Hemophilia Treatment Centers Research Articles

Improved outcomes and cost savings for patients with bleeding disorders: a quality improvement project

BackgroundProviding optimal care for patients with bleeding disorders according to national standards remains a challenge at designated Hemophilia Treatment Centers (HTCs). Improved care may reduce bleeds and costs. ObjectivesTo improve care and demonstrate cost savings by 1) reducing preventable hospitalizations and emergency room visits (PHER) for bleeding, 2) increasing use of prophylaxis in severe hemophilia, and 3) improving patient-HTC communication and primary care engagement. MethodsProspective quality improvement project using the Define, Measure, Analyze, Improve, and Control methodology to implement uniform guideline-based bleeding disorder care at a rural HTC (N = 88). Intervention used a standardized physician checklist, improved communication, and reserved physician time for urgent management. Outcomes were determined by retrospective chart review; urgent management was tracked prospectively. ResultsIntervention significantly reduced PHER by 85.4%. Use of prophylaxis in persons with severe hemophilia increased from 58.8% to 100%; attainment of a primary care physician and electronic portal enrollment met outcomes for intervention success. HTC clinic visit attendance was low at 55.2%. The majority of patients (71.6%) had at least 1 outpatient urgent episode (mean, 0.72 episode per year), and 93% had nonurgent management (mean, 9.3 episodes per year) occurring outside of a clinic visit. Hospital PHER factor cost in the group was reduced by 94.5%, from $11,800 to $640 per patient per year—a cost savings of $982,088 yearly. ConclusionThis collaborative study shows that implementation of a carefully designed quality improvement project, such as uniform guidelines with focus on strengthening ambulatory management, led to improved outcomes and cost savings.

Study of Factor VIII Inhibitor and F8 Gene Mutations in Persons with Hemophilia A from Benin

Aim: determine the prevalence of a FVIII inhibitors and identify the genetic mutations associated with their development in beninese personne with hemophilia (PwH) A. Study Design: this is cross-sectional descrptive study conducted from June 2022 to May 2023 in hemophilia treatment centers in Benin. Methodology: Inhibitor screening was carried out systematically in all PwHs A receiving FVIII infusion through determination of the circulating anticoagulant index and the Nijmegen-Bethesda assay. The molecular study strategy used for the F8 gene associated with hemophilia A is dependent on the severity of the hemophilia. Other data were collected either from patients' responses to the questionnaire or by studying their medical records and the center's hemophilia registry. Results: Of the 97 PwHs A followed up, 57 had been treated with FVIII infusion. Of these, 21 had developed inhibitors, representing a frequency of 36.8% of treated PwHs A and 43.75% of severe PwHs. None of the moderate or mild PwHs A had developed anti-FVIII antibodies. PwHs A with inhibitors had a median age of 11 years, ranging from 1 to 66 years. The Nijmegen-Bethesda test revealed 11 high responders and 10 low responders. Mutation analysis of the F8 gene revealed seven cases of intron 22 inversion, seven cases of nonsense mutations, three cases of deletion and one case of missense mutation. Mutations weren’t identified in three patients because their DNA did not amplify on long-distance PCR. In terms of therapy, immune tolerance induction wasn’t achieved in any of the 21 patients, but they are treated with emicizumab and bypass depending on the context. Conclusion: Although a cross-sectional study with a limited sample size, this study provides valuable information on beninese PwHs A with inhibitors. The frequency of inhibitors is high in treated PwHs A, and almost all patients who have developed inhibitors have high-risk genetic mutations.

A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement.

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

Joint bleeds in mild hemophilia: Prevalence and clinical characteristics.

Joint bleeds are a common and frequent complication associated with hemophilia, increasing the risk of hemophilic arthropathy. It is important to define and characterize the presence of joint complications in mild hemophilia to develop strategies to mitigate disease burden. To characterize the prevalence, clinical characteristics of joint bleeds, and risk factors that may lead to hemarthrosis in people with mild hemophilia. Following Institutional Review Board approval, a retrospective chart review was conducted for patients with mild hemophilia seen at the Yale Hemophilia Treatment Center or Classical Hematology Program. The medical records of 70 patients were reviewed. Eighty one percent were male and 19 percent were female. Twenty individuals with mild hemophilia had a history of joint bleeding, 13 were traumatic bleeds, 7 were spontaneous. The age of first joint bleed ranged from 4 to 58 years old, with an average age of 20.8-years old. Ten patients developed joint bleeds between the ages of 10 and 20 years old. The most common locations of joint bleeding were the knee (n=11) and ankle (n=7). Eight of 70 patients had hepatitis C (HCV), 6 experienced joint bleeding. In this study, almost one third of patients with mild hemophilia experienced joint bleeding, often without history of trauma. Joint range of motion was abnormal in more than a third of the patients with mild hemophilia regardless. These data highlight the need for ongoing evaluation and characterization of joint health in individuals with mild hemophilia. Twenty-nine percent of individuals with mild hemophilia had history of joint bleed. PwH and mild diseases with previous or current hepatitis C had higher likelihood of joint bleeding. Approximately 15% of PwH and mild diseases had abnormal joint examinations without a confirmed history of joint bleeding.

Adult People with Hemophilia A Have Low Annualized Bleeding Rate, However the Arthropathy Remains a Burden: A Retrospective Cohort Study.

