewardship recommendations. While this interim analysis did not show statistically significant changes in clinical outcomes such as LOS or time to achieve therapeutic anticoagulation, we believe this reflects the early stage of implementation. As the program matures and more data accrues, we anticipate further improvements in these metrics. This initiative provides a strong foundation for ongoing quality improvement efforts aimed at optimizing anticoagulation safety and outcomes.

Introduction: People with mild to moderate hemophilia are frequently underrepresented in clinical trials and registries, leading to gaps in evidence-based guidance. While early prophylaxis is standard in severe hemophilia, treatment approaches for non-severe disease remain inconsistent. This is often driven by the misconception that prophylaxis is appropriate only for individuals with residual factor ≤2%, despite increasing evidence of recurrent bleeds in non-severe cases. Heterogeneous bleeding phenotypes, evolving patient preferences, and provider uncertainty further contribute to this variation. Real-world data describing the use, selection, and safety of prophylaxis are essential to improving care for this population. Methods: ATHN Transcends (NCT04398628) is a prospective, longitudinal, cohort study conducted at over 60 ATHN-affiliated sites across the United States. The Hemophilia Natural History Arm captures safety and effectiveness of hemophilia therapies including clinical and participant-reported outcomes. This analysis includes demographic and baseline clinical data for participants with mild (residual levels 6-<40%) or moderate (residual levels 1-5%) Hemophilia A (HA) or Hemophilia B (HB) enrolled participants from March 2021 to April 2025. Results: A total of 158 participants were included: 110 with HA and 48 with HB. Participants with HA, 50 had moderate disease (mean FVIII 3.1% (1.4), median 3.0%) and 60 had mild disease (mean FVIII 18.1% (11.5), median 14.0%). Participants with HB, 26 had moderate disease (mean FIX 2.4% (1.0), median 2.0%) and 22 had mild disease (mean FIX 7.6% (10.4), median 15.5%). The mean age at enrollment was 16.4 years (min=0, max=78) for moderate HA and 29.4 years (2, 86) for mild HA. For HB, the mean age was 28.6 years (0, 71) for moderate and 18.7 years (2, 55) for mild disease. Females accounted for 13 (21.7%) of mild HA and 6 (27.3%) of mild HB participants; no females with moderate disease were enrolled. A target joint was reported in 6 (12%) of moderate HA, 4 (15.4%) of moderate HB, and 5 (8.3%) of mild HA participants. The mean age at first bleed was earlier in moderate compared to mild participants: 2.1 years (3.9) vs. 6.4 years (9.4) in HA, and 3.3 years (5.0) vs. 7.4 years (8.5) in HB. For HA participants, the head was the most reported site of first bleeding in both moderate and mild cases. In contrast, the most frequent site of first bleed for HB participants was the mouth. At enrollment, 58% of moderate HA and 37% of moderate HB participants reported use of continuous prophylaxis. In mild participants, 21.8% of HA and 15.8% of HB were also receiving prophylaxis. Short-term/intermittent prophylaxis was reported in 2% and 4.2% of moderate HA and HB, and in 7.3% and 10.5% of mild HA and HB, respectively. Females with mild HA, 2 (15%) reported continuous prophylaxis use. Among HA participants, emicizumab was the most used prophylactic agent (82.8% in moderate, 50.0% in mild), followed by standard half-life (SHL) recombinant FVIII concentrates in moderate HA (6.9%) and ultra-extended half-life (UEHL) FVIII concentrates for mild HA (21.4%). Most emicizumab users reported SHL concentrates as their as-needed therapy (41.9% in moderate, 58.3% in mild HA). The 2 females with mild HA on prophylaxis, one reported use of SHL and the other UEHL recombinant FVIII concentrates. In HB, extended half-life (EHL) recombinant factor IX concentrates were the most used prophylactic agents (77.8% in moderate, 60.0% in mild). Conclusions: In this analysis, we demonstrate that over one third of ATHN Transcends participants with non-severe hemophilia were already receiving continuous prophylaxis, including a significant subset with mild disease. Prior publications reported prophylaxis use in fewer than one-third of moderate and under 30% of mild cases*. This shift reflects growing recognition that bleeding risk may not correlate with factor levels and supports a phenotype-driven approach to care. Our findings also highlight the role of emicizumab in HA, while HB patients still rely on FIX concentrates for prophylaxis. Ongoing follow-up will determine whether treatment patterns and adoption of newer hemostatic agents continue to evolve. These findings underscore the need to revisit prophylaxis guidelines and reinforce the importance of real-world data in shaping evidence-based, personalized care in non-severe hemophilia. *Iorio A, et al. Haemophilia. 2023 Jan;29(1):33-44.

