Expert Consensus on Unmet Needs and Barriers to Optimal Hemophilia Care in Brazil: Results from a Modified Delphi Study

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Ozelo, Bruna Webler, Julia Lima, Mariana Alves, Ana Karolina de Nunes, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9471111/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Despite therapeutic advances, important gaps persist in hemophilia care within public healthcare systems in middle-income countries. In Brazil, universal access to prophylaxis is ensured through a centralized public system, however, the available treatments remain limited compared to international standards. This study aimed to identify unmet needs, barriers to optimal care, and priority attributes for emerging therapies in hemophilia A and hemophilia B within the Brazilian Unified Health System (SUS), using expert consensus. Results: A modified Delphi study was conducted with twelve hematologists experienced in hemophilia care from all Brazilian regions. Consensus indicated persistent unmet needs among individuals with moderate to severe hemophilia A without inhibitors (100%) and with inhibitors (80.0%), as well as hemophilia B without inhibitors (100%) and with inhibitors (91.7%). Consolidation of national clinical protocols into a single guideline was considered important to standardize care (83.3%). Key extrinsic barriers included limited access to treatment centers for patients in remote areas (83.3%), social vulnerability (83.3%), restricted access to arthropathy management and rehabilitation services (91.7%), and limited access to specialized care for acute bleeding events (83.3%). Additional barriers included shortages of trained professionals outside specialized centers (91.7%), delayed incorporation of new technologies (91.7%), insufficient integration across levels of care (83.3%), an inadequate number of specialized centers (90.0%), failures in referral and counter-referral systems (90.0%), and lack of specialized technical support in emergency settings (100%). Intrinsic barriers to adherence included difficult venous access in children aged 0 to 6 years (100%), reduced adherence during transition to self-infusion in adolescents (91.7%), lack of adequate self-infusion training (83.3%), and venous access difficulties with functional limitations in older adults (83.3%). Panelists also estimated that, among individuals receiving prophylaxis with factor replacement therapy, the mean proportion with compromised adherence was 33% (SD: 2.0). Regarding emerging therapies, consensus supported less invasive subcutaneous administration (100%), reduced dosing frequency (100%), and therapies not requiring routine laboratory monitoring (83.3%) as facilitators of adherence. Conclusions: This expert consensus highlights persistent unmet needs and structural and individual barriers to optimal hemophilia care in Brazil. The findings support health system reorganization and the incorporation of innovative therapies to improve adherence and clinical outcomes in the SUS. Hematology Hemophilia A Hemophilia B Needs Assessment Medication adherence Delphi Technique Brazil Figures Figure 1 Figure 2 Figure 3 1. Introdution Over the last decade, hemophilia care has improved significantly in Brazil. However, Brazil represents a relevant setting for examining persistent gaps in hemophilia care within a universal health system. The management of hemophilia is predominantly conducted through the Brazilian Unified Health System (SUS), supported by a structured national program in which blood transfusion centers and specialized units serve as hemophilia reference centers. These units function as central hubs, concentrating key clinical and operational responsibilities, including diagnosis, treatment dispensing, patient monitoring, and the provision of longitudinal care to a large and diverse patient population ( 1 , 2 ). The national network is structurally robust and ensures universal access for patients with inherited bleeding disorders, including prophylaxis for patients with severe hemophilia. This achievement represents a major milestone in the public health model. Nevertheless, logistical complexity and regional disparities may still compromise the continuity and quality of care ( 3 ). Compared with the international context, the Brazilian program has achieved notable success in promoting access to specialized health care. However, the adoption of innovations occurs more gradually than in high-income countries, where extended half-life (EHL) factors and other technologies have already been established as the standard of care ( 4 ). In Brazil, the implementation of primary prophylaxis for patients with severe hemophilia in 2012, along with the more recent incorporation of emicizumab into SUS for hemophilia A pediatric patients, and for all hemophilia A without inhibitors, represents significant therapeutic advances. However, important barriers and unmet needs remain, particularly regarding optimal adherence, long-term effectiveness, and sustainability of prophylaxis strategies ( 5 ). Replacement therapy based on standard half-life (SHL) clotting factor concentrates (CFCs) continues to play a significant role in the therapeutic arsenal, reflecting a relatively slow pace of therapeutic modernization and possible limitations in achieving improvements in convenience, sustained adherence, and quality of life ( 4 , 6 ). Clinical practice evidence suggests that the expected benefit of CFCs as primary prophylaxis is not always achieved, largely due to limitations in adherence and the operational viability of care ( 7 , 8 ). Treatment with CFCs requires recurrent infusions and imposes a high therapeutic burden related to the frequency of regimens and venous access challenges. These implementation gaps arise from the interaction of intrinsic determinants – such as venous access difficulties, lack of social support, functional limitations, severity of the disease– with extrinsic determinants associated with care organization and the lag between evidence generation and technology incorporation ( 9 – 11 ). Consequently, national studies report substantial variability in adherence rates, with estimates ranging from 25% and 72%, resulting in a higher risk of potentially avoidable bleeding and progressive musculoskeletal damage ( 10 , 12 ). Evidence indicates that simpler therapeutic regimens may mitigate part of these limitations. For example, studies evaluating the EHL factor IX have reported adherence rates above 95%, along with a potential reduction in bleeding episodes associated with irregular use of daily regimens ( 13 ). In this context, hematologists working in transfusion blood centers are uniquely positioned to identify barriers in clinical practice and assess how emerging technologies could mitigate the limitations of the current model. As these implementation challenges are not fully characterized by clinical trials and available evidence remains fragmented, structured consensus methods, such as the Delphi technique, enable the systematic capture and prioritization of specialist perceptions ( 14 , 15 ). Therefore, this study applied a modified Delphi panel with Brazilian to identify unmet needs, barriers to optimal care, and priority attributes for emerging therapies in hemophilia A and hemophilia B within the Brazilian public health system, SUS. 2. Methods 2.1 Delphi design A modified Delphi consensus study was conducted to obtain structured expert agreement on priority domains and unmet needs in hemophilia A and hemophilia B care within the SUS. The Delphi method was selected given the limited disease-specific evidence, heterogeneity in routine practice, and fragmented information across care settings, which may hinder consistent decision making. The study was reported in accordance with the Delphi Studies in Social and Health Sciences: Recommendations for an Interdisciplinary Standardized Reporting (DELPHISTAR) ( 16 ) guideline, ensuring transparency, methodological rigor, and completeness of reporting. The process comprised three rounds conducted between October and December 2025: two asynchronous rounds using anonymized online questionnaires followed by a structured synchronous online consensus meeting focused on unresolved items. This study followed a prospectively developed protocol, although it was not registered in a publicly accessible database. 2.2 Steering committee and methodological oversight Methodological oversight of the Delphi process was provided by three investigators with expertise in Delphi methodology (FI, BW, and JL). These investigators supported the study design, drafting of the initial set of statements, refinement of the consensus process, and pre-definition of analytical and consensus criteria. A scientific committee composed of two hematologists with experience in hemophilia care within the SUS (ISSP and MCO) reviewed the draft statements to ensure clinical relevance and alignment with routine practice challenges and areas of uncertainty. All authors drafted the initial statements and coordinated revisions throughout the Delphi rounds, while the scientific committee ensured clinical alignment and contextual adequacy for the Brazilian public health setting. 2.3 Statement generation and questionnaire development To inform statement development, a targeted literature review was conducted to identify evidence related to hemophilia A and hemophilia B care in Brazil. Searches were performed in PubMed (via MEDLINE) and LILACS (via the Virtual Health Library). The search strategy combined the keywords “hemophilia”, “treatment”, “unmet needs” and “Brazil, covering English and Portuguese publications. Searches were conducted up to April 2025. Evidence from the targeted review was used to contextualize current practice patterns and inform the formulation of clinically relevant statements. Guided by the review findings and the scope defined by the scientific committee, the questionnaire was structured into five thematic domains: unmet needs according to hemophilia type; treatment-related aspects including adherence and residual disease burden; extrinsic and intrinsic barriers to optimal care within the SUS; and priority attributes of emerging technologies (Fig. 1 ). This approach aimed to ensure that the statements were grounded in existing knowledge while systematically addressing areas of uncertainty and variability observed in routine clinical practice. 2.4 Panel selection, recruitment and blinding procedures The expert panel included physicians specialized in hematology and hemotherapy who met the following eligibility criteria: (a) at least five years of clinical experience in the care or management of people with hemophilia A or hemophilia B; (b) regular clinical practice in hemophilia treatment centers; (c) at least 50% of declared clinical workload dedicated to public hospitals; (d) at least 10% of declared clinical workload dedicated to bleeding disorders; (e) management of at least 15 patients with hemophilia per month, including individuals with and without inhibitors; (f) care provision to at least two age groups among children, adolescents, adults, and older adults; and (g) confirmed availability to participate in three consecutive Delphi rounds. The selection aimed to achieve proportional regional representation across Brazilian centers, including the North, Northeast, Midwest, Southeast, and South regions, based on availability identified during the screening process. Panel members who agreed to participate received honoraria for participation. Panel selection and recruitment were conducted by an independent team with experience in Delphi studies, which was responsible for screening potential participants, coordinating invitations, managing informed consent, distributing questionnaires, monitoring response rates, and overseeing compliance with predefined timelines across all Delphi rounds. To reduce bias and preserve independence of responses, panelists were not informed about other participants’ identities or about the funding source. Sponsor blinding was ensured, given that the sponsor had no access to participants’ identities or workplace affiliations, and no access to individual-level responses. No additional recruitment occurred after the first round. Experts who did not complete a Delphi round within the allotted time were not eligible to participate in subsequent rounds. All participants provided electronic informed consent prior to study participation. 2.5 Delphi panel size, rounds and implementation The size of the Delphi panel was defined in accordance with methodological guidance indicating that panels of approximately 10 to 15 experts are sufficient when participants share a homogeneous professional background and high level of subject-matter expertise. Considering the specialized focus on hemophilia care within the SUS and the need to ensure complete participation across three consecutive Delphi rounds, a panel of 12 hematologists was considered adequate to support a robust and feasible consensus process ( 17 , 18 ). Three rounds were conducted (Fig. 2 ). The Round 1 questionnaire was distributed by electronic mail to all 12 panelists and completed October 10–20, 2025. Round 2 was conducted between October 31 and November 10, 2025. Round 3 took place on December 15, 2025. All 12 panelists completed Rounds 1 and 2, and 10 participated in Round 3. In Rounds 1 and 2, participants individually evaluated the statements using anonymous online questionnaires accessed via electronic voting links. Responses were collected electronically to ensure confidentiality and to reduce the risk of dominance bias. Participants rated each statement using a five-point Likert scale with the following response options: strongly disagree, partially disagree, neutral, partially agree, and strongly agree. A secondary set of questions used single-choice responses or priority ranking formats. Completion of all items was mandatory. Statements not reaching the predefined consensus threshold were carried forward to the subsequent round. Prior to Round 2, participants received controlled feedback summarizing group-level results from Round 1, including agreement rates and the distribution of responses across Likert categories, alongside anonymized summary comments. Round 3 consisted of a structured synchronous meeting involving all panelists and focused on items that remained without consensus after Round 2. The discussion was guided by aggregated results from previous rounds and aimed to clarify divergent perspectives while preserving a structured consensus process. Following discussion, outstanding statements were re-rated using anonymous electronic voting. 2.6 Definition of consensus and statistical analysis Panel characteristics were summarized using descriptive statistics. The Delphi questionnaire comprised different types of items, including agreement-based Likert-scale statements, single-choice questions, numerical estimation questions, and priority-ranking items. Likert-type statements were rated on a five-point ordinal scale (strongly disagree, partially disagree, neutral, partially agree, and strongly agree) and were summarized using medians and interquartile ranges (IQR), as well as response distributions. For each Likert-type statement, the level of agreement was calculated as the proportion of responses rated as partially agree or strongly agree. Statements were classified as: (i) consensus in agreement (≥ 80% partially agree/strongly agree); (ii) consensus in disagreement (≥ 80% strongly disagree or partially disagree); or (iii) no consensus (all other response distributions). Single-choice questions were summarized using absolute and relative frequencies. Numerical estimation questions (e.g., annual bleeding rates, proportions of patients with adherence issues or joint outcomes) were summarized using means, standard deviations (SD), medians, and IQR, reflecting expert-perceived estimates rather than patient-level measurements. Priority-ranking items were summarized descriptively based on the distribution of assigned ranks across panelists. Quantitative analyses were performed in Microsoft Excel ( 19 , 20 ). 3. Results 3.1 Demographic and clinical profile of the panelists The Delphi panel comprised 12 hematologists with heterogeneous demographic and professional profiles. Most panelists were aged 40–49 years (41.7%) and 58.3% were male. Panelists represented all five Brazilian geographic regions, with the highest representation from the Northeast (33.3%). All panelists practiced in municipalities with > 50,000 inhabitants. Most panelists reported 11–20 years of experience in hemophilia management (66.7%), and 25.0% reported > 20 years. Half of participants held a master’s degree (50.0%), while 16.7% held a PhD. Regarding clinical volume, 58.3% reported managing > 50 patients with hemophilia A per month. Most panelists reported managing up to 15 patients per month for hemophilia A with inhibitors (75.0%) and hemophilia B with inhibitors (83.3%). Panel characteristics are summarized in Table 1 . Table 1 Demographic and professional characteristics of Delphi panelists. Variable n (%) Age Under 30 years 1 (8.3) 30–39 years 2 (16.7) 40–49 years 5 (41.7) 50–59 years 3 (25.0) Over 60 years 1 (8.3) Gender Female 5 (41.7) Male 7 (58.3) Region of practice in Brazil North 3 (25.0) Northeast 4 (33.3) Central-West 1 (8.3) Southeast 2 (16.7) South 2 (16.7) Population size of municipality Large size, over 50,000 inhabitants 12 (100) Years of experience with hemophilia 5–10 years 1 (8.3) 11–20 years 8 (66.7) More than 20 years 3 (25.0) Educational level Medical Doctor (MD) degree 4 (33.3) Master’s degree 6 (50.0) Doctoral degree (PhD) 2 (16.7) Hemophilia A, all forms > 50 patients/month 7 (58.3) 31–50 patients/month 3 (25.0) 16–30 patients/month 2 (16.7) Hemophilia A with inhibitors Up to 15 patients/month 9 (75.0) 31–50 patients/month 2 (16.7) > 50 patients/month 1 (8.3) 16–30 patients/month 0 (0.0) Hemophilia B, all forms 16–30 patients/month 7 (58.3) Up to 15 patients/month 3 (25.0) > 50 patients/month 2 (16.7) 31–50 patients/month 0 (0.0) Hemophilia B with inhibitors Up to 15 patients/month 10 (83.3) 16–30 patients/month 2 (16.7) 31–50 patients/month 0 (0.0) > 50 patients/month 0 (0.0) 3.2 Domain 1: Unmet needs by hemophilia type and inhibitor status This domain comprised five statements addressing unmet needs according to the hemophilia type and inhibitor status, as well as aspects related to health system organization. Consensus was achieved for all five statements (100%), indicating a uniform perception among panelists that relevant unmet needs persist across hemophilia A and B, both with and without inhibitors. Panelists unanimously agreed that unmet needs persist among individuals with moderate to severe hemophilia A without inhibitors (100%) and hemophilia B without inhibitors (100%). Agreement was also reached for patients with inhibitors, with consensus at the predefined threshold for hemophilia A with inhibitors (80.0%) and a higher level of agreement for hemophilia B with inhibitors (91.7%). With respect to health system organization, panelists reached consensus on the importance of consolidating the Clinical Protocols and Therapeutic Guidelines (PCDT) into a single document to promote standardized and comprehensive hemophilia care within the SUS (83.3%) (Table 2 ). Table 2 Expert consensus on unmet needs across hemophilia A and B, by inhibitor status. Statement Agreement Median (IQR) Likert scale ranking a Considering treatments currently available in SUS (plasma-derived Factor VIII concentrate; recombinant Factor VIII concentrate), there are unmet needs for people living with moderate to severe Hemophilia A without inhibitors Yes b 5.0 (4.2–5.0) Considering treatments currently available in SUS (immune tolerance induction therapy, bypassing agents, and emicizumab), there are unmet needs for people living with moderate to severe Hemophilia A with inhibitors Yes c 4.0 (3.7–4.25) Considering treatments currently available in SUS (plasma-derived Factor IX concentrate), there are unmet needs for people living with moderate to severe Hemophilia B without inhibitors Yes b 5.0 (5.0–5.0) Considering treatments currently available in SUS (bypassing agents), there are unmet needs for people living with moderate to severe Hemophilia B with inhibitors Yes b 5.0 (4.2–5.0) Consolidating PCDT into a single document to guide hemophilia management in SUS is important to ensure comprehensive care and standardized assistance Yes b 5.0 (4.2–5.0) Abbreviations: IQR = interquartile range; SUS = Brazilian Unified Health System; PCDT = Clinical Protocols and Therapeutic Guidelines. a Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1 = strongly disagree, 2 = disagree, 3 = somewhat disagree, 4 = agree, 5 = strongly agree. b Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 2 of surveying. c Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 3 of surveying. Table 3 Numerical questions on perception of treatment adherence, annualized bleeding rate, and joint complications. Statement Mean (SD) Median (IQR) On average, what is the number of bleeding episodes per year among people living with Hemophilia A without inhibitors, on continuous prophylactic treatment with Factor VIII replacement? 