Hemophilia Treatment Centers Research Articles

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 & Hemostasis Network (ATHN 10) in 19% (n=30). F7 gene mutation was the most commonly identified mutation and variants c.1238G>A (p.Arg413Gln), c.1172G>A (p.Arg353Gln), and c.1091G>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.

Female Hemophilia in a Set of Triplets

Female Hemophilia In A Set Of Triplets Introduction: Hemophilia A (HA) and B (HB) are the most common inherited bleeding disorders. Gene sequencing identifies specific mutations and their associations with plasma factor levels and clinical phenotypes. Both HA and HB are X-linked recessive disorders, where the female carriers pass the gene onto their descendants. Males who inherit the mutated gene from their mothers develop the disease, whereas females are carriers due to having one normal gene, they typically do not display the characteristic features of hemophilia and have moderately low factor VIII levels of less than 40%. Female carriers may have bleeding symptoms, yet they do not experience as severe morbidities as the male hemophilia patients, due to having higher plasma factor VIII levels. Rarely female carriers can be severely affected and may have plasma factor VIII activities comparable to those with severe hemophilia. Here we are presenting a set of triplets, where the male infant and one of his sisters have severe hemophilia while the other sister is a hemophilia carrier. Methods: A set of triplets a male and two female neonates were born after 33 weeks of gestation to a healthy mother. Female neonates were dichorionic but shared the same placenta. The male infant had a circumcision at six weeks of age, which was complicated with prolonged bleeding. He was brought to the hospital and was diagnosed with severe HA. (Table.1). Infant #2 was admitted to the hospital for skin rash at age 8 weeks. She had staphylococcal scalded skin syndrome and was treated with vancomycin and cephalexin. She was noted to have prolonged bleeding from needle puncture sites. She was diagnosed with severe HA. The bleeding was controlled with tight packing. After a week of treatment her rash cleared, and she was discharged home. (Table 1). Infant #3 She was a healthy baby with no bleeding problems. (Table 1). Results and conclusions: We presented three infant-triplets-with factor VIII deficiency; infant #1 and infant #2 have severe HA. Infant #3 is an asymptomatic carrier. They all have the same mutation as their asymptomatic carrier mother. Infant #1 the male infant developed severe HA due to having the hemophilia allele on his “X” chromosome. Infant #3 a female infant is an asymptomatic carrier. She inherited the hemophilia allele on the X chromosome from her carrier mother and has an X chromosome bearing the normal allele, thus is able to produce factor VIII of 40%. Infant #2 the other female infant had severe HA, with a factor VIII activity of <0.3%. Female hemophilia is rare occurrence. Hemophilia treatment center (HTT) population profile (PP) reported that of the 1,676 females attending to HTC, 47.6% of them had less than 40% factor level, 0.48% of them had severe, 1.4% had moderate and 17.9% had mild hemophilia[Haemophilia. 2021:27(6):1037-1044. Doi:10.1111}. This can occur, in the setting of monosomy X (Turner syndrome-XO), due to having one X chromosome carrying the hemophilic gene or in the setting of compound heterozygosity: the female product of a father with hemophilia and the mother being a carrier. Similarly, hemizygosity of the hemophilic gene on both parents would result in hemophilia in their daughters. Another mechanism that plays a role in the pathogenesis of female hemophilia is the “X chromosome inactivation (XCI). This has been described as the most common cause of female hemophilia. One of the two X chromosomes in females is randomly and permanently inactivated in cells to ensure the balance with one X chromosome of males and limit the overproduction of potentially toxic gene proteins. The degree of inactivation determines the plasma levels of the gene products, in hemophilia the factor levels. The chromosome analysis of infant #2 revealed normal 46XX. Structural chromosomal abnormality is ruled out as she did not have Turner syndrome “XO”, or “45XY” with androgen insensitivity syndrome, nor did she have compound heterozygosity or hemizygosity of the X chromosome. The father had normal coagulation studies and factor VIII activity. Therefore, we believe infant #2 had extremely skewed XCI and the inactivation is skewed in favor of hemophilic X chromosome. This mechanism resulted in severe HA in this infant. The infants are now seven months old and have no bleeding problems, as infant #1 and #2 are on prophylaxis with emicizumab (Hemlibra), they both have 1% factor activity by chromogenic assay and do not have inhibitors. (Table 1)

Appropriateness of Immunosuppression and Blood Product Utilization in Acquired Hemophilia A: A Multicentre Provincial Practice Audit