Prognostic factors for residual thrombosis (RT) and complete veno-occlusion (CVO) after 6 weeks of anticoagulation in pediatric acute VTE remain unknown. This study assessed the frequency and predictors of RT and CVO through a pre-specified secondary analysis of the Kids-DOTT randomized clinical trial. Per trial protocol, RT and CVO were radiologically assessed six weeks after acute VTE diagnosis. Univariate logistic regression analyses were performed for both outcomes, and variables with p-value 0.05 were included in a multivariable models, where a p-value of <0.05 denoted statistical significance. Among 532 enrolled patients, 28.8% demonstrated RT and 12.6% CVO after six weeks of treatment. Age and sex distributions did not differ significantly by RT and CVO status. In multivariable analysis, cerebral venous sinus location of VTE (OR 2.52, 95% CI=1.22-5.21; p=0.01) and comorbid infection (OR 1.61, 95% CI=1.00-2.58; p=0.049) were independently associated with RT. Internal jugular vein (OR 3.97, 95% CI=1.26-12.48; p=0.02) and lower extremity VTE (OR 2.28, 95% CI=1.01-5.15; p= 0.046) were independently associated with CVO. Approximately 29% of young patients developed RT, and 13% CVO, after six weeks of anticoagulation. VTE location and comorbid infection were identified as predictors for RT and CVO. These findings highlight the need for further studies on long-term outcomes of RT and CVO, particularly their impact on post thrombotic syndrome development and quality of life measures in pediatric VTE.

Background: Ifosfamide, an alkylating agent used for treating various cancers, can cause encephalopathy in 10–30% of adults and 8% of children. Methylene blue has been used to treat ifosfamide-induced encephalopathy (IIE). This study aimed to describe our institutional experience with IIE in children and young adults with cancer, including its clinical manifestations, treatment, and outcomes. Methods: We reviewed the clinical records of patients with cancer aged up to 30 years who developed IIE over 10 years. Results: Twenty-four patients (median age: 17.6 years, range: 4–30 years) were included; 54% were male, and 71% had bone/soft tissue sarcomas. Ifosfamide was administered alone or with other drugs (dose range: 1.5–3.3 g/m2/day). Twelve patients developed IIE after short intermittent infusions (1–3 h), and twelve developed it after continuous infusions (12–24 h). IIE occurred at a median cumulative ifosfamide dose of 18 g/m2. Symptoms appeared within hours to five days and resolved within 24–120 h. An altered mental status was present in all except one patient. Twelve patients had grade 3 IIE (severe somnolence, agitation, and confusion), and five had grade 4 IIE (coma and seizures). Twenty patients (83%) received methylene blue, with symptom resolution in nineteen patients (83%). Imaging studies showed nonspecific findings. Ten patients were re-challenged with ifosfamide; five received prophylactic methylene blue treatment, of whom three had recurrence. Conclusions: IIE can occur with both short intermittent and continuous ifosfamide infusions and presents as an altered mental status, seizures, and, rarely, hemiparesis. Symptoms are transient, and methylene blue may help alleviate this neurotoxicity, but it does not completely prevent its recurrence.

The needs of haemophilia carriers (HC) have been historically overlooked. It is now recognised that HC manifests bleeding symptoms, including haemarthrosis. The natural history of joint health in HC is not yet defined. A multi-institutional cross-sectional study aimed to evaluate the characteristics of joint disease in HC, aged 18-40 years, compared to age-matched controls. The carrier cohort included females with confirmed HC status. Controls had no personal or family history of bleeding disorders. All females with a history of joint trauma or surgery within 12 months or any history of joint replacement were excluded. Joint health was assessed by clinical history, Haemophilia Joint Health Score (HJHS) and point-of-care musculoskeletal ultrasonography (POC-MSKUS). Thirty HC and 30 controls were enrolled. For HC, the median factor activity level was 52% (range 17%-100%). Carriers, regardless of baseline factor activity levels, reported higher prevalence of chronic joint pain (p < .001) and swelling (p = .002) than controls. Heavy menstrual bleeding, epistaxis, gingival bleeding and easy bruising were also more prevalent in HC (p < .001). Despite HC having a higher median HJHS score (5 vs. 0, p < .001), no differences were observed when using POC-MSKUS. HC with a body mass index ≥25 mg/m reported more haemarthrosis (p = .037). HC are at increased risk of joint-related symptoms and poorer joint health than age-matched controls. Dedicated follow-up to prevent and treat joint disease in HC is imperative. This study is also a call for additional investigation to clarify the association, or lack thereof, between factor activity and joint disease.