3.3 (2.0) 3.0 (2.2–4.0) On average, what is the number of bleeding episodes per year among people living with Hemophilia A with inhibitors, on treatment with immune tolerance induction protocol and/or prophylaxis with bypassing agents? 5.6 (2.0) 6.0 (5–6.0) On average, what is the number of bleeding episodes per year among people living with Hemophilia A with inhibitors, using emicizumab? 0.9 (1.0) 1.0 (0.0–1.7) On average, what is the number of bleeding episodes per year among people living with Hemophilia B without inhibitors, on continuous prophylactic treatment with Factor IX replacement (plasma-derived)? 2.3 (2.0) 2.0 (1.25–3.0) On average, what is the number of bleeding episodes per year among people living with Hemophilia B with inhibitors? 5.2 (2.0) 5.0 (3.2–6.7) On average, what is the increase in the number of bleeding episodes per year among people living with Hemophilia A and B, with and without inhibitors, due to reduced adherence to factor replacement therapy? 6.1 (2.0) 5.0 (5.0–3.7) Considering people with hemophilia who had access to primary prophylaxis, what percentage of patients develop arthropathy due to joint bleeding? 27 (2.0) 30.0 (16.25–38.7) Considering people with hemophilia who had access to primary prophylaxis, what percentage of patients progress to indication for surgery or use of joint prostheses? 10.4 (2.0) 13.0 (1.0–15.0) Considering people with hemophilia who had access to secondary prophylaxis, what percentage of patients develop arthropathy due to joint bleeding? 42.5 (2.0) 40.0 (31.25–50.0) Considering people with hemophilia who had access to secondary prophylaxis, what percentage of patients progress to indication for surgery or use of joint prostheses. 20.1 (2.0) 20.0 (11.25–28.7) In your clinical experience, what percentage of people with hemophilia on prophylaxis with factor replacement therapy have adherence impacted? 33 (2.0) 20.0 (15.0–47.5) What percentage of children aged 0 to 6 years have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy? 25 (2.0) 18.0 (6.2–35.0) What percentage of children aged 7 to 12 years have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy? 14.5 (2.0) 10.0 (6.2–17.5) What percentage of adolescents have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy? 23.5 (2.0) 20.0 (11.2–28.7) What percentage of adults have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy? 24.5 (2.0) 23.0 (16.2–30) Abbreviation: IQR = interquartile range; SD = standard deviation. 3.3 Domain 2: Treatment-related aspects (adherence and residual disease burden) This domain included a set of numerical estimation questions exploring expert perceptions regarding bleeding frequency, treatment adherence, and joint-related outcomes under different prophylactic strategies. As these items were designed to capture descriptive clinical estimates rather than agreement-based judgments, no formal consensus classification was applied. Results are presented as descriptive summaries, reflecting the overall clinical experience of the panel. Among individuals with hemophilia A without inhibitors receiving continuous prophylaxis with factor VIII replacement therapy, the estimated annual number of bleeding episodes had a mean of 3.3 (SD: 2.0), with a median of 3.0 (IQR: 2.2–4.0). For individuals with hemophilia A with inhibitors treated with immune tolerance induction protocols and/or prophylaxis with bypassing agents, bleeding frequency was higher, with a mean of 5.6 episodes per year (SD: 2.0) and a median of 6.0 (IQR: 5.0–6.0). In contrast, among individuals with hemophilia A with inhibitors receiving emicizumab, the estimated bleeding burden was substantially lower, with a mean of 0.9 episodes per year (SD: 1.0) and a median of 1.0 (IQR: 0.0–1.7). For individuals with hemophilia B without inhibitors receiving continuous prophylaxis with plasma-derived factor IX, the mean estimated number of bleeding episodes per year was 2.3 (SD: 2.0), with a median of 2.0 (IQR: 1.2–3.0). Among individuals with hemophilia B with inhibitors, the mean estimated annual number of bleeding episodes was 5.2 (SD: 2.0), with a median of 5.0 (IQR: 3.2–6.7). Panelists also estimated the impact of reduced adherence to factor replacement therapy on bleeding frequency. The mean estimated increase in the number of bleeding episodes per year associated with reduced adherence was 6.1 (SD: 2.0), with a median increase of 5.0 episodes (IQR: 3.7–5.0). Regarding joint outcomes, among individuals with access to primary prophylaxis, the mean estimated proportion of patients developing arthropathy due to joint bleeding was 27% (SD: 2.0), with a median of 30.0% (IQR: 16.2–38.7). The mean estimated proportion of patients progressing to an indication for surgery or joint prosthesis use in this group was 10.4% (SD: 2.0), with a median of 13.0% (IQR: 1.0–15.0). Among individuals with access to secondary prophylaxis, the mean estimated proportion developing arthropathy was 42.5% (SD: 2.0), with a median of 40.0% (IQR: 31.2–50.0), while the mean estimated proportion progressing to surgical indication or joint prosthesis use was 20.1% (SD: 2.0), with a median of 20.0% (IQR: 11.2–28.7). Estimates related to treatment adherence indicated that the mean proportion of individuals receiving prophylaxis with factor replacement therapy who experienced compromised adherence was 33% (SD: 2.0), with a median of 20.0% (IQR: 15.0–47.5). When stratified by age, the mean estimated proportion of compromised adherence was 25% among children aged 0–6 years (SD: 2.0; median: 18.0%, IQR: 6.2–35.0), 14.5% among children aged 7–12 years (SD: 2.0; median: 10.0%, IQR: 6.2–17.5), 23.5% among adolescents (SD: 2.0; median: 20.0%, IQR: 11.2–28.7), and 24.5% among adults (SD: 2.0; median: 23.0%, IQR: 16.2–30.0). 3.4 Domain 3: Extrinsic barriers (health system and access barriers) This domain comprised 16 statements, of which 13 reached the predefined consensus threshold, addressing extrinsic barriers related to health system organization and access to hemophilia care within the SUS (Table 4 ). The central theme identified was limited access to specialized and integrated services, particularly outside reference centers. The most critical barrier was the absence of specialized technical support in emergency settings, which achieved unanimous consensus (100%). High levels of agreement were also observed for shortages of healthcare professionals with expertise in hemophilia outside specialized centers (91.7%), delays in the incorporation of new technologies and continued reliance on obsolete treatments (91.7%), and restricted access to services for the management and rehabilitation of hemophilic arthropathy (91.7%). Living in remote areas (83.3%) and socially vulnerable conditions (83.3%) were also reported as barriers. Table 4 Expert consensus on extrinsic barriers to optimal hemophilia care within the SUS. Statement Option(s) Agreement Median (IQR) Likert scale ranking a Patients living in remote or distant areas have greater difficulty maintaining continuous access to factor replacement therapy due to access issues to Blood Centers/Satellite Blood Centers compared to those living closer to specialized services NA Yes b 5.0 (4.0–5.0) Patients in socially vulnerable situations or with precarious housing conditions have compromised optimal care NA Yes b 5.0 (4.25–5.0) Access to specialized services for managing and rehabilitating arthropathy is limited and compromises hemophilia care NA Yes b 5.0 (4.0–5.0) Access to specialized services for acute management of bleeding complications is limited and compromises hemophilia care NA Yes b 4.0 (4.0–4.75) Patients experience difficulty managing hemorrhagic complications, such as joint bleeding, at home. NA No 4.0 (3.5–5.0) Patients experience difficulties maintaining treatment with coagulation factor replacement due to episodes of reduced supply. NA No 4.0 (1.75–5.0) Patients experience difficulty maintaining treatment with coagulation factor replacement due to episodes of reduced supply of emicizumab or the unavailability of this medication in their region. NA No 2.0 (1.0–4.0) Extrinsic factors that may compromise treatment adherence in patients with hemophilia. Shortage of specialized professionals Yes b 5.0 (4.25–5.0) Lack of integration Yes b 5.0 (4.0–5.0) Delay in the incorporation Yes b 5.0 (4.0–5.0) Insufficient specialized hemophilia centers (Blood Centers/Satellite Blood Centers) Yes d 5.0 (4.0–5.0) Failures in the patient referral and counter-referral system Yes d 4.5 (4.0–5.0) Absence of specialized technical support, especially in emergency situations Yes d 4.5 (4.0–5.0) Extrinsic barriers that may compromise treatment adherence in women with hemophilia Lack of awareness and education among healthcare professionals regarding bleeding disorders in women Yes b 4.0 (4.0–5.0) Lack of integration among hematology, gynecology, obstetrics, and primary care services Yes b 4.0 (4.0–5.0) Lack of research and data on hemophilia in women Yes b 4.0 (4.0–4.75) Abbreviation: IQR = interquartile range; NA = not applicated. a Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1 = strongly disagree, 2 = disagree, 3 = somewhat disagree, 4 = agree, 5 = strongly agree. b Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 1 of surveying. c Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 2 of surveying. d Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 3 of surveying. System fragmentation and care coordination emerged as additional high-impact barriers. Insufficient integration across levels of care reached consensus (83.3%), alongside an inadequate number of specialized hemophilia treatment centers (90.0%) and failures in referral and counter-referral systems (90.0%). In contrast, three statements did not reach consensus, including difficulties in managing hemorrhagic complications at home and interruptions in factor replacement therapy due to supply shortages or regional unavailability of emicizumab. All statements addressing extrinsic barriers affecting women with hemophilia reached consensus, including lack of professional awareness (83.3%), limited integration between hematology and women’s health services (83.3%), and scarcity of research and data on hemophilia in women (83.3%). 3.5 Domain 4: Intrinsic barriers (patient-level adherence barriers) Intrinsic barriers related to treatment adherence were assessed through 35 statements, of which 14 reached the predefined consensus threshold. The most relevant barriers were those directly affecting the feasibility of infusion and self-management. In children aged 0 to 6 years, difficulty in venous access emerged as the single most critical barrier, achieving complete consensus (100%). In adolescents, the transition of infusion responsibility from caregivers to patients represented the highest-impact barrier (91.7%), underscoring the vulnerability of this developmental stage; lack of adequate self-infusion training also reached high consensus (91.7%). Among older adults, venous access difficulties combined with functional impairments such as visual limitations, tremors, and cognitive changes were consistently associated with reduced adherence (83.3%). Reduced adherence was also recognized among individuals with neurobehavioral conditions, including autism spectrum disorder (83.3%). In contrast, several barriers did not reach consensus, indicating variability in real-world experience. These included venous access difficulties in children aged 7 to 12 years, upper limb arthropathy, moderate to severe obesity, and most psychosocial factors among adults. Within children under 12 years, consensus was achieved for family or social support deficits, infusion-related discomfort, needle phobia, mental health conditions, and prolonged time to gain confidence in home infusions (83.3–90.0%), whereas lack of perceived immediate benefit, denial of disease severity, and fear of adverse events did not reach consensus. Among women with hemophilia, only delayed diagnosis due to low clinical suspicion achieved unanimous agreement (100%), while other intrinsic barriers, such as social stigma, absence of symptoms, and uncertainty regarding pregnancy or breastfeeding, failed to reach consensus.(Table 5 ). Table 5 Expert consensus on intrinsic barriers to treatment adherence in hemophilia. Statement Option(s) Agreement Median (IQR) Likert scale ranking a In children with hemophilia aged 0 to 6 years, difficulty in venous access is associated with reduced adherence to coagulation factor replacement therapy. NA Yes c 4.5 (4.0–5.0) In children with hemophilia aged 7 to 12 years, difficulty in venous access is associated with reduced adherence to coagulation factor replacement therapy NA No 2.0 (1.0–2.0) In adolescents with hemophilia, the transition of infusion responsibility from caregivers to the patient is associated with reduced adherence to factor replacement therapy NA Yes b 4.0 (4.0–4.7) In older adults with hemophilia, difficulty in venous access, combined with limitations such as impaired visual acuity, tremors, and cognitive changes, is associated with reduced adherence to coagulation factor replacement therapy. NA Yes c 4.0 (4.0–4.7) Patients with upper limb arthropathy experience difficulty achieving optimal adherence to coagulation factor replacement therapy due to challenges with self-infusion NA No 2.0 (1.7–4.0) Patients with hemophilia and neurobehavioral conditions, such as autism spectrum disorder, have reduced adherence to coagulation factor replacement therapy NA Yes c 4.0 (4.0–5.0) Patients with moderate to severe obesity experience greater difficulty achieving optimal adherence to coagulation factor replacement therapy NA No 3.0 (1.7–4.0) In women, diagnosis usually occurs later due to lower prevalence of bleeding phenotype and low clinical suspicion NA Yes b 5.0 (4.0–5.0) Intrinsic barriers that may compromise treatment adherence among women with hemophilia. Absence or low frequency of symptoms No 3.0 (2.0–4.0) Uncertainty about treatment compatibility with pregnancy and breastfeeding No 3.0 (2.0–4.0) Social stigma No 2.5 (2.0–3.7) Lack of adequate self-infusion training for hemophilia patients is a major barrier to optimized treatment adherence NA Yes b 4.0 (4.0–5.0) Intrinsic barriers that may compromise treatment adherence in children (under 12 years) with hemophilia. Lack of family or social support Yes b 4.0 (4.0–5.0) Discomfort during the infusion procedure Yes b 4.0 (4.0–4.0) Patient resistance during peripheral venous access attempts due to needle phobia Yes c 4.0 (4.0–4.7) Mental health conditions Yes c 4.0 (4.0–4.0) Prolonged time to gain confidence in home infusions requiring self-infusion. Yes d 4.0 (4.0–4.2) Lack of perceived immediate benefit from treatment No 2.0 (1.0–2.0) Denial or minimization of hemophilia severity No 2.0 (1.0–2.5) Fear of treatment-related complications (e.g., adverse reactions) No 2.0 (1.0–4.0) Intrinsic barriers that may compromise treatment adherence in adolescents (12 to under 18 years) with hemophilia. Lack of support Yes b 4.0 (4.0–5.0) Mental health conditions Yes c 4.0 (4.0–4.7) Pain and discomfort during the infusion procedure. Yes d 4.0 (3.5–4.0) Patient resistance during attempts at peripheral venous access due to needle phobia No 3.0 (2.0–4.0) Lack of perceived immediate benefit from treatment No 2.0 (1.0–4.0) Denial or minimization of hemophilia severity No 4.0 (2.0–4.2) Prolonged time required to develop confidence in home-based infusions requiring self-infusion No 2.0 (2.0–4.0) Fear of treatment-related complications (e.g., adverse reactions) No 2.0 (1.0–4.0) Intrinsic barriers that may compromise treatment adherence among adult patients with hemophilia. Lack of family or social support No 4.0 (3.5–5.0) Patient resistance during attempts at peripheral venous access due to needle phobia No 2.0 (1.0–2.2) Lack of perception of immediate treatment benefit No 2.0 (1.0–4.0) Pain and discomfort during infusion procedures No 3.0 (1.7–4.0) Denial or minimization of hemophilia severity No 3.0 (2.0–4.0) Long time required to gain confidence in home infusions, which require self-infusion No 2.0 (1.0–3.2) Fear of treatment-related complications (e.g., adverse reactions) No 2.0 (1.0–4.0) Abbreviation: IQR = interquartile range; NA = not applicated. a Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1 = strongly disagree, 2 = disagree, 3 = somewhat disagree, 4 = agree, 5 = strongly agree. b Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 1 of surveying. c Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 2 of surveying. d Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 3 of surveying. Table 6 Delphi consensus on priority attributes of emerging therapeutic technologies Statement Agreement Median (IQR) Likert scale ranking a Availability of less invasive therapeutic alternatives via subcutaneous administration could increase adherence to prophylactic treatment Yes b 5.0 (5.0–5.0) Availability of therapeutic alternatives requiring less frequent administration could increase adherence to prophylactic treatment Yes b 5.0 (5.0–5.0) Availability of therapeutic alternatives that do not require laboratory monitoring could increase adherence to prophylactic treatment Yes b 5.0 (4.0–5.0) Providing therapeutic alternatives with weight independent dosing could improve adherence to prophylactic treatment. No 4.0 (1.75–4.0) In your perception, what should be the reduction in annual bleeding events, compared to baseline, for a new technology to be considered clinically relevant? NA 1.0 (1.0–4.0) Abbreviation: IQR = interquartile range; NA = not applicated. a Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1 = strongly disagree, 2 = disagree, 3 = somewhat disagree, 4 = agree, 5 = strongly agree. b Statement reached consensus (≥ 80% partially agree/strongly agree) in the Round 1 of surveying. 