Congenital Hemophilia A is a complex disease to treat, especially in places without access to hemophilia treatment centers (HTCs). The primary aim of this study was to analyze the outcomes of a cohort of adult people with congenital hemophilia A in an HTC localized in the Bajio region of Mexico. Observational retrospective study of a cohort of 82 adult people with congenital hemophilia A treated in a tertiary-level hospital in the Bajio region of Mexico, between June 2022 and June 2023. The median age of the patients was 29.5years, 60.9% with severe hemophilia A, 53.6% were under some factor VIII prophylaxis regimen, and 52.4% had home therapy. The median annualized bleeding rate (ABR) was one bleed/year (IQR 0-3 bleeds/year) including a median of zero joint bleeds/year (IQR 0-3 bleeds/year). The presence of high-response inhibitors was detected in 8.5%, with an overall incidence of inhibitors of 14.6% of the cohort. Univariate analysis showed that inhibitors (OR 21.10; CI 95% 1.20-370.3; P = 0.03) and clinical arthropathy (OR 6.14; CI 95% 2.13-17.68; P = 0.001) were significantly higher in severe hemophilia. Clinically significant arthropathy was found in 71.9% of patients. Ultrasonography of the target joints showed that mainly cartilage degeneration was affected. Blood transfusion-associated viral infections were detected in 10.9% of patients. In our HTC, current treatment with hemostatic agents allows adequate control of ABR with acceptable inhibitor rates. However, we still have joint damage in most patients, which is partly explained by the fact that prophylaxis was introduced only in recent years.

Defining the impact of immune tolerance induction on clinically relevant outcomes in a US cohort of severe hemophilia A

AbstractAlthough the near-term benefit of immune tolerance induction (ITI) for the treatment of people with severe hemophilia A with inhibitor is apparent, the magnitude of the longer-term impact of ITI on clinical outcomes remains undefined. We examined the association between receiving ITI and the success of ITI on clinical outcomes including (1) clinical events, (2) health care use, (3) quality of life/function, (4) socioeconomic status, and (5) death, using the Community Counts (CC) registry of US Hemophilia Treatment Centers between 2013 and 2017. Multivariate logistic regression, negative binomial, and Poisson models were used. Included in this study were 3659 people with severe hemophilia A with median age of 21 years when entering the CC registry. Among 576 participants with inhibitors, 485 had received ITI (84%). ITI was successful in 299 (61.7%) and partially successful or failed in 95 (19.5%) or 91 (18.7%), respectively. Those that received ITI had fewer treated bleeds, less chronic pain, better function, and higher educational attainment than those not receiving ITI. Successful vs partially successful and failed ITI was associated with fewer treated bleeds, less health care use, less chronic pain, better function, and fewer missed days of school or work. Mortality was not associated with ITI, regardless of its success. Those with successful ITI had similar rates of treated bleeds, chronic pain, and health care use as those with no inhibitors. Undergoing ITI, particularly if successful, improved clinical outcomes but not mortality. These findings support decision making regarding initiation of ITI and inform future clinical trials.

Health-related quality of life and its associated factors among hemophilia patients: experience from Ethiopian Hemophilia Treatment Centre

BackgroundHemophilia is a rare genetic condition that is often overlooked and underdiagnosed, particularly in low-income countries. Long-term spontaneous joint bleeding and soft tissues can have a significant negative impact on a patient’s health-related quality of life (HRQoL). The objective of this study was to assess HRQoL and its associated factors in Ethiopian patients with hemophilia.MethodsA cross-sectional survey was conducted among patients with hemophilia at Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa, Ethiopia. Patients were recruited consecutively during follow-up visits. The European Quality of Life Group’s 5-Domain Questionnaires at five levels (EQ-5D-5L) and Euro Quality of Life Group’s Visual Analog Scale (EQ-VAS) instruments were used to assess HRQoL. The EQ-5D-5L utility score was computed using the disutility coefficients. We applied the Krukal-Wallis and Mann–Whitney U tests to determine the differences in EQ-5D-5L and EQ-VAS utility scores between patient groups. A multivariate Tobit regression model was used to identify factors associated with HRQoL. Statistical analyses were performed using STATA version 14 and statistical significance was determined at p < 0.05.ResultsA total of 105 patients with hemophilia participated in the study, with a mean (standard deviation (SD) age of 21.09 (± 7.37] years. The median (IQR) EQ-5D-5L utility and EQ-VAS scores were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Age was significantly negatively associated with the EQ-5D-5L utility index and EQ-VAS (β = -0.020, 95 CI = -0.034, -0.007) and β = -0.974, 95% CI = -1.72, 0.225), respectively. The duration since hemophilia diagnosis (β-0.011, 95% CI, 0.001–0.023) and living out of Addis Ababa (β = -0.128, 95% CI, -0.248-, -0.007) were also significantly negatively associated with the EQ-5D-5L utility index..ConclusionThe median EQ-5D-5L utility and EQ-VAS scores of patients with hemophilia were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Older age, living far from the Hemophilia Treatment Center (HTC), and longer duration since diagnosis were significantly negatively associated with HRQoL. HRQoL may be improved by providing factor concentrates, decentralizing HTCs in different parts of the country, increasing awareness of bleeding disorders among health professionals, and providing psychosocial support to affected patients.

Evaluation of the Oral Health of Hemophiliac Patients in Cameroon

Introduction: The aim of our study was to identify oral pathologies, determine their frequencies and assess the oral care needs of hemophilia patients in Cameroon. Method: A descriptive cross-sectional study was conducted from January 2021 to June 2021 in the approved Hemophilia Treatment Centres in Cameroon, one in the Yaounde University Teaching Hospital and the other one in the Gynaeco-obstetric and Paediatric Hospital of Douala. A survey form was used to collect data for the description of our sample. The patients’s files were useful for additional information. Mucosal, dental and periodontal conditions were described using the hygiene indices of Silness and Loë, DMFT and CPITN. The data were entered into the Google forms mask and analysed using SPSS 20. Results: A total of 52 hemophiliac patients were included in our study, all of them males aged between 15 months and 42 years. The mean age of our sample was 14.6 years old ± 10.7. The CAO index was 1.71. 88.46% had episodes of gingivorrhagia caused by brushing. Only 21.15% had a history of dental consultations. Only 7.69% had good hygiene. The oral pathologies encountered were gingivitis 78.85% and periodontitis 1.92%. Conclusion: In view of these results, it would be necessary to integrate regular oral care into the follow-up of haemophilia patients in order to improve their quality of life.