Introduction: Acquired hemophilia A (AHA) is a life-threatening bleeding disorder associated with significant morbidity and mortality. Despite publication of international consensus guidelines, quality of care and guideline adherence have not been examined. While some jurisdictions have reference centres for AHA management, in Canadian provinces outside of Quebec, AHA is managed in both hemophilia treatment centres (HTCs) and community hospitals. We performed a multicentre practice audit in a Canadian province to assess use of immunosuppressive therapy (IST), blood product utilization, and evaluate treatment burden and outcomes. Methods: We included adults diagnosed with AHA (January 2000-December 2021) in Alberta, Canada, and examined the following quality of care indicators: delayed IST initiation from diagnosis, corticosteroid use alone in high-risk AHA (FVIII <0.01 IU/ml or FVIII inhibitor >20 BU/ml), cyclophosphamide use in low-risk patients (FVIII ≥0.01 IU/ml and inhibitor ≤20 BU/ml), prolonged cyclophosphamide use (>6 weeks), and inappropriate use of plasma, intravenous immunoglobulin (IVIG) and hemostatic products. Outcome measures included response, length of stay (LOS) and 30-day readmission. We evaluated treatment burden including frailty syndromes, increased level of care and hospitalization for treatment-related adverse events. Results: Of the 38 patients diagnosed with AHA, 25 (66%) were female, the median age was 74 years (IQR 61-81), and median Charlson comorbidity index was 5 (IQR 3-7). Cardiovascular comorbidities were common, including venous thromboembolism (5; 13%), atrial fibrillation (5; 13%), and myocardial infarction (4; 11%). Fifteen (39%) had ≥1 frailty syndromes, including functional dependence (6; 16%), dementia (6; 16%), falls/fractures (5; 13%), and depression/anxiety (3; 8%). Five (13%) patients required higher levels of care (long term care placement) following discharge. Twenty-one (55%) patients had high-risk disease and 17 (45%) had low-risk. In those with low-risk disease, 11 (29%) had inhibitor titres 5-20 BU/ml and 6 (16%) had inhibitors <5 BU/ml. Despite diagnostic delays ≥7 days from bleeding in 15 (39%), most received prompt initiation of IST (median 0 days [IQR 0-3] from diagnosis). First-line IST included: prednisone (38; 100%), cyclophosphamide (23; 61%), and rituximab (13; 34%). IVIG was prescribed in 5 (13%), out of keeping with guideline recommendations. We observed very high rates of first-line cyclophosphamide use in low risk AHA (11/17; 65%), including 4/6 with inhibitor titres <5 BU/ml (Table 1). First-line cyclophosphamide was also used in 3 reproductive-aged women. Prolonged courses of cyclophosphamide >6 weeks and >6 months were used in 21/23 (91%) and 7/23 (30%) patients, respectively. Two high-risk patients did not receive cyclophosphamide or rituximab-containing therapy. Of the 58 episodes of bleeding events, 41 (71%) were ISTH major bleeds. Fifteen (26%) bleeding events did not receive hemostatic therapy, whereas 27 (47%), 19 (33%), and 3 (5%) were treated with recombinant factor VIIa, activated prothrombin complex concentrates, and porcine FVIII, respectively. Dosing of bypassing agents was in keeping with guidelines. DDAVP and human FVIII were inappropriately used in 3/58 (5%) and 1 (2%) bleeding episodes, respectively. Most patients (24; 63%) received red cell transfusions with a median of 2 (IQR 0-7) units each. Five (13%) patients received a total of 18 units of plasma. Clinical responses included: complete remission (CR) in 30 (79%), partial remission in 3 (8%), and unevaluable due to early deaths in 5 (13%). All 5 patients who relapsed (13%) achieved second CR. The median LOS was 38 days (IQR 19-57) across 95 hospitalizations. The 30-day readmission rate was 24%. Reasons for admission included bleeding (50/95; 53%), infections (14/95; 15%), and other treatment side-effects (13/95; 14%). Conclusion: In this provincial cohort of AHA patients with high comorbidity and frailty, we identified gaps in quality of care including overuse of cyclophosphamide in patients with low-titre inhibitors, prolonged duration of cyclophosphamide, and inappropriate use of IVIG and plasma. Aggressive cytotoxic therapy predisposes patients to unnecessary risks of infections and malignancies. Our findings highlight the need for centralization of care in specialized centres and education initiatives.

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.

Impact of COVID-19 Epidemics on Paediatric and Adult Patients with Haemophilia Treated in a Haemophilia Therapeutic Centre

Abstract Introduction: The pandemic of coronavirus disease 2019 (COVID-19) has posed an unprecedented health crisis for all humans, including people with haemophilia. Aim: To investigate the impacts of COVID-19 pandemic on the infection, symptoms, drug use, and social intercourses of patients with haemophilia. Methods: 265 adults or children with haemophilia followed up in the Haemophilia Diagnosis and Treatment Center of Fujian Medical University Union Hospital during the COVID-19 pandemic were collected and analyzed between January 2022 and January 2023. Results: A total of 265 patients participated in this survey, 30.2% were children and 69.8% were adults. During the COVID-19 pandemic, coagulation factors were not associated with the type and severity of haemophilia, residence, or infection. Compared with adult patients, more children reduced social intercourses and outdoor activities due to the fear of COVID-19 (85.0% vs 66.5%; p = 0.002). The bleeding events were also significantly lower in children than in adult patients (61.2% vs 81.1%; p = 0.001). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in rural areas (74.3% vs 53.6%; p < 0.001). The lasting time of symptoms after infection was not significantly associated with hemorrhage, type and classification of haemophilia, presence of inhibitors, complications, and vaccination. Conclusions: The accompaniment of COVID-19 did not significantly influence the symptoms and treatments in patients with haemophilia. Compared with adults, the number of pediatric patients with bleeding events was significantly lower . Keyword: COVID-19, haemophilia, hemorrhage, infection, symptoms