3.6 Domain 5: Priority attributes of emerging technologies This domain evaluated five items addressing priority attributes of emerging therapeutic technologies. Three items were agreement-based statements assessed for consensus, while one item was exploratory and aimed at capturing expert perceptions rather than achieving consensus. The central finding was a strong preference for treatment simplification and reduction of therapeutic burden as key strategies to improve adherence within the SUS. Unanimous consensus was reached for less invasive therapies administered via the subcutaneous route (100%) and for therapies requiring less frequent administration (100%). Consensus was also achieved regarding therapeutic options that do not require routine laboratory monitoring (83.3%). In contrast, the statement evaluating whether weight-independent dosing could improve adherence to prophylactic treatment did not reach the predefined consensus threshold. The item exploring the minimum reduction in annual bleeding events required for a new technology to be considered clinically relevant was exploratory in nature and not intended to reach consensus; responses to this question are therefore presented descriptively. The distribution of priority scores assigned by the Delphi panel for the evaluated therapeutic attributes is summarized in Fig. 3 . Panelists assigned priority scores ranging from Priority 1, corresponding to the highest priority, to Priority 6, corresponding to the lowest priority. Overall, the central theme emerging from this ranking exercise was a clear prioritization of robust and sustained bleeding prevention, while attributes related to convenience and system-level facilitation were consistently assigned lower priority. The attribute with the highest relevance was continuous and effective prevention of bleeding with sustained and reliable coagulation factor levels, which was predominantly ranked as the top priority. Most panelists assigned this attribute as Priority 1 (70.0%), followed by Priority 2 (20.0%), with only a small proportion classifying it as the lowest priority (Priority 6; 10.0%). In contrast, the attribute related to effective control of acute bleeding using alternative therapeutic options during prophylaxis showed a broader distribution of rankings, reflecting intermediate priority. This attribute was most frequently classified as Priority 3 (40.0%), followed by Priority 2 (30.0%) and Priority 1 (20.0%), with a minority assigning lower priority (Priority 5; 10.0%). Attributes associated with treatment convenience were consistently assigned intermediate to lower priority levels. Technologies characterized by less invasive administration and reduced dosing frequency were most often ranked as Priority 4 (40.0%), with fewer panelists assigning higher priority (Priority 1–2; 40.0%). A similar pattern was observed for a favorable safety profile, particularly regarding thrombotic risk, which was predominantly ranked as Priority 4 (50.0%) or Priority 5 (30.0%). Greater dispersion toward lower priorities was observed for attributes related to reduction in travel and increased patient autonomy, with most responses concentrated in Priority 5 (30.0%) and Priority 6 (30.0%). Finally, the absence of a requirement for laboratory monitoring was consistently considered the least relevant attribute, being assigned the lowest priority by the majority of panelists (Priority 6: 60.0%; Priority 5: 30.0%). 4. Discussion Through a modified Delphi consensus methodology, this study identified and prioritized key unmet needs and structural barriers to optimal hemophilia care in Brazil. The results reveal a robust agreement among experts that, despite the national implementation of prophylaxis, substantial and persistent gaps in care remain. The panel reached a unanimous consensus (100%) that significant unmet needs persist among patients with moderate to severe hemophilia A and B without inhibitors. This scenario is corroborated by Souza et al. ( 21 ) who conducted a study in Amazonas, Brazil, involving 164 individuals with hemophilia A. The authors showed that, even with access to CFCs, 77.3% of participants continued to suffer from joint pain (arthralgia) and 78.4% experienced bleeding episodes ( 21 ). Furthermore, the persistence of joint disease was quantified by Soares et al ( 22 ). in the Federal District. Even in this region with a high Human Development Index, adult patients presented a mean Hemophilia Joint Health Score (HJHS) of 18.0 (SD 10.8), with 80.6% exhibiting ankle impairments ( 22 ). Finally, evidence from the HERO study ( 23 ), in Brazil, reported that 64.0% of people with hemophilia still experience extreme or moderate pain, and 71.0% reported a negative impact on employment. The persistence of suboptimal clinical outcomes despite access to CFCs establishes a direct link with the remaining unmet needs and the identified priorities identified by this Delphi panel. Ongoing high rates of established arthropathy and chronic pain suggest that the current standard of care, predominantly based on intravenous prophylaxis, continues to impose a substantial treatment burden, which may compromise adherence in real-world settings. These findings indicate that although significant logistical and organizational advances have been achieved in Brazil over the past decade, they may no longer be sufficient to address current unmet needs. Within this context, the Delphi panel identified structural barriers to access and continuity of care as key determinants underlying these outcomes. Distance from hemophilia reference centers emerged as a major constraint, with 83.3% of experts agreeing that patients living in remote or geographically distant areas face greater difficulty maintaining continuous access to therapy. This perception aligns closely with national and regional data. Feijó et al. ( 24 ) found, in Southern Brazil, that 58.3% of patients resided outside the municipality where a Hemocentro, a Brazilian public blood center, was located, while Custódio et al. ( 25 ) reported, in Alagoas, that 58.0% of patients lived more than 30 km away from the treatment center. In addition, Sarmento et al. ( 26 ) conducted a retrospective review of records from Department of Informatics of SUS (DataSUS) and found that 55.4% of all hemophilia-related hospital admissions occurred in the Southeast region. Furthermore, receiving treatment at a specialized hemophilia center was found to be a positive and independent factor associated with adherence to treatment protocols (Odds Ratio: 2.38; 95% CI: 1.05–5.41) ( 27 ). This geographical challenge is not unique to Brazil but reflects a broader structural barrier affecting access to hemophilia care across different health systems. In the United States, findings from the B-HERO-S study ( 28 ) showed that travel time (43.0%), travel-related costs (43.0%), and long distances (50.0%) were among the most frequently reported barriers to accessing hemophilia treatment centers. Similarly, in China, Liu et al. ( 29 ) reported that patients living in rural areas often travel up to five hours to obtain coagulation factor concentrates, a logistical burden that discourages prophylaxis and delays the management of acute bleeding events. In response to this structural limitation, Brazil has intensified efforts since 1999 to expand home-based treatment, aiming to reduce hospital visits, alleviate pain episodes, and minimize absenteeism from school and work ( 30 ). However, participation rates vary widely across regions and patient cohorts, ranging from 33.0% to 90.0%, indicating uneven program reach and differences in patients’ ability to perform self-infusion ( 12 ). The persistence of distance from treatment centers as a prioritized barrier in this Delphi panel suggests that, despite these advances, logistical challenges and treatment burden remain significant. This finding reinforces the expert consensus on the need for therapeutic strategies that further simplify administration, particularly subcutaneous options, and reduce dependence on centralized services to ensure more equitable and effective hemophilia care in Brazil. Social vulnerability emerged as another extrinsic barrier with high consensus (83.3%). In the Brazilian context, socioeconomic status is a determinant of clinical outcomes. Custódio et al. ( 25 ) reported that 78.0% of Brazilian hemophilia patients had a monthly personal income of up to only one minimum wage. This economic precarity has direct clinical implications. According to Soares et al. ( 22 ), a monthly household income greater than two Brazilian minimum wages showed an independent and statistically significant association with improved HJHS (p = 0.033). These data strongly support the Delphi panelists' view that clinical efficacy cannot be divorced from the patient's social context, necessitating therapeutic strategies that reduce the indirect costs and logistical burdens of care. To mitigate the impact of social vulnerability, strategies must extend beyond the provision of coagulation factors alone and address the indirect costs and logistical barriers associated with treatment. Therapeutic approaches that reduce infusion complexity, decrease the frequency of administration, and minimize the need for travel to specialized centers may help offset socioeconomic disparities. In addition, strengthening home-based treatment programs, expanding decentralized care networks, and integrating social support services into hemophilia care pathways may contribute to more equitable outcomes ( 31 ). Regarding intrinsic barriers, the panel reached complete consensus (100%) in identifying difficult venous access as a primary obstacle to treatment adherence in children aged 0 to 6 years. This finding converges with results from a Brazilian Delphi study conducted by Magliano et al. ( 32 ), in which experts identified "difficulty in venous access" as the leading indication (89.0% agreement) for switching to non-factor therapies such as emicizumab. The reliance on frequent intravenous infusions imposes a substantial burden. Mancuso et al. ( 33 ) further highlighted that maintaining such infusion regimens often requires the use of central venous access devices (CVADs), which are associated with significant risks of surgical complications, infection, and thrombosis, particularly in infants. The transition from caregiver-administered to self-administered prophylaxis in adolescents was identified as a critical vulnerability, achieving 91.7% consensus as a cause for reduced adherence. This expert perception is supported by Geragthy et al. ( 34 ), who reported that adherence rates decline precipitously with age, from 90.0% in children (0–12 years) to 54.0% in adolescents (13–18 years). Similarly, in the TEEN/TWEN ( 35 )observational study, 38 late adolescents and young adults (median age 19.5 years) were assessed to evaluate the consequences of discontinuing long-term prophylaxis. Participants who voluntarily discontinued prophylaxis ≤ 12 months or ≥ 13 months prior to study entry experienced markedly higher median annualized bleeding rates (4.8 and 24 events per year, respectively) compared with a median of no events per year among those who continued prophylaxis. Health-related quality of life measures were also generally worse among individuals who discontinued prophylaxis, indicating that the transition from caregiver-administered to self-managed treatment is associated with increased bleeding and reduced well-being in this age group ( 35 ). Further evidence from a comprehensive systematic literature review ( 36 ) reinforces adolescence and early adulthood as periods of increased vulnerability to reduced adherence. In a synthesis of 31 studies comprising 2,379 individuals with hemophilia, Sun et al. ( 36 ) consistently observed lower adherence rates among adolescents and young adults compared with younger children, alongside higher annualized bleeding rates and less favorable joint outcomes. Collectively, these findings are consistent with the Delphi panel’s assessment that adolescence may represent a phase in which adherence challenges become more pronounced, particularly in the context of increasing treatment responsibility, reduced caregiver supervision, and treatment fatigue. This evidence supports consideration of adolescents as a priority population for interventions focused on simplifying prophylactic regimens and strengthening structured transition processes to promote sustained adherence across the life course. The absolute consensus regarding the diagnostic “invisibility” of women with hemophilia is supported by clinical evidence suggesting a substantial and often underrecognized disease burden in this population. In a multicenter retrospective chart review, Chaudhury et al. ( 37 ) evaluated 47 women and girls with hemophilia and reported a median age at diagnosis of 22.6 years, indicating diagnostic delay despite the presence of bleeding manifestations. Although 79.0% of patients were classified as having mild hemophilia, clinically relevant bleeding events were frequent, including spontaneous or traumatic bleeds, joint bleeding, and heavy menstrual bleeding ( 37 ). Importantly, bleeding symptoms in women often overlap with conditions considered physiological, such as menstruation, childbirth, and postpartum bleeding, contributing to symptom normalization and delayed recognition. This clinical overlap is compounded by gender-related factors within the healthcare system and at the patient level. In Brazil, Lorenzato et al. ( 23 ) reported that 86.0% of caregivers of individuals with hemophilia are women, predominantly mothers, who frequently assume the dual role of primary caregiver while potentially being undiagnosed symptomatic carriers themselves. This dual burden may further contribute to self-neglect, delayed care-seeking, and prioritization of family needs over personal health. The panel also addressed the intersection of neurobehavioral comorbidities and adherence, agreeing (83.3%) that conditions such as autism spectrum disorder significantly compromise treatment. This aligns with the high prevalence of mental health struggles reported in the literature. Lorenzato et al. ( 23 ) found that 18.0% of Brazilian patients had undergone treatment for depression or anxiety. The mental health burden is further quantified by Garbin et al. ( 38 ), who showed that "emotional aspects" had the lowest scores among health domains in Brazilian patients (mean 58.88). A systematic review with meta-analysis including 28 studies and 2,926 individuals from multiple countries, verified significantly increased odds of depression (OR: 2.45; 95% CI: 1.64–3.68), anxiety (OR: 1.74; 95% CI: 1.01–3.00), combined anxiety/depression (OR: 2.60; 95% CI: 2.35–2.87), and attention-deficit/hyperactivity disorder (OR: 3.48; 95% CI: 1.74–6.96) compared with the general population ( 39 ). However, evidence regarding the effectiveness and availability of psychosocial interventions remains limited. In a Cochrane systematic review of psychological interventions for people with hemophilia, Palareti et al. ( 40 ) identified only seven randomized or quasi-randomized trials involving 362 participants, with overall low to very low certainty of evidence. Psycho-educational and computerized learning interventions showed modest improvements in self-efficacy, coping strategies, and transition readiness in children and adolescents, but effects on adherence, bleeding outcomes, and quality of life were inconsistent, and data on long-term clinical impact were scarce. Importantly, the review highlighted substantial heterogeneity across interventions and outcome measures, as well as the absence of integrated mental health care models within hemophilia services ( 40 ). Together, these findings suggest that, despite recognition of psychosocial burden, access to effective and standardized mental health support for people with hemophilia has not improved proportionally to advances in hemostatic therapies. This gap reinforces the Delphi panel’s view that optimal hemophilia care requires both systematic psychosocial support and therapeutic strategies that reduce procedural stress and treatment burden, particularly for individuals with neurobehavioral comorbidities. Furthermore, the panel reached 100% consensus on the absence of specialized technical support in emergency settings as a major extrinsic barrier. This expert perception reflects a systemic vulnerability quantified by Soares et al. ( 41 ) in the Federal District; using the Haem-A-QoL questionnaire, they observed that the item eliciting the highest concern within the "Treatment" domain was the fear of being attended by non-specialized professionals during emergencies (score 72.6). The B-HERO-S study ( 42 ) found that 17.0% of patients reported difficulty gaining access to Hemophilia Treatment Centers, often relying on non-specialized emergency rooms. Although Brazil has a well-established network of Hemophilia Treatment Centers that provide highly specialized care and ensure effective routine management, the Delphi results suggest that this concentration of expertise does not consistently translate into preparedness across general emergency settings, particularly for patients residing far from reference centers. These findings highlight the need for targeted training of generalist emergency providers and clearer referral pathways to ensure timely and appropriate management of acute bleeding events. The evaluation of emerging technologies revealed a clear preference for subcutaneous administration and reduced dosing frequency, both achieving 100% consensus as drivers for adherence. The panel estimated that individuals with Hemophilia A without inhibitors on prophylaxis experience a mean of 3.30 bleeds per year. This aligns with the Kenet et al. study ( 43 ), which reported a mean Annualized Bleeding Rate (ABR) of 2.42 for Brazilian patients on prophylaxis. These data validate the Delphi consensus that while current prophylaxis has improved outcomes, it has not achieved the "zero bleed" benchmark, reinforcing the clinical relevance of novel therapies with higher efficacy profiles. Crucially, the areas where the panel did not reach consensus offer valuable insights into the heterogeneity of the Brazilian context, such as the lack of agreement regarding treatment discontinuation due to factor supply shortages (60.0% agreement). This divergence likely reflects the dichotomy between successful federal procurement and inequitable regional distribution. On one hand, data from the HERO study ( 23 ) indicated that 58.0% of patients and 68.0% of caregivers did not experience difficulties obtaining factor in the previous 5 years, suggesting that the Ministry of Health's centralized purchasing strategies have largely stabilized the macro-availability of products. However, the persistence of this concern among a subset of experts is validated by the stark regional disparities, in which CFCs utilization, based on factor VIII per capita, varies drastically from 7.22 IU in the Federal District to a critical low of 0.27 IU in peripheral states like Roraima ( 44 ). Therefore, the lack of consensus accurately depicts a system where access is geographically determined. While the supply exists federally, logistical failures in specific regions continue to disrupt maintenance for vulnerable populations. Notably, the panel was divided on the influence of obesity on treatment adherence, with only half of the experts (50.0%) agreeing. This lack of consensus may reflect a perspective among Brazilian hematologists who primarily consider obesity as a factor that exacerbates joint health problems, rather than as a direct barrier to infusion and adherence. In contrast, existing literature points out that obesity can complicate venous access and reduce mobility, thereby indirectly hindering effective care ( 45 ). Finally, the interpretation of these findings must consider the study's limitations and strengths. A primary limitation is the sample size of 12 experts. However, this is consistent with the Delphi methodology for specialized topics and is counterbalanced by the participants' extensive experience in the public system (> 15 years) and large number of patients attending. One of the key strengths of this study is the inclusion of experts from all regions, ensuring a comprehensive representation of perspectives across Brazil. Additionally, the methodological rigor of the Delphi process, which adhered strictly to the DELPHISTAR protocol ( 16 ), enhances the reliability and quality of the consensus findings. Conclusions This Delphi consensus on hemophilia care in Brazil indicates that extrinsic barriers related to health system organization and access to specialized services, together with intrinsic barriers affecting treatment adherence across the life course, negatively influence clinical outcomes. The identification of unmet needs across diverse patient groups, including women, children, adolescents, and older adults, underscores the need for more integrated and patient-centered care strategies. In addition, expert alignment regarding the potential benefits of less invasive hemophilia therapies with reduced administration frequency supports the prioritization of innovations aimed at lowering treatment burden and improving adherence. Overall, these findings provide a structured basis for updating clinical protocols, informing public health policy, and guiding the incorporation of new therapeutic options to promote more equitable, efficient, and sustainable hemophilia care within the public healthcare setting. Declarations 7.1 Ethics Approval and Consent to Participate Ethical approval was not required for this type of study. All participants provided electronic informed consent prior to their inclusion in the study. 