US Hemophilia Treatment Centers Research Articles

Epidemiology of Inhibitors in Persons with Severe Hemophilia a in the United States: Analyses of a National Database

Background:Development of inhibitory alloantibodies, commonly known as “inhibitors,” against exogenously infused factor VIII (FVIII) is the most significant complication of hemophilia therapy. The aim of this study was to understand the epidemiology of inhibitors in persons with severe hemophilia A (PWHA) in the United States using a national database, the Community Counts Registry for Bleeding Disorders Surveillance.Methods:The Community Counts Registry collects detailed medical information on patients with bleeding disorders who receive treatment within the US Hemophilia Treatment Center Network (USHTCN). Patients with severe hemophilia A with (PWHA-I) and without an inhibitor (PWHA-NI) enrolled in the registry between 12/1/2013 and 7/9/2018 were included in this cross-sectional exploratory analysis. PWHA designated as having an unknown history of inhibitor were excluded. Data elements included basic demographics (age, sex/gender, race, ethnicity, employment, insurance status), clinical characteristics (age of diagnosis, treatment characteristics), inhibitor characteristics (age at detection, inhibitor-specific treatments, titers, status), and outcome data (bleeding events, joint disease and procedures, intracranial hemorrhage, ED visits, hospitalizations, chronic pain, opioid use, and days missed from school/work). Data were categorized with reported frequencies, and comparisons between PWHA-I and PWHA-NI were made using Chi-square tests.Results:Of 4375 patients with severe hemophilia A, 1142 (26.1%) had a reported history of inhibitor. Among the cohort were 13 (0.30%) female and 7 (0.16%) transgender patients. PWHA-I and PWHA-NI were similarly distributed among sex/gender categories. PWHA-I were more frequently Hispanic, Latino/a, or Spanish origin or black or African American and less frequently white. Nearly all patients were insured, although PWHA-I more frequently utilized public insurance as opposed to commercial insurance as primary insurance, which may align with the lower rate of employment among PWHA-I (Table 1).PWHA-I more frequently reported a history of intracranial hemorrhage. Notably, no association was identified between inhibitor history and history of joint bleed, history of invasive joint procedure, or limitations of activity level at the time of assessment. During the 12 months prior to assessment, a lower percentage of PWHA-I reported hemophilia-related chronic pain, but those PWHA-I with chronic pain reported opioid use at a modestly increased rate. PWHA-I were more frequently seen in the emergency department and hospitalized than PWHA-NI during the 12 months prior to reporting, and PWHA-I reported more days missed from work or school (Table 1).Within the PWHA-I cohort, 45.7% of patients had inhibitors detected prior to age 2 years. The majority (64.8%) of PWHA-I had a history of immune tolerance induction and 56.3% reported using routine doses of FVIII concentrates to treat bleeding events. Bypassing agents and increased FVIII concentrates were each used for ~20% of PWHA-I (Table 2).Conclusions:This study provides an estimate of the burden of inhibitors in persons with severe hemophilia A in the US, representing approximately 52.9% of all severe hemophilia A patients treated in the USHTCN (CDC, unpublished data). History of an inhibitor reduced patient productivity and increased ED and hospital utilization. Future efforts will focus on a longitudinal analysis of this cohort to better understand the natural history and outcome of inhibitors and their impact on patient quality of life and health care utilization.Acknowledgments:This study was performed with the advice of the Community Counts Inhibitor Interest Group and was supported by funds from an ASH HONORS Award for Mr. Sande. [Display omitted] DisclosuresPayne:Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation. Kempton:Novo Nordisk: Research Funding; Genetech, Inc: Honoraria, Research Funding; Shire: Honoraria; Bayer AG: Honoraria; Spark Therapeutics: Honoraria; Grifols: Honoraria; Catalyst Biosciences: Honoraria. Manco-Johnson:CSL Behring: Honoraria; Novo Nordisk: Honoraria; Biogentek: Honoraria; Bayer AG: Honoraria, Research Funding; Baxalta, now part of Shire: Honoraria. Sharathkumar:CSL Behring: Honoraria; Shire: Honoraria; Bayer: Honoraria.