Proactive Systematic Hemophilia Carrier Screening: A Step Towards Gender Equity in Hemophilia Care

Introduction Despite multiple awareness-raising initiatives, and in contrast with male persons with hemophilia (PwH), a considerable number of carriers and female PwH still go undiagnosed. We here present the findings of a proactive and extensive hemophilia carrier screening project. Methods From May 2021 until April 2023, potential and obligate carriers of hemophilia A (HA) and B (HB) were identified by updating family trees of all PwH regularly followed at the Cliniques universitaires Saint-Luc. Data from previously screened female individuals (bleeding history, coagulation factor assays and testing for the index patient's pathological genetic variant) were collected retrospectively through electronic medical records (EMRs). Female individuals who had not been previously screened or with missing data were provided with a total of 125 invitation letters by related index hemophilia patients. The study protocol received approval of the local ethics committee. Results All 287 male PwH (226 HA, 61 HB) from 228 families (180 HA, 48 HB) were included in the analysis. Seven female PwH (3 HA, 4 HB) were considered as index cases in their families. In total, based on the family trees, there were 900 females, among which 454 were obligate and/or genetically proven carriers of hemophilia and 118 were found to be non-carriers (Figure 1). Mean age at diagnosis was 30.7 years (range 1-82) in families with HA and 30.1 years (range 0.5-93) in families with HB, without significant difference between these two groups (p=0.809) or between families with severe, moderate or mild hemophilia (p=0.535). Genetic testing for pathological variants has been conducted in 133 obligate, 237 potential and 4 sporadic carriers, and remains to be performed in 190 obligate and 328 potential carriers. Eight females were obligate non-carriers. The group of mothers, sisters and daughters of PwH comprised 543 females, of which at least 178 (35.7% of those with known date of birth) were of reproductive age (18-49 years). Seventy-three percent of females in the latter group have had genetic testing. The proportion of female individuals genetically tested did not significantly differ between families of different severities of HA (p=0.132). In families with moderate HB, female individuals were more likely to be tested (genetic status known in 59.4%) than in other HB severity groups (p=0.01), yet this may be attributed to the presence of one large family comprising 6 male persons with moderate HB and 22 female individuals, of whom a large proportion (n=18, 82%) has had genetic testing. Among carriers with known coagulation factor levels (261/454), 42 (23.0%) and 23 (29.5%) carriers of HA and HB, respectively, had a factor level below 40 IU/dL, and 65 (35.5 %) and 32 (41.0%) had a factor level below 50 IU/dL. The proportion of carriers with a factor level below 40 IU/dL did not significantly differ between families with severe, moderate and mild hemophilia (22.6%, 34.7% and 22.7% respectively, p=0.213), neither did mean coagulation factor levels in carriers with a factor deficiency in these groups (26.2, 30.4 and 27.1 IU/dL in families with severe, moderate and mild HA and HB, p=0.344). Carriers with a coagulation factor deficiency of less than 40 IU/dL were screened earlier than other female individuals (mean age at diagnosis 25.8 and 31.8 years, respectively, p=0.034). Conclusions This study represents the first reported attempt to systematically identify all (potential) hemophilia carriers within families of all PwH followed at a single hemophilia treatment center. To date, this initiative has allowed 44% of the entire cohort to be screened, and carrier status to be genetically confirmed in 73% of mothers, sisters and daughters of PwH who are of childbearing age, based on the date of birth documented in their EMR. Although original and promising, these data reflect the major challenges and difficulties in reaching out and providing appropriate screening to all women genetically linked to one or more PwH. The carrier screening efforts that have been initiated in our center, and which should ideally be replicated across the hemophilia community globally, appear as a critical step towards providing equal access to haemophilia diagnosis and care to all potentially affected individuals, regardless of their gender.

Developing an Algorithm to Better Identify Pregnant Women with Inherited Bleeding Disorders within Electronic Health Records