7.2 Consent for Publication All authors consent to the publication of this manuscript. 7.3 Availability of Data and Materials The datasets generated and/or analyzed during the study are available from the corresponding author upon reasonable request. 7.4 Competing Interests JL, FI, and BW are employees of IQVIA, which received funding from Pfizer for the conduct of this study. DP, MA, AKN, RFA, and AD are current employees of Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. 7.5 Funding This study was sponsored by Pfizer, which commissioned IQVIA for its execution. 7.6 Authors’ Contributions FI, BW, and JL provided methodological oversight of the Delphi process, contributed to the study design, supported the development and refinement of the consensus statements, performed data analysis, and contributed substantially to the drafting of the manuscript. ISSP and MCO contributed to the clinical evaluation of the statements and critically reviewed the content. DP, MA, AKN and AD supervised the project and participated in the final review of the manuscript. 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Haemophilia 12(1):75–81 Manco-Johnson MJ, Sanders J, Ewing N, Rodriguez N, Tarantino M, Humphries T et al (2013) Consequences of switching from prophylactic treatment to on-demand treatment in late teens and early adults with severe haemophilia A: the TEEN/TWEN study. Haemophilia 19(5):727–735 Sun J, Zhou X, Hu N (2021) Factor VIII replacement prophylaxis in patients with hemophilia A transitioning to adults: a systematic literature review. Orphanet J Rare Dis 16(1):287 Chaudhury A, Sidonio R Jr., Jain N, Tsao E, Tymoszczuk J, Oviedo Ovando M et al (2021) Women and girls with haemophilia and bleeding tendencies: Outcomes related to menstruation, pregnancy, surgery and other bleeding episodes from a retrospective chart review. Haemophilia 27(2):293–304 Garbin LMCE, Canini SRMS, Dantas RAS (2007 Apr-Jun) Avaliação da qualidade de vida relacionada à saúde em pacientes portadores de hemofilia. Cienc Cuid Saude 6(2):197–205 Al-Huniti A, Reyes Hernandez M, Ten Eyck P, Staber JM (2020) Mental health disorders in haemophilia: Systematic literature review and meta-analysis. Haemophilia 26(3):431–442 Palareti L, Melotti G, Cassis F, Nevitt SJ, Iorio A (2020) Psychological interventions for people with hemophilia. Cochrane Database Syst Rev 3(3):CD010215 Soares BMD, Imoto AM, Simeoni LA, de Almeida KJQ, Braverman MS, Bezerra LB et al (2022) Health-related quality of life and associated factors: Results from the haemophilia QOL questionnaire for adults (Haem-A-QOL) in a low-income country with public policies to improve haemophilia care. Haemophilia 28(5):e125–e8 Witkop M, Wang M, Hernandez G, Recht M, Baumann K, Cooper DL (2021) Impact of haemophilia on patients with mild-to-moderate disease: Results from the P-FiQ and B-HERO-S studies. Haemophilia 27(Suppl 1):8–16 Kenet G, Chen YC, Lowe G, Percy C, Tran H, von Drygalski A et al (2021) Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study. J Clin Med. ;10(24) Sayago M, Lorenzo C (2020) O acesso global e nacional ao tratamento da hemofilia: reflexões da bioética crítica sobre exclusão em saúde. Interface - Comunicação, Saúde, Educação. ;24:e180722–e Lim MY, Wei G, Presson AP, Bray P, Rodgers GM (2020) High prevalence of overweight/obesity in adult persons with hemophilia in Utah and a review of the literature. Blood Coagul Fibrinolysis 31(8):522–529 Additional Declarations The authors declare potential competing interests as follows: JL, FI, and BW are employees of IQVIA, which received funding from Pfizer for the conduct of this study. DP, MA, AKN, RFA, and AD are current employees of Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9471111","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626246776,"identity":"b3e6dcb8-7f55-4f38-9fca-61d78b7493b0","order_by":0,"name":"Margareth C. Ozelo","email":"","orcid":"https://orcid.org/0000-0001-5938-0675","institution":"Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Margareth","middleName":"C.","lastName":"Ozelo","suffix":""},{"id":626246777,"identity":"75a15c39-fa5e-4566-a9bd-aebaa4975fea","order_by":1,"name":"Bruna Webler","email":"","orcid":"https://orcid.org/0000-0002-1453-7728","institution":"IQVIA Solutions, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Bruna","middleName":"","lastName":"Webler","suffix":""},{"id":626246778,"identity":"f1b0e82d-621e-41f0-acfe-b0b2fface036","order_by":2,"name":"Julia Lima","email":"","orcid":"","institution":"IQVIA Solutions, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Lima","suffix":""},{"id":626246779,"identity":"a68a839d-d375-46a8-b527-280ab378a9b1","order_by":3,"name":"Mariana Alves","email":"","orcid":"","institution":"Pfizer, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Mariana","middleName":"","lastName":"Alves","suffix":""},{"id":626246780,"identity":"f1dca65d-dea5-4084-b304-e82444e0cd50","order_by":4,"name":"Ana Karolina de Nunes","email":"","orcid":"","institution":"Pfizer, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Karolina","lastName":"de Nunes","suffix":""},{"id":626246781,"identity":"b55df4ab-1c8d-4a55-916d-7e04dd4efc09","order_by":5,"name":"Ana Dantas","email":"","orcid":"","institution":"Pfizer, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Dantas","suffix":""},{"id":626246782,"identity":"a1d8ff17-efab-4953-bfa3-659bc11452b6","order_by":6,"name":"Rodrigo F. Alexandre","email":"","orcid":"https://orcid.org/0000-0002-1010-276X","institution":"Pfizer, São Paulo, SP, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"F.","lastName":"Alexandre","suffix":""},{"id":626246783,"identity":"c6700bcb-0573-4853-97b6-90fe8e3e286d","order_by":7,"name":"Daniela V. Pachito","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIiWNgGAWjYDCCAyBUAGayMSQwMMgxMB9sIEKLAUxLAoMxA1siYS0McC1AaxIb2BLw6+A7fvbggQ8Gdgzm7IefPXj4wyZ9Oxtz84ePexjk+cUOYNUieSYv4eAMg2QGy540c4OEhLTcnW2MDYYznjEYzpyN3TqDAzkGh3kMmEEMNomEhMO5G+43NiTzHGBIMLiNQ8v5NwaH/xjUgxhgLekGxxgbDv/Bp+UG0BYGELoBsSUBqKWxmQGPFskbbwwO9hgc57Gc8cxMIiEtzRDol2bGngMSOP3Cdz7H+MOPimo5c/7kZ5I/bGzkzdnYH3/4ccBGnl8auxYY4DGAOxVCSeBVjqwSiTEKRsEoGAWjAAoAG9Zjisguv98AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-7052-7735","institution":"Pfizer, São Paulo, SP, Brazil","correspondingAuthor":true,"prefix":"","firstName":"Daniela","middleName":"V.","lastName":"Pachito","suffix":""},{"id":626246784,"identity":"f88840fc-313b-4320-bd7d-4a5da6579b4c","order_by":8,"name":"Ieda Solange de Souza Pinto","email":"","orcid":"","institution":"Fundação HEMOPA, Belém, PA, Brazil","correspondingAuthor":false,"prefix":"","firstName":"Ieda","middleName":"Solange de Souza","lastName":"Pinto","suffix":""}],"badges":[],"createdAt":"2026-04-20 11:01:18","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9471111/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9471111/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107488589,"identity":"b81ebce3-6514-429f-aac4-cf656d659a40","added_by":"auto","created_at":"2026-04-22 02:45:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":347005,"visible":true,"origin":"","legend":"\u003cp\u003eThe five thematic domains structuring the questionnaire applied in the Delphi panel.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9471111/v1/966ceaef972d177e39445d19.png"},{"id":107488705,"identity":"9eea2f01-2b08-4eca-ae61-82e1cfab90e1","added_by":"auto","created_at":"2026-04-22 02:45:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":298360,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of consensus process in the Delphi panel.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9471111/v1/8a48f2616f123bff2807012a.png"},{"id":107488603,"identity":"4161a7a6-1a6d-46e8-abf5-e9ea6700e5ae","added_by":"auto","created_at":"2026-04-22 02:45:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58143,"visible":true,"origin":"","legend":"\u003cp\u003ePriority ranking of attributes for the incorporation of new technologies into the SUS\u003cem\u003e \u003c/em\u003e(1 = Highest Priority; 6 = Lowest Priority).\u003c/p\u003e","description":"","filename":"Figure3300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-9471111/v1/23ca5e398de0ad6530bbfad0.png"},{"id":107489832,"identity":"717dd7c4-ea55-4aa9-ac4f-eae7b378ed76","added_by":"auto","created_at":"2026-04-22 02:49:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1609141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9471111/v1/206e7558-2b5c-4ba7-b74d-421b8785f7a9.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: JL, FI, and BW are employees of IQVIA, which received funding from Pfizer for the conduct of this study. DP, MA, AKN, RFA, and AD are current employees of Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. ","formattedTitle":"\u003cp\u003e\u003cstrong\u003eExpert Consensus on Unmet Needs and Barriers to Optimal Hemophilia Care in Brazil: Results from a Modified Delphi Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introdution","content":"\u003cp\u003eOver the last decade, hemophilia care has improved significantly in Brazil. However, Brazil represents a relevant setting for examining persistent gaps in hemophilia care within a universal health system. The management of hemophilia is predominantly conducted through the Brazilian Unified Health System (SUS), supported by a structured national program in which blood transfusion centers and specialized units serve as hemophilia reference centers. These units function as central hubs, concentrating key clinical and operational responsibilities, including diagnosis, treatment dispensing, patient monitoring, and the provision of longitudinal care to a large and diverse patient population (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The national network is structurally robust and ensures universal access for patients with inherited bleeding disorders, including prophylaxis for patients with severe hemophilia. This achievement represents a major milestone in the public health model. Nevertheless, logistical complexity and regional disparities may still compromise the continuity and quality of care (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Compared with the international context, the Brazilian program has achieved notable success in promoting access to specialized health care. However, the adoption of innovations occurs more gradually than in high-income countries, where extended half-life (EHL) factors and other technologies have already been established as the standard of care (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn Brazil, the implementation of primary prophylaxis for patients with severe hemophilia in 2012, along with the more recent incorporation of emicizumab into SUS for hemophilia A pediatric patients, and for all hemophilia A without inhibitors, represents significant therapeutic advances. However, important barriers and unmet needs remain, particularly regarding optimal adherence, long-term effectiveness, and sustainability of prophylaxis strategies (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Replacement therapy based on standard half-life (SHL) clotting factor concentrates (CFCs) continues to play a significant role in the therapeutic arsenal, reflecting a relatively slow pace of therapeutic modernization and possible limitations in achieving improvements in convenience, sustained adherence, and quality of life (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinical practice evidence suggests that the expected benefit of CFCs as primary prophylaxis is not always achieved, largely due to limitations in adherence and the operational viability of care (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Treatment with CFCs requires recurrent infusions and imposes a high therapeutic burden related to the frequency of regimens and venous access challenges. These implementation gaps arise from the interaction of intrinsic determinants \u0026ndash; such as venous access difficulties, lack of social support, functional limitations, severity of the disease\u0026ndash; with extrinsic determinants associated with care organization and the lag between evidence generation and technology incorporation (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Consequently, national studies report substantial variability in adherence rates, with estimates ranging from 25% and 72%, resulting in a higher risk of potentially avoidable bleeding and progressive musculoskeletal damage (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEvidence indicates that simpler therapeutic regimens may mitigate part of these limitations. For example, studies evaluating the EHL factor IX have reported adherence rates above 95%, along with a potential reduction in bleeding episodes associated with irregular use of daily regimens (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In this context, hematologists working in transfusion blood centers are uniquely positioned to identify barriers in clinical practice and assess how emerging technologies could mitigate the limitations of the current model. As these implementation challenges are not fully characterized by clinical trials and available evidence remains fragmented, structured consensus methods, such as the Delphi technique, enable the systematic capture and prioritization of specialist perceptions (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, this study applied a modified Delphi panel with Brazilian to identify unmet needs, barriers to optimal care, and priority attributes for emerging therapies in hemophilia A and hemophilia B within the Brazilian public health system, SUS.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Delphi design\u003c/h2\u003e \u003cp\u003e A modified Delphi consensus study was conducted to obtain structured expert agreement on priority domains and unmet needs in hemophilia A and hemophilia B care within the SUS. The Delphi method was selected given the limited disease-specific evidence, heterogeneity in routine practice, and fragmented information across care settings, which may hinder consistent decision making. The study was reported in accordance with the Delphi Studies in Social and Health Sciences: Recommendations for an Interdisciplinary Standardized Reporting (DELPHISTAR) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) guideline, ensuring transparency, methodological rigor, and completeness of reporting. The process comprised three rounds conducted between October and December 2025: two asynchronous rounds using anonymized online questionnaires followed by a structured synchronous online consensus meeting focused on unresolved items. This study followed a prospectively developed protocol, although it was not registered in a publicly accessible database.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Steering committee and methodological oversight\u003c/h2\u003e \u003cp\u003eMethodological oversight of the Delphi process was provided by three investigators with expertise in Delphi methodology (FI, BW, and JL). These investigators supported the study design, drafting of the initial set of statements, refinement of the consensus process, and pre-definition of analytical and consensus criteria. A scientific committee composed of two hematologists with experience in hemophilia care within the SUS (ISSP and MCO) reviewed the draft statements to ensure clinical relevance and alignment with routine practice challenges and areas of uncertainty. All authors drafted the initial statements and coordinated revisions throughout the Delphi rounds, while the scientific committee ensured clinical alignment and contextual adequacy for the Brazilian public health setting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statement generation and questionnaire development\u003c/h2\u003e \u003cp\u003eTo inform statement development, a targeted literature review was conducted to identify evidence related to hemophilia A and hemophilia B care in Brazil. Searches were performed in PubMed (via MEDLINE) and LILACS (via the Virtual Health Library). The search strategy combined the keywords \u0026ldquo;hemophilia\u0026rdquo;, \u0026ldquo;treatment\u0026rdquo;, \u0026ldquo;unmet needs\u0026rdquo; and \u0026ldquo;Brazil, covering English and Portuguese publications. Searches were conducted up to April 2025. Evidence from the targeted review was used to contextualize current practice patterns and inform the formulation of clinically relevant statements.\u003c/p\u003e \u003cp\u003e Guided by the review findings and the scope defined by the scientific committee, the questionnaire was structured into five thematic domains: unmet needs according to hemophilia type; treatment-related aspects including adherence and residual disease burden; extrinsic and intrinsic barriers to optimal care within the SUS; and priority attributes of emerging technologies (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This approach aimed to ensure that the statements were grounded in existing knowledge while systematically addressing areas of uncertainty and variability observed in routine clinical practice.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Panel selection, recruitment and blinding procedures\u003c/h2\u003e \u003cp\u003eThe expert panel included physicians specialized in hematology and hemotherapy who met the following eligibility criteria: (a) at least five years of clinical experience in the care or management of people with hemophilia A or hemophilia B; (b) regular clinical practice in hemophilia treatment centers; (c) at least 50% of declared clinical workload dedicated to public hospitals; (d) at least 10% of declared clinical workload dedicated to bleeding disorders; (e) management of at least 15 patients with hemophilia per month, including individuals with and without inhibitors; (f) care provision to at least two age groups among children, adolescents, adults, and older adults; and (g) confirmed availability to participate in three consecutive Delphi rounds.