Moderate Hemophilia Research Articles

Reduced Vitamin C Levels in Patients with Bleeding of Unknown Cause and Generalized Joint Hypermobility

Introduction Vitamin C is essential for the synthesis of collagen. Ehler-Danlos syndrome (EDS) is a group of collagen disorders associated with generalized joint hypermobility (HM), bleeding and bruising. The genetic cause of the HM EDS subtype (hEDS) is unknown. Referral to haematology clinics may result in the diagnosis: bleeding of unknown cause (BUC), where no specific haemostatic treatment is available. However, it is a clinical experience, published in many textbooks, that bleeding, and bruising associated with EDS improve by oral intake of vitamin C. No previous studies examined vitamin C levels in patients with BUC. The aim of the study is to investigate the association of vitamin C levels with HM and vascular fragility in patients with BUC. Methods Patients with bleeding tendency are referred to our Haemophilia Center. Following ISTH-BAT score, normal coagulation test (INR, APTT, fibrinogen, F8, F9, F11, F13, VWFAg, VWFRist) and inconclusive results of flow cytometry analysis of platelet function, patients are diagnosed with BUC. Patients with a high ISTH-BAT score > 10 were included in this study. We performed clinical examinations by a tourniquet test for capillary fragility and a Beighton score for generalized HM. A skin extensibility test was performed by pulling on the skin off the forearm and the lateral side of the throat until resistance was met. The test was considered positive (abnormal) if the skin extended more than 2 cm in both sites when pulled. Germline DNA was analyzed by whole genome sequencing (WGS) analysis and an in silico panel of 170 genes associated with bleeding and generalized HM was examined. Additionally, homozygous polymorphism in vitamin C genes ( GULOP, SLC23A1, SLC23A2, SVCT1, HP, GST and SOD2) known to cause reduced vitamin C levels, were assessed Vitamin C analysis: The participants received oral and written guidelines regarding intake of vitamin C in relation to the blood sample. The guidelines included no vitamin C supplements for 3 days before the blood sampling and no intake of vitamin C rich food on the day of the appointment. Plasma samples were immediately acidified by addition of 10% meta-phosphoric acid to ensure the stability of ascorbic acid, and subsequently analyzed by high-performance liquid chromatography. Severe vitamin C deficiency was defined as <11µM, deficiency as < 23 µM, suboptimal status as 23-49 µM and adequate status as >49 µM. Results Sixty probands and 20 healthy age- and gender-matched controls (HC) were included. Most patients were women (56/60, 93%), median age 48 (range 21- 75) and median BAT score 13 (range 10-21). By WGS a 67-year woman with Beighton score 7 was diagnosed with Noonan syndrome due to a pathogenic variant in PTPN11 (c.922A>G). Also, a 62-year woman without HM was diagnosed with mild FV deficiency due to a heterozygous variant in F5 (c.449A>G). No other causal variants were identified. In a patient with a homozygous variant in SLC23A1, vitamin C level was suboptimal 42µM.Suboptimal vitamin C levels were found in 19/60 patients and 2/20 HC. One patient was severely vitamin C deficient (7µM). Vitamin C levels were significantly lower in patients compared to HC (median 56 µM vs 76 µM; p = 0.012). Beighton score was positive in 29/60 patients and 1/20 HC (p<0.001). In 18/60 patients versus 0/20 HC the skin extensibility test was abnormal (p = 0.01). In 12/29 patients with a positive Beighton score the test for skin extensibility was also positive indicating a diagnosis of hEDS. Tourniquet test was positive (> 10 petechiae) in 18/60 patients and 4/20 HC (p>0.5). Patients with positive Beighton scores had significantly higher BAT scores than patients without HM (P= 0.014). No significant associations were found between vitamin C levels, a positive Beighton score, a positive Tourniquet test or a high BAT score respectively. Conclusions We found that a high proportion of patients with BUC have generalized HM, abnormal skin extensibility and positive tourniquet test. Indeed, patients with HM had increased ISTH-BAT scores compared to patients with negative Beighton scores. Our data support that hEDS may be an underlying cause of BUC. Further studies are needed to determine the genetic background of hEDS. Levels of vitamin C were reduced in patients with BUC compared to age and sex matched control. Our results could pave the way for a randomized study of vitamin C supplements versus placebo for bleeding and bruising in patients with generalized HM and BUC.

Chinese Severe Hemophilia a Children with High-Titer Inhibitors Obtain More Benefit from Intermediate-Dose Immune Tolerance Induction: The Interim Result of Lome Part a

Background We previously showed that low-dose immune tolerance induction (LD-ITI) strategy [incorporating immunosuppressants (IS) partially] for severe hemophilia A (SHA) patients with high-titer inhibitors (HTI) had relatively equivalent success rate with lower cost compared to those on high-dose ITI from international (I)-ITI randomized clinical trial (RCT). However, it is lack of RCT to compare the efficacy, safety, and cost of LD-ITI strategy to higher-dose ITI [intermediate-dose (MD)-ITI] strategy in China. Currently, the domestic recombinant FVIII (rFVIII) sponsored by the SinoCelltech Ltd., provides an opportunity to conduct the LOME study: a multicenter controlled randomized clinical trial of LOw- versus InterMEdiate-dose immune tolerance induction with recombinant factor VIII in China, to answer this question. Objectives Conduct the RCT to compare the efficacy, safety and cost of LD- to MD-ITI strategy using rFVIII (Omfiloctocog alfa, SCT800) for SHA children with HTI in China. Methods A perspective, multicenter RCT, enrolled SHA children ≤8year-old at enrollment, with peak historical inhibitor-titer 5 - 200 Bethesda Unit (BU)/mL, 1:1 randomized in LD- (Omfiloctocog alfa, rFVIII 50 IU/kg once-every-day) or MD- (Omfiloctocog alfa, rFVIII 100IU/kg/day) ITI group. IS was added (the initial regimen) in patients who met the criteria as follows: (i) the inhibitor titer during ITI increased to ≥200 BU/mL; (ii) the peak titer did not appear within 3 months after ITI-start; (iii) inadequate reduction (<20%) in titer over 6 months. Success: negative inhibitor titer twice consecutively at least 4 weeks apart and FVIII recovery ≥66% of expected within 24 months of treatment. Partial success: negative inhibitor titer twice consecutively at least 4 weeks apart, but with persistently abnormal FVIII recovery. Average consumption cost (per kg body weight) was calculated based on the median number of treatment doses consumed to achieve success. This included the cost of rFVIII and rituximab for ITI, PCC and rFVIIa for treatment of breakthrough bleeding, and IVIG for infection prevention in IS patients. The rituximab and IVIG were calculated based on the actual IS-using rate in 2 groups. Additionally, PCC and rFVIIa were calculated based on the actual using-rate in all breakthrough bleedings. Trial registration number: ChiCTR2200056603. This was the interim analysis. The first participant was enrolled on March 2022. Results Total 31 patients (16 in MD-, 15 in LD-ITI group) from 3 hemophilia centers with median followed-up 9 months since ITI-start (Table 1). A total 26 (83.9%) patients underwent peripherally inserted central catheter (PICC) (14 in MD-, 12 in LD-ITI group). A total 10 (32.3%, 2 in MD-, and 8 in LD-ITI group) patients received IS at median 2.9 months since ITI-start. Among them, 6 patients added IS because of inhibitor titer ≥200BU/mL during ITI, and the rest for delayed-occurred peak-titer or unsatisfactory decrease of titer. The MD- and LD-ITI group achieved similar success rate (75% vs. 40%). None success patients relapsed over a median follow-up period of 5.1 months since achieving success. The Kaplan-Meier curves demonstrated that patients in MD-ITI group had significantly shorter time to success (median, 2.9 months vs. 9.0 months), and partial success (2.4 months vs. 5.7 months). (Figure 1A and Figure 1B) Patients in MD-ITI group had lower mean bleeding rate (bleedings/month) (0.38 vs. 1.40) and joint bleeding rate (0.11 vs. 0.83) before achieving partial success, compared with those in LD-ITI group (Figure 1C and Figure 1D). But during the phase from achieving partial success to achieving success, the 2 groups had similar bleeding rate (0.09 vs. 0.11) and joint bleeding rate (0.07 vs. 0.16). A total 6 (23.1%) patients occurred PICC-related complications (5 in MD-, 1 in LD-ITI group) with mean follow-up period of 270 days. All complications including infection (1 person-time), thrombosis (1 person-time), rashes (3 person-time), accidental detachment (3 person-time). Similar per kg treatment cost from ITI-start to ITI success was found in 2 groups (US$ 2905.18 vs. US$ 2838.23). Conclusions Similar success rate was found in LD-ITI (rFVIII) strategy and MD-ITI (rFVIII) strategy for SHA children with HTI. On the premise of similar cost, shorter time to success, less bleedings were observed in MD-ITI strategy. PICC implantation is a safe option to conduct ITI.