Background: When using electronic health records (EHRs) to conduct population-based studies on inherited bleeding disorders (IBDs), multiple studies demonstrated that using diagnoses codes alone result in a high number of false positive identifications (J Blood Med. 2017 Aug 30;8:131-139). To improve data integrity, in-depth chart reviews are often required which typically can only be done from a local institutional level. This limits the potential to use national research infrastructure such as the National Patient-Centered Clinical Research Network (PCORnet) which draws its data from millions of EHRs across healthcare institutions in the United States. Objective: The objective of this study was to test the diagnostic accuracy of an algorithm that utilized common data definitions and multiple data elements in EHR to identify pregnant women with IBDs. Methods: We used data for pregnant women with IBDs who delivered at our institution from January 1, 2016 to December 31, 2020 to test the accuracy of the algorithm. Women with IBD included those with the following diagnoses: hemophilia and hemophilia carriers, von Willebrand disease and rarer bleeding disorders including factor II, V, VII, X, XI and XIII deficiencies. We did not include the following diagnoses: Platelet function disorder, fibrinogen disorder or hereditary hemorrhagic telangiectasia. We used EHR data elements from EPIC Clarity data model that conformed to those from the PCORnet Common Data Model (CDM). The PCORnet CDM can help ensure consistent data definitions and formats across multiple sites to facilitate large-scale patient-centered research. The original version of our algorithm included the following: (i) ICD-9/10 codes for an inherited bleeding disorder (Table 1) based on discharge diagnosis of any patient encounter visit types including inpatient, outpatient and emergency visits (criterion 1); (ii) Medications used for management of IBD (criterion 2); and (iii) Coagulation factor test and results (criterion 3). A validated diagnosis of IBD required fulfilling either criteria (1) and (2) or criteria (1) and (3). To develop our algorithm in an iterative fashion, we ran sequential queries (queries 1.0-1.1) with revisions to our initial criteria. The results of our retrospective queries were confirmed to have an IBD (true positive) using our local registry and by manual chart review. The local registry is a clinical database that is housed with EPIC and includes accurate demographic, phenotypic, and laboratory data of all persons with a confirmed diagnosis of IBD seen at our federally-funded adult hemophilia treatment center. Sensitivity and the positive predictive value of the algorithm to identify pregnant women with IBDs were calculated. Results: Using our original algorithm (query 1.0), there were 301 pregnant women who fulfilled criterion 1 and had at least one live birth or fetal death (>20 weeks gestation) at our institution during the study period. Of these, only 25 fulfilled criteria 2 and/or criteria 3. For the 276 cases that did not fulfill criteria 2 or 3, we verified the diagnosis through our local registry or through a manual review of the charts. We found that the following ICD-diagnosis codes for IBD - Z14.8; 286.9/D68.8/D68.9; 286.3/D68.2 - resulted in contamination and could not be used to diagnose carriers of IBD or the rarer bleeding disorders. These diagnoses codes were removed and we added a fourth criteria in our revised algorithm (Table 2). For cases that did not fulfill criteria 2 or 3, a case was considered as having a diagnosis of IBD if they had at least two identical ICD diagnosis code for an IBD in at least 2 separate patient encounter visit types (criterion 4). The revised algorithm (query 1.1) identified 35 pregnant women with IBD, of which 32 were confirmed to be true positive. The 3 women incorrectly identified (false positive) by our revised algorithm had seen a hematologist for work-up for a possible IBD which was eventually ruled out. From the original cohort of 301 pregnant women who had an ICD diagnosis code of an IBD, one patient who was a carrier for hemophilia A was missed (false negative) by our revised algorithm. The sensitivity of the revised algorithm was 97.0% and the PPV was 91.4% Conclusion: This study demonstrates the feasibility of an algorithm to accurately identify pregnant women with specific types of IBD within an EHR.

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.

Factor XI Deficiency in Chinese Patients: Results from a Nationwide Multicenter Retrospective Study

Background: Factor XI(FXI) deficiency is a rare and relatively mild bleeding disorder. To date, data for China is limited. Our study aimed to investigate the clinical phenotype, F11 genotype and management of individuals diagnosed with FXI deficiency from throughout China. Methods: The study retrospectively analyzed patients with FXI activity (FXI:C) <50% registered from the National Hemophilia Registration System. The study collected patient characteristics, F11 gene mutations, clinical history, bleeding events, and treatment strategy by telephone follow-up. RESULTS: The study included 234 patients throughout 27 provincial districts registered in 38 Chinese hemophilia treatment centers. Among these patients, 192 (82.1%) had severe FXI deficiency (FXI:C <15%), and 42 (17.9%) had non-severe FXI deficiency (15%≤FXI:C<50%). The median age was 30 (1-87) years at diagnosis. There were 19 patients (8.1%) who reported a family history of bleeding. Five patients (2.1%) reported having consanguineous marriages in their families. There were 57 patients (24.4%) had their F11 gene tested. We detected 44 kinds of variants on 99 alleles, including nine that have never been reported to the F11 database. The most frequent variants were missense (44, 44.4%) and nonsense mutations (35, 35.4%). Among the genotyped subjects, F11 mutations were homozygous in 12 (21.0%), compound heterozygous in 29 (50.9%), and heterozygous in 16 (28.1%) patients. The FXI:C among patients with homozygous/compound heterozygous mutations was significantly lower than among patients with heterozygous mutations (2.1±2.3% vs. 14.8±12.9%, P<0.001). In total, 91 (38.9%) reported bleeding symptoms to varying degrees. Among these patients, 79 (33.8%) experienced spontaneous bleeding, with menorrhagia, epistaxis, and dermatorrhagia being the most prevalent manifestations. Twenty-one (26.6%) patients were administered on-demand replacement therapy. There were 129 patients underwent 220 invasive procedures with a total of 22 bleeding episode. The risk of bleeding was found to be significantly higher when sites with high fibrinolysis were involved, as compared to sites without fibrinolysis (Chi2=3.976, P=0.046). The prophylactic replacement treatment was administered to 50 cases (22.8%), and three bleeding events occurred, compared to 19 bleeding events in the 170 cases without prophylaxis. It was observed that prophylaxis did not reduce bleeding events (Chi2=1.150, P=0.283). A total of 83 deliveries were recorded in 58 female patients, and four bleeding events occurred. The blood group-O is a risk factor for bleeding [odds ratio (OR)=2.429, 95% confidence interval (CI) 1.139-5.182]. Conclusion: Most patients had no or mild bleeding symptoms. Most F11 variants were missense. The FXI:C among patients with homozygous/compound heterozygous mutations was significantly lower than among patients with heterozygous mutations. The risk of bleeding was higher when procedure sites with high fibrinolysis were involved. Prophylactic repalcement treatment could not reduce the risk of hemorrhages after invasive procedure. There is increased risk of bleeding in patients with blood group-O. Table 1 Table 2