\u003c/p\u003e \u003cp\u003eThe selection aimed to achieve proportional regional representation across Brazilian centers, including the North, Northeast, Midwest, Southeast, and South regions, based on availability identified during the screening process. Panel members who agreed to participate received honoraria for participation.\u003c/p\u003e \u003cp\u003ePanel selection and recruitment were conducted by an independent team with experience in Delphi studies, which was responsible for screening potential participants, coordinating invitations, managing informed consent, distributing questionnaires, monitoring response rates, and overseeing compliance with predefined timelines across all Delphi rounds.\u003c/p\u003e \u003cp\u003eTo reduce bias and preserve independence of responses, panelists were not informed about other participants\u0026rsquo; identities or about the funding source. Sponsor blinding was ensured, given that the sponsor had no access to participants\u0026rsquo; identities or workplace affiliations, and no access to individual-level responses. No additional recruitment occurred after the first round. Experts who did not complete a Delphi round within the allotted time were not eligible to participate in subsequent rounds. All participants provided electronic informed consent prior to study participation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Delphi panel size, rounds and implementation\u003c/h2\u003e \u003cp\u003eThe size of the Delphi panel was defined in accordance with methodological guidance indicating that panels of approximately 10 to 15 experts are sufficient when participants share a homogeneous professional background and high level of subject-matter expertise. Considering the specialized focus on hemophilia care within the SUS and the need to ensure complete participation across three consecutive Delphi rounds, a panel of 12 hematologists was considered adequate to support a robust and feasible consensus process (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThree rounds were conducted (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The Round 1 questionnaire was distributed by electronic mail to all 12 panelists and completed October 10\u0026ndash;20, 2025. Round 2 was conducted between October 31 and November 10, 2025. Round 3 took place on December 15, 2025. All 12 panelists completed Rounds 1 and 2, and 10 participated in Round 3.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn Rounds 1 and 2, participants individually evaluated the statements using anonymous online questionnaires accessed via electronic voting links. Responses were collected electronically to ensure confidentiality and to reduce the risk of dominance bias. Participants rated each statement using a five-point Likert scale with the following response options: strongly disagree, partially disagree, neutral, partially agree, and strongly agree. A secondary set of questions used single-choice responses or priority ranking formats. Completion of all items was mandatory.\u003c/p\u003e \u003cp\u003eStatements not reaching the predefined consensus threshold were carried forward to the subsequent round. Prior to Round 2, participants received controlled feedback summarizing group-level results from Round 1, including agreement rates and the distribution of responses across Likert categories, alongside anonymized summary comments.\u003c/p\u003e \u003cp\u003eRound 3 consisted of a structured synchronous meeting involving all panelists and focused on items that remained without consensus after Round 2. The discussion was guided by aggregated results from previous rounds and aimed to clarify divergent perspectives while preserving a structured consensus process. Following discussion, outstanding statements were re-rated using anonymous electronic voting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Definition of consensus and statistical analysis\u003c/h2\u003e \u003cp\u003ePanel characteristics were summarized using descriptive statistics. The Delphi questionnaire comprised different types of items, including agreement-based Likert-scale statements, single-choice questions, numerical estimation questions, and priority-ranking items. Likert-type statements were rated on a five-point ordinal scale (strongly disagree, partially disagree, neutral, partially agree, and strongly agree) and were summarized using medians and interquartile ranges (IQR), as well as response distributions. For each Likert-type statement, the level of agreement was calculated as the proportion of responses rated as partially agree or strongly agree. Statements were classified as: (i) consensus in agreement (\u0026ge;\u0026thinsp;80% partially agree/strongly agree); (ii) consensus in disagreement (\u0026ge;\u0026thinsp;80% strongly disagree or partially disagree); or (iii) no consensus (all other response distributions). Single-choice questions were summarized using absolute and relative frequencies. Numerical estimation questions (e.g., annual bleeding rates, proportions of patients with adherence issues or joint outcomes) were summarized using means, standard deviations (SD), medians, and IQR, reflecting expert-perceived estimates rather than patient-level measurements. Priority-ranking items were summarized descriptively based on the distribution of assigned ranks across panelists. Quantitative analyses were performed in Microsoft Excel (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Demographic and clinical profile of the panelists\u003c/h2\u003e \u003cp\u003eThe Delphi panel comprised 12 hematologists with heterogeneous demographic and professional profiles. Most panelists were aged 40\u0026ndash;49 years (41.7%) and 58.3% were male. Panelists represented all five Brazilian geographic regions, with the highest representation from the Northeast (33.3%). All panelists practiced in municipalities with \u0026gt;\u0026thinsp;50,000 inhabitants. Most panelists reported 11\u0026ndash;20 years of experience in hemophilia management (66.7%), and 25.0% reported\u0026thinsp;\u0026gt;\u0026thinsp;20 years. Half of participants held a master\u0026rsquo;s degree (50.0%), while 16.7% held a PhD. Regarding clinical volume, 58.3% reported managing\u0026thinsp;\u0026gt;\u0026thinsp;50 patients with hemophilia A per month. Most panelists reported managing up to 15 patients per month for hemophilia A with inhibitors (75.0%) and hemophilia B with inhibitors (83.3%). Panel characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and professional characteristics of Delphi panelists.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnder 30 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;39 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (41.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOver 60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (41.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegion of practice in Brazil\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCentral-West\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoutheast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePopulation size of municipality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarge size, over 50,000 inhabitants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears of experience with hemophilia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u0026ndash;10 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u0026ndash;20 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMore than 20 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducational level\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical Doctor (MD) degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaster\u0026rsquo;s degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDoctoral degree (PhD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemophilia A, all forms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u0026ndash;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u0026ndash;30 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemophilia A with inhibitors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUp to 15 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u0026ndash;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u0026ndash;30 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemophilia B, all forms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u0026ndash;30 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUp to 15 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u0026ndash;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemophilia B with inhibitors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUp to 15 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (83.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u0026ndash;30 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u0026ndash;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50 patients/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Domain 1: Unmet needs by hemophilia type and inhibitor status\u003c/h2\u003e \u003cp\u003eThis domain comprised five statements addressing unmet needs according to the hemophilia type and inhibitor status, as well as aspects related to health system organization. Consensus was achieved for all five statements (100%), indicating a uniform perception among panelists that relevant unmet needs persist across hemophilia A and B, both with and without inhibitors.\u003c/p\u003e \u003cp\u003ePanelists unanimously agreed that unmet needs persist among individuals with moderate to severe hemophilia A without inhibitors (100%) and hemophilia B without inhibitors (100%). Agreement was also reached for patients with inhibitors, with consensus at the predefined threshold for hemophilia A with inhibitors (80.0%) and a higher level of agreement for hemophilia B with inhibitors (91.7%). With respect to health system organization, panelists reached consensus on the importance of consolidating the Clinical Protocols and Therapeutic Guidelines (PCDT) into a single document to promote standardized and comprehensive hemophilia care within the SUS (83.3%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eExpert consensus on unmet needs across hemophilia A and B, by inhibitor status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgreement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003cp\u003eLikert scale\u003c/p\u003e \u003cp\u003eranking\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering treatments currently available in SUS (plasma-derived Factor VIII concentrate; recombinant Factor VIII concentrate), there are unmet needs for people living with moderate to severe Hemophilia A without inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (4.2\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering treatments currently available in SUS (immune tolerance induction therapy, bypassing agents, and emicizumab), there are unmet needs for people living with moderate to severe Hemophilia A with inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.0 (3.7\u0026ndash;4.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering treatments currently available in SUS (plasma-derived Factor IX concentrate), there are unmet needs for people living with moderate to severe Hemophilia B without inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (5.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering treatments currently available in SUS (bypassing agents), there are unmet needs for people living with moderate to severe Hemophilia B with inhibitors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (4.2\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsolidating PCDT into a single document to guide hemophilia management in SUS is important to ensure comprehensive care and standardized assistance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (4.2\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: IQR\u0026thinsp;=\u0026thinsp;interquartile range; SUS\u0026thinsp;=\u0026thinsp;Brazilian Unified Health System; PCDT\u0026thinsp;=\u0026thinsp;Clinical Protocols and Therapeutic Guidelines.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1\u0026thinsp;=\u0026thinsp;strongly disagree, 2\u0026thinsp;=\u0026thinsp;disagree, 3\u0026thinsp;=\u0026thinsp;somewhat disagree, 4\u0026thinsp;=\u0026thinsp;agree, 5\u0026thinsp;=\u0026thinsp;strongly agree.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eb\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 2 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ec\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 3 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNumerical questions on perception of treatment adherence, annualized bleeding rate, and joint complications.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003cp\u003e(IQR)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the number of bleeding episodes per year among people living with Hemophilia A without inhibitors, on continuous prophylactic treatment with Factor VIII replacement?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.3 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.0 (2.2\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the number of bleeding episodes per year among people living with Hemophilia A with inhibitors, on treatment with immune tolerance induction protocol and/or prophylaxis with bypassing agents?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.6 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.0 (5\u0026ndash;6.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the number of bleeding episodes per year among people living with Hemophilia A with inhibitors, using emicizumab?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.9 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0 (0.0\u0026ndash;1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the number of bleeding episodes per year among people living with Hemophilia B without inhibitors, on continuous prophylactic treatment with Factor IX replacement (plasma-derived)?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.3 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.0 (1.25\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the number of bleeding episodes per year among people living with Hemophilia B with inhibitors?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (3.2\u0026ndash;6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn average, what is the increase in the number of bleeding episodes per year among people living with Hemophilia A and B, with and without inhibitors, due to reduced adherence to factor replacement therapy?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (5.0\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering people with hemophilia who had access to primary prophylaxis, what percentage of patients develop arthropathy due to joint bleeding?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30.0 (16.25\u0026ndash;38.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering people with hemophilia who had access to primary prophylaxis, what percentage of patients progress to indication for surgery or use of joint prostheses?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.0 (1.0\u0026ndash;15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering people with hemophilia who had access to secondary prophylaxis, what percentage of patients develop arthropathy due to joint bleeding?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42.5 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.0 (31.25\u0026ndash;50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsidering people with hemophilia who had access to secondary prophylaxis, what percentage of patients progress to indication for surgery or use of joint prostheses.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.0 (11.25\u0026ndash;28.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn your clinical experience, what percentage of people with hemophilia on prophylaxis with factor replacement therapy have adherence impacted?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.0 (15.0\u0026ndash;47.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhat percentage of children aged 0 to 6 years have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.0 (6.2\u0026ndash;35.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhat percentage of children aged 7 to 12 years have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.5 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0 (6.2\u0026ndash;17.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhat percentage of adolescents have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.5 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.0 (11.2\u0026ndash;28.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhat percentage of adults have compromised prophylactic treatment due to difficulty adhering to factor replacement therapy?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24.5 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.0 (16.2\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviation: IQR\u0026thinsp;=\u0026thinsp;interquartile range; SD\u0026thinsp;=\u0026thinsp;standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Domain 2: Treatment-related aspects (adherence and residual disease burden)\u003c/h2\u003e \u003cp\u003eThis domain included a set of numerical estimation questions exploring expert perceptions regarding bleeding frequency, treatment adherence, and joint-related outcomes under different prophylactic strategies. As these items were designed to capture descriptive clinical estimates rather than agreement-based judgments, no formal consensus classification was applied. Results are presented as descriptive summaries, reflecting the overall clinical experience of the panel.\u003c/p\u003e \u003cp\u003eAmong individuals with hemophilia A without inhibitors receiving continuous prophylaxis with factor VIII replacement therapy, the estimated annual number of bleeding episodes had a mean of 3.3 (SD: 2.0), with a median of 3.0 (IQR: 2.2\u0026ndash;4.0). For individuals with hemophilia A with inhibitors treated with immune tolerance induction protocols and/or prophylaxis with bypassing agents, bleeding frequency was higher, with a mean of 5.6 episodes per year (SD: 2.0) and a median of 6.0 (IQR: 5.0\u0026ndash;6.0). In contrast, among individuals with hemophilia A with inhibitors receiving emicizumab, the estimated bleeding burden was substantially lower, with a mean of 0.9 episodes per year (SD: 1.0) and a median of 1.0 (IQR: 0.0\u0026ndash;1.7).\u003c/p\u003e \u003cp\u003eFor individuals with hemophilia B without inhibitors receiving continuous prophylaxis with plasma-derived factor IX, the mean estimated number of bleeding episodes per year was 2.3 (SD: 2.0), with a median of 2.0 (IQR: 1.2\u0026ndash;3.0). Among individuals with hemophilia B with inhibitors, the mean estimated annual number of bleeding episodes was 5.2 (SD: 2.0), with a median of 5.0 (IQR: 3.2\u0026ndash;6.7). Panelists also estimated the impact of reduced adherence to factor replacement therapy on bleeding frequency. The mean estimated increase in the number of bleeding episodes per year associated with reduced adherence was 6.1 (SD: 2.0), with a median increase of 5.0 episodes (IQR: 3.7\u0026ndash;5.0).