Emicizumab Prophylaxis in People with Moderate or Mild Hemophilia A Aged ≥40 Years, with and without Comorbidities - Findings from the Phase III HAVEN 6 Study

Background: Emicizumab is a bispecific antibody licensed by the FDA and other regulatory authorities for prophylaxis in people of all ages with hemophilia A (HA) of any severity, with or without factor (F)VIII inhibitors (label varies by country). Few data exist specifically on older people with HA (PwHA), particularly those with comorbidities, such as cardiovascular (CV) conditions, hepatitis, and human immunodeficiency virus (HIV), and in people with moderate or mild HA. Therefore, we present a post hoc analysis of PwHA aged ≥40 years from the HAVEN 6 study (NCT04158648), which was conducted to evaluate the safety and efficacy of emicizumab in people with non-severe HA without FVIII inhibitors. Methods: HAVEN 6 is a global, multicenter, open-label, single-arm, Phase III trial conducted in individuals of all ages with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) HA without FVIII inhibitors, warranting prophylaxis as assessed by the investigator (Negrier et al. Lancet Haematol 2023). As a loading dose, emicizumab was administered subcutaneously once weekly at 3mg/kg for 4 weeks. This was then followed by the participant's choice of maintenance dose, which included the options of 1.5mg/kg weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. The primary study objective was safety, including thromboembolic events (TEs) and thrombotic microangiopathy (TMA). The primary efficacy endpoint was the annualized bleed rate (ABR) for treated bleeds. An age cut-off of ≥40 years was selected for this exploratory analysis in order to obtain a population with a high proportion of PwHA with comorbidities. In this analysis, comorbidities included CV risk factors (past medical history of CV disease; hypertension; hyperlipidemia; diabetes; body mass index ≥30kg/m 2), HIV, and current or previous history of hepatitis C virus (HCV) infection. Results: At data cut-off (Oct 30, 2021), 72 participants were enrolled in HAVEN 6. Of these, 16 individuals were aged ≥40 years and were included in this analysis; among the 16 participants aged ≥40 years, 8 (50%) were aged ≥50 years. The median (range) age was 50.5 (41-71) years and all were male. Ten (62.5%) participants had moderate HA and 6 (37.5%) had mild HA. Prior to study entry, 6 (37.5%) participants had been receiving prophylactic FVIII, while the other 10 (62.5%) had been receiving episodic FVIII infusions. In the 24 weeks prior to study entry, the median (range) number of bleeds reported by these 16 participants was 3.5 (0-60) and the mean (SD) was 7.4 (14.5), with two individuals experiencing ≥9 bleeds. Nine (56.3%) of the 16 participants had at least one CV risk factor, with 5 (31.3%) having two or more. Three (18.8%) individuals had HCV only, 1 (6.3%) had HIV only, and 2 (12.5%) had HCV and HIV co-infection. Five (31.3%) of the 16 participants did not have any of the comorbidities defined in this analysis. At the data cut-off, the median (range) duration of emicizumab exposure for the 16 participants aged ≥40 years was 1.09 (0.61-1.72) years. Fifteen (93.8%) of the 16 participants experienced ≥1 adverse event (AE) during the study. Three (18.8%) individuals experienced a serious AE and 1 (6.3%) a Grade 3/4 AE; all were deemed unrelated to emicizumab ( Table 1). There were no fatal AEs, AEs leading to withdrawal from treatment or dose modification/interruption, or TMAs. One individual, who had no CV risk factors or HIV/HCV infection, experienced a TE (Grade 1 thrombosed hemorrhoids); this was deemed unrelated to emicizumab. Three participants experienced a total of six treatment-related AEs; three of these were local injection-site reactions, with the other three being fatigue, head discomfort, and accidental overdose. During the study, the mean (95% confidence interval) ABR for treated bleeds for the 16 participants aged ≥40 years was 1.03 (0.03, 5.62), which is similar to that recorded for the overall population of HAVEN 6 (0.94 [0.02, 5.48]; Table 2). A total of 11 (68.8%) participants had zero bleeds during the study, which is comparable with the 66.7% reported for the total population. Conclusions: The small number of individuals aged ≥40 years included in the current analysis is a limitation that precludes drawing firm conclusions from the data. However, the safety and efficacy of emicizumab in these participants did not differ notably from those observed in the overall population of people with moderate or mild HA in HAVEN 6.

Adherence to Clotting Factor Treatment and Association with Bleeding and Health-Related Quality of Life in Persons with Hemophilia

Introduction: Measuring patient adherence to prophylactic treatment with clotting factor in persons with hemophilia includes both subjective and objective measurements. There are limited studies conducted in adherence research using objective measures and a few studies revealed lack of correlation between subjective and objective adherence measurement. The study objectives are 1) to develop an objective adherent measurement; and 2) to assess it's association with bleeding and health-related quality of life (HRQoL) using the data collected from the Hemophilia Utilization Group Study Part VI (HUGS VI), which was an observational, non-interventional study investigating adherence to factor replacement therapy among persons with hemophilia A or B. Methods: HUGS VI enrolled participants from eight U.S. federally-supported hemophilia treatment centers in seven states (California, Colorado, Georgia, Indiana, Pennsylvania, Texas, and Washington) from 2015 to 2017. We enrolled eligible participants who either used standard half-life (SHL) products or used extended half-life (EHL) products for less than six weeks. We collected data on socio-demographics, bleeds, joint problems, and pain via surveys, as well as HRQoL, as measured by SF-12 at enrollment and at each three-month follow-up. We collected monthly factor prescription data from the clinical chart, and monthly factor dispensing records from the participants' pharmacy. We calculated factor treatment for the proportion of days covered (PDC) as the sum of the days of treatment available based on dispensing records, divided by the sum of the days of treatment prescribed based on prescription records for nine months post-enrollment. PDC ≥0.8 was considered an objective measure of adherence to factor treatment. The number of bleeds was summed from each of three quarterly follow-up surveys. We defined EHL users as participants who started an EHL product during the study period, either six weeks prior to enrollment or anytime during the nine months follow up. Association of PDC with nine months bleeds, ratings of chronic pain, and SF-12 scores in the nine-month follow-up were analyzed using Pearson correlation and Student T-Tests. Results: We analyzed a sample of 69 adults (age ≥18 years) with moderate or severe hemophilia using prophylactic treatment who completed at least baseline and nine-month follow-up surveys and had both prescription and dispensing records. Mean age was 28.9±10.3 (standard deviation) years, 91.3% were hemophilia A, and 65.2% were adherent to clotting factor treatment with PDC ≥0.8. EHL users were less likely to be adherent to the treatment than non-EHL users (adherence rate was 47.4% vs. 72.0%, p=0.06). PDC was significantly and negatively correlated with nine months of joint bleeds (correlation coefficient r=-0.30, p=0.01), and total bleeds (r=-0.33, p=0.026), but positively correlated with SF-12 physical composite score (r=0.32, p=0.009). PDC was not correlated with chronic pain (r=0.08, p=0.51) or SF-12 mental composite score (r=0.03, p=0.79). The participants who were adherent to factor treatment had fewer mean joint and total bleeds (2.6±4.1 vs. 1.3±2.1, p=0.08, and 4.9±5.6 vs. 2.9±3.8, p=0.07, respectively) than those non-adherent to treatment, although the differences did not reach statistical significance. Compared to participants who were adherent to treatment, non-adherent participants had a lower SF-12 physical composite score, with an approximately 5-point difference (43.4±10.6 vs. 48.0±9.1, p=0.07). Conclusions: As the data collection period occurred when EHL products became commercially available, treatment adherence may have led to treatment selection as participants switched from SHL to EHL products. Our data showed that participants who were non-adherent to treatment were more likely to be EHL users. Better adherence with higher PDC was moderately correlated with fewer bleeds, but higher HRQoL physical health composite score. The objective adherence measurement developed in this study should be further studied to investigate whether switching from SHL to EHL improves treatment adherence and its association with clinical outcomes.