Levels of Anti-FVIII IgG4 and Total IgG Are Biomarkers of Immune Tolerance Induction Failure in Patients with Inherited Hemophilia a and High-Responding Inhibitors

Background: The development of inhibitors in patients with inherited hemophilia A (PwHA) is an important complication of the treatment with exogenous factor VIII (FVIII), leading to inefficient replacement therapy. Immune tolerance induction (ITI) is the standard treatment to eradicate inhibitors in HA. The immune biology and biomarkers related with ITI outcome are still unclear. Few studies have investigated this, of which most included few PwHA. Furthermore, such studies have not assessed samples in specific time-points, but have rather grouped patients into categories of inhibitors and non-inhibitors. Aims: This study aimed to investigate specific anti-FVIII immunoglobulins IgG1, IgG4 and total IgG as biomarkers of ITI outcome at the completion of ITI. Methods: We included PwHA from 15 hemophilia treatment centers, participants of the Brazilian Immune Tolerance (BrazIT) Cohort Study. Inclusion criteria were severe and moderately-severe (<2% FVIII) PwHA, with high-responding (>5.0BU/mL) inhibitors, who completed a first course of ITI. All patients were treated with the same ITI protocol, i.e., 50 international units (IU)/kilogram (kg) of FVIII. In case ITI titers did not decrease by at least 20% first 3-6 months after inhibitor peak, FVIII was increased to 100 IU/kg daily. We collected socio-demographic, clinical and laboratory data using standardized forms. Outcome of ITI was defined according to published classification as failure, partial and total successes. For this analysis, plasma samples were collected in citrate at completion of ITI and frozen at -80°C until assessment. We measured plasma levels of anti-FVIII IgG1, IgG4 and total IgG in ELISA using immobilized recombinant (r) FVIII (alfaoctocogue, Takeda, USA). Local ethics committees approved this study and all patients/guardians signed informed consent. Results: We included 98 PwHA, median age of 11.0 years (interquartile range [IQR] 7.0-23.0), 94 (95.9%) severe HA (<1%). According to ITI outcome, 40 (40.8%) had ITI failure, 37 (37.8%) had partial success and 21 (21.4%) had total success (Table 1). Levels of total IgG in patients who failed ITI (median optical density [OD], 0.37; IQR 0.15-0.73) were significantly higher when compared to the levels of patients with partial (median OD, 0.03; IQR 0.00-0.14; p<0.0001) and complete (median OD, 0.04; IQR 0.00-0.07; p<0.0001) success. Levels of total IgG anti-FVIII were not different between partial and complete success groups. Levels of anti-FVIII IgG4 were significantly higher in PwHA who failed ITI (median OD, 2.19; IQR 0.74-2.52) compared with those who had partial (median OD, 0.39; IQR 0.09-1.11; p<0.0001) and complete success (median OD, 0.07; IQR 0.06-0.40; p<0.0001). Anti-FVIII IgG4 levels were higher in PwHA presenting partial success compared with those with complete success (p=0.02). Levels of anti-FVIII IgG1 were not different between PwHA who failed ITI (median OD, 0.03; IQR 0.01-0.21), in comparison with the ones who achieved partial success (median OD, 0.03; IQR 0.01-0.08; p=0.35) and achieved complete success (median OD, 0.03; IQR 0.02-0.05; p=0.72) (Table 2). Conclusion: We conclude that anti-FVIII IgG4 and IgG total are good biomarkers of ITI outcome. Levels of IgG4 are associated with ITI outcome in a dose-dependent manner, with failure>partial>complete success. Anti-FVIII IgG1 is not a useful biomarker of ITI outcome. This study was fully supported by Brazilian Governmental grants from Fapemig, CNPq and Ministry of Health of Brazil (Fundo Nacional de Saúde).

Risk Factors for Joint Bleeding in Severe Hemophilia a and B: Analysis of the Community Counts Longitudinal Surveillance Cohort