A pilot study of US HTC physical therapists' concordance of PT MASAC recommendations and educational needs.

Physical therapists (PTs) are essential providers within the Hemophilia Treatment Centers (HTCs) team caring for persons with inherited blood disorders (PWBD). Little is known regarding PTs understanding and concordance of MASAC PT Recommendations (MASAC#238), educational resources used to maintain competency and support for a mentorship programme. PTs at federally funded HTCs were eligible to participate in a descriptive non-validated study exploring: (i) demographics, (ii) educational background, (iii) experience in evaluation and treatment of PWBD, (iv) practice patterns indicative of concordance with MASAC#238 and (v) opinion regarding PT mentorship. Respondents experience caring for PWBD ranged 1-36 years, treating both adults and children. Although most acknowledged awareness of MASAC#238, dropout (14/44, 31.8%) was noted; 28/30 (93.3%) who continued were aware of the recommendations. Level of concordance with MASAC#238 varied (range 64.3%-96.2%) regarding: signs/symptoms, treatment of muscle/joint bleeding and pre/post synovectomy and knee replacement treatment. Many PTs identified patients as individual and unique, thus not all recommendations may apply. PTs utilised available educational programmes. No relationships were noted regarding years of practice, education and years caring for PWBD. All respondents favoured a mentorship programme citing benefits, but also outlined barriers. Provision of necessary financial support for optimal function of a full-time PT within the HTC can enhance standards of care for PWBD. Supporting educational opportunities may enhance concordance with current MASAC PT Recommendations. Respondents valued development of a structured, hands-on mentorship programme. MASAC#23 has recently been updated in May 2023 to MASAC#275.

Real-world data on the use of emicizumab in patients with haemophilia A with and without inhibitors in Singapore.

Emicizumab is a bispecific monoclonal antibody that mimics the function of factor VIII by binding to factor IXa and factor X to achieve haemostasis in haemophilia A. The long half-life and subcutaneous mode of administration makes emicizumab a compelling treatment option for bleeding prophylaxis. There is still limited real-world data on its use and management considerations, especially during surgical procedures. The objective of the study is to describe the real-world experience of emicizumab in a cohort of adult and paediatric haemophilia A patients in Singapore, including its use in the periprocedural setting. This was an observational study conducted at the 2 main haemophilia treatment centres in Singapore. All haemophilia A patients who commenced treatment with emicizumab before 1 July 2022 were recruited. A total of 18 patients with haemophilia A were included in this study. Ten (55.6%) patients had active inhibitors. The median annual bleeding rate for all patients before emicizumab use was 4.5 events (interquartile range [IQR] 2.8-8.3) compared with 0 events (IQR 0-0) after emicizumab was commenced (P=0). There were no adverse events of venous or arterial thrombosis, thrombotic microangiopathy, or death. A total of 6 procedures in 5 patients were performed during the study period with no major bleeding complications. Emicizumab effectively protects against bleeding in haemophilia A patients with and without inhibitors, including in children less than 12 years old. More studies are required to address clinical nuances, such as periprocedural management and the role of immune tolerance in patients with inhibitors on emicizumab.

Comparison of Projected Hemophilia a Populations Residing in Hospital Referral Regions with and without Hemophilia Treatment Centers in the US

Introduction: Among the approximately 53,000 people with hemophilia A (PwHA) in the US, a majority receive care at federally supported hemophilia treatment centers (HTCs). PwHA treated at HTCs have more favorable outcomes and are more likely to receive advanced therapies than PwHA receiving care external to the HTC network. Identifying geographic, socioeconomic and racial disparities among populations residing in hospital referral regions (HRRs) with and without HTCs will support efforts to improve care access and advance health equity. The objective of this study was to evaluate geographic, socioeconomic and racial differences in modeled US populations of PwHA who reside within HRRs with and without HTCs. Methods: Characteristics of HRRs with and without HTCs were compared using the Centers for Disease Control and Prevention (CDC) HTC listings. The study cohorts included individuals who resided in HRRs with and without an HTC based on modeled US populations of projected PwHA (pPwHA). The number of males with hemophilia A in each HRR was calculated at a rate of 12 cases per 100,000 males in the region of interest based on CDC estimates, and the number of females who were carriers of hemophilia A was calculated at a rate of 0.6 female carriers per male case as defined by the International Society of Thrombosis and Haemostasis Scientific and Standardization Committee. Demographic characteristics for each HRR were derived from the 2020 5-year American Community Survey; zip code tabulation areas were crosswalked to 5-digit zip codes and aggregated to HRRs.Differences in population characteristics in HRRs with and without HTCs were evaluated for statistical significance using the Wilcoxon rank sum test. Results: In 307 HRRs in the US, 109 had an associated HTC, while 198 did not (Figure). However, larger mean (SD) populations comprised HRRs with HTCs than those without (3,183,191 [2,752,401] vs 906,047 [814,847]; P&amp;lt;0.001; Table). Findings from this modeling work indicate that 78% of pPwHA reside in HRRs with an HTC. HRRs with HTCs served populations with greater proportions of Asian (5.3% vs 3.0%) and Black (14% vs 11%) individuals than those without HTCs ( P&amp;lt;0.001 for both). Compared with those in HRRs without HTCs, individuals residing in HRRs with HTCs had a wider range of median incomes ($27,978-$184,456 vs $35,087-$138,168; P&amp;lt;0.001) and a greater likelihood of falling above the 150% federal poverty line (77.9% vs 76.3%; P=0.014). Additionally, those residing in HRRs with HTCs were less likely to drive to work (75.0% vs 79.0%) and more likely to take public transit (4.4% vs 1.7%) or walk (3.0% vs 2.1%) than people in HRRs without HTCs ( P&amp;lt;0.001 for all). Conclusions: This analysis estimated that in the US, 4 of 5 pPwHA reside in an HRR with HTC access. HRRs with HTCs served larger populations with greater racial and socioeconomic diversity than HRRs without HTCs. While it is possible that PwHA who reside in HRRs without HTCs can still receive adequate care via outreach clinics, mobile units or virtual appointments, this work highlights that geographic barriers to HTC access remain incompletely addressed. Future efforts should focus on accurately identifying US hemophilia A populations and their locations relative to HTCs and comparing the impact on care and outcomes in those who rely on outreach efforts or mobile programs.