Assessing Treatment Burden in Pediatric Hemophilia: Validation of the Observer-Reported Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Despite treatment safety and efficacy advancements for children with hemophilia (CwH), home treatment can be complicated and burdensome. Treatment burdens are major contributing factors to adherence issues. The Child Hemo-TEM is a patient-centric outcome measure developed following the United States (US) Food and Drug Administration guidance for patient-reported outcome measure development. Designed to assess the treatment burden for CwH, the measure is a caregiver observer-reported outcome (ObsRO) measure where questions are answered by the caregiver about the child's treatment experience based on what the caregiver has seen, heard, or been told by the child. Aim: The purpose of this study was to psychometrically validate the Child Hemo-TEM ObsRO. Methods: Data was collected through a cross-sectional, web survey from a population of caregivers of CwH aged 2 to < 12 years in the US. The survey consisted of the Child Hemo-TEM, sociodemographic items, child's hemophilia medical history, and supporting items/measures required to assess the measure's psychometric properties. The survey took up to 45 minutes to complete and was administered at a single time point. To be eligible for the study, caregivers needed to be: aged ≥ 18 years; a caregiver of a male child with a diagnosis of severe to moderate hemophilia A or B, with a factor level of < 2%, with or without an inhibitor, and currently receiving either prophylactic or on-demand treatment; and living in the same residence as the child over the past 2 weeks. Recruitment was conducted by a patient advocacy group and a professional market research firm. Recruitment quotas were targeted to ensure a diverse population and mix of frequency of prophylactic treatment(s) and treatment administration type. All psychometric analyses were conducted following an a-priori statistical analysis plan, which included examination of measurement characteristics, item reduction, factor analysis, measure scoring, internal consistency, reliability, and validity. Results: Caregivers ( n=187) of CwH completed the web survey. The respondents were, on average, 37.8 years of age, mothers (84.0%), and predominantly White/Caucasian (74.3%). Twelve items were dropped from the validation-ready, 19-item measure: 5 items due to high ceiling effects at baseline (>50%) mirrored by the Rasch results and 1 item as it was highly correlated with a retained item. Further, as there were only a small number of children who self-injected, 6 items designed to assess child self-injection were removed. The remaining items underwent further psychometric testing. An exploratory factor analysis generated a single, 7-item factor. The Child Hemo-TEM was found to be internally consistent with a Cronbach's α of 0.855. A-priori validity hypotheses were adapted to match the final factor structure. Hypothesized associations were predominantly confirmed with a few exceptions. For convergent validity (Pearson's r significance set at α = 0.05), a few of the associations, although significant, were below 0.30 (Table 1). The Child Hemo-TEM was able to discriminate between levels of self-complaining about their infusions (p < 0.001), psychological stress reported by parent (p < 0.001), and ease/difficulty of their medication in its current form, among other variables. Based on psychometric findings and taking into consideration learnings from the concept elicitation during measure development, the brief, 7-item Child Hemo-TEM was finalized with 1 domain capturing information from all the hypothesized concepts of treatment concerns (3 items), adherence (1 item), physical impact (1 item), and interference with daily life (2 items) (Figure 1). A five-point Likert response scale with ranges from “Never” to “Always”, or a “Don't know” option, is used. Conclusion: The Child Hemo-TEM ObsRO has been found to be conceptually sound with adequate evidence to support its reliability and validity. Incorporation of the measure into both clinical and research settings will help assess the pediatric patient's experience of living with hemophilia as well as aid clinicians in tailoring treatments to patient characteristics and situations. Future studies are needed to assess test-retest reproducibility, sensitivity to change, and meaningful change thresholds of this new measure.

Predictors of Liver Disease Outcomes in People with Hemophilia and HCV Infection

Introduction: Hemophilia is an X-linked bleeding disorder among whom the majority have chronic hepatitis C (HCV) from past factor infusion. With among the longest duration HCV infection, now 30+ years from their first factor infusion, better predictors of HCV outcomes are needed now that liver-based gene therapy is FDA-approved. While antiviral therapy clears HCV viral load and reduces end-stage liver disease (ESLD), it may not reverse fibrosis/ cirrhosis or prevent hepatocellular carcinoma (HCC). We, therefore, studied the natural history of HCV in a well-characterized cohort of men with hemophilia and HCV to determine HCV prevalence and cumulative incidence of ESLD, HCC, and mortality. Methods: This was a retrospective cohort study of 121 men with HCV and hemophilia cared for at the Hemophilia Center of Western PA, whose medical outpatient charts were reviewed under University of Pittsburgh IRB exempt determination, #21100086. HCV outcomes, including ESLD, HCC, platelet count (PLT)<100,000 (100K) u/L, and mortality were analyzed by age, ethnicity, HIV status, hemophilia type, inhibitor status, and antiviral therapy. Liver biopsies available on 32 patients were assessed for steatosis, Knodell, Ishak and Metavir scores. Fisher's exact test was used to compare outcomes by discrete variables. Kaplan Meier time to event analyses log-rank test was used to determine time-to-event outcomes for HCC and mortality, and logistic regression was used to determine variables predictive of HCV outcomes. Results: The mean duration of HCV infection in 121 subjects was 54 years (range: 36-80 yr). Of these, 48 (39.6%) had received antiviral therapy (IFN-based or DAA-based): of those untreated, most died prior to its availability. A total of 31(25.6%) were HIV+, 24 (19.8%) had ESLD, and 7 (5.8%) had HCC. Among the 34 (25.9%) who died, ESLD was the cause in 11 (32.3%), HCC in 6 (20.6%), bleeding in 9 (26.5%), sepsis in 3 (8.8%), and AIDS, Parkinson disease, intravenous drug use, and suicide in 1(2.9%) each. The overall prevalence of ESLD was 0.365 per 100 person-years (py); PLT<100K, 0.173 per 100py; HCC, 0.106 per 100 py; and HCV-associated mortality, 0.335 per 100py. Significant risk factors for ESLD included PLT<100K/uL, OR=6.159, p=0.014; HIV infection, OR=3.883, p=0.001; and age>50, OR=2.460, p=0.023. No antiviral-treated subject developed ESLD, p=0.001. The presence of ESLD was the most significant predictor of HCC, OR=11.476, p=0.003. An elevated Knodell score was a significant predictor of HCC, OR =2.450, p=0.044, while an elevated Ishak score was a significant predictor of ESLD, OR 1.930, p=0.030. Neither Metavir nor steatosis scores were predictive of ESLD or HCC, and no score was predictive of HCV mortality. Kaplan Meier time-to-event survival analysis for all-cause mortality, 95% confidence interval (dotted lines) based on ESLD, HIV, treatment status, HCC, and age is shown in Figure 1a-1e. The overall mean ± SE (standard error) survival from initial HCV infection was 8890 ± 240 days. Comparing ESLD with non-ESLD, mean survival was 5321 ± 649 vs. 9773 ± 152 days, p=0.001 (Fig. 1a); for HIV+ vs. HIV-, 7032 ± 676 vs. 9530 ± 178 days, p=0.001 (Fig. 1b); for antiviral-treated vs. untreated, 10210 ± 19 vs. 8094 ± 365 days, p=0.001 (Fig. 1c); for HCC vs. non-HCC, 8433 ± 614 vs. 8918 ± 251 days, p=0.027 (Fig. 1d); and for age > 50 vs. ≤ 50 yr , 9588 ± 173 vs. 8052 ± 460 days, p=0.001 (Fig. 1e). The cumulative incidence (CI) of ESLD was 16.86% overall. Comparing HIV+ vs. HIV-, ESLD-CI was 41.44% vs. 7.36%, p= 0.001; in antiviral-treated vs. untreated, 0% vs. 27.08%, p=0.001; in age > 50 vs. ≤ 50 yr, 13.10% vs. 14.03%, p<0.001; and in PLT<100K/uL vs. PLT≥100K/uL, 48.15% vs. 1.61%, p<0.001. The HCC-CI was 2.88% overall, including in HIV+ vs. HIV-, 0% vs. 3.71%, p= 0.27; in antiviral untreated vs. treated, 2.00% vs. 3.85%, p=0.760; in age > 50 vs. age ≤ 50, 5.63% vs. 0% , p=0.040; and in PLT<100K/uL vs. PLT ≥ 100K/uL, 33.3% vs.1.61%, p=0.001. HCC-CI was similar between those with vs. without ESLD, 6.67% vs 2.04%, p=0.27. Conclusion: ESLD in people with hemophilia and HCV is associated with increased risk of mortality, HCC, and PLT<100K. The risk for ESLD is increased in those with HIV and antiviral untreated. HCV remains an important cause of major morbidity and mortality in this cohort of people with hemophilia and HCV, despite antiviral therapy. This suggests ESLD, HCC, HIV, PLT<50K/uL, and antiviral Rx assessment before hemophilia liver-based gene therapy.