Background: One of the most devastating complications of Hemophilia A or B (HemA, HemB) is end-stage joint damage characterized by chronic pain and functional disability. Joint bleeding is the best predictor of joint damage in hemophilia. A wide range of new therapeutics from extended half-life factor (EHL) concentrates to non-factor therapies such as factor VIII mimetics, hemostatic rebalancers and gene therapy have been recently approved or are in late-stage clinical trials that hold the promise of decreased joint disease in severe hemophilia. Specific Aim: Given the progressive improvements in the therapeutic armamentarium of hemophilia care, this study aimed to determine current predictors of joint bleeding in individuals with severe hemophilia on continuous prophylaxis in the context of a national surveillance project. Methods: Eligible participants were males with severe HemA or HemB, aged 2 to 44 years, on continuous prophylaxis therapy and participating in Community Counts (CC) during the period December 2013 to November 30, 2022. CC is a bleeding disorders surveillance project funded by the Centers for Disease Control and Prevention and administered through the American Thrombosis and Hemostasis Network in 141 federally funded Hemophilia Treatment Centers across the United States. CC collects data on sociodemographics, bleeding episodes, treatment products, and health outcomes during patients' annual comprehensive care visits. Data were analyzed using annualized joint bleeding rates (AJBR), calculated using the number and location of all joint bleeds occurring in 10 joints (shoulders, elbows, hips, knees, ankles) during the year since the last surveillance visit based on infusion logs and/or other patient records. Age and other demographic subgroups were compared via rate ratios (RR) and 95% confidence intervals (CI). Methods accounting for multiple measurements from the same individuals over time were used for multivariate analyses. AJBR differences according to demographic and clinical variables were assessed via p values comparing Beta coefficients from these models. Results: The HemA cohort included 2505 persons, 8542 observations years and 13,224 joint bleeds for an overall AJBR of 1.55. The HemB cohort included 439 persons, 1488 observation years and 1326 joint bleeds for an overall AJBR of 0.89. Joint bleeding increased with age. In comparison to those ages 2-9 years, RRs were significantly increased for ages 10-19 and 20-44 for both HemA (1.23 [CI 1.1-1.3]) and 3.17 [CI 3-3.4], respectively), and HemB (2.2 [1.8-2.7] and 5.8 [4.8-7], respectively). Uninsured persons had higher AJBR than insured (HemA, RR 1.8 [1.6-2.1] and HemB, RR 6.9 [5.2-9.]. Table 1 compares characteristics associated with AJBR in multivariate analysis. The use of the FVIII mimetic in persons with HemA was associated with fewer joint bleeds (-1.00 joint bleeds per year). Persons with HemA showed modest decreases in AJBR with EHL therapies (-0.26), a finding not observed in persons with HemB. Worse AJBR outcomes were associated with missed doses for persons with both HemA and HemB. Joint bleeding was significantly associated with unemployment with disability for persons with HemA but not HemB. Trends in AJBR were similar between HemA and HemB for the following: adults had more joint bleeding than children, including adolescents aged 10-19 who are often engaged in team sports; compared with the Northeast, AJBR were higher in all other geographic regions; persons on Government insurance had higher AJBR than persons on Commercial insurance. Discussion: In a multivariate analysis of data on a large longitudinal cohort of persons with severe hemophilia on prophylaxis, use of the FVIII mimetic, ≥90% treatment adherence and treatment in the Northeast United States were associated with significantly lower AJBR. The increased joint bleeding rate in adults compared with children and adolescents may be related to pre-existing joint disease, less intense prophylactic regimens or decreased activity and fitness. Additional studies can further inform optimal hemophilia therapy regimens.

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.

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.

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.

Incidence of Postoperative Venous Thromboembolism, Hemorrhage, and Infection in Patients with Bleeding Disorders after Hip and Knee Arthroplasty

Introduction: Patients undergoing hip or knee arthroplasty (HA or KA) developed asymptomatic postoperative (post-op) venous thromboembolism (VTE) in around 30% of cases without any pharmacologic thromboprophylaxis (ThPPx). The use of pharmacological ThPPx after HA or KA has reduced the incidence of post-op VTE within 90 days to around 0.6-1.5%. People with bleeding disorders tend to have chronic joint damage from recurrent hemarthroses and frequently require HA or KA. This was especially true in the era before chronic factor prophylaxis. The exact risk estimate of post-op VTE in this population is unclear. Furthermore, the exact risk benefit for pharmacologic ThPPx is also unknown. Methods: A retrospective cohort study was conducted by looking at patients who underwent HA or KA and stratifying them based upon whether they had bleeding disorder diagnosis. Data was collected from the Health Facts database, which contains de-identified information from the electronic medical records of all US hospitals in which Cerner© has a data use agreement. Patients with bleeding disorders included Hemophilia A, B, C and Von Willebrand disease. Incidence rates of post-op VTE, hemorrhage (Hge) and infection (Inf) were calculated and compared between patients with bleeding disorders and those without bleeding disorders regardless of pharmacologic ThPPx. The same outcomes were obtained and compared between patients with/without bleeding disorders who received ThPPx. Chi-square and Fischer exact test were used to determine statistical significance. Results: 333,584 patients underwent HA or KA. Out of these, 438 patients had bleeding disorder. The incidence rates of post-op VTE were 0.01% in patients with bleeding disorders vs 0.02% in those without (p=0.1850) regardless of ThPPx which was not statistically significant. The incidence rate of post-op Hge was higher in patients with bleeding disorders (0.01%) compared to patients without bleeding disorder (0.004%; p=0.0404). The difference in incidence rate of Inf was not statistically significant between the two groups (p=0.1768). Out of total patients, 202,936 patients who underwent KA or HA received ThPPx. The difference in incidence rates of VTE as well as Inf were not statistically significant between patients with and without bleeding disorders who received ThPPx (p=0.2357 for VTE and p=0.2519 for Inf). The incidence rate of post-op Hge in patients who received ThPPX and had bleeding disorder was 0.014% in contrast to 0.004% in patients without bleeding disorder, though, it did not reach statistical significance (p=0.0684). Conclusion: Patients with bleeding disorders have a similar risk of post-op VTE as the general population after HA or KA. Patients with bleeding disorders have higher post-op hemorrhagic complications. However, when comparing only those patients who received ThPPx, the difference in incidence of post-op Hge was not statistically significant. This implies that all patients including the ones with bleeding disorders, undergoing HA or KA may be treated with a similar ThPPx approach. Patients with bleeding disorders undergoing HA or KA do not have a higher predisposition to infections compared to the general population and may not require additional infection control measures. We did not look at the differences in factor treatment perioperatively which would have been standard for all bleeding disorder patients if they followed in a hemophilia treatment center. Our study limitation was its retrospective nature as well as all HA, KA, post-op VTE, Hge and Inf were identified by CPT and ICD codes.