\u003c/p\u003e \u003cp\u003eRegarding joint outcomes, among individuals with access to primary prophylaxis, the mean estimated proportion of patients developing arthropathy due to joint bleeding was 27% (SD: 2.0), with a median of 30.0% (IQR: 16.2\u0026ndash;38.7). The mean estimated proportion of patients progressing to an indication for surgery or joint prosthesis use in this group was 10.4% (SD: 2.0), with a median of 13.0% (IQR: 1.0\u0026ndash;15.0). Among individuals with access to secondary prophylaxis, the mean estimated proportion developing arthropathy was 42.5% (SD: 2.0), with a median of 40.0% (IQR: 31.2\u0026ndash;50.0), while the mean estimated proportion progressing to surgical indication or joint prosthesis use was 20.1% (SD: 2.0), with a median of 20.0% (IQR: 11.2\u0026ndash;28.7).\u003c/p\u003e \u003cp\u003eEstimates related to treatment adherence indicated that the mean proportion of individuals receiving prophylaxis with factor replacement therapy who experienced compromised adherence was 33% (SD: 2.0), with a median of 20.0% (IQR: 15.0\u0026ndash;47.5). When stratified by age, the mean estimated proportion of compromised adherence was 25% among children aged 0\u0026ndash;6 years (SD: 2.0; median: 18.0%, IQR: 6.2\u0026ndash;35.0), 14.5% among children aged 7\u0026ndash;12 years (SD: 2.0; median: 10.0%, IQR: 6.2\u0026ndash;17.5), 23.5% among adolescents (SD: 2.0; median: 20.0%, IQR: 11.2\u0026ndash;28.7), and 24.5% among adults (SD: 2.0; median: 23.0%, IQR: 16.2\u0026ndash;30.0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Domain 3: Extrinsic barriers (health system and access barriers)\u003c/h2\u003e \u003cp\u003eThis domain comprised 16 statements, of which 13 reached the predefined consensus threshold, addressing extrinsic barriers related to health system organization and access to hemophilia care within the SUS (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The central theme identified was limited access to specialized and integrated services, particularly outside reference centers. The most critical barrier was the absence of specialized technical support in emergency settings, which achieved unanimous consensus (100%). High levels of agreement were also observed for shortages of healthcare professionals with expertise in hemophilia outside specialized centers (91.7%), delays in the incorporation of new technologies and continued reliance on obsolete treatments (91.7%), and restricted access to services for the management and rehabilitation of hemophilic arthropathy (91.7%). Living in remote areas (83.3%) and socially vulnerable conditions (83.3%) were also reported as barriers.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eExpert consensus on extrinsic barriers to optimal hemophilia care within the SUS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOption(s)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAgreement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003cp\u003eLikert scale\u003c/p\u003e \u003cp\u003eranking\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients living in remote or distant areas have greater difficulty maintaining continuous access to factor replacement therapy due to access issues to Blood Centers/Satellite Blood Centers compared to those living closer to specialized services\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients in socially vulnerable situations or with precarious housing conditions have compromised optimal care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.25\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccess to specialized services for managing and rehabilitating arthropathy is limited and compromises hemophilia care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccess to specialized services for acute management of bleeding complications is limited and compromises hemophilia care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients experience difficulty managing hemorrhagic complications, such as joint bleeding, at home.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (3.5\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients experience difficulties maintaining treatment with coagulation factor replacement due to episodes of reduced supply.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (1.75\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients experience difficulty maintaining treatment with coagulation factor replacement due to episodes of reduced supply of emicizumab or the unavailability of this medication in their region.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eExtrinsic factors that may compromise treatment adherence in patients with hemophilia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eShortage of specialized professionals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.25\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of integration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDelay in the incorporation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInsufficient specialized hemophilia centers (Blood Centers/Satellite Blood Centers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFailures in the patient referral and counter-referral system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.5 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence of specialized technical support, especially in emergency situations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.5 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eExtrinsic barriers that may compromise treatment adherence in women with hemophilia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of awareness and education among healthcare professionals regarding bleeding disorders in women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of integration among hematology, gynecology, obstetrics, and primary care services\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of research and data on hemophilia in women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviation: IQR\u0026thinsp;=\u0026thinsp;interquartile range; NA\u0026thinsp;=\u0026thinsp;not applicated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1\u0026thinsp;=\u0026thinsp;strongly disagree, 2\u0026thinsp;=\u0026thinsp;disagree, 3\u0026thinsp;=\u0026thinsp;somewhat disagree, 4\u0026thinsp;=\u0026thinsp;agree, 5\u0026thinsp;=\u0026thinsp;strongly agree.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 1 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 2 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 3 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSystem fragmentation and care coordination emerged as additional high-impact barriers. Insufficient integration across levels of care reached consensus (83.3%), alongside an inadequate number of specialized hemophilia treatment centers (90.0%) and failures in referral and counter-referral systems (90.0%). In contrast, three statements did not reach consensus, including difficulties in managing hemorrhagic complications at home and interruptions in factor replacement therapy due to supply shortages or regional unavailability of emicizumab. All statements addressing extrinsic barriers affecting women with hemophilia reached consensus, including lack of professional awareness (83.3%), limited integration between hematology and women\u0026rsquo;s health services (83.3%), and scarcity of research and data on hemophilia in women (83.3%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Domain 4: Intrinsic barriers (patient-level adherence barriers)\u003c/h2\u003e \u003cp\u003eIntrinsic barriers related to treatment adherence were assessed through 35 statements, of which 14 reached the predefined consensus threshold.\u003c/p\u003e \u003cp\u003eThe most relevant barriers were those directly affecting the feasibility of infusion and self-management. In children aged 0 to 6 years, difficulty in venous access emerged as the single most critical barrier, achieving complete consensus (100%). In adolescents, the transition of infusion responsibility from caregivers to patients represented the highest-impact barrier (91.7%), underscoring the vulnerability of this developmental stage; lack of adequate self-infusion training also reached high consensus (91.7%). Among older adults, venous access difficulties combined with functional impairments such as visual limitations, tremors, and cognitive changes were consistently associated with reduced adherence (83.3%). Reduced adherence was also recognized among individuals with neurobehavioral conditions, including autism spectrum disorder (83.3%).\u003c/p\u003e \u003cp\u003eIn contrast, several barriers did not reach consensus, indicating variability in real-world experience. These included venous access difficulties in children aged 7 to 12 years, upper limb arthropathy, moderate to severe obesity, and most psychosocial factors among adults. Within children under 12 years, consensus was achieved for family or social support deficits, infusion-related discomfort, needle phobia, mental health conditions, and prolonged time to gain confidence in home infusions (83.3\u0026ndash;90.0%), whereas lack of perceived immediate benefit, denial of disease severity, and fear of adverse events did not reach consensus. Among women with hemophilia, only delayed diagnosis due to low clinical suspicion achieved unanimous agreement (100%), while other intrinsic barriers, such as social stigma, absence of symptoms, and uncertainty regarding pregnancy or breastfeeding, failed to reach consensus.(Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eExpert consensus on intrinsic barriers to treatment adherence in hemophilia.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOption(s)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAgreement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003cp\u003eLikert scale\u003c/p\u003e \u003cp\u003eranking\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn children with hemophilia aged 0 to 6 years, difficulty in venous access is associated with reduced adherence to coagulation factor replacement therapy.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.5 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn children with hemophilia aged 7 to 12 years, difficulty in venous access is associated with reduced adherence to coagulation factor replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn adolescents with hemophilia, the transition of infusion responsibility from caregivers to the patient is associated with reduced adherence to factor replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn older adults with hemophilia, difficulty in venous access, combined with limitations such as impaired visual acuity, tremors, and cognitive changes, is associated with reduced adherence to coagulation factor replacement therapy.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with upper limb arthropathy experience difficulty achieving optimal adherence to coagulation factor replacement therapy due to challenges with self-infusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.7\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with hemophilia and neurobehavioral conditions, such as autism spectrum disorder, have reduced adherence to coagulation factor replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with moderate to severe obesity experience greater difficulty achieving optimal adherence to coagulation factor replacement therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (1.7\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn women, diagnosis usually occurs later due to lower prevalence of bleeding phenotype and low clinical suspicion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eIntrinsic barriers that may compromise treatment adherence among women with hemophilia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence or low frequency of symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUncertainty about treatment compatibility with pregnancy and breastfeeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSocial stigma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.5 (2.0\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLack of adequate self-infusion training for hemophilia patients is a major barrier to optimized treatment adherence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eIntrinsic barriers that may compromise treatment adherence in children (under 12 years) with hemophilia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of family or social support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscomfort during the infusion procedure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient resistance during peripheral venous access attempts due to needle phobia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMental health conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProlonged time to gain confidence in home infusions requiring self-infusion.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of perceived immediate benefit from treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDenial or minimization of hemophilia severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;2.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFear of treatment-related complications (e.g., adverse reactions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eIntrinsic barriers that may compromise treatment adherence in adolescents (12 to under 18 years) with hemophilia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMental health conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (4.0\u0026ndash;4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePain and discomfort during the infusion procedure.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (3.5\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient resistance during attempts at peripheral venous access due to needle phobia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of perceived immediate benefit from treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDenial or minimization of hemophilia severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (2.0\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProlonged time required to develop confidence in home-based infusions requiring self-infusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFear of treatment-related complications (e.g., adverse reactions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eIntrinsic barriers that may compromise treatment adherence among adult patients with hemophilia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of family or social support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (3.5\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient resistance during attempts at peripheral venous access due to needle phobia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of perception of immediate treatment benefit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePain and discomfort during infusion procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (1.7\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDenial or minimization of hemophilia severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLong time required to gain confidence in home infusions, which require self-infusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFear of treatment-related complications (e.g., adverse reactions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviation: IQR\u0026thinsp;=\u0026thinsp;interquartile range; NA\u0026thinsp;=\u0026thinsp;not applicated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1\u0026thinsp;=\u0026thinsp;strongly disagree, 2\u0026thinsp;=\u0026thinsp;disagree, 3\u0026thinsp;=\u0026thinsp;somewhat disagree, 4\u0026thinsp;=\u0026thinsp;agree, 5\u0026thinsp;=\u0026thinsp;strongly agree.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 1 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 2 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 3 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDelphi consensus on priority attributes of emerging therapeutic technologies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgreement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003cp\u003eLikert scale\u003c/p\u003e \u003cp\u003eranking\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvailability of less invasive therapeutic alternatives via subcutaneous administration could increase adherence to prophylactic treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (5.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvailability of therapeutic alternatives requiring less frequent administration could increase adherence to prophylactic treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (5.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvailability of therapeutic alternatives that do not require laboratory monitoring could increase adherence to prophylactic treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 (4.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProviding therapeutic alternatives with weight independent dosing could improve adherence to prophylactic treatment.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.0 (1.75\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn your perception, what should be the reduction in annual bleeding events, compared to baseline, for a new technology to be considered clinically relevant?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0 (1.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviation: IQR\u0026thinsp;=\u0026thinsp;interquartile range; NA\u0026thinsp;=\u0026thinsp;not applicated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003e Level of agreement on the 5-point agreement-based Likert scale was interpreted as follows: 1\u0026thinsp;=\u0026thinsp;strongly disagree, 2\u0026thinsp;=\u0026thinsp;disagree, 3\u0026thinsp;=\u0026thinsp;somewhat disagree, 4\u0026thinsp;=\u0026thinsp;agree, 5\u0026thinsp;=\u0026thinsp;strongly agree.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eb\u003c/sup\u003e Statement reached consensus (\u0026ge;\u0026thinsp;80% partially agree/strongly agree) in the Round 1 of surveying.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Domain 5: Priority attributes of emerging technologies\u003c/h2\u003e \u003cp\u003eThis domain evaluated five items addressing priority attributes of emerging therapeutic technologies. Three items were agreement-based statements assessed for consensus, while one item was exploratory and aimed at capturing expert perceptions rather than achieving consensus.\u003c/p\u003e \u003cp\u003eThe central finding was a strong preference for treatment simplification and reduction of therapeutic burden as key strategies to improve adherence within the SUS. Unanimous consensus was reached for less invasive therapies administered via the subcutaneous route (100%) and for therapies requiring less frequent administration (100%). Consensus was also achieved regarding therapeutic options that do not require routine laboratory monitoring (83.3%).\u003c/p\u003e \u003cp\u003eIn contrast, the statement evaluating whether weight-independent dosing could improve adherence to prophylactic treatment did not reach the predefined consensus threshold. The item exploring the minimum reduction in annual bleeding events required for a new technology to be considered clinically relevant was exploratory in nature and not intended to reach consensus; responses to this question are therefore presented descriptively.