Characteristics Associated with the Success of Immune Tolerance Induction Among People with Severe Hemophilia a in the United States

Introduction: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A with inhibitors (PwSHAi). An earlier study reported lower receipt of ITI treatment in non-Hispanic (NH) Black and Hispanic compared to NH White PwSHAi (Kempton CL, 2022). Since risk of inhibitor development is greater among Black and Hispanic persons with hemophilia, it has been hypothesized that race and ethnicity may impact the success of ITI. Limited studies have evaluated this hypothesis. This study examined the success of ITI by race and ethnicity among PwSHAi in the Community Counts (CC) Registry between 2013-2017 in the United States (US). Methods: This cross-sectional study used data from the CC Registry, which is a collaboration of the American Thrombosis & Hemostasis Network (ATHN), Centers for Disease Control and Prevention (CDC), and the Hemophilia Center Network (HTCN) using ATHN Study Manager. The CC Registry collects data from people who received care from >135 US hemophilia treatment centers (HTCs). PwSHAi who entered the CC Registry between 2013-2017 and received ITI were selected (n=679); those who were <3 years old at Registry enrollment (n=41) and had history of an inhibitor for <3 years (n=79) were excluded, resulting in 559 people were available for the analyses. Data from 2013-2017 were chosen to represent the pre-emicizumab era where ITI was the standard of care without debate. The 3-year age and inhibitor history cut-point was chosen to ensure ample time for PwSHAi to receive and respond to ITI. The primary outcome was ITI response defined as 1) successful (PwSHAi receiving FVIII replacement therapy at standard doses); 2) partially successful (receiving FVIII replacement therapy at increased dosing); and 3) failed (receiving bypassing agents). Primary independent variables included race/ethnicity, likelihood of ITI success defined with pre-ITI peak inhibitor values alone, grouped as very good [<25 Bethesda Units (BU)], good (25-199 BU), poor (200-999 BU), and very poor (≥1000 BU) prognosis, based on the Future of Immunotolerance Treatment (FIT) group's recent management algorithm (Carcao, 2019). Unadjusted (PR) and adjusted prevalence ratios (aPR) and corresponding 95% confidence intervals (CI) were computed with logistic models with predicted marginals. Results: Among 559 PwSHAi included, 318 (56.9%) were NH White, 107 (19.1%) were NH Black, 101 (18.1%) were Hispanic, 24 (4.3%) were Asian, and 9 (1.7%) were coded as other or missing (Table 1). The median age at Registry enrollment and inhibitor detection was 16 years and 2 years, respectively. Approximately 64% of NH Black, Hispanic, and NH White PwSHAi had either good or very good prognosis, though less than half (41.7%) of Asian PwSHAi had very good or good prognosis. While 59.7% of PwSHAi achieved successful ITI, 20.7% and 19.5% only achieved partially successful or experienced failed ITI, respectively (Table 1). Success of ITI linearly increased according to prognostic group where 21.7%, 36.3%, 55.6% and 69.6% of those with very poor, poor, good, and very good prognosis achieved successful ITI, respectively (χ 2 p-value<.001, Cochran-Armitage Trend p-value<.001). The proportion with successful ITI was non-significantly lower in NH Black (54.2%; PR=0.87,95%CI 0.71,1.05), Hispanic (55.4%; PR=0.89,95%CI 0.73,1.08), and Asian (58.3%; PR=0.93, 95%CI 0.66,1.32) PwSHAi relative to NH White (62.6%) PwSHAi in both crude and adjusted analyses (Table 2). In analyses restricted to those PwSHAi with very good or good prognosis, successful ITI prevalence was nearly identical in NH Black (63.8%) and NH White (64.9%). ITI success was similar across age at inhibitor detection, registry enrollment, health insurance and HTC size (Table 2). Conclusion: Using US CC Registry data, approximately 60% of PwSHAi treated with ITI had a successful response, a proportion similar to previous studies. The proportion of PwSHAi who had successful ITI linearly improved with predicted prognosis, defined by the peak inhibitor titer alone. In our study, prognosis category was generally similar in Hispanic, NH White, and NH Black PwSHAi and the proportion with successful ITI did not vary significantly according to race/ethnicity. These findings do not support the hypothesis that ITI response varies according to race/ethnicity, and it suggests that the benefits of ITI are similar across race and ethnicity.

Bone Health of Hemophilia Ａ Patients Using Emicizumab

Background: Hemophilia patients have been observed to exhibit a higher prevalence of osteoporosis compared to age-matched general population. However, the underlying mechanism responsible for this association remains poorly understood. One hypothesis proposes that factor VIII itself may possess additional physiological functions that contribute to bone health. Conversely, alternative viewpoints suggest that overall coagulation function or thrombin generation may play a pivotal role in maintaining optimal bone health. The introduction of emicizumab, a bispecific antibody that mimics the coagulation function of factor VIII but possesses a structurally distinct composition, presents an opportunity to shed light on this matter. Therefore, the primary objective of this study is to explore and compare the bone health status of hemophilia patients, distinguishing between those utilizing emicizumab and those who are emicizumab-naïve. Method: From June 2019 to June 2023, at the hemophilia center of National Taiwan University Hospital, additional examinations to assess the patients' bone health were performed with routine annual joint health evaluations for patients with hemophilia A (PwHA) and B (PwHB). This included the use of dual-energy X-ray absorptiometry scan (DEXA) to measure the bone mineral density (BMD) of the lumbar spine, hip, and femur. Furthermore, the serum levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX) were measured as reference markers for bone formation and bone resorption, respectively. The Kruskal-Wallis test was utilized to statistically evaluate the observations among the three groups. Results: The study population was divided into three distinct groups based on their hemophilia subtype and treatment: PwHA who had been utilizing emicizumab for more than one year (n=8), PwHA individuals receiving regular factor VIII treatment (n=16), and PwHB (n=10). The analysis of the collected data, as presented in the accompanying table, revealed that the three groups exhibited similar characteristics in terms of age, annual bleeding rate, and joint conditions. Moreover, no statistically significant differences were detected in the measurements of bone mineral densities (BMDs) and biomarkers. However, it is worth noting that there appeared to be a potential trend toward higher levels of P1NP in the PwHB group.In the case of PwHA patients using emicizumab, we examined the longitudinal changes in T-score of BMD over time. Notably, three PwHA patients with baseline T-scores below zero demonstrated improvements in their T-scores after one year of emicizumab treatment. Conclusion: The results of this study indicate a lack of significant disparities in bone health between individuals utilizing emicizumab and those who are not. Furthermore, our findings suggest that emicizumab usage does not lead to a decline in bone health over the observed period.

Post-Immune Tolerance Induction Prophylactic FVIII Infusions May Not be Necessary for Tolerized Hemophilia a Patients on Emicizumab