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.

Trends in Invasive Orthopedic Interventions in Patients with Hemophilia Enrolled in the Community Counts Program (2015-2021)

Background Recurrent joint bleeding due to hemophilia often leads to the development of chronic joint disease resulting in chronic pain, decreased joint function and a significant decline in quality of life. Invasive orthopedic interventions (IOI) such as arthroplasty and arthrodesis for end stage joint disease have historically been pursued to decrease pain and improve joint function especially in patients with severe hemophilia and joint disease. Using data collected on patients receiving care in a large network of hemophilia treatment centers in the United States (USHTCN), Tobase et al have previously reported a 5.6% decline in all IOI in patients with hemophilia during the period 2000-2010 (1). Aims The primary objective of the current analysis was to extend those findings using similar data collected during the period 2015-2021 with a focus on IOI indicative of end stage joint disease such as arthrodesis and arthroplasty. Data on IOI were collected annually during the period 2015-2021 from patients who participated in the Community Counts (CC) surveillance project at the 147 member USHTCN using standardized data collection tools. The proportion of patients having IOI in each year was calculated by dividing the total number of patients who reported an IOI by the total number of patients who had a CC visit in that year. Trends in proportions were plotted over time and assessed for statistical significance using the Cochran-Armitage trend test. Results In total, 8,378 CC patients with a diagnosis of hemophilia A or B, over the age of 2 years who completed a subsequent CC visit within last 12 months of last surveillance visit during the years 2015-2021 were included in this study. Enrollees reported a total of 28 arthrodesis and 168 arthroplasty procedures during a total of 21,082 clinic visits over the entire study period. We found that arthroplasty represented 42.6 %, 68.8%, 17.9%, 26.3%, and 7.4% of all procedures reported in the knee, hip, ankle, shoulder, and elbow, respectively (Figure 1). The rate of IOI during the study timeframe remained very low, with only 2.4% of all participants reporting an IOI. During 2015-2021 there was a statistically significant decline in IOI among all patients >=60 years of age (0.59% in 2015 vs. 0.27% in 2021) (p=0.0325) (Figure 2). Similarly, patients with severe hemophilia regardless of age experienced a significant decline in invasive procedures during the study period (1.69% in 2015 vs. 0.88% in 2021) (p=0.021). Conclusions The rates of IOI reported during the years 2015-2021 remained very low (~2.4%). This suggests less joint morbidity and a continued decline in the rates of end stage joint disease during the study period, likely due, at least in part, to improved therapy and early adoption of preventative factor replacement protocols.

Native American Ancestry Is Associated with Successful Immune Tolerance Induction in Admixed Brazilians with Hemophilia a

Immune tolerance induction (ITI) is the treatment of choice for eradicating neutralizing antibodies (inhibitors) against factor VIII (FVIII) in patients with hemophilia A (PwHA). Previous studies have investigated the association of ethnicity with inhibitor development with conflicting results. However, to our concern, studies targeting the role of ethnicity on ITI outcomes are still missing. Since unfavorable ITI response occurs in 30%-40% of these patients, establishing predictors of ITI response is needed. To evaluate genetic determinants of ITI outcome beyond FVIII genotype, we investigated the association of genomic ancestry and ITI response by analyzing the exomes of PwHA from the Brazilian Immune Tolerance Study (Camelo et al. 2021). PwHA were enrolled in 15 hemophilia treatment centers from all Brazilian regions. We collected clinical data and blood samples for DNA extraction. ITI was carried out using a single protocol, regardless of selection based on “good” or “bad” risk of ITI outcome. Inclusion criteria comprised patients with severe and moderately-severe (FVIII<2%) HA with high-responding inhibitors who completed a first course of ITI. Since the characteristics of PwHA who responded with partial and complete success yielded similar results, these groups were analyzed together. Exomes were obtained with high quality using the xGen Exome Research Panel v2 (Illumina). Quality control filters evaluated average coverage and deep coverage, phred score, genomic position, sex, heterozygosity, and duplicated SNPs. In a multiple regression analysis, we used geographic location, inhibitor levels, presence or absence of null mutations (i.e., frameshift, deletions, nonsense, and inversions; Oldenburg et al., 2002), and kinship coefficients as explanatory variables. Inhibitor levels were evaluated as historical inhibitor peak, titer immediately before the start of ITI, and inhibitor peak during ITI. We included 150 PwHA, of whom 136 (91%) had severe (FVIII<1%) HA, median age 0.9 years [IQR, 0.5,1.4] at diagnosis of HA. A total of 44 (29%) PwHA had ITI failure, 60 (40%) had partial success, and 46 (31%) had complete ITI success. Functional annotation showed that most SNPs were intronic (48%) and exonic (29%). We identified 808,706 variants, of which 90,075 were not reported in the dbSNP. Average ancestries of European, African, and Native American were 79.4% [IQR:75.4,83.4], 17.3% [IQR:17.0,17.6), and 3.3% [IQR:2.6,4.0], respectively (Table 1). There was an association between a higher Native American ancestry in patients with successful ITI (2% [IQR:1.95,2.05] ancestry mean) when compared with patients who failed ITI (1% [IQR:0.97,1.03] ancestry mean). A 1% increase in the Native American ancestry proportion was associated with a rise of ~10% in the probability of successful ITI ( odds ratio [OR], 10.43 [95% CI,7.45,13.41], p = 0.040 (Table 2). Neither European nor African ancestry was associated with ITI outcome. In conclusion, Native American ancestry was associated with successful ITI. To our concern, this is the first study to evaluate genomic ancestry as a predictor of ITI response and the first to enroll an admixed population of HA. Identifying ancestry as a predictor of ITI outcome may elicit different therapeutic approaches for inhibitor eradication. However, our findings may not apply to other populations due to a particular characteristic of admixture of the Brazilian population. REFERENCES Camelo, R.M. et al. (2021) ‘Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BRAZIT) study protocol’, PLOS ONE, 16(8). doi:10.1371/journal.pone.0256265. Oldenburg, J., El-Maarri, O. and Schwaab, R. (2002) ‘Inhibitor development in correlation to factor VIII genotypes’, Haemophilia, 8(s2), pp. 23-29. doi:10.1046/j.1351-8216.2001.00134.x.