Reporting of Race and Ethnicity and Representation in Hemophilia Clinical Trials

Background: Racial and ethnic representativeness in clinical trials is a crucial step to mitigate disparities in outcomes. In 2017, the United States (US) Food and Drug Administration (FDA) issued a final ruling requiring trial sponsors to report race/ethnicity data to the clinicaltrials.gov registry. Black and Hispanic persons are underrepresented in clinical trials for several diseases, including hematologic malignancies (Hantel, Luskin et al. 2021). However, the reporting and representation of race and ethnicity for hemophilia interventional trials is unknown. Congenital Hemophilia is a rare bleeding disorder for which there have been significant treatment advances leading to substantial gains in life expectancy and improvements in quality of life for those with access to treatment. The aims of the current study are to assess 1) the frequency of race and ethnicity reporting; and 2) the racial and ethnic distribution of participants in interventional clinical trials enrolling persons with hemophilia (PwH). Methods: In this cross-sectional study, the clinicaltrials.gov database was queried in April 2023. All studies with “hemophilia” as the condition, coded as “interventional” and with “results” were selected (n=157). The proportion of trials reporting race/ethnicity and the distribution of race/ethnicity based on the US Office of Budget Management Categories (OBM) was computed according to trial characteristics. The racial/ethnic distribution of trial participants (observed) was compared to what would be expected based on United States (US) hemophilia treatment center (HTC) data and census data from four countries (Brazil, Canada, United Kingdom, and US) with observed-to-expected ratios (O/E) and 95% Confidence Intervals (CI). Results: Of the 157 trials identified, 28 were excluded because they were prematurely terminated. Of the 129 completed trials, the completion year ranged from 2007 to 2022, the large majority were industry sponsored (94.6%), and included an average of 62 participants with an average age of 26.8 years. Overall, 52.0% (n=66) of trials reported race/ethnicity data, which increased from 41.0% before 2017 to 100% in 2017 or later (p-value=.001) (Table 1). Among the 66 trials that reported race/ethnicity data, 49 (74.2%) were conducted in two or more countries, and the most common sites included the US (n=42 trials, 63.6%), Italy (n=26, 39.4%), Poland (n=24, 36.3%), Germany (n=22, 23.3%), and France (n=22, 33.3%). In terms of race/ethnicity, 65.1% of trial participants were White, 22.6% were Asian, 5.0% were Hispanic, 3.9% were Black, 2.3% were other race/ethnicity, and 3.8% were missing data on race/ethnicity. The proportion of trial participants who were White was approximately 20% lower than the US HTC population (O/E=0.83, 95%CI 0.80, 0.86) and 10-20% lower than the total population of the US (O/E=0.85, 95%CI 0.82,0.87), United Kingdom (O/E=0.80, 95%CI 0.78, 0.82), and Canada (O/E=0.91, 95% CI 0.88, 0.94) (Table 2). The proportion of trial participants who were Black or Hispanic was approximately 75% lower than the US HTC and the US total population. The percentage of trial participants who were Asian was 1.6 to 3 times higher than general population in the US, Canada, and UK (Table 2). We were unable to assess the number of racial/ethnic minorities enrolled in the US as these detailed data are not reported in clinicaltrials.gov. Another limitation is that ethnicity definitions vary across country's censuses. Conclusions: Our study found that less than half of interventional hemophilia trials conducted before the 2017 FDA requirement to collect data on race/ethnicity did so, whereas all trials conducted in 2017 and later reported race/ethnic data. Compared to the US HTC and total population, Black and Hispanic people with hemophilia are especially underrepresented in hemophilia interventional trials. In 2020, the US FDA provided guidance on eligibility criteria, enrollment practices, and trial designs to increase diversity in underrepresented racial and ethnic participants. Rare diseases, including hemophilia, require additional efforts to improve diversity in clinical trials given the smaller patient population (The FDA, 2020). These efforts may include engaging patient advocacy groups in the trials process and leveraging international HTC networks.

Reducing Preventable Bleeding Visits and Institutional Factor Costs for Patients with Bleeding Disorders with a Prospective Quality Improvement Project