Background: Hemophilia A is a hereditary bleeding disorder characterized by low factor VIII (FVIII) activity. Patients with severe bleeding phenotypes are at risk for significant bleeding-related morbidity and mortality including the development of hemophilic arthropathy. In recent years, prophylaxis with emicizumab, a bispecific monoclonal antibody, has supplanted prophylactic FVIII infusions due to its ease of self-administration, long half-life, and low annual bleeding rate (ABR), independent of tolerization status to alloantibodies against FVIII (inhibitors). However, it is unclear if emicizumab FVIII-mimic activity is sufficient to achieve hemostasis in moderate-severe bleeds, and therefore, FVIII replacement may still be necessary. Despite its well-established benefits, the use of emicizumab in previously untreated patients (PUPs), and patients with under 20 exposures to FVIII is still not well understood due to a lack of long-term experience and understanding of its impact on the pathophysiology of FVIII inhibitors. Further investigation is also needed regarding the risk of inhibitor recurrence in patients with previous inhibitors and the concomitant use of emicizumab. At our institution, patients on emicizumab with a history of inhibitors do not continue post-immune tolerance induction prophylactic FVIII infusions. We also initiate emicizumab before 20 exposures to FVIII, and sometimes before immune tolerance induction (ITI). We explored our patient population to understand inhibitor incidence and recurrence amidst emicizumab prophylaxis. Methods: We performed a single center retrospective analysis of patients served by the Hemophilia Center of Western Pennsylvania. We identified patients with Hemophilia A on emicizumab prophylaxis. Relevant data was collected including demographics, inhibitor status at time of transition to emicizumab and in the available follow-up period, bleeding events after transition, and number of FVIII exposures before and after transition. Inhibitor recurrence was defined as laboratory evidence of inhibitor using chromogenic Bethesda assay and/or unexplained breakthrough bleeding events despite on-demand FVIII infusions. Results: Data was reviewed for 36 patients on emicizumab prophylaxis. Three patients were lost to follow-up. Median age was 15.3 years (range 1.2 - 82). Median follow-up time on emicizumab was 3.5 years (range 0.5 - 5). Two patients had < 20 FVIII exposures prior to emicizumab, and one of those had an inhibitor before emicizumab. In total, 15 patients (45%) were diagnosed with an inhibitor prior to emicizumab. Of these, 8 patients (53%) were tolerized prior to emicizumab, and 7 patients (47%) were not tolerized prior to emicizumab. Median peak inhibitor titer was 4.2 Bethesda units (range 0.7 - 281 Bethesda units). After transition to emicizumab, no tolerized patients for which inhibitor status was tested during the follow-up period had inhibitor recurrence, and 1 non-tolerized patient's inhibitor became undetectable after 4 years of emicizumab therapy (the same patient who had developed an inhibitor with < 20 FVIII exposures prior to emicizumab). Mean ABR was 0.33 events/year for tolerized patients (median 0, range 0 - 3); 0.17 events/year for non-tolerized patients (median 0, range 0 - 1); and 0.60 events/year for patients with no history of inhibitor (median 0, range 0 - 4). Mean number of FVIII exposures per year was 0.09 for tolerized patients (median 0, range 0 - 1); 0.07 for non-tolerized patients (median 0, range 0 - 1); and 1.2 for patients with no history of inhibitor (median 0, range 0 - 20). Conclusion: In our small cohort, no patient who was tolerized prior to emicizumab had recurrence of clinical or laboratory evidence of inhibitor while on emicizumab therapy, despite infrequent exposure to FVIII infusion. We did not have enough power to determine whether patients with < 20 FVIII exposures before emicizumab developed inhibitors, though one such patient had inhibitor resolution on emicizumab without ITI. Consistent with other works, overall ABRs in all patients on emicizumab therapy were low. These findings add to other studies on the safety of emicizumab and its impact on the natural history of FVIII inhibitors. Our study also suggests that continuing post-ITI prophylactic FVIII infusions in tolerized patients on emicizumab may not be necessary. Larger-scale studies are required to substantiate our findings.

The frequency of complications in a cohort of patients diagnosed with hemophilia A and hemophilia B receiving prophylactic treatment in Colombia: A retrospective noninterventional study.

Hemophilia A and B are disorders associated with the deficit of coagulation factors VIII and IX. Was to determine the incidence of complications in a cohort of patients diagnosed with moderate and severe hemophilia A or B under treatment in a specialized institution. A retrospective study of a cohort of patients with replacement therapy for hemophilia A or B, evaluating treatment and complications between January/2012 and July/2019. Sociodemographic, clinical and disease management-related variables were extracted from the medical records. Time to inhibitor development and rate associated with bleeding and hospitalizations were evaluated. A total of 159 male patients were identified with hemophilia A (n = 140; 88.1%) and B (n = 19; 11.9%) with a mean follow-up of 5.9±2.3 years. The mean age was 23.6±16.1 years, hemophilia was reported as severe in 125 patients in hemophilia A (89.3%) and 13 patients in hemophilia B (68.4%). Primary prophylaxis was registered in 17.0% of patients, 44.7% secondary, and 38.3% tertiary, with recombinant factors (n = 84; 52.8%) followed by plasma derived factors (n = 75; 47.2%). The incidence of inhibitor development was 0.3 per 100 patients/year, with mean time to event of 509 days. The incidence of bleeding was 192 per 100 patients/year, especially at the joint (n = 99; 62.3%) and muscle (n = 25; 15.7%) level. The incidence of hospitalization was 3.7 per 100 patients/year. The most common complication was joint bleeding which was expected in this type of patients. Low proportion of patients developed factor inhibitors during the follow up.

Descriptive and Epidemiological Study of Joint Damage in Non-Severe Hemophilia: Update of the Damage Study of the Mediterranean Group

Introduction: There is growing evidence indicating joint damage (JD) in non-severe hemophilia (nSH) patients. Although age and baseline factor (F) VIII/FIX levels have been proposed as good predictors of JD in mild hemophilia (MiH), data are scarce and in moderate hemophilia (MoH) are lacking. Besides, global hemostatic capacity (GHC) in this population and its contribution to JD has not been assessed. Methods: We designed a cross-sectional, observational and multicenter study carried out in 12 Spanish hospitals (Mediterranean Group). We evaluated JD in nSH patients and its correlation with age, baseline FVIII/FIX and GHC. JD was defined as a HEAD-US score >0. Baseline FVIII (chromogenic assay), FIX (clotting assay) and GHC (assessed by thrombin generation test, TGT, Genesia ®, Stago) were evaluated in a central laboratory. Results were expressed as median (25 th-75 th percentiles). Categorical variables were expressed with percentage. A p value<0.05 was considered statistically significant. Results: A total of 98 nSH patients were included: 10 (10.2%) MoH (9 HA: age= 35.6 [21.7-45.0] years old (YO); FVIII = 4.0 [4.0-5.0] IU/dL; 1 HB: FIX= 2 IU/dL) and 88 MiH (84 HA: age= 38.6 [19.0-52.1 YO]; FVIII= 15.5 [11.0-24.0] IU/dL; 4 HB: FIX= 30.0 [16.8-35.4] IU/dL). Target joints were observed in patients with MiH (7/88: 8.6% of the MiH patients). HEAD-US score was obtained in 73 patients (74.5% of the total participating patients): nine MoH patients presented a HEAD-US= 1 (0-6) (age: 32.7 [21.7-42.9] YO) while 64 MiH patients presented a HEAD-US= 0 (0-3) (age: 37.9 [17.8-48.7] YO) (comparison between MoH and MiH patients: HEAD-US: p=0.427, age: p= 0.614). Only 55.5% (5/9) MoH patients and 45.3% (29/64) MiH patients, presented JD (p=0.725). Baseline FVIII/FIX was 13.0 (7.0-20.0) IU/dL and 16.0 (11.0-22.5) IU/dL in patients with or without JD respectively (p= 0.311). These mild difference of number of patients with JD and degree of JD between MiH and MoH were corroborated by not detecting correlation between baseline FVIII/FIX levels and JD (r= -0.095; p= 0.426) (Figure 1). JD increased with age (r= 0.380; p= 0.001) reinforcing previous findings. GHC correlated with baseline FVIII/FIX (Table 1) but not with the degree of JD, suggesting that thrombin generation, with the used conditions, might not be helpful to predict JD in this population. Conclusions: Around 50% of patients with nSH presented JD. This JD increased with age, supporting previous data. Although there was a correlation between baseline FVIII/FIX levels and thrombin generation, none of the TGT parameters were predictive of the degree of JD, enhancing that other variables might be influencing the development of JD in nSH patients. Of note, MiH individuals may develop severe JD due to presence of target joints. In summary, our results highlight the importance of evaluating JD in nSH in order to determine whether new protocols are required for the diagnosis, prevention, and treatment of JD in nSH patients.

Real-World Unmet Needs in Patients with Hemophilia A without Inhibitors in the US: Results from the PicnicHealth Database