\u003c/p\u003e \u003cp\u003eThe distribution of priority scores assigned by the Delphi panel for the evaluated therapeutic attributes is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Panelists assigned priority scores ranging from Priority 1, corresponding to the highest priority, to Priority 6, corresponding to the lowest priority. Overall, the central theme emerging from this ranking exercise was a clear prioritization of robust and sustained bleeding prevention, while attributes related to convenience and system-level facilitation were consistently assigned lower priority.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe attribute with the highest relevance was continuous and effective prevention of bleeding with sustained and reliable coagulation factor levels, which was predominantly ranked as the top priority. Most panelists assigned this attribute as Priority 1 (70.0%), followed by Priority 2 (20.0%), with only a small proportion classifying it as the lowest priority (Priority 6; 10.0%). In contrast, the attribute related to effective control of acute bleeding using alternative therapeutic options during prophylaxis showed a broader distribution of rankings, reflecting intermediate priority. This attribute was most frequently classified as Priority 3 (40.0%), followed by Priority 2 (30.0%) and Priority 1 (20.0%), with a minority assigning lower priority (Priority 5; 10.0%).\u003c/p\u003e \u003cp\u003eAttributes associated with treatment convenience were consistently assigned intermediate to lower priority levels. Technologies characterized by less invasive administration and reduced dosing frequency were most often ranked as Priority 4 (40.0%), with fewer panelists assigning higher priority (Priority 1\u0026ndash;2; 40.0%). A similar pattern was observed for a favorable safety profile, particularly regarding thrombotic risk, which was predominantly ranked as Priority 4 (50.0%) or Priority 5 (30.0%). Greater dispersion toward lower priorities was observed for attributes related to reduction in travel and increased patient autonomy, with most responses concentrated in Priority 5 (30.0%) and Priority 6 (30.0%). Finally, the absence of a requirement for laboratory monitoring was consistently considered the least relevant attribute, being assigned the lowest priority by the majority of panelists (Priority 6: 60.0%; Priority 5: 30.0%).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e Through a modified Delphi consensus methodology, this study identified and prioritized key unmet needs and structural barriers to optimal hemophilia care in Brazil. The results reveal a robust agreement among experts that, despite the national implementation of prophylaxis, substantial and persistent gaps in care remain.\u003c/p\u003e \u003cp\u003eThe panel reached a unanimous consensus (100%) that significant unmet needs persist among patients with moderate to severe hemophilia A and B without inhibitors. This scenario is corroborated by Souza et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) who conducted a study in Amazonas, Brazil, involving 164 individuals with hemophilia A. The authors showed that, even with access to CFCs, 77.3% of participants continued to suffer from joint pain (arthralgia) and 78.4% experienced bleeding episodes (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Furthermore, the persistence of joint disease was quantified by Soares et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). in the Federal District. Even in this region with a high Human Development Index, adult patients presented a mean Hemophilia Joint Health Score (HJHS) of 18.0 (SD 10.8), with 80.6% exhibiting ankle impairments (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Finally, evidence from the HERO study (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), in Brazil, reported that 64.0% of people with hemophilia still experience extreme or moderate pain, and 71.0% reported a negative impact on employment. The persistence of suboptimal clinical outcomes despite access to CFCs establishes a direct link with the remaining unmet needs and the identified priorities identified by this Delphi panel. Ongoing high rates of established arthropathy and chronic pain suggest that the current standard of care, predominantly based on intravenous prophylaxis, continues to impose a substantial treatment burden, which may compromise adherence in real-world settings. These findings indicate that although significant logistical and organizational advances have been achieved in Brazil over the past decade, they may no longer be sufficient to address current unmet needs.\u003c/p\u003e \u003cp\u003eWithin this context, the Delphi panel identified structural barriers to access and continuity of care as key determinants underlying these outcomes. Distance from hemophilia reference centers emerged as a major constraint, with 83.3% of experts agreeing that patients living in remote or geographically distant areas face greater difficulty maintaining continuous access to therapy. This perception aligns closely with national and regional data. Feij\u0026oacute; et al. (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) found, in Southern Brazil, that 58.3% of patients resided outside the municipality where a Hemocentro, a Brazilian public blood center, was located, while Cust\u0026oacute;dio et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) reported, in Alagoas, that 58.0% of patients lived more than 30 km away from the treatment center. In addition, Sarmento et al. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) conducted a retrospective review of records from Department of Informatics of SUS (DataSUS) and found that 55.4% of all hemophilia-related hospital admissions occurred in the Southeast region. Furthermore, receiving treatment at a specialized hemophilia center was found to be a positive and independent factor associated with adherence to treatment protocols (Odds Ratio: 2.38; 95% CI: 1.05\u0026ndash;5.41) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis geographical challenge is not unique to Brazil but reflects a broader structural barrier affecting access to hemophilia care across different health systems. In the United States, findings from the B-HERO-S study (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) showed that travel time (43.0%), travel-related costs (43.0%), and long distances (50.0%) were among the most frequently reported barriers to accessing hemophilia treatment centers. Similarly, in China, Liu et al. (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) reported that patients living in rural areas often travel up to five hours to obtain coagulation factor concentrates, a logistical burden that discourages prophylaxis and delays the management of acute bleeding events. In response to this structural limitation, Brazil has intensified efforts since 1999 to expand home-based treatment, aiming to reduce hospital visits, alleviate pain episodes, and minimize absenteeism from school and work (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). However, participation rates vary widely across regions and patient cohorts, ranging from 33.0% to 90.0%, indicating uneven program reach and differences in patients\u0026rsquo; ability to perform self-infusion (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The persistence of distance from treatment centers as a prioritized barrier in this Delphi panel suggests that, despite these advances, logistical challenges and treatment burden remain significant. This finding reinforces the expert consensus on the need for therapeutic strategies that further simplify administration, particularly subcutaneous options, and reduce dependence on centralized services to ensure more equitable and effective hemophilia care in Brazil.\u003c/p\u003e \u003cp\u003eSocial vulnerability emerged as another extrinsic barrier with high consensus (83.3%). In the Brazilian context, socioeconomic status is a determinant of clinical outcomes. Cust\u0026oacute;dio et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) reported that 78.0% of Brazilian hemophilia patients had a monthly personal income of up to only one minimum wage. This economic precarity has direct clinical implications. According to Soares et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), a monthly household income greater than two Brazilian minimum wages showed an independent and statistically significant association with improved HJHS (p\u0026thinsp;=\u0026thinsp;0.033). These data strongly support the Delphi panelists' view that clinical efficacy cannot be divorced from the patient's social context, necessitating therapeutic strategies that reduce the indirect costs and logistical burdens of care. To mitigate the impact of social vulnerability, strategies must extend beyond the provision of coagulation factors alone and address the indirect costs and logistical barriers associated with treatment. Therapeutic approaches that reduce infusion complexity, decrease the frequency of administration, and minimize the need for travel to specialized centers may help offset socioeconomic disparities. In addition, strengthening home-based treatment programs, expanding decentralized care networks, and integrating social support services into hemophilia care pathways may contribute to more equitable outcomes (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding intrinsic barriers, the panel reached complete consensus (100%) in identifying difficult venous access as a primary obstacle to treatment adherence in children aged 0 to 6 years. This finding converges with results from a Brazilian Delphi study conducted by Magliano et al. (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), in which experts identified \"difficulty in venous access\" as the leading indication (89.0% agreement) for switching to non-factor therapies such as emicizumab. The reliance on frequent intravenous infusions imposes a substantial burden. Mancuso et al. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) further highlighted that maintaining such infusion regimens often requires the use of central venous access devices (CVADs), which are associated with significant risks of surgical complications, infection, and thrombosis, particularly in infants.\u003c/p\u003e \u003cp\u003eThe transition from caregiver-administered to self-administered prophylaxis in adolescents was identified as a critical vulnerability, achieving 91.7% consensus as a cause for reduced adherence. This expert perception is supported by Geragthy et al. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), who reported that adherence rates decline precipitously with age, from 90.0% in children (0\u0026ndash;12 years) to 54.0% in adolescents (13\u0026ndash;18 years). Similarly, in the TEEN/TWEN (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)observational study, 38 late adolescents and young adults (median age 19.5 years) were assessed to evaluate the consequences of discontinuing long-term prophylaxis. Participants who voluntarily discontinued prophylaxis\u0026thinsp;\u0026le;\u0026thinsp;12 months or \u0026ge;\u0026thinsp;13 months prior to study entry experienced markedly higher median annualized bleeding rates (4.8 and 24 events per year, respectively) compared with a median of no events per year among those who continued prophylaxis. Health-related quality of life measures were also generally worse among individuals who discontinued prophylaxis, indicating that the transition from caregiver-administered to self-managed treatment is associated with increased bleeding and reduced well-being in this age group (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Further evidence from a comprehensive systematic literature review (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) reinforces adolescence and early adulthood as periods of increased vulnerability to reduced adherence. In a synthesis of 31 studies comprising 2,379 individuals with hemophilia, Sun et al. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) consistently observed lower adherence rates among adolescents and young adults compared with younger children, alongside higher annualized bleeding rates and less favorable joint outcomes. Collectively, these findings are consistent with the Delphi panel\u0026rsquo;s assessment that adolescence may represent a phase in which adherence challenges become more pronounced, particularly in the context of increasing treatment responsibility, reduced caregiver supervision, and treatment fatigue. This evidence supports consideration of adolescents as a priority population for interventions focused on simplifying prophylactic regimens and strengthening structured transition processes to promote sustained adherence across the life course.\u003c/p\u003e \u003cp\u003eThe absolute consensus regarding the diagnostic \u0026ldquo;invisibility\u0026rdquo; of women with hemophilia is supported by clinical evidence suggesting a substantial and often underrecognized disease burden in this population. In a multicenter retrospective chart review, Chaudhury et al. (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) evaluated 47 women and girls with hemophilia and reported a median age at diagnosis of 22.6 years, indicating diagnostic delay despite the presence of bleeding manifestations. Although 79.0% of patients were classified as having mild hemophilia, clinically relevant bleeding events were frequent, including spontaneous or traumatic bleeds, joint bleeding, and heavy menstrual bleeding (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Importantly, bleeding symptoms in women often overlap with conditions considered physiological, such as menstruation, childbirth, and postpartum bleeding, contributing to symptom normalization and delayed recognition. This clinical overlap is compounded by gender-related factors within the healthcare system and at the patient level. In Brazil, Lorenzato et al. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) reported that 86.0% of caregivers of individuals with hemophilia are women, predominantly mothers, who frequently assume the dual role of primary caregiver while potentially being undiagnosed symptomatic carriers themselves. This dual burden may further contribute to self-neglect, delayed care-seeking, and prioritization of family needs over personal health.\u003c/p\u003e \u003cp\u003eThe panel also addressed the intersection of neurobehavioral comorbidities and adherence, agreeing (83.3%) that conditions such as autism spectrum disorder significantly compromise treatment. This aligns with the high prevalence of mental health struggles reported in the literature. Lorenzato et al. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) found that 18.0% of Brazilian patients had undergone treatment for depression or anxiety. The mental health burden is further quantified by Garbin et al. (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), who showed that \"emotional aspects\" had the lowest scores among health domains in Brazilian patients (mean 58.88). A systematic review with meta-analysis including 28 studies and 2,926 individuals from multiple countries, verified significantly increased odds of depression (OR: 2.45; 95% CI: 1.64\u0026ndash;3.68), anxiety (OR: 1.74; 95% CI: 1.01\u0026ndash;3.00), combined anxiety/depression (OR: 2.60; 95% CI: 2.35\u0026ndash;2.87), and attention-deficit/hyperactivity disorder (OR: 3.48; 95% CI: 1.74\u0026ndash;6.96) compared with the general population (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). However, evidence regarding the effectiveness and availability of psychosocial interventions remains limited. In a Cochrane systematic review of psychological interventions for people with hemophilia, Palareti et al. (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) identified only seven randomized or quasi-randomized trials involving 362 participants, with overall low to very low certainty of evidence. Psycho-educational and computerized learning interventions showed modest improvements in self-efficacy, coping strategies, and transition readiness in children and adolescents, but effects on adherence, bleeding outcomes, and quality of life were inconsistent, and data on long-term clinical impact were scarce. Importantly, the review highlighted substantial heterogeneity across interventions and outcome measures, as well as the absence of integrated mental health care models within hemophilia services (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Together, these findings suggest that, despite recognition of psychosocial burden, access to effective and standardized mental health support for people with hemophilia has not improved proportionally to advances in hemostatic therapies. This gap reinforces the Delphi panel\u0026rsquo;s view that optimal hemophilia care requires both systematic psychosocial support and therapeutic strategies that reduce procedural stress and treatment burden, particularly for individuals with neurobehavioral comorbidities.\u003c/p\u003e \u003cp\u003eFurthermore, the panel reached 100% consensus on the absence of specialized technical support in emergency settings as a major extrinsic barrier. This expert perception reflects a systemic vulnerability quantified by Soares et al. (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) in the Federal District; using the Haem-A-QoL questionnaire, they observed that the item eliciting the highest concern within the \"Treatment\" domain was the fear of being attended by non-specialized professionals during emergencies (score 72.6). The B-HERO-S study (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) found that 17.0% of patients reported difficulty gaining access to Hemophilia Treatment Centers, often relying on non-specialized emergency rooms. Although Brazil has a well-established network of Hemophilia Treatment Centers that provide highly specialized care and ensure effective routine management, the Delphi results suggest that this concentration of expertise does not consistently translate into preparedness across general emergency settings, particularly for patients residing far from reference centers. These findings highlight the need for targeted training of generalist emergency providers and clearer referral pathways to ensure timely and appropriate management of acute bleeding events.\u003c/p\u003e \u003cp\u003eThe evaluation of emerging technologies revealed a clear preference for subcutaneous administration and reduced dosing frequency, both achieving 100% consensus as drivers for adherence. The panel estimated that individuals with Hemophilia A without inhibitors on prophylaxis experience a mean of 3.30 bleeds per year. This aligns with the Kenet et al. study (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e), which reported a mean Annualized Bleeding Rate (ABR) of 2.42 for Brazilian patients on prophylaxis. These data validate the Delphi consensus that while current prophylaxis has improved outcomes, it has not achieved the \"zero bleed\" benchmark, reinforcing the clinical relevance of novel therapies with higher efficacy profiles.