Ranges and drivers of risk associated with sports and recreational activities in people with haemophilia: results of the Activity-Intensity-Risk Consensus Survey of US physical therapists.

Limited evidence describes physical activity-associated bleeding risks for people with haemophilia, and risks are usually described only generically. To assess activity-specific ranges of risk for joint, soft tissue and head bleeds by identifying inherent and modifiable risk factors associated with each activity, based on opinions of expert physical therapists (PTs). Physical therapists from US haemophilia treatment centres (HTCs) participated in a survey of 101 physical activities. For each activity, PTs provided minimum/maximum risk scores (low=1; high=5), and indicated specific bleeding risks in six joints and three injury types (bruising, muscle bleeding, head injury). Risk drivers were identified from free-text comments and explored at a consensus meeting, where they were categorized as inherent or modifiable and activity-driven or patient-driven. Of 32 invited PTs, 17 participated; median experience was 24years as a PT and 16years at an HTC. Only a few activities had a wide range of risk assessments encompassing both lower and upper ends of the response range. Joint injury risks were consistent with position and physical requirements, and head and muscle bleed risks were associated with physical contact. Eight PTs participated in the consensus meeting; key risk drivers identified included progression from seasonal to year-round participation, overtraining and improper body mechanics. Inherent risks included impact with surface/ball/equipment and field/surface condition; modifiable risks included safety equipment and tricks/stunts. These data provide a framework for discussion with patients/families, recognizing how certain activities may be modified to decrease risk, and identifying activities with nonmodifiable inherent risks.

A cross-sectional study of non-attendance among patients at a US hemophilia treatment center 2010-2014.

Among patients with chronic disease, non-attendance at scheduled healthcare visits is associated with poor outcomes. The impact of non-attendance among patients with bleeding disorders is unknown. Scheduling and medical record data over a 5-year period for all individuals with at least one scheduled appointment during 2010-2014 at a US Hemophilia Treatment Center (HTC) were analysed. Non-attendance rates were calculated as the number of non-attended visits divided by the number of years as a patient during the time period. Consistent non-attenders were patients who did not attend more than one scheduled appointment per person-year on average. Logistic regression determined characteristics associated with consistent non-attendance and Poisson regression estimated adjusted incidence rate ratios (aIRRs) describing associations between non-attendance and emergency department (ED) visits and hospitalizations. There were 8028 appointments scheduled for 950 individuals; 12% were not attended. Consistent non-attenders (n=62; 7% of the HTC patient population) accounted for over one-third of non-attended appointments and over one-quarter of hospitalizations. Characteristics associated with consistent non-attendance included public health insurance and black race. Higher non-attendance rates were associated with more ED visits (aIRR 1.78; 95% CI: 1.37-2.30) and hospitalizations (aIRR 2.73; 95% CI: 2.18-3.42). Consistent non-attenders had more ED visits (aIRR 2.49; 95% CI: 1.56-3.96) and hospitalizations (aIRR 4.73; 95% CI: 2.96-7.57) compared with patients who never missed appointments. Frequent non-attendance identified a small but at-risk population. Interventions to improve disease management that target them may have an impact on health outcomes and healthcare utilization.

A cross-sectional analysis of cardiovascular disease in the hemophilia population

AbstractMen with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.

Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A.

Prophylaxis with extended half-life factor VIII (FVIII) is approved for haemophilia A, but data regarding routine clinical use are limited. To assess real-world experience of ADYNOVATE® (Antihemophilic Factor (Recombinant), PEGylated prophylaxis in children and adults with haemophilia A. A retrospective chart review was conducted in three US haemophilia treatment centres. Records of all patients who began Adynovate prophylaxis in routine clinical practice were identified. Demographic, clinical and patient-reported information beginning 6months before initiation of Adynovate until the record review was analysed. Fifteen patients (aged 9months to 28years), with median 9months' use of Adynovate (range 1-15months), were identified. All had switched from another prophylactic regimen, 13 (87%) from standard half-life recombinant FVIII. Nine (60%) patients had ≥1 bleed within 6months preswitch. The most frequent reason for switching was to reduce infusion frequency (14 patients). After switching, infusion frequency reduced for 13 patients, and overall weekly factor consumption decreased by 19%. Eight (53%) patients had no bleeds postswitch, three (20%) had spontaneous joint bleeds (vs four pre-switch), and three (20%) had only mild traumatic bleeds. Patient/parental satisfaction with Adynovate was documented as positive in 13 of 15 (87%) cases; 2 patients were not satisfied and discontinued Adynovate. No adverse events were considered related to Adynovate. In patients who switched from a standard half-life FVIII to Adynovate prophylaxis in routine clinical practice, bleeding control was generally improved or maintained, with a lower infusion frequency and factor consumption in most patients.