Introduction Hemophilia A is a rare X-linked bleeding disorder characterized by deficiency of the coagulation factor VIII (FVIII). The standard-of-care for hemophilia A includes prophylaxis (PPX) with factor replacement therapy or emicizumab to prevent bleeding. The World Federation of Hemophilia guidelines suggest FVIII trough levels of >3-5% or higher are adequate for PPX. While the importance of maintaining high FVIII levels is well recognized, real-world levels in patients with hemophilia A are often sub-optimal. Aim To understand unmet needs in patients with moderate or severe hemophilia A by assessing bleeding outcomes and patient-reported outcomes (PROs). Methods Patients from the United States (US) were recruited by PicnicHealth, a patient-centric data retrieval platform working with individuals who contribute their medical record data to research across various disease areas. Patients consented for PicnicHealth to retrieve their medical records from all care sites or providers and receive access to their records in the US. Patients were invited to complete bleed, treatment, and quality of life surveys. The analysis included medical record data (2015-2022) and PRO survey data (2022) from patients with moderate or severe hemophilia A (endogenous factor level ≤5%). Three cohorts were defined for the analysis of bleed outcomes, based on patients' PPX product class exposure (standard half-life [SHL] factor, extended half-life [EHL] factor, and emicizumab). Index date was defined as the first observed PPX product use within the class beginning on or after January 1, 2015, and patients were censored at the earliest of switch to another product class, end of patient data, death, or data cut-off (October 3, 2022). Patients who switched product classes during the study period were included in multiple cohorts. The PRO instrument used was the 29-item, 7-domain PROMIS-29 questionnaire (range 1-5; scale scores standardized to a general US adult population with mean [SD] score of 50 [10]). A custom instrument designed to assess patients' “worst pain intensity” was also used (from 0 = no pain to 10 = worst imaginable pain). An additional Medication and Bleed Survey was administered biweekly to collect patient-reported treatment and bleed event information. Results Of the 354 patients recruited, 293 had moderate or severe hemophilia A, of which 291 patients had a record of treatment. After excluding patients with inhibitors on index date or a non-hemophilia A bleeding disorder diagnosis on or prior to index date, 141 patients met the criteria for SHL, 88 for EHL, and 82 for emicizumab PPX cohorts (non-exclusive). Patients' mean (SD) age in years at index were as follows: SHL, 26.7 (13.3); EHL, 26.2 (11.8); and emicizumab, 29.8 (14.9). Considering only individual bleed events documented in medical records, 57.3% of the SHL cohort, 47.1% of the EHL cohort, and 55.2% of the emicizumab cohort had at least one recorded bleed within the first year post-index date. When also including bleed rates reported to the provider by the patient (for more complete data capture from the medical record) the respective values were 61.4%, 70.8% and 62.1%. Out of 293 patients with moderate or severe hemophilia A, the PROMIS-29 questionnaire was completed by 142 patients who were ≥18 years of age at the time of survey completion. Scores were similar across patients' self-reported treatment class at the time of survey ( Table). Physical functioning and ability to participate in social roles and activities were the most affected areas; the most frequently reported symptoms were sleep disturbance (84.5%) and inability to participate in social roles and activities (69.7%). Adult patients completing the custom survey (n=140/293) rated their worst pain intensity as a mean (SD) of 7.7 (2.1); in patients with a recent bleed, this was 8.4 (1.5). Overall, patients reporting a recent bleed had worse scores. Conclusion This real-word study provides insights into the unmet needs in patients with hemophilia A receiving regular PPX. Irrespective of treatment received, a majority of patients still bleed at least once a year, struggle with pain and participating in social roles and activities, and have sleep disturbances. This indicates a need for improvement in the quality of life of this population and further highlights the need for understanding the patient perspective with hemophilia A.

Emicizumab Use in Infancy: A Survey of United States Pediatric Hemophilia Treatment Center Medical Directors

Introduction: Emicizumab, a bispecific antibody directed against activated factor IX and factor X, is a subcutaneous non-factor prophylactic option for individuals with hemophilia A (HA). The safety and efficacy of emicizumab has been demonstrated in both adult and pediatric patients. It was approved by the United States (U.S.) Food and Drug Administration for routine prophylaxis to prevent or reduce bleeding episodes in individuals with HA, ages newborn and older, both with (2017) and without (2018) factor VIII (FVIII) inhibitors. Despite this approval, data on emicizumab in infants are limited. The HAVEN 2 pediatric clinical trial had only two infants under 24 months of age, though interim analysis of the HAVEN 7 trial demonstrated emicizumab efficacy and safety in infants. Thus, the optimal use of emicizumab in infants under 12 months of age remains unclear. The objective of this study was to understand the rationale and treatment decisions regarding initiation of emicizumab prophylaxis in children under 12 months of age among pediatric Hemophilia Treatment Center (HTC) Medical Directors in the U.S. Methods: An electronic survey was conducted from April to May 2023 of U.S. HTC Medical Directors via REDCap. Invitations were sent to all individuals listed as HTC Directors at pediatric medical centers on the Center for Disease Control and Prevention database. The survey included two hemophilia patient case scenarios associated with 15 multiple-choice questions and additional free-text options. The first case was of a 9-month-old male with severe HA, without prior bleeding history or exposure to FVIII, who presented for his initial visit to an HTC. The second case was a 3-month-old male with severe HA receiving FVIII replacement therapy for an intracranial hemorrhage. This study was approved by the Baylor College of Medicine Institutional Review Board. Results: Overall, 33 of 97 (34%) pediatric HTC Medical Directors participated in the survey. One survey was minimally completed and excluded for a total of 32 surveys included in the final analysis. The majority of participants had over 15 years of experience caring for patients with HA (n=21, 65.6%) and represented HTCs with over 250 patients (n=22, 68.8%; Table 1). For previously untreated or minimally treated infants (Case 1), 96.9% of responses (n=31) stated they would consider starting emicizumab prophylaxis; 45.2% (n=14) would consider initiating it as young as 1 week of age. The most common reason cited for starting emicizumab in an infant was to prevent an intracranial hemorrhage (n=17, 53.1%) followed by the desire to avoid central line placement (n=7, 21.9%). The majority of respondents did not wait for a minimum number of factor exposure days prior to starting emicizumab (n=31, 96.9%) nor did they report regularly exposing infants to FVIII concentrate until 50 EDs are reached (n=29, 90.6%). After the initial loading phase, the majority of respondents selected an emicizumab dosing regimen of every 2 weeks (n=19, 59.4%). There was a varied approach to monitoring for inhibitor development after starting emicizumab; 40.6% (n=13) reported monitoring at regular intervals between every 6 to 24 months, whereas 46.8% (n=15) did not report following a set schedule and instead obtain FVIII inhibitor testing only after FVIII exposure (Table 2). For infants receiving FVIII replacement for treatment of an intracranial hemorrhage (Case 2), 96.9% (n=31) of participants stated they would transition to emicizumab as a prophylactic agent. Over half (n=16, 51.6%) stated they would initiate emicizumab during the treatment period for the hemorrhage rather than waiting until therapy completion. For providers that use emicizumab in moderate hemophilia, emicizumab was reported to be used routinely by 27.3% (n=6) and on a case-by-case basis in 40.9% (n=9, Table 2) in infants with moderate HA. Conclusion: Pediatric HTC Medical Directors in the U.S. report commonly utilizing emicizumab in infants under 12 months of age despite the lack of robust data in this age group. This practice is consistent with recommendations by the National Hemophilia Foundation's Medical and Scientific Advisory Council. With the completion of clinical trials focused on infants with HA, along with additional long-term outcomes data, more specific guidance around initiation, follow-up and monitoring may be available to inform the optimal management for these patients.

Emicizumab: the hemophilia A game-changer.

In hemophilia, the unmet needs regarding adherence to prophylaxis and lack of effective long-term prophylaxis regimens, especially in patients with inhibitors, led to the production of emicizumab, the first non-factor medicine for subcutaneous administration in patients with severe and moderate hemophilia A with or without factor VIII inhibitors. This review describes the research steps behind the development of this game-changing medication as well as its success in the prophylaxis of bleeding episodes, as witnessed by the results of pivotal clinical trials but also by real-life use in the frame of a still expanding global market. We also discuss potential and actual adverse events and the nuances related to clinical use, such as laboratory monitoring, development of neutralizing antidrug antibodies, risk of thrombosis/hypercoagulability and role in the management of surgical operations. The potential of emicizumab to prevent bleeding in other congenital and acquired coagulation disorders is also outlined.