Providing optimal care to patients with bleeding disorders requires specialized physician, laboratory, pharmacy, nursing, and institutional resources best achieved at Hemophilia Treatment Centers (HTCs). Current systems for managing the care of a resource intensive patient population may be suboptimal. We observed frequent bleeding related hospitalizations and emergency room (ER) visits in patients with bleeding disorders treated at our HTC that could have been potentially prevented by changes in outpatient care delivery. We initiated a prospective quality improvement (QI) project to improve care delivery and to reduce preventable bleeding related hospitalizations and ER visits for adult patients treated at our HTC. The interventions targeted patient-level and systems-level factors contributing to preventable visits, and barriers to care in our patient population. We compared preventable bleeding related hospitalizations and ER visits, institutional factor cost, use of prophylaxis in severe hemophilia, primary care physician attainment, and patient electronic portal enrollment before and after the QI intervention. In our population of adult patients with bleeding disorders (N=88), the intervention significantly reduced the primary outcome of preventable bleeding hospitalization or ER visit (P=0.0082, Figure), and reduced such visits by 85.4%, meeting the pre-specified criteria for success. Institutional factor acquisition costs to treat preventable bleeding were reduced by 94.5%, from $11,800 to $640 per patient per year; a projected savings of $982,088 yearly. Use of factor prophylaxis in patients with severe hemophilia increased from 58.8% to 100%, attainment of a primary care physician increased from 69.4% to 86.4%, and use of the electronic patient portal increased from 53.2% to 83%; all secondary outcomes met pre-specified criteria of success and were statistically significant. HTC clinic visit attendance was low at 55.2%. The majority of patients (71.6%) had at least one outpatient urgent episode (mean 0.72 episode per year), and 93% had non-urgent management (mean 9.3 episodes per year) occurring outside of a clinic visit. These data demonstrate that concerted outpatient management of patients with bleeding disorders with a quality improvement framework can reduce preventable hospitalization and ER visits. Decreased inpatient utilization resulted in substantial reductions in factor costs at the health system level. The clinical effort required to achieve these results was substantial, and required frequent provider engagement outside of regular clinic visits. The HTC can improve patient outcomes and reduce institutional costs from preventable bleeding episodes by supporting a collaborative quality improvement process led by physician, nursing, and laboratory coagulation experts.

Prevalence and Risk Factors of Diagnostic Delays in Acquired Hemophilia A

Introduction: Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies against factor VIII (FVIII). Delayed diagnosis is frequent, resulting in morbidity and health resource utilization. Predictors of diagnostic delays and their impact on outcomes are unclear. Aims: 1) Evaluate the time from presentation to AHA diagnosis, in a large Canadian province, 2) examine predictors of diagnostic delays, and 3) assess the impact of delays on outcomes and resource utilization. Methods: This multicentre retrospective cohort study included adults (≥18 years) diagnosed with AHA (January 2000-December 2021) in Alberta, Canada. Alberta's 661,848 km 2 geographic area encompasses two adult hemophilia treatment centres (HTCs). We assessed the prevalence of delayed diagnosis (from bleeding or first prolonged aPTT) and examined the impact of sociodemographic variables (age, sex, rural residence, living arrangement, initial presentation to HTC) and disease variables (AHA etiology, major bleed at presentation, comorbidities, FVIII activity and inhibitor titre) on the diagnostic delays. Case-based analysis and logistic regression were used to identify contributory factors and predictors of diagnostic delays, respectively. Kaplan-Meier curves were used to estimate overall survival (OS), and Cox proportional hazards regression analysis was used to assess the impact of diagnostic delays on OS. Ethics board approval was obtained. Results: Of the 38 patients diagnosed with AHA, 25 (66%) were female, 8 (21%) resided in rural areas, and 10 (26%) resided &amp;gt;100 km from HTC. Median age was 74 years (IQR 61-81), with marked comorbidities (median Charlson comorbidity index [CCI] 5, IQR 3-7). Most patients (27; 71%) initially presented to non-HTCs while 32 (84%) were eventually admitted to HTCs. At presentation, 27 (71%) had ISTH major bleeding and 13 (34%) were on anticoagulants or antiplatelets/NSAIDs. The median time from bleeding symptom and prolonged aPTT to diagnosis was 3.5 days (IQR 0-11.0) and 3.5 days (IQR 1.3-9.5), respectively. From first bleeding symptom, diagnosis was delayed ≥7 days in 15 (39%) patients and &amp;gt;30 days in 2 (5%). Case-based analysis identified the top reasons for delays ≥7 days: delayed ordering of aPTT from 7-62 days after bleeding (6/15; 40%), delayed ordering of mixing study following first abnormal aPTT from 7 days to &amp;gt;1 year (9/15; 60%) and attribution of bleeding to antiplatelets/anticoagulants (5/15; 33%). Neither demographic nor disease characteristics were identified as significant predictors of delayed diagnosis by logistic regression (Table 1). Initial presentation to HTCs had no impact on time to diagnosis. While non-statistically significant, there appears to be a clinically significant temporal gradient suggesting higher odds of diagnostic delays in 2010-2015 (OR 1.4) and 2016-2021 (OR 2.1) compared to pre-2010. Delayed diagnosis was not significantly associated with hospitalization rates, LOS, bypassing agent consumption, or units of packed red cells or plasma transfused. At a median follow-up of 3 years, 18 patients (47%) died at a median of 7 months (IQR 3-30). The most common causes of death included: infection (4), malignancy (3), bleeding (2), and thrombosis (2). Delayed diagnosis ≥7 days was associated with a non-significant trend towards worse 3-month OS (80% vs 91%) and 1-year OS (67% vs 87%, log-rank P=0.40; Figure 1). On Cox proportional hazards analysis, male sex (HR 4.0, 95% CI 1.5-10.5) and CCI 4-5 vs 0-3 (HR 7.0, 95% CI 1.5-32.3), but not delayed diagnosis (HR 1.5, 95% CI 0.6-3.9) were associated with increased hazard of death. Conclusion: In our large geographic catchment area, in the absence of an AHA reference centre, the median time to diagnosis (3.5 days) was markedly shorter than that reported in other single-centre studies (14-19 days), although delayed diagnosis ≥7 days was common. We did not identify statistically significant predictors of diagnostic delays, likely limited by small numbers. However, case-based analysis highlighted knowledge gaps as contributory factors, such as delayed ordering of aPTT in bleeding patients and delayed mixing study if aPTT is prolonged. Interestingly, time to diagnosis did not improve in recent years or with initial presentation to HTCs. Given the potential impact of delays on morbidity/mortality, further education is needed to expedite diagnosis in both HTCs and community settings.