Economic Burden of Illness among Persons with Hemophilia B from HUGS Vb: Examining the Association of Severity and Treatment Regimens with Costs and Annual Bleed Rates.

To determine US societal burden of illness, including direct and indirect costs and annual bleed rate (ABR), for persons with hemophilia B (HB), a rare and debilitating genetic disorder, and to examine associations of hemophilia severity and treatment regimens with costs and ABR. From 2009 to 2014, the Hemophilia Utilization Group Studies Part Vb collected prospective data from 10 US hemophilia treatment centers. Participants with HB completed initial surveys on sociodemographic characteristics, clinical characteristics, and treatment patterns. During the 2-year follow-up, participants reported bleeding episodes, work absenteeism, and caregiver time quarterly. These data were used to calculate ABR and indirect costs. Direct costs were calculated using 1-year clinical chart records and 2-year dispensing records. Of the 148 participants, 112 with complete medical records and one or more follow-up survey were included. Total mean annual per-person costs were $85,852 (median $20,160) for mild/moderate HB, $198,733 (median $147,891) for severe HB, and $140,240 (median $63,617) for all participants without inhibitors (P < 0.0001). Mean ABR for participants with severe HB on prophylaxis (5.5 ± 7.9 bleeds/y) was almost half that of those treated episodically. Clotting factor and indirect costs accounted for 85% and 9% of total costs, respectively. Compared with episodic treatment, prophylaxis use was associated with 2.5-fold higher clotting factor costs (P < 0.01), low but significantly more missed parental workdays (P < 0.0001) and clinician (P < 0.001) or nursing visits (P < 0.0001), less part-time employment and unemployment, and lower hospitalizations costs (P = 0.17) and ABR (P < 0.0001). HB is associated with high economic burden, primarily because of clotting factor costs. Nevertheless, prophylaxis treatment leads to clinical benefits and may reduce other nonfactor costs.

The effects of joint disease, inhibitors and other complications on health-related quality of life among males with severe haemophilia A in the United States.

Health-related quality of life (HRQoL) is reduced among persons with haemophilia. Little is known about how HRQoL varies with complications of haemophilia such as inhibitors and joint disease. Estimates of preference-based HRQoL measures are needed to model the cost-effectiveness of prevention strategies. We examined the characteristics of a national sample of persons with severe haemophilia A for associations with two preference-based measures of HRQoL. We analysed utility weights converted from EuroQol 5 Dimensions (EQ-5D) and the Short Form 6 Dimensions (SF-6D) scores from 1859 males aged ≥14years with severe haemophilia A treated at 135 US haemophilia treatment centres in 2005-2011. Bivariate and regression analyses examined age-group-specific associations of HRQoL with inhibitor status, overweight/obesity, number of bleeds, viral infections, indicators of liver and joint disease, and severe bleeding at the time of the first HRQoL measurement. Overall mean HRQoL utility weight values were 0.71 using the SF-6D and 0.78 using the EQ-5D. All studied patient characteristics except for overweight/obesity were significantly associated with HRQoL in bivariate analyses. In a multivariate analysis, only joint disease was significantly associated with utility weights from both HRQoL measures and across all age groups. After adjustment for joint disease and other variables, the presence of an inhibitor was not significantly associated with HRQoL scores from either of the standardized assessment tools. Clinically significant complications of haemophilia, especially joint disease, are strongly associated with HRQoL and should be accounted for in studies of preference-based health utilities for people with haemophilia.

Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project

AbstractThis analysis of the US Hemophilia Treatment Center Network and the Centers for Disease Control and Prevention surveillance registry assessed trends in prophylaxis use and its impact on key indicators of arthropathy across the life-span among participants with severe hemophilia A. Data on demographics, clinical characteristics, and outcomes were collected prospectively between 1999 and 2010 at annual clinical visits to 134 hemophilia treatment centers. Trends in treatment and outcomes were evaluated using cross-sectional and longitudinal analyses. Data analyzed included 26 614 visits for 6196 males; mean age at first registry visit was 17.7 years; and median was 14 (range, 2 to 69). During this time, prophylaxis use increased from 31% to 59% overall, and by 2010, 75% of children and youths <20 years were on prophylaxis. On cross-sectional analysis, bleeding rates decreased dramatically for the entire population (P < .001) in parallel with increased prophylaxis usage, possibly because frequent bleeders adopted prophylaxis. Joint bleeding decreased proportionately with prophylaxis (22%) and nonprophylaxis (23%), and target joints decreased more with prophylaxis (80% vs 61%). Joint, total, and target joint bleeding on prophylaxis were 33%, 41%, and 27%, respectively, compared with nonprophylaxis. On longitudinal analysis of individuals over time, prophylaxis predicted decreased bleeding at any age (P < .001), but only prophylaxis initiation prior to age 4 years and nonobesity predicted preservation of joint motion (P < .001 for each). Using a national registry, care providers in a specialized health care network for a rare disorder were able to detect and track trends in outcomes over time.

Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.

To describe the prevalence and complications in babies ≤2 years with haemophilia. We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.

Men with severe hemophilia in the United States: birth cohort analysis of a large national database

AbstractThe availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti–hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes.

Von Willebrand factor for menorrhagia: a survey and literature review.

von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

US Hemophilia Treatment Center population trends 1990–2010: patient diagnoses, demographics, health services utilization

For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population.

Multidisciplinary management of patients with haemophilia with inhibitors undergoing surgery in the United States: perspectives and best practices derived from experienced treatment centres

Since the 1980s, major surgical interventions in patients with congenital haemophilia with inhibitors have been performed utilizing bypassing agents for haemostatic coverage. While reports have focused on perioperative management and haemostasis, the US currently lacks consensus guidelines for the management of patients with inhibitors during the surgical procedure, and pre- and postoperatively. Many haemophilia treatment centres (HTCs) have experience with surgery in haemophilia patients, including those with inhibitors, with approximately 50% of these HTCs having performed orthopaedic procedures. The aim of this study was to present currently considered best practices for multidisciplinary care of inhibitor patients undergoing surgery in US HTCs. Comprehensive haemophilia care in the US is provided by ~130 federally designated HTCs staffed by multidisciplinary teams of healthcare professionals. Best practices were derived from a meeting of experts from leading HTCs examining the full care spectrum for inhibitor patients ranging from identification of the need for surgery through postoperative rehabilitation. HTCs face challenges in the care of inhibitor patients requiring surgery due to the limited number of surgeons willing to operate on this complex population. US centres of excellence have developed their own best practices around an extended comprehensive care model that includes preoperative planning, perioperative haemostasis and postoperative rehabilitation. Best practices will benefit patients with inhibitors and allow improvement in the overall care of these patients when undergoing surgical procedures. In addition, opportunities for further education and outcomes assessment in the care of this patient population have been identified.

Current prescription of prophylactic factor infusions and perceived adherence for children and adolescents with haemophilia: a survey of haemophilia healthcare professionals in the United States

The primary goal of prophylaxis in patients with severe haemophilia is to convert the phenotype from severe to moderate and to prevent the development of chronic arthropathy. Prior studies have demonstrated that prophylaxis decreases episodes of joint bleeds and chronic arthropathy. Effectiveness depends on prescription of prophylaxis and adherence to the prescribed regimen. The aim of this study was to determine if prescription of prophylaxis for children with haemophilia and perceptions of adherence to prophylaxis have changed since publication of the Joint Outcome Study (JOS). A questionnaire was sent, in electronic and written formats, to health professionals who provide care to children with haemophilia at US haemophilia treatment centres (HTCs). The response rate was 56 of 128 (44%) of the targeted HTCs. There were a few missing data and denominators are provided. All responses agreed with the results of the JOS and 30/55 (55%) reported the JOS increased their prescription of prophylaxis. Nineteen of 56 (34%) physicians or HTC staff reported that they had not prescribed prophylaxis within the last year due to concerns about adherence, and 19/56 (34%) reported they had stopped prophylaxis due to concerns about adherence within the last year. Predicted adherence decreased with increasing age. Prescription of prophylaxis appears to be increasing since publication of the JOS. Strategies to improve adherence may increase the likelihood of physician prescription of prophylaxis and make prophylaxis easier to implement for individual patients, thereby improving the clinical outcome of children and adults with haemophilia.

Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres

Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web-based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.3%), but after the first bleed in only 28 HTCs (25.2%). Among 226 newborns with severe haemophilia A in 62 HTCs, 1.82 births/HTC/year, the median age at first bleed, excluding circumcision, is 7 months. Of the 113 (53.5%) newborns who underwent circumcision, 62 (54.9%) bled. Despite a recommended standard of three times weekly prophylaxis, over half of surveyed HTCs do not follow these guidelines, and nearly one-third begin prophylaxis on a once weekly schedule to delay or avoid the need for central venous access.

Factor VIII prophylaxis for adult patients with severe haemophilia A: results of a US survey of attitudes and practices

The emergence of a population of relatively healthy adults with severe haemophilia A presents a unique challenge for haemophilia care in the 21st century. Understanding how best to continue, restart, initiate or modify prophylaxis in younger and older adult patients is essential to optimizing their care. To elucidate practice and outcome data, a survey was sent to 23 US hemophilia treatment centers (HTCs); 10 centers responded, providing data concerning up to 145 adults (mean age of 34 years). Forty-eight patients (33%) were on regular prophylaxis when first seen at the HTC; the prophylactic regimen was modified for 22/48 (46%), often because of breakthrough bleeding. Five of 21 patients (24%) for whom data were available discontinued prophylaxis. Three of those five patients (60%) experienced increased bleeding episodes and the other two (40%) subsequently resumed regular prophylactic infusions because of the increased bleeding. Of the 77 patients not initially receiving prophylaxis for whom data were available, prophylaxis was started or resumed in all. The prophylactic regimen was modified in 57/77 patients (74%) at some point during treatment, often because of breakthrough bleeding. Of the 55 patients whose prophylactic regimens were modified for whom data were available, 22 (40%) discontinued prophylaxis. Thirteen of 20 patients (65%) for whom data were available experienced an increase in bleeding episodes and 7/18 patients (39%) who had discontinued prophylaxis and for whom data were available subsequently resumed regular prophylactic infusions because of bleeding. These findings suggest that prophylaxis prevents bleeding in adults with severe haemophilia A and that discontinuation of the prophylactic regimen is associated with increased bleeding events.

Females with Severe or Moderate Hemophilia A or B: A U.S. Study.