Assessment of Haemophilia Patients' and Other Bleeding Disorders Needs of Psychosocial Support and Health Care Needs and Their Utilization in Haemophilia Treatment Centres (ILLUSTRATE Study)

Background: Psychological support for chronically ill patients as an integral component of medical care could improve health-related quality of life (HRQoL) of patients and contribute to a reduction in treatment costs. A meta-analysis including almost 3,000 patients revealed that persons with hemophilia (PWH) are at increased risk for depression, anxiety, and ADHD compared to the general population (Al-Huniti et al., 2020). Studies have shown that the self-efficacy, coping mechanisms, and HRQoL of parents of hemophilic children were improved by self-help programs, and depression, anxiety, and parenting stress were reduced. Although different psychological interventions have been used to help PWH to cope with their psychological problems, there is a gap between patients' need for psychosocial support from the perspective of health care professionals (HCPs) and their utilization by PWH. The aim of the ILLUSTRATE study was to assess the need for psychosocial support and medical care in patients with inherited bleeding disorders (IBD) and in HCPs and their use in hemophilia centers. Methods: Patients with IBD (PIBD) were invited by different German patient organizations (Deutsche Bluthilfe, DHG, IGH, Hämophilie 2000) to participate in an on-line surevey (from December 2022-June 2023). In addition, HCPs were asked to complete a similar on-line survey via the mailing list of the German Society for Thrombosis and Hemostaseology. A positive ethical approval for the study was obtained by the Local Psychological Ethics Committee at the University Medical Centre in Hamburg, Germany (LPEK-0578). The questionnaire for patients consisted of the following aspects: socio-demographic data, medical background, care services and psycho-social support, dealing with stress and difficult situations, dealing with special situations that may arise or be exacerbated by the bleeding disorder, offer of psycho-social counseling/support, and need for expansion. The questionnaire for HCPs contained the following themes: personal background, need of patients for psycho-social counseling/support (PSCS), supply of PSCS and need for expansion, utilization, and benefits of PSCS. Results: In total, 154 patients and parents of children with an IBD participated (72 PIBD,80 parents, 2 others) with a mean age of 41.06±13.3 years, 60.4% were female. In addition, 65 HCPs completed the respective survey (34 physicians, 27 nurses and 4 others) with a mean age of 48.11 ± 12.7 years, in average they worked since 13.1±10.8 years in haemostaseology, 78.5% worked in a hemophilia comprehensive care center (HCCC), 20% in a hemophilia treatment center (HTC) and 1.5% in a homecare service. In the IBD group (patients, parents) most were married (59.1%), lived with a partner (83.8%) and worked full- or part-time (66%). Most PIBD had hemophilia (74%) with a severe form (81.8%). 28.6% of the IBD group felt little to not at all supported to overcome psycho-social challenges. It was demonstrated that they had an intermediate stress resilience (14.76±3.1), with 1/3 showing a low resilience. When asking what coping strategies they used in stress situations, 26% mentioned that they ignore difficult situations and 16% compensated their stress with drugs and alcohol. 20% often to always felt helpless and overwhelmed due to their IBD and 31% rarely to never received support in these situations. 71% reported to have a need for PSCS, 57% wished more support services (69% mainly at the HTC), 71% felt not to have enough information about these services and 64% would use them more often if they were more accessible. 52% of HCPs found that the IBD group has a need of PSCS, they assumed that parents and adolescent patients would benefit most of these services and expected the highest advantage from psychological counseling. 60% thought that there is a need for information and education. The IBD group and HCPs preferred PSCS in presence, the IBD group would use services as well via phone or digital. Conclusions: Although offered psycho-social support programs are rarely used by patients, a large proportion of the IBD group and HCPs confirmed a need for it. Increased accessibility to PSCS and more information were identified as a factor for increased use of this support programs. Additional digital psycho-social support services were desired and represent a helpful alternative if services are not available on site.

Treatment-Related Clinical and Humanistic Unmet Needs in Hemophilia A without Inhibitors

Introduction: Patients with hemophilia still experience significant burden of disease despite the growing availability of efficacious treatment options. Presented here are the final patient-reported data from a non-interventional study of treatment and disease burden in US patients with hemophilia A without inhibitors (HAwoI). Methods: Patients with HAwol were recruited to the PicnicHealth research platform using digital marketing, referrals and community partnerships. PicnicHealth collects and extracts medical records on behalf of the patient, provides them with their records and invites them to participate in recurring patient-reported outcome surveys. Hemophilia severity reported here was based on baseline factor values and medical records. Two validated questionnaires, Hemophilia Treatment Experience Measure (Hemo-TEM)(Brod, M. et al., J Patient Rep Outcomes. 2023) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile v2.0 (Hays, R.D., et al., Qual Life Res. 2018)were used to collect data on treatment and disease burden. Patients were also asked about their prophylactic medication, if any, as well as two independent questions on anxiety and/or worry concerning bleed protection with current treatment. All surveys were administered between April 2022 and April 2023, with the most recent survey included in this analysis for patients who completed multiple surveys during the study period. Hemo-TEM domain scores were transformed onto a 0 to 100-point scale with higher scores indicating greater burden. PROMIS-29 scores were transformed into T-scores, based on a reference sample with a mean of 50 and standard deviation of 10, except for the pain intensity score, which was rated 0-10. The directionality of impact was specific for each domain (Hays, R.D., et al., Qual Life Res. 2018). Results are presented as proportions, median and interquartile range (IQR, Q1-Q3). Informed consent was obtained. Results: Out of 230 patients with HAwol (91% male; median age: 33.3 years; IQR: 23.9-41.7), 147 (64%) had severe, 41 (18%) had moderate and 42 (18%) had mild hemophilia. Use of prophylactic FVIII was reported by 74 (50%), 16 (39%) and 13 (31%) patients with severe, moderate and mild hemophilia, respectively, while prophylactic non-factor replacement therapy use was reported by 64 (44%), 8 (20%) and 5 (12%) patients, respectively (treatment classes are not mutually exclusive). Treatment class was unspecified (includes patients who did not report prophylactic medication use) for 58 (25%) patients. Treatment burden was observed through Hemo-TEM scores across all subgroups of disease severity and treatment class (n=223), with the strongest drivers being physical impact (median: 25 [IQR: 12-38]), treatment bother (21 [9-32]) and emotional impact (21 [6-38]) domains (Table 1). The PROMIS-29 scores and its directionality shown in Figure 1 demonstrated comparable disease burden in all domains regardless of disease severity or treatment class (n=228). Patients with severe disease on prophylactic FVIII/prophylactic non-factor replacement therapy reported scores of 42 (37-50)/46 (39-57) in physical functioning and 51 (49-61)/49 (46-55), 57 (52-64)/56 (42-60) and 52 (48-56)/52 (46-56) in domains of fatigue, pain interference and sleep disturbance, respectively. Impact on mental well-being for these patients were shown by scores of 56 (49-61)/54 (41-59) and 58 (51-63)/56 (51-61) in domains of depression and anxiety, respectively. Pain intensity for all patients with severe disease was 4 (2-6) out of 10. In response to two independent survey questions, patients with severe HAwol reported feeling anxious (42%) and/or worried (39%) at least sometimes that their current treatment might not adequately protect them from bleed. Conclusion: Patients with HAwoI continue to experience treatment and disease burden, across treatment class and disease severity subgroup. Despite improved outcomes with current treatment strategies, there remains a need to continue to address disease burden. Greater understanding is required of the driving factors behind similar treatment and disease burden between the subgroups to facilitate individualized care.

Hereditary Hemorrhagic Telangiectasia May be the Most Clinically Significant and Morbid Inherited Bleeding Disorder of Women

Background Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder (1 in 5000 people) behind von Willebrand disease (VWD) and has no FDA- or EMA-approved therapies. HHT causes serious bleeding resulting in severe iron deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in brain, lung, and liver that can cause life-threatening hemorrhage, stroke, and other morbid complications. While HHT prevalence is equal in men and women, manifestations may be worse in women (as evidenced by a female predominance in HHT clinical trials). Due to the focus on hemophilia (an X-linked disease nearly exclusive to men) in the hemostasis research community, no study has examined the relative morbidity of the most common inherited bleeding disorders in women: HHT and VWD. Methods We performed an observational cohort study of women with HHT or VWD cared for at our institutional Comprehensive Hemophilia and Von Willebrand Disease Treatment Center or HHT Center of Excellence. Using an electronic patient data registry, a representative sample of 100 randomly selected women with HHT were age-matched to 100 randomly selected women with VWD for analysis. All data was extracted and confirmed using manual chart review; we quantified and compared bleeding and healthcare utilization outcomes. Results Patient Population. The mean (range) age in both groups was 49 (14-87) years. Mean BMI was 27 in both groups, and racial/ethnic breakdown was similar in both groups. Mean follow-up durations were 9.07 years (HHT) and 14.83 years (VWD) per patient. The VWD group included 86 patients with type 1 VWD and 14 with type 2 VWD. Bleeding Outcomes. Bleeding outcomes are detailed in TABLE 1. In women with HHT compared with VWD, recurrent epistaxis and GI bleeding were more likely (odds ratio [OR] [95% CI] = 32.73 [13.81-71.80], P<0.0001 and 5.69 [2.59-12.89], P<0.0001, respectively), and heavy menstrual bleeding was less likely (OR 0.32 [0.18-0.57], P<0.0001). Iron deficiency anemia was significantly more likely, and lowest hemoglobin significantly lower, in HHT versus VWD. Requirements for IV iron and RBC transfusion were significantly more likely in HHT versus VWD. Women with HHT had 17-fold higher odds of iron infusion dependence and 8-fold higher odds of requiring hemostatic surgical procedures than women with VWD. Healthcare Utilization for HHT or VWD Management. Healthcare utilization is detailed in TABLE 2. In women with HHT compared with VWD, emergency department (ED) visits and hospital admissions specifically to manage disease complications were significantly more likely (OR [95% CI] = 3.83 [1.67-8.48], P=0.001 and 7.33 [3.57-14.73], P<0.0001, respectively). Rates of ED visitation, admission, and outpatient encounters specifically for HHT or VWD management were significantly higher in women with HHT vs. women with VWD: ED visits, 10.3 per 100 patient-years (pt-yrs) vs. 0.74 per 100 pt-yrs, P=0.001; admissions, 14.4 per 100 pt-yrs vs. 1.0 per 100 pt-yrs, P<0.0001; outpatient encounters, 386.5 per 100 pt-yrs vs. 43.7 per 100 pt-yrs, P<0.0001. Adjusting these rates for the prevalence of HHT (1 in 5000) and VWD (1 in 1000) at the population level, all rates were still higher in the HHT group. Infusion visits, radiology encounters, and nearly all subspecialty provider visit types were much higher in women with HHT ( TABLE 2). Conclusions Analyzing matched populations of women at a health system that serves as a tertiary referral center for both diseases, HHT, a historically neglected bleeding disorder, was responsible for much higher morbidity and healthcare utilization in women than VWD, certainly at the individual patient level and possibly at the population level (prevalence-adjusted). Overall incidence of disease complications in each group was consistent with the published literature for both HHT and VWD, supporting the generalizability of our findings. These findings are critically important in achieving gender equity in the hemostasis field, given that both government and industry funding for VWD research is many times greater than for HHT research and such funding for hemophilia research, a disease of men, is at least 10-fold greater than for HHT research. Continued neglect of funding for clinical care and research of HHT within the hemostasis academic community and industry will only sustain and exacerbate gender inequities in hematology.