Advancing Hemophilia Prophylaxis: Personalized Low-Dose CFC and Emicizumab in Resource-Limited Settings

Introduction: Hemophilia, a congenital bleeding disorder resulting from clotting factor deficiency, significantly impacts the lives of persons due to recurrent bleeding. Prophylaxis, involving clotting factor replacement, has been recognized as a vital approach to reduce complications and to improve the quality of life in people with hemophilia. However, access to this remains limited, in low-income countries like India. This study examines the effectiveness of personalized low-dose clotting factor concentrates (CFC) prophylaxis and Emicizumab in children with hemophilia, aiming to achieve zero annual bleed rates (ABR), thereby enhancing their well-being and reducing healthcare burden. Patients and Methods: This retrospective observational study was conducted at the Hemophilia Treatment Centre (HTC) in Aluva, Kerala, India, spanning from May 31, 2022, to June 1, 2023. Study included children under 18 years with hemophilia A/B, with or without inhibitors, who had commenced prophylaxis with personalized low-dose CFC since 2015 and completed one year of prophylaxis. The total sample size was 31. Data on ABR, Annual Joint Bleed Rate (AJBR), Hemophilia Joint Health Status (HJHS) score, and Functional Independence Score Hemophilia (FISH) were extracted from the HTC registry.Standard half-life CFCs were used for prophylaxis, with a starting frequency of twice a week for Factor VIII and once a week for Factor IX. Patients were regularly followed up in the Hemophilia Clinic, and the frequency/doses of prophylaxis were increased in case of breakthrough bleeds. Additionally, children were advised to organize peak activities to coincide with the days of CFC injections. Personalization of doses was not based on pharmacokinetic software but was determined through close monitoring and individual adjustments.Health education on identifying and managing bleeding episodes followed ISTH guidelines. Prophylaxis outcomes were assessed with changes in ABR and AJBR during the last year of prophylaxis and compared to the bleed rates in the one year prior to prophylaxis. Changes in HJHS and FISH were documented for older children. All analysis were done using SPSS version24. For quantitative variables results were presented as mean with standard deviation and for qualitative variables, results were presented in percentages. Comparison achieved with standard paired t-test, and p value &amp;lt; 0.05 considered as significant. Results: Out of 36 children receiving prophylaxis, 31 met the inclusion criteria. Among them,10 (32%) received Emicizumab prophylaxis, while 21 (68%) were managed with personalized low-dose CFC prophylaxis. Hemophilia A constituted 24(77%) of cases, mostly classified as severe disease-29 (94%). Table :1 summarises the patient characteristics, prophylaxis dose, cost and outcome measures of the study population.The personalized low-dose CFC prophylaxis had significant measurable improvements, reducing the ABR from 14.90 to 2.90( p 0.000) and the AJBR from 4.95 to 1.43( p 0.004). Additionally, HJHS improved from 3.30 to 0.95( p 0.102), and FISH increased from 29.90 to 32.00( p 0.020).Children on Emicizumab achieved exceptional results, with all reporting zero ABR ( p 0.027), and AJBR ( p 0.131) even with lower than recommended doses(1.02mg/kg/week). In contrast, personalized low-dose CFC prophylaxis (Factor VIII: 36.35/kg/week, Factor IX:32/kg/week) showed varied outcomes, with only 4(19%) achieving zero ABR. HJHS and FISH were not evaluated in Emicizumab group as 7(70%) were belonging to the age group of less than 5 years. Conclusion: This study highlights the effectiveness of personalized low-dose CFC prophylaxis and Emicizumab in reducing bleeding rates and improving musculoskeletal health and functional independence in children with hemophilia. Emicizumab prophylaxis demonstrated remarkable outcomes, achieving zero bleeds even with lower doses. However, personalized low-dose CFC prophylaxis struggled to achieve zero bleed rates for most of them. The findings underscore the need for alternative strategies and increased accessibility to Emicizumab and other newer drugs to achieve the goal of zero bleed rates for children with hemophilia in resource-limited settings. The study's results provide hope for achieving zero bleed rates, ultimately enhancing the well-being of children with hemophilia in resource-limited regions.

Factor First: An Assessment of Emergency Department Care of Patients with Hemophilia

Background: With the establishment of hemophilia treatment centres (HTCs) and home infusion programs for factor replacement therapy, emergency department use among patients with hemophilia occurs less frequently, with patients often presenting for significant bleeding events only. As a result, the management of patients with hemophilia can represent a challenge to emergency department (ED) physicians and staff. Both delays in diagnosis of a bleeding event, and timely administration of hemostatic therapy have been associated with patient morbidity and mortality. The World Federation of Hemophilia, in addition to other organizations, emphasize the importance of timely receipt of clotting factor replacement therapy, providing treatment at the time a bleed is suspected. If a patient with hemophilia is registered with a HTC, they often carry a wallet card, or have a formalized treatment plan, outlining their diagnosis and emergency treatment of bleeding recommendations to ensure timely access to hemostatic therapy. The aim of this study was to describe ED management of patients with hemophilia at a single Canadian HTC, with a focus on use of individualized emergency bleeding management protocols, and time to receipt of hemostatic therapy within the ED. Methods: Adult patients with hemophilia A or B (FVIII or FIX ≤40%), of any severity, followed at the Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, were identified for inclusion. ED health utilization and ED encounter management data for each of the four hospital sites in Calgary, AB was obtained from the electronic health record for the cohort, through to 2022. Results: A total of 191 patients with hemophilia A and B were identified for study inclusion. 153 patients with hemophilia A (mild 64.7%; moderate 5.9%; severe 28.8%) and 38 patients with hemophilia B (mild 44.7%; moderate 36.8%; severe 18.4%). Males comprised 77.5% of the patient cohort. A total of 393 ED visits occurred over the study period. Less than a third of ED visits were associated with receipt of hemostatic therapy (either desmopressin or clotting factor concentrate). The median time from triage to ordering of hemostatic therapy was 2.9 hrs (IQR 2.3-3.2), and median time from triage to administration of hemostatic therapy was 4.2 hrs (IQR 3.1-4.2). For ED visits due to suspected bleeds, the proportion of patients who received either coagulation factor replacement or desmopressin within two hours of ED triage is depicted in Figure 1. Time to receipt of hemostatic therapy did not significantly differ whether desmopressin or clotting factor concentrate was administered. The number of ED visits in which the individualized emergency bleeding management protocol was accessed is depicted in Figure 2. Among those accessed in 2022, the proportion of protocols that were updated within the last 365 days was 86.8%. Less than 20% of ED visits were associated with a hematology consultation. Conclusions: Increasing utilization of individualized emergency bleeding management protocols for patients with hemophilia was observed; however, significant delays in timely receipt of hemostatic therapy remains, with infrequent involvement of hematology in consultation. Time to receipt of potentially life-saving hemostatic therapy for our cohort falls outside of hemophilia care standards. This data provides a better understanding of the experience of patients with hemophilia in the ED and provides an opportunity to define further quality improvement interventions to ensure quality care metrics in this population are met.