According to the CDC's 2006 National Hemophilia Data Set, females comprise 0.7% of the moderately and severely affected hemophilia A (HA) population and 1.3% of those similarly affected with hemophilia B (HB) in the US. Since no comprehensive data have been published on this patient group since 1978, we conducted this study to collect and analyze epidemiological, clinical, psychosocial, and molecular genetic data on females with severe (s) or moderate (mod) HA or HB. Potential subjects with factor VIII or IX activity levels <0.06u/ml were identified through the CDC database and direct contact with US hemophilia treatment centers (HTC). HTC personnel extracted information from the medical record on diagnosis, laboratory evaluation, bleeding history, menstrual/pregnancy history, hemophilia treatment and complications, as well as chromosomal and molecular genetic test results when available. Subjects completed a quality of life (QOL) instrument as follows: SF-36 if ≥ 14 years or PEDS-QL if < 14 years. Of 28 females identified, 22 from 18 HTCs agreed to participate in the study. The characteristics of this population are summarized in the table below. Six had HB and 16 had HA. The diagnosis was made after spontaneous bleeding, mostly mucocutaneous, in 73% of the cohort. The bleeding phenotype is also outlined in the table.In addition to unexpectedly few reports of menorrhagia, 4 women, 2 with severe and 2 with moderate hemophilia, had five live births with minimal complications: no reported miscarriages, one report of placental bleeding, one post-partum hemorrhage. Complications documented in this cohort include 41% with target joints, 14% with hepatitis B surface antigen positivity, and 22% with a positive hepatitis C viral load. Three subjects (14%) developed inhibitors. Karyotype and/or molecular diagnostic studies were available in 73% of the cohort and suggest significant genotypic heterogeneity in this population. With respect to QOL, overall physical and mental health composite scores on the SF-36 did not differ significantly from the general population. In adults, menorrhagia and viral infection appeared to have a negative impact on QOL. These data represent the most comprehensive characterization to date of the epidemiology, clinical presentation, morbidity, and genotypic etiology of moderate and severe hemophilia in the female population. Preliminary analysis also suggests that this population has fewer obstetric/gynecological complications than expected, although the cohort remains relatively young. In order to further characterize genetic mutations in this population, a collaborative study is planned, which will include both US and international subjects. The research was funded by grants from CSL Behring Foundation and the National Hemophilia Foundation.SHA/HB (<0.01 u/ml)Mod HA/HB (0.01–0.05 u/ml)Demographics/PresentationSubject (# subjects)148HA/HB13/13/5Median current age (range) (yrs)17 (2–45)26 (12–42)Median age at diagnosis (range) (mos)9 (3–72)48 (14–312)Bleeding History (# subjects)Median age at first bleed (range) (mos)9 (12–18)14 (6–72)Joint bleeds13/147/8Mucocutaneous bleeds10/138/8Intracranial hemorrhage1/140/8Menstrual History (# subjects)Currently menstruating87Menorrhagia (subjective)0/83/7Pain at ovulation or menses5/86/7

Human parvovirus B19 in young male patients with hemophilia A: associations with treatment product exposure and joint range-of-motion limitation.

To evaluate the risk of human parvovirus B19 (B19) transmission in recombinant antihemophilic factor, the seroprevalence among 798 two- to seven-year-old boys with hemophilia was compared. Also, data collected on joints were used to assess relations between B19 serostatus and joint range-of-motion (ROM) limitation. Staff at US hemophilia treatment centers collected data on product exposures and ROM of 10 joints and provided blood specimens as part of blood safety surveillance. Blood was tested for immunoglobulin G anti-B19. Associations between B19 seropositivity and treatment products and joint ROM limitations were examined in multivariate analyses. Compared to children who received no product, the odds of B19 seropositivity were 0.8 (p = 0.5), 1.9 (p = 0.05), and 7.6 (p < 0.001) for those children who received recombinant antihemophilic factor only, both recombinant antihemophilic factor and plasma-derived factor, and plasma-derived factor only, respectively. Children who were anti-B19 positive had an average 8 degrees less overall ROM (p = 0.002) than those who were B19 antibody negative after adjustment for other risk factors. The risk of B19 transmission by recombinant antihemophilic factor is low. Previous B19 infection is associated with ROM limitations in very young male patients with hemophilia. Virus inactivation techniques effective against B19 and other nonenveloped viruses are needed.

Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors

AbstractChronic joint disease from repeated bleeding into joints is a serious complication of hemophilia. To measure the extent of and to identify risk factors for deviations from normal in joint range of motion (ROM), we used cross-sectional data collected from 4343 males with hemophilia aged 2 to 19 years who received care at 136 US hemophilia treatment centers (HTCs). Factors examined included age, race/ethnicity, family history, insurance status, age at diagnosis and first HTC visit, frequency of HTC visits, hemophilia type, bleeding frequency, prophylaxis use, inhibitor status, body mass index (BMI), and recent orthopedic procedures. Trained personnel using a standard protocol obtained ROM measurements on 10 joints (hips, knees, shoulders, elbows, and ankles). Analyses used multiple linear regression to model overall ROM limitation separately by disease severity. For persons in all severity groups, joint ROM limitation was positively associated with older age, nonwhite race, and increased BMI. For those with severe disease, ROM limitation was also positively associated with number of bleeds and was greater for those with inhibitors or recent orthopedic procedures. We conclude that ROM limitations begin at an early age, especially for those with severe and moderate disease, and that BMI is an important, potentially modifiable risk factor.

Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.

Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.