\u003c/p\u003e \u003cp\u003eCrucially, the areas where the panel did not reach consensus offer valuable insights into the heterogeneity of the Brazilian context, such as the lack of agreement regarding treatment discontinuation due to factor supply shortages (60.0% agreement). This divergence likely reflects the dichotomy between successful federal procurement and inequitable regional distribution. On one hand, data from the HERO study (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) indicated that 58.0% of patients and 68.0% of caregivers did not experience difficulties obtaining factor in the previous 5 years, suggesting that the Ministry of Health's centralized purchasing strategies have largely stabilized the macro-availability of products. However, the persistence of this concern among a subset of experts is validated by the stark regional disparities, in which CFCs utilization, based on factor VIII per capita, varies drastically from 7.22 IU in the Federal District to a critical low of 0.27 IU in peripheral states like Roraima (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Therefore, the lack of consensus accurately depicts a system where access is geographically determined. While the supply exists federally, logistical failures in specific regions continue to disrupt maintenance for vulnerable populations.\u003c/p\u003e \u003cp\u003eNotably, the panel was divided on the influence of obesity on treatment adherence, with only half of the experts (50.0%) agreeing. This lack of consensus may reflect a perspective among Brazilian hematologists who primarily consider obesity as a factor that exacerbates joint health problems, rather than as a direct barrier to infusion and adherence. In contrast, existing literature points out that obesity can complicate venous access and reduce mobility, thereby indirectly hindering effective care (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFinally, the interpretation of these findings must consider the study's limitations and strengths. A primary limitation is the sample size of 12 experts. However, this is consistent with the Delphi methodology for specialized topics and is counterbalanced by the participants' extensive experience in the public system (\u0026gt;\u0026thinsp;15 years) and large number of patients attending. One of the key strengths of this study is the inclusion of experts from all regions, ensuring a comprehensive representation of perspectives across Brazil. Additionally, the methodological rigor of the Delphi process, which adhered strictly to the DELPHISTAR protocol (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), enhances the reliability and quality of the consensus findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis Delphi consensus on hemophilia care in Brazil indicates that extrinsic barriers related to health system organization and access to specialized services, together with intrinsic barriers affecting treatment adherence across the life course, negatively influence clinical outcomes. The identification of unmet needs across diverse patient groups, including women, children, adolescents, and older adults, underscores the need for more integrated and patient-centered care strategies. In addition, expert alignment regarding the potential benefits of less invasive hemophilia therapies with reduced administration frequency supports the prioritization of innovations aimed at lowering treatment burden and improving adherence. Overall, these findings provide a structured basis for updating clinical protocols, informing public health policy, and guiding the incorporation of new therapeutic options to promote more equitable, efficient, and sustainable hemophilia care within the public healthcare setting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e7.1 Ethics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this type of study. All participants provided electronic informed consent prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.2 Consent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors consent to the publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.3 Availability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.4 Competing Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJL, FI, and BW are employees of IQVIA, which received funding from Pfizer for the conduct of this study. DP, MA, AKN, RFA, and AD are current employees of Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.5 Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was sponsored by Pfizer, which commissioned IQVIA for its execution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.6 Authors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFI, BW, and JL provided methodological oversight of the Delphi process, contributed to the study design, supported the development and refinement of the consensus statements, performed data analysis, and contributed substantially to the drafting of the manuscript. ISSP and MCO contributed to the clinical evaluation of the statements and critically reviewed the content. DP, MA, AKN and AD supervised the project and participated in the final review of the manuscript. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7.7 Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Delphi Panel participants for their contributions and Franciele Iachecen for her methodological support.\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoberti M, Gea Y, Marinho IA, Inacio PP, Camelo RM, de Castro TF et al (2025) Public health assistance for people with haemophilia in Brazil (PATCH study): a cross-sectional study protocol. BMJ Open 15(11):e111031\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnzi Pietrobelli TM, Sponchiato D (2022) Retrato sobre a hemofilia A no Brasil: como \u0026eacute; a jornada do paciente e quais s\u0026atilde;o seus principais desafios. Jornal De Assist\u0026Ecirc;ncia Farmac\u0026Ecirc;utica E Farmacoeconomia 1(s3):\u0026ndash;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaim J, Travassos C, Almeida C, Bahia L, Macinko J (2011) The Brazilian health system: history, advances, and challenges. Lancet 377(9779):1778\u0026ndash;1797\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOzelo MC, Antunes SV, Villaca PR, Oliveira LC, Pinto IS, Lorenzato CS et al (2024) Extended half-life recombinant factor VIII treatment of hemophilia A in Brazil: an expert consensus statement. Hematol Transfus Cell Ther 46(1):36\u0026ndash;41\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSrivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW et al (2020) WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. ;26 Suppl 6:1\u0026ndash;158\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoivusalo M, Szanto T, Kovalainen T, Vesikansa A, Laine O, Partanen A et al (2025) Switching From Standard to Extended Half-Life Coagulation Factor Replacement in Haemophilia: Clinical Outcomes and Costs of Care in Finland. Haemophilia 31(4):722\u0026ndash;733\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrijvers LH, Beijlevelt-van der Zande M, Peters M, Lock J, Cnossen MH, Schuurmans MJ et al (2016) Adherence to prophylaxis and bleeding outcome in haemophilia: a multicentre study. Br J Haematol 174(3):454\u0026ndash;460\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarneiro JDA, Blanchette V, Ozelo MC, Antunes SV, Villaca PR, Young NL et al (2017) Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the Sao Paulo-Toronto Hemophilia Study. Haemophilia 23(5):682\u0026ndash;688\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerntorp E (2009) Joint outcomes in patients with haemophilia: the importance of adherence to preventive regimens. Haemophilia 15(6):1219\u0026ndash;1227\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTavares NU, Bertoldi AD, Mengue SS, Arrais PS, Luiza VL, Oliveira MA et al (2016) Factors associated with low adherence to medicine treatment for chronic diseases in Brazil. Rev Saude Publica 50(suppl 2):10s\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThornburg CD, Duncan NA (2017) Treatment adherence in hemophilia. Patient Prefer Adherence 11:1677\u0026ndash;1686\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider NB, de Araujo CLP, Godoy Dos Santos HW, Lima S, Falavigna M, Pachito DV (2024) Epidemiology, patient journey and unmet needs related to hemophilia in Brazil: a scoping review with evidence map. 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Lancet Infect Dis 24(8):e513\u0026ndash;e21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJunger S, Payne S, Brearley S, Ploenes V, Radbruch L (2012) Consensus building in palliative care: a Europe-wide delphi study on common understandings and conceptual differences. J Pain Symptom Manage 44(2):192\u0026ndash;205\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon der Gracht HA (2012) Consensus measurement in Delphi studies. Technol Forecast Soc Chang 79(8):1525\u0026ndash;1536\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBentes MN, Oliveira VMAd, Crispim MAE, Souza CRS, Bentes RL (2022) Perfil epidemiol\u0026oacute;gico de pacientes com Hemofilia A e doen\u0026ccedil;as associadas ao uso do fator VIII/recombinante. Revista de Ci\u0026ecirc;ncias M\u0026eacute;dicas e Biol\u0026oacute;gicas. 20(4):568\u0026ndash;574\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoares BMDIA, Ribeiro AJT, Simeoni LA, Almeida KJQ, Bezerra LB et al (2023) Evaluation of functional and joint health and associated factors in adults with hemophilia from a developing country with government-backed efforts to improve hemophilia care. Perm J 27:23009\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLorenzato CS, Santos RB, Fagundes GZZ, Ozelo MC (2019) Haemophilia Experiences, Results and Opportunities (HERO study) in Brazil: Assessment of the psychosocial effects of haemophilia in patients and caregivers. Haemophilia 25(4):640\u0026ndash;650\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeij\u0026oacute; AM, Schwartz E, Lise F, Santos, BPd (2018) Spagnolo LMdL. \u003cb\u003eCaracter\u0026iacute;sticas sociodemogr\u0026aacute;ficas de homens com hemofilia no sul do brasil / Sociodemographic characteristics of men with hemophilia in the south of brazil\u0026thinsp;\u0026lt;\u0026thinsp;b\u0026gt;. Ci\u0026ecirc;ncia\u003c/b\u003e. Cuidado e Sa\u0026uacute;de 17(4):e45048\u0026ndash;e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCust\u0026oacute;dio RMBP, Sousa MCDA, Costa PJMdS (2022). Impacto da hemofilia na qualidade de vida em rela\u0026ccedil;\u0026atilde;o \u0026agrave; sa\u0026uacute;de de pacientes acompanhados pelo hemocentro de Alagoas. Med (Ribeir\u0026atilde;o Preto). ;55(3)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarmento T, Picoli R, Renni M, Sato-Kuwabara Y, Mata VE (2022) Analysis of epidemiological and economic data of hemophilia A patients in Brazil. Jornal Brasileiro de Economia da Sa\u0026uacute;de 14(3):272\u0026ndash;281\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoares BMD, Simeoni LA, de Almeida KJQ, de Souza JL, Mizusaki Imoto A, Swain Braverman M et al (2020) Factors Associated with Compliance with the Treatment Protocol and Mortality in Adults with Hemophilia. Patient Prefer Adherence 14:2279\u0026ndash;2285\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuckner TW, Witkop M, Guelcher C, Frey MJ, Hunter S, Peltier S et al (2017) Management of US men, women, and children with hemophilia and methods and demographics of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study. Eur J Haematol 98(Suppl 86):5\u0026ndash;17\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Z, Feng J, Fang Y, Cheng Y, Li S (2023) Barriers to prophylactic treatment among patients with haemophilia A in Shandong Province, China: a qualitative study. Orphanet J Rare Dis 18(1):226\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira AA (2018) Hemofilia: valida\u0026ccedil;\u0026atilde;o da vers\u0026atilde;o brasileira do VERITAS-Pro para avalia\u0026ccedil;\u0026atilde;o da ades\u0026atilde;o \u0026agrave; profilaxia e custo-an\u0026aacute;lise do tratamento. Tese (Doutorado) \u0026ndash; Universidade Federal de Juiz de Fora, Juiz de Fora, 2018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewandowska M, Nasr S, Shapiro AD (2025) Emerging Therapies in Hemophilia: Improving Equitable Access to Care. J Blood Med 16:95\u0026ndash;115\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMagliano CA, Pereira AC, Fernandes R, Sato-Kuwabara Y, Loze P, Carlos N et al (2022) Statements about hemophilia A in Brazil: an expert Delphi panel. Jornal Brasileiro de Economia da Sa\u0026uacute;de 14(1):96\u0026ndash;103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMancuso ME, Mahlangu JN, Pipe SW (2021) The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet 397(10274):630\u0026ndash;640\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeraghty S, Dunkley T, Harrington C, Lindvall K, Maahs J, Sek J (2006) Practice patterns in haemophilia A therapy -- global progress towards optimal care. Haemophilia 12(1):75\u0026ndash;81\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManco-Johnson MJ, Sanders J, Ewing N, Rodriguez N, Tarantino M, Humphries T et al (2013) Consequences of switching from prophylactic treatment to on-demand treatment in late teens and early adults with severe haemophilia A: the TEEN/TWEN study. Haemophilia 19(5):727\u0026ndash;735\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun J, Zhou X, Hu N (2021) Factor VIII replacement prophylaxis in patients with hemophilia A transitioning to adults: a systematic literature review. Orphanet J Rare Dis 16(1):287\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaudhury A, Sidonio R Jr., Jain N, Tsao E, Tymoszczuk J, Oviedo Ovando M et al (2021) Women and girls with haemophilia and bleeding tendencies: Outcomes related to menstruation, pregnancy, surgery and other bleeding episodes from a retrospective chart review. Haemophilia 27(2):293\u0026ndash;304\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarbin LMCE, Canini SRMS, Dantas RAS (2007 Apr-Jun) Avalia\u0026ccedil;\u0026atilde;o da qualidade de vida relacionada \u0026agrave; sa\u0026uacute;de em pacientes portadores de hemofilia. Cienc Cuid Saude 6(2):197\u0026ndash;205\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Huniti A, Reyes Hernandez M, Ten Eyck P, Staber JM (2020) Mental health disorders in haemophilia: Systematic literature review and meta-analysis. Haemophilia 26(3):431\u0026ndash;442\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalareti L, Melotti G, Cassis F, Nevitt SJ, Iorio A (2020) Psychological interventions for people with hemophilia. Cochrane Database Syst Rev 3(3):CD010215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoares BMD, Imoto AM, Simeoni LA, de Almeida KJQ, Braverman MS, Bezerra LB et al (2022) Health-related quality of life and associated factors: Results from the haemophilia QOL questionnaire for adults (Haem-A-QOL) in a low-income country with public policies to improve haemophilia care. Haemophilia 28(5):e125\u0026ndash;e8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitkop M, Wang M, Hernandez G, Recht M, Baumann K, Cooper DL (2021) Impact of haemophilia on patients with mild-to-moderate disease: Results from the P-FiQ and B-HERO-S studies. Haemophilia 27(Suppl 1):8\u0026ndash;16\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKenet G, Chen YC, Lowe G, Percy C, Tran H, von Drygalski A et al (2021) Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study. J Clin Med. ;10(24)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSayago M, Lorenzo C (2020) O acesso global e nacional ao tratamento da hemofilia: reflex\u0026otilde;es da bio\u0026eacute;tica cr\u0026iacute;tica sobre exclus\u0026atilde;o em sa\u0026uacute;de. Interface - Comunica\u0026ccedil;\u0026atilde;o, Sa\u0026uacute;de, Educa\u0026ccedil;\u0026atilde;o. ;24:e180722\u0026ndash;e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim MY, Wei G, Presson AP, Bray P, Rodgers GM (2020) High prevalence of overweight/obesity in adult persons with hemophilia in Utah and a review of the literature. Blood Coagul Fibrinolysis 31(8):522\u0026ndash;529\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"db665651-7309-4a8d-ab9a-3d6d7ac66ec3","identifier":"10.13039/100004319","name":"Pfizer","awardNumber":"Not applicable.","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Pfizer (Brazil)","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hemophilia A, Hemophilia B, Needs Assessment, Medication adherence, Delphi Technique, Brazil","lastPublishedDoi":"10.21203/rs.3.rs-9471111/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9471111/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eDespite therapeutic advances, important gaps persist in hemophilia care within public healthcare systems in middle-income countries. In Brazil, universal access to prophylaxis is ensured through a centralized public system, however, the available treatments remain limited compared to international standards. This study aimed to identify unmet needs, barriers to optimal care, and priority attributes for emerging therapies in hemophilia A and hemophilia B within the Brazilian Unified Health System (SUS), using expert consensus.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eA modified Delphi study was conducted with twelve hematologists experienced in hemophilia care from all Brazilian regions. Consensus indicated persistent unmet needs among individuals with moderate to severe hemophilia A without inhibitors (100%) and with inhibitors (80.0%), as well as hemophilia B without inhibitors (100%) and with inhibitors (91.7%). Consolidation of national clinical protocols into a single guideline was considered important to standardize care (83.3%). Key extrinsic barriers included limited access to treatment centers for patients in remote areas (83.3%), social vulnerability (83.3%), restricted access to arthropathy management and rehabilitation services (91.7%), and limited access to specialized care for acute bleeding events (83.3%). Additional barriers included shortages of trained professionals outside specialized centers (91.7%), delayed incorporation of new technologies (91.7%), insufficient integration across levels of care (83.3%), an inadequate number of specialized centers (90.0%), failures in referral and counter-referral systems (90.0%), and lack of specialized technical support in emergency settings (100%). Intrinsic barriers to adherence included difficult venous access in children aged 0 to 6 years (100%), reduced adherence during transition to self-infusion in adolescents (91.7%), lack of adequate self-infusion training (83.3%), and venous access difficulties with functional limitations in older adults (83.3%). Panelists also estimated that, among individuals receiving prophylaxis with factor replacement therapy, the mean proportion with compromised adherence was 33% (SD: 2.0). Regarding emerging therapies, consensus supported less invasive subcutaneous administration (100%), reduced dosing frequency (100%), and therapies not requiring routine laboratory monitoring (83.3%) as facilitators of adherence.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eThis expert consensus highlights persistent unmet needs and structural and individual barriers to optimal hemophilia care in Brazil. The findings support health system reorganization and the incorporation of innovative therapies to improve adherence and clinical outcomes in the SUS.\u003c/p\u003e","manuscriptTitle":"Expert Consensus on Unmet Needs and Barriers to Optimal Hemophilia Care in Brazil: Results from a Modified Delphi Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 15:31:09","doi":"10.21203/rs.3.rs-9471111/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eec302c3-f9bc-4f46-97bf-8ad5ffd5dcba","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66647967,"name":"Hematology"}],"tags":[],"updatedAt":"2026-04-21T15:31:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 15:31:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9471111","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9471111","identity":"rs-9471111","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}