Evaluation of Innovative Laboratory Tests to Predict a Thrombotic Phenotype in a Family with Dysfibrinogenemia and a Novel FGG Mutation

Background: Hypodysfibrinogenemia is a rare hereditary fibrinogen disorder characterized by quantitative and qualitative fibrinogen defects. These fibrinogen defects can cause thrombotic and hemorrhagic phenotypes. Unfortunately, predicting the phenotype in a specific patient is often not possible with routine coagulation tests. Aims: To characterize the phenotype and the genetic profile of a family with hypodysfibrinogenemia and to investigate the ability of innovative tests to predict bleeding and/or thrombotic phenotypes in asymptomatic family members. Methods: The proband, a 60-year-old woman with both bleeding and thrombotic complications who is currently on DOAC treatment, and two daughters were referred to our Hemophilia Treatment Center (HTC) for phenotypical and genotypical analysis of a congenital fibrinogen disorder (CFD). Extensive laboratory testing was done, as well as DNA-sequence analysis and molecular modelling. Thrombin generation and microfluidic testing were also performed to investigate their ability in phenotype prediction. Results: Fibrinogen activity and antigen levels led to the diagnosis of dysfibrinogenemia in the proband and hypodysfibrinogenemia in both daughters. In all three cases, the same heterozygous missense mutation in the FGG gene was uncovered. This likely pathogenic mutation leads to the p.(Tyr375Cys) amino acid change. Molecular modeling predicted possible conformational changes or covalent dimerization of the fibrinogen molecule. Thrombin generation was elevated in one daughter. Microfluidic testing showed enhanced fibrin formation in both daughters, regardless of the coagulation trigger. Conclusion: We described a family with hypodysfibrinogenemia in whom a novel heterozygous missense mutation in the FGG gene was found, possibly leading to conformational changes or covalent dimerization of the fibrinogen molecule. Furthermore we showed that microfluidic testing and thrombin generation can indicate a thrombotic phenotype in these patients, not detected with routine coagulation tests.

First Real-World Experience Administering Etranacogene Dezaparvovec Gene Therapy for People with Hemophilia B

Research in gene therapy for hemophilia B has been ongoing for decades. Etranacogene dezaparvovec-drlb (CSL Behring) is the first gene therapy for hemophilia B to be approved by the United States Food and Drug Administration (2022) and the European Medicines Agency (EMA) (2023). The gene therapy treatment journey is a multistep process and requires coordination between multiple stakeholders within a hemophilia treatment center (HTC). The first 2 patients to receive etranacogene dezaparvovec-drlb since approval were successfully infused at the Hemophilia Outreach Center in Green Bay, Wisconsin. Here we describe the process by which the Hemophilia Outreach Center prepared their center and patients for the administration of etranacogene dezaparvovec-drlb. Early education, both for HTC stakeholders and patients, was critical in addressing key steps in the treatment journey, including patient eligibility, preparation, administration, and post administration monitoring and management. The education was iterative, involved multiple stakeholders (physician, pharmacist, nurse, social worker, and patient) and required an open channel of communication among the HTC stakeholders, the patients, and manufacturer when appropriate. Although no certification process was required, the manufacturer provided education to the HTC stakeholders in the format of ongoing trainings and a detailed handbook describing the gene therapy process as it relates to etranacogene dezaparvovec-drlb. This education provided a foundation for the HTC stakeholders to develop their own center-specific protocols, checklists, and worksheets. These protocols provided clear guidance on how to manage every step of the process in addition to providing a contingency plan for different scenarios (e.g., infusion reactions and transaminitis), ensuring the center's preparedness for administration. By implementing early and iterative education and developing center-specific protocols, the Hemophilia Outreach Center was able to successfully administer etranacogene dezaparvovec-drlb. These elements are crucial to ensure smooth execution and optimal patient outcomes.