The World Federation of Hemophilia World Bleeding Disorders Registry: insights from the first 10,000 patients

BackgroundThe prevalence of hemophilia varies globally, with close to 100% of patients diagnosed in high-income countries and as low as 12% diagnosed in lower-income countries. These inequalities in the care of people with hemophilia exist across various care indicators. ObjectivesThis analysis aims to describe the clinical care outcomes of patients in the World Bleeding Disorders Registry (WBDR). MethodsIn 2018, the World Federation of Hemophilia developed a global registry, the WBDR, to permit hemophilia treatment centers to collect clinical data, monitor patient care longitudinally, and identify gaps in management and treatment. ResultsAs of July 18, 2022, 10,276 people with hemophilia were enrolled from 87 hemophilia treatment centers in 40 countries. Nearly half (49%, n = 5084) of patients had severe hemophilia; 99% were male, 85% had hemophilia A, and 67% were from low-middle-income countries. Globally, the age of diagnosis for people with severe hemophilia has improved considerably over the last 50 years, from 82 months (∼7 years) for those born before 1980 to 11 months for those born after 2010, and most prominently, among people with severe hemophilia in low- and low-middle-income countries, the age of diagnosis improved from 418 months (∼35 years) for those born before 1970 to 12 months for those born after 2010. Overall, the age of diagnosis of people with hemophilia in low- and low-middle-income countries is delayed by 3 decades compared to patients in upper-middle-income countries and by 4 decades compared to patients in high-income countries. ConclusionData reveal large treatment and care disparities between socioeconomic groups, showing improvements when prophylaxis is initiated to prevent bleeding. Overall, care provided in low-income countries lags behind high-income countries by up to 40 years. Limitations in the interpretation of data include risk of survival and selection bias.

Posttraumatic stress disorder and posttraumatic stress symptoms among adults with hemophilia A and B

BackgroundPersons with hemophilia may encounter various traumatic experiences related to their bleeding disorder throughout their lifetime. Little is known about the clinical impact of disease-related trauma on this population. ObjectivesTo explore the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms in adults with hemophilia A and B and characterize the traumatic experiences they report. MethodsAn online survey tool collecting data on participant characteristics and a validated questionnaire containing the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders 5 were distributed via Research Electronic Data Capture to adults with hemophilia A and B during their annual visit to their hemophilia treatment center. Participants were asked about traumatic experiences specific to their hemophilia prior to self-administering the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders 5 questionnaire. ResultsSurvey responses from 178 individuals across 3 hemophilia treatment centers were included in the analysis, representing a 70% response rate. One hundred one (56.7%) participants identified a hemophilia-related traumatic event, and 21 (11.8%) participants met criteria for a provisional diagnosis of PTSD. Multivariable analysis showed higher odds of a positive PTSD screen in participants with noninfectious (odds ratio [OR], 13.89; 95% CI, 2.23-86.62) and infectious comorbidities (OR, 11.18; 95% CI, 1.34-93.45) and in participants with >1 mental health comorbidity (OR, 10.07; 95% CI, 2.39-42.52). On the contrary, age >46 years (OR, 0.6; 95% CI, 0.01-0.62) and higher education (OR, 0.25; 95% CI, 0.07-0.88) reduced odds of PTSD. ConclusionPersons with hemophilia are at risk of developing PTSD and posttraumatic stress symptoms. These data support the need for trauma screening, psychosocial services in the bleeding disorders community, and provision of trauma-informed care by providers.