Heterotopic Ossification in Hemophilia: A Multi-Center Case Series

CONCLUSION Heterotopic Ossification (HO), or Myositis Ossificans Traumatica, is the post-traumatic formation of unwanted abnormal benign lamellar ectopic bone within extra skeletal tissue locations. HO can form in varying sizes and sites in the body and can significantly impair muscle performance, range of motion (ROM), and function. Since the recent adoption of diagnostic musculoskeletal ultrasound (MSKUS) in hemophilia care, providers and physical therapists have deepened their understanding of hemarthropathic and hemarthrosis progression. MSKUS has also aided in detecting soft tissue injuries, muscle hematoma, and resultant HO formation. Despite advances in therapies for hemophilia, HO is emerging as an unforeseen complication of contusion and injury-related muscle bleeding in hemophilia. Its detection is important as delayed or inappropriate rehabilitation may prolong recovery and disability time. This multicenter retrospective case series sought to verify and confirm HO detection and investigate whether specific types and severities of hemophilia are at increased risk of HO. Deidentified data and MSKUS images from 29 cases were collected from 9 Hemophilia Treatment Centers from the USA, the Netherlands, and Canada from 2016 to June 2023. The case series was declared exempt from IRB approval. Diagnostic and evaluative data was compiled in Redcap. Images were reviewed and diagnostically confirmed by an RMSK-certified Doctor of Physical Therapy and a Radiologist. A single clinic subset was compared to the national hemophilia incidence taken from the ATHN dataset 2022. We detected HO formation in 29 patients across 9 HTCs. Trauma-induced HO was observed in all bleeding disorder types and severities. (See Table 1). The patients' ages at the time of the inciting injury ranged from 7-56 years, with a mean age of 22.3 and a median of 16.The study's highest incidence of HO cases occurred in patients with type A hemophilia totaling 22/29 subjects or 74.8% of all cases. Except for one severe A, one severe B and a moderate B, the patients were not on prophylactic hemostatic management at the time of injury. The majority of HO (n=24, 82.8%) occurred in the anterior and lateral compartments of the thigh and hip. There were 5 incidents in the upper extremity (4 in the upper anterior arm, 1 in the hand). 24 cases were due to blunt trauma except for 4 in the psoas at the level of the anterior hip and 1 in the elbow flexors of the upper arm. HO formation was mostly associated with deep muscle bleeds next to the bony cortex (n=24). HO was detected on average at 22.97 days after injury (median 21, range 11 to 60), with most detected with MSKUS (n=24) by the physical therapist (n=22) and physician (n=2) in clinic. At the Washington Center for Bleeding Disorders (WACBD), where strict MSKUS follow-up was possible in 7 patients, HO induction was confirmed at day 23, 26, 18, 11, 14, 20, and 22 for a mean of 19.14 days (SD = 5.24). Our study shows that HO occurs regularly in Hemophilia despite its omission in the recently revised 2020 World Federation of Hemophilia guidelines. Notably, the severity or type did not appear to be the sole determinant of HO formation, as the combined total of mild and moderate hemophilia genotypes was 21 (72.4%). Conversely, though limited by the study's small sample size, 74.8% of the HO incidence was reported in type A hemophilia, which appears to be an overrepresentation when compared to the ATHN dataset 2022 report, which indicates an overall 45.59% type A hemophilia incidence. The increased detection of HO in hemophilia may be explained by the growing use of MSKUS by HTC physicians and physical therapists. MSKUS has the advantages of safety and earlier HO detection than radiography. As shown in Fig. 1, HO bears the sonographic signature of hyperechoic contours and deeper acoustic shadowing. The WACBD conducted a review yielding an HO incidence of 23.68% (9 of 38 contusion events) compared to 9-17% in the non-hemophilia population. Though the single-center report is of limited significance, the suggestion of increased HO risk to hemophilia patients merits further study. This case series acknowledges HO as a complication of deep contusions in people with bleeding disorders, especially those not on hemostatic prophylaxis. Further study is needed to determine HO's incidence and risk in Hemophilia. Hemophilia treatment guidelines must be revised to include this complication.

Epidemiological study of hereditary hemorrhagic disorders in Najaf province, Iraq.

Hemophilia and Von Willbrand disease (VWD) are the most well known types of hereditary hemorrhagic disorders (HHD). Hemophilia affects about 200 000 people worldwide, while VWD affects about 80 000. Because there is a scarcity of epidemiologic studies on hemophilia in Iraq, this study was carried out to evaluate the prevalence and incidence trends, as well as to identify some clinical and epidemiological features of hemophilia patients in Najaf province, Iraq. This study was carried out in the Najaf's hemophilia center. The data were obtained by reviewing all patients' documents, as well as the center registration book from 2011 to 2021. In addition, the Ministry of Health provided relevant population data for Najaf. Notably, there are currently 214 patients registered in Najaf province. The results revealed that the severe form of hemophilia A was the permanent type of HHDs in the patients compared with the rest of the types that include HHD with no significant difference Pat least 0.05. The frequency of this group of disorders appeared to increase in the period between 2011 and 2013, especially in 2012 followed by a decline in the incidence until 2021, which recorded a sudden increase in these disorders. These findings highlight that hemophilia types A and B were the most prevalent disorders of HHD in Najaf province, and the increase in number of newly recorded cases because of consanguineous marriage increased recently in this area.

Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A

AbstractThe severity of the bleeding phenotype in patients with hemophilia A (HA) broadly correlates with the degree of coagulation factor VIII (FVIII) deficiency in plasma. However, the FVIII level necessary to achieve the goal of zero joint bleeds remains unclear. This study aimed to identify the minimum FVIII level necessary to prevent joint bleeds in patients with HA. In this retrospective study, patients with congenital mild HA treated on demand, aged ≥16 years, with no history of FVIII inhibitors, followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, were enrolled. We investigated 270 male patients with a median age of 45 years (16-88) and median lifelong FVIII of 21 IU/dL. One hundred patients (37%) had a lifelong history of at least 1 joint bleed. The mean annualized joint bleeding rate (AJBR) and spontaneous AJBR were 0.016 (standard deviation [SD], 0.032) and 0.001 (SD, 0.010), respectively. After adjusting for age, for each IU/dL increase in FVIII, there was a 6% reduction in AJBR and an 11% reduction in spontaneous AJBR. The minimum FVIII levels needed to prevent lifelong any joint bleeds and spontaneous joint bleeds resulted to be 19.2 IU/dL and 17.7 IU/dL, respectively. In this large cohort of persons with mild HA, we identified the minimum FVIII levels needed to prevent total and spontaneous joint bleeds (19.2 IU/dL and 17.7 IU/dL, respectively). These findings could suggest important implications for the accurate design of prophylactic therapies for persons with moderate and severe HA, including gene therapy.