“Hermes” - Hemophilia Related Mental Illness: A Cross-Sectional, Multicenter Study in Switzerland

Background: The availability of clotting factor concentrates and prophylactic home treatment for patients with hemophilia (PWH) A and B in developed countries greatly improved clinical outcomes. As the life expectancy of affected patients has increased, the management of comorbidities has become a greater focus within the comprehensive care setting. However, most studies focus on somatic complications. The past two decades revealed a growing body of work reporting increased prevalence of mental health problems in PWH. Given the severity and chronicity of the disease, internalizing disorders (i.e. anxiety, depression) as well as externalizing disorders (i.e. substance dependency, irritability and aggression) seem to go hand in hand with hemophilia. We aimed to assess the prevalence of comorbid mental health problems among PWH in Switzerland. We investigated age effects on this relationship as well as potentially influencing factors (illness factors and environmental factors) that may account for these. We also aimed to assess health-related quality of life (HRQoL) and age dependency in this setting. We are heading to identify targets of prevention/early intervention of mental health problems and foster improvement of evidence-based interdisciplinary treatment in PWH. Methods:This multicenter, cross-sectional study was conducted within six hemophilia treatment centers in Switzerland. Study participants were aged 6-99 years with congenital hemophilia of any severity. All participants or their legal guardians provided written informed consent, and the study was approved by the cantonal medical ethics committee of the responsible states. Participants aged 12 or older underwent a detailed personal psychological assessment followed by completing an online survey utilizing validated psychological measures (HRQoL, psychosocial functioning, somatic comorbidities/parental factors). Participants younger than 12 years underwent a detailed personal psychological assessment with one parent/legal guardian followed by an online survey to be completed by their parent/guardian. In all participants younger than 18 years, we assessed one parent/legal guardian additionally. Results:A total of n=164 PWH participated in the study (133 adult and 31 pediatric participants). Data analyses showed a median age of 39.26 years (SD 20.41). The majority of participants had hemophilia A (n=134, 82%), while hemophilia B was diagnosed in n=30 (18%) of participants. A severe hemophilia was reported in n=85 (52%), a moderate in n=31 (19%) and a mild hemophilia in n=48 (29%). Prophylactic treatment regimen was used in n=97 (59%). Out of n=156 participants with completed neuropsychiatric diagnostic interview, n=38 (24%) participants showed a psychiatric disorder over lifetime. This was significantly associated with disease severity, being more prevalent in moderate and severe hemophilia. We could not detect an association with age, so age does not moderate this association. In n=153 participants with available data on HRQoL, we found a lower HRQoL also to be associated with disease severity (moderate and severe). Moderation analyses could not confirm an association with age. Conclusion:Our data show an association of (lifetime) psychiatric diagnoses and a lower health-related quality of life in hemophilia depending on disease severity. This association is evident in moderate and severe hemophilia and is independent of age despite recent progress in development and use of new therapies going along with suggested lower hemophilia disease burden. Further analyses including somatic and treatment factors as well as parenting are ongoing and will be presented.

Prevalence of Rare Bleeding Disorders in the Central California Cohort: A Retrospective Single Institution Analysis

Abstract Rare bleeding disorders (RBD) constitute 3- 5% of all inherited clotting factor deficiencies and include inherited deficiencies of fibrinogen (FI), factors II, V, VII, X, XI and XIII, and combined factor V and VIII, and affect both sexes in an autosomal recessive manner. Rare platelet disorders can also present with bleeding diathesis which are recessively inherited. Significant clinical heterogeneity is present in these disorders with varying bleeding symptomatology causing diagnostic and therapeutic challenges. The objective of this study was to analyze the prevalence, characteristics, and treatment of rare bleeding disorders at the Valley Children's Hemophilia Treatment Center(HTC) in Central California.We conducted a retrospective analysis of all individuals who were referred for abnormal bleeding to our institution from 2018- 2023. We analyzed the clinical features, laboratory variables, and treatment of patients identified with RBD. Rare platelet disorders were included in this study. We excluded factor VIII, IX deficiencies and Von Willebrand disease (VWD) from this analysis. Results We identified a total of 157 patients (age range 18 months-46 years old) with RBD, 46% were of female gender (Table 1). Majority of the patients (n=92, 58%) were of Hispanic ethnicity. Major RBD in the cohort was Factor 7 (F7) deficiency (n= 96, 60.4%). F11 deficiency constituted 10.1%, followed by fibrinogen deficiency (6.3%), and F13 deficiency (5.7%). F2 and Plasminogen activator inhibitor-1 (PAI-1) deficiency was identified in one individual each. Glanzmann thrombasthenia was the most common platelet disorder noted in our population (n=7, 4.4%), followed by giant platelet disorder (n=6, 3.8%). MYH9- related disorder was identified in 5 (3.1%) individuals with macrothrombocytopenia and bleeding. Wiskott-Aldrich Syndrome was detected in 3 (1.9%) cases of RBD. Combined bleeding disorders (CBDs) were observed in 15 individuals (9.5%) (Table 2). These disorders were distinguished by genotyping, factor activity, and chromogenic activity assays. F7 and Type 1 VWD combined disorder was observed in 46.7% (n=7) of these individuals. Genetic testing was done in 38% (n=60) of the affected individuals. Genetic analysis was done through American Thrombosis &amp; Hemostasis Network (ATHN 10) in 19% (n=30). F7 gene mutation was the most commonly identified mutation and variants c.1238G&amp;gt;A (p.Arg413Gln), c.1172G&amp;gt;A (p.Arg353Gln), and c.1091G&amp;gt;A (p.Arg364Gln) were observed in those with F7 deficiency. All individuals with F7 deficiency with variants of uncertain significance were presumed to be positive. Treatment was specific to the factor deficiency. Most individuals received additional anti-fibrinolytic therapy during acute bleeding episodes. Recombinant F7 was used in platelet disorders for bleeding. Major bleeding events and death in the cohort was 1.2% (n= 2), and 2 individuals with F13 deficiency developed inhibitors to F13 concentrate. These individuals have been managed with recombinant F7 and anti-fibrinolytic therapy. Conclusion Ethnically diverse distribution of rare bleeding disorders was evident in our Central California cohort. Similar to previous reports, F7 deficiency was of the highest prevalence. A high prevalence of CBDs was also observed in this cohort. Genetic testing enabled diagnosis in some complex cases and needs to be used more widely to facilitate timely and accurate identification, and treatment of CBDs, and RBD in general. Further, these results help to identify novel mutations in different ethnicities, and provide additional information in understanding the clinical impact of new mutations.