INTRODUCTION: Therapies for people with hemophilia (PwH) A (HA) and B (HB) are evolving. While offering significant benefits and addressing unmet needs, long-term monitoring of their safety is essential. To that end, the American Thrombosis and Hemostasis Network (ATHN) captures data from PwH including the use and safety of all available HA and HB therapies through their more than 140 ATHN-affiliated hemophilia treatment centers (HTCs) in the United States (US). METHODS: ATHN Transcends (NCT4398628) is a longitudinal, prospective cohort study currently conducted at over 60 ATHN-affiliated sites in the US. The study is approved by central and local institutional review boards. Any person with a diagnosis of congenital HA or HB (factor VIII (FVIII) or IX (FIX) activity <50% and females known to be genetic carriers regardless of their baseline factor activity level) who receive care at a participating site are eligible for inclusion. All participants or their guardians are required to sign informed consent and/or assent prior to participation. Participants are excluded if they have any other known congenital bleeding disorder. Demographic and clinical information are collected at baseline and quarterly. Therapy-related adverse events, including those designated by the European Haemophilia Safety Surveillance group (EUHASS), as well as adverse events of special interest, are recorded and monitored. Health status is measured using the 5-level EuroQol-5D questionnaire (EQ-5D-5L). Descriptive statistics of the baseline medical history and demographic data characterized the enrolled population. RESULTS: We obtained consent on the first Hemophilia Natural History Arm's participant in March 2021. As of July 15, 2024, 149 participants (146 male assigned at birth) were enrolled at 17 sites, 121 with HA and 28 with HB. Mean age at enrollment was 20 years (SD: 19.18, range 0 - 86). For those with HA, 83 (68%) had severe, 19 (16%) had moderate, and 19 (16%) had mild FVIII deficiency. For those with HB, 10 (36%) had severe, 13 (46%) had moderate, and 5 (18%) had mild FIX deficiency. Overall, 110 (74%) participants used prophylaxis as their primary therapy, 92 (99%) with severe deficiency. For participants with HA on prophylaxis, 73 (76%) were treated with bispecific antibodies. The only adverse events reported were upper respiratory infection (URI) (2 participants) and the development of a FVIII inhibitor (after 9 exposure days to FVIII concentrate in one participant on bispecific antibody as primary prophylactic therapy). A single serious adverse event (anemia requiring hospitalization) was reported in a participant with severe hemophilia B on extended half-life factor IX concentrate. Ninety-eight participants, with a mean age of 28 years (SD: 18.7, range 9 - 86) completed the EQ-5D-5L at baseline. Most (60.2%, n=59) had severe hemophilia, while 21.4% (n=21) and 18.3% (n=18) had moderate and mild deficiencies. Problems with mobility, completing usual activities, and self-care were reported by 21%, 15%, and 7% of these participants. The majory of participants (71.4%) reporting problems with mobility had severe hemophilia. Participants with severe hemophilia also accounted for the majority of those reporting problems with self-care and completing usual activies (71.4%, n=5 and 73.3%, n=11). Problems with pain and anxiety/depression were reported by 34% and 23% of participants at baseline; most had severe hemophilia (69.7%, n=23 and 60.8%, n=14; respectively). The mean health status rating at baseline was 85 out of 100. DISCUSSION: The ATHN Transcends Hemophilia Natural History Arm has the capability of enrolling a large cohort of PwH from multiple ATHN-affiliates across the US, monitoring safety events and assessing health status related to living with and being treated for HA and HB. During the first 40 months of data collection of the ATHN Transcends Hemophilia Natural History Arm, we observed no unexpected adverse events associated with contemporary hemophilia therapy. Similar to ATHN 7 (NCT03619863), ATHN's previous hemophilia natural history study, ATHN Transcends Hemophilia Natural History Arm confirms the high prevalence of pain, mobility impairment, and mental health concerns in PwH. Despite advances in therapy, hemophilia continues to significantly impact the lives of PwH. Corrales-Medina:Bayer: Other: Scientific advisory board, Research Funding; Octapharma: Other: Scientific advisory board, Research Funding; Takeda: Other: Scientific advisory board; Sanofi: Other: Scientific advisory board; CSL Behring: Other: Scientific advisory board; Genentech: Other: Scientific advisory board. Carpenter:Genentech, Inc., Kedrion, Novo Nordisk: Honoraria. Chrisentery-Singleton:Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; hema biologics: Consultancy, Honoraria, Speakers Bureau; kedrion: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Speakers Bureau. Zia:Star Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; COR2ED GmbH: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Membership on an entity's Board of Directors or advisory committees. Recht:Bayer: Research Funding; CSL Behring: Ended employment in the past 24 months, Research Funding; Genentech: Consultancy, Research Funding; Grifols: Research Funding; HEMA Biologics: Consultancy, Research Funding; LFB: Research Funding; Novo Nordisk: Consultancy, Research Funding; Octapharma: Research Funding; Pfizer: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; uniQure: Consultancy, Research Funding; Spark Therapeutics: Research Funding; Partners in Bleeding Disorders: Membership on an entity's Board of Directors or advisory committees.