Introduction: Hemophilia, an inherited bleeding disorder leading to deficiency of clotting factor VIII (hemophilia A) or factor IX (hemophilia B), affects approximately 30,000 people in the United States. Widespread availability of factor replacement products led to reductions in bleeding complications, but contamination of the blood supply prior to implementation of mitigation measures led to increased rates of chronic viral infections among persons with hemophilia (PWH). However, mortality rates among PWH have not been systematically evaluated in a decade. Evaluation of mortality rates helps quantify the burden of hemophilia and helps identify trends, should they exist. Methods: Deaths among PWH in the United States were identified through mortality reporting to bleeding disorder surveillance programs. Deaths occurring 2000-2011 were reported to the Universal Data Collection (UDC) system, a collaboration with the Centers for Disease Control and Prevention (CDC) and the U.S. Hemophilia Treatment Center Network (USHTCN). Deaths occurring during 2012-2021 were reported to the Community Counts (CC) system, a collaboration between CDC, the American Thrombosis and Hemostasis Network (ATHN), and the USHTCN. Deaths were reported using standardized mortality forms. The total population under study was estimated using information from the CC HTC Population Profile, an annual census of the Hemophilia Treatment Center (HTC) patient populations, and UDC Registration records. Data collection included patient demography and disease characteristics. Mortality rates, adjusted for age, severity, and race/ethnicity, were estimated, assuming a Poisson distribution. Trends over time were assessed by including time period in the model. Non-overlapping confidence intervals and p for trend < 0.05 were considered statistically significant. Results: For the time period 2000-2021 1,673 deaths among PWH A and 401 deaths among PWH B were reported from participating HTCs in the United States. Of these, over 97% were male, 1,649 hemophilia A and 349 hemophilia B. Thus, stratum-specific mortality rates were only calculable among males with hemophilia A (MWH-A) or hemophilia B (MWH-B). For both MWH-A and MWH-B mortality rates were highest among the oldest age groups across all time periods. Mortality rates among MWH-A decreased after the 2000-2004 period but remained stable thereafter, with the mortality rate during the 2020-2021 period being 28.1 (95% Confidence Interval [CI]: 23.2 - 34.1) deaths per 10,000 population (Panel A). While confidence intervals overlapped, mortality rate estimates among MWH-A with mild or moderate disease generally rose over each time period and the trend was statistically significant (p < 0.05). In 2020-2021, the mortality rate among MWH-A with mild or moderate disease was 27.7 (95% CI: 18.4 - 41.6) deaths per 10,000 population. In contrast, mortality rate estimates among MWH-A with severe disease declined over each time period; while confidence intervals overlapped, the trend was significant (p < 0.05). In 2020-2021, the mortality rate among MWH-A with severe disease was 35.9 (95% CI: 24.2 - 53.2) deaths per 10,000 population. There were no clear temporal mortality trends among Hispanic, non-Hispanic Black, or non-Hispanic White MWH-A. Mortality rates among MWH-B remained relatively stable across all time periods, with confidence intervals overlapping; the mortality rate among MWH-B was similar to that among MWH-A in the 2020-2021 period (36.5 [95% CI: 25.8 - 51.7] deaths per 10,000 population) (Panel B). Severity-specific and race/ethnicity-specific mortality rate estimates among MWH-B were similar across all time periods, but the analysis was underpowered. Of note, the mortality rate among non-Hispanic Black MWH-B was significantly higher than that among non-Hispanic White MWH-B during the 2020-2021 period (71.4 [95% CI: 42.0 - 121.7] and 22.3 [95% CI: 13.9 - 35.6], respectively). Conclusions: This assessment of mortality rates among PWH using national data indicates there have been improvements in mortality rates among MWH-A, but this improvement may be limited to males with severe disease. Limitations related to estimate precision preclude the assessment of trends in mortality rates among MWH-B and among females with hemophilia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

Problem/Condition: Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in bloodclotting proteins. Hemophilia A is a deficiency in factor VIII, and hemophilia B is a deficiency in factor IX. Approximately one in 5,000 males are born with hemophilia, and hemophilia A is about four times as common as hemophilia B. Both disorders are characterized by spontaneous internal bleeding and excessive bleeding after injuries or surgery. Hemophilia can lead to repeated bleeding into the joints and associated chronic joint disease, neurologic damage, damage to other organ systems, and death. Although no precise national U.S. prevalence estimates for hemophilia exist because of the difficulty identifying cases among persons who receive care from various types of health care providers, two previous state-based studies estimated hemophilia prevalence at 13.4 and 19.4 per 100,000 males. In addition, these studies showed that 67% and 82% of persons with hemophilia received care in a federally funded hemophilia treatment center (HTC), and 86% and 94% of those with the most severe cases of hemophilia (i.e., those with the lowest levels of clotting factor activity in the circulating blood) received care in a federally funded HTC. As of January 2020, the United States had 144 HTCs. Period Covered: 1998-2019. Description of the System: Surveillance for hemophilia, which is a complex, chronic condition, is challenging because of its low prevalence, the difficulty in ascertaining cases uniformly, and the challenges in routinely characterizing and tracking associated health complications. Over time, two systems involving many stakeholders have been used to conduct ongoing hemophilia surveillance. During 1998-2011, CDC and the HTCs collaborated to establish the Universal Data Collection (UDC) surveillance system. The purposes of the UDC surveillance system were to monitor human immunodeficiency virus (HIV) and bloodborne viral hepatitis in persons with hemophilia, thereby tracking blood safety, and to track the prevalence of and trends in complications associated with hemophilia. HTC staff collected clinical data and blood specimens from UDC participants and submitted them to CDC. CDC tested specimens for viral hepatitis and HIV. In 2011, the UDC surveillance system was replaced by a new hemophilia surveillance system called Community Counts. CDC and the HTCs established Community Counts to expand laboratory testing and the collection of clinical data to better identify and track emerging health issues in persons with hemophilia. Results: This report is the first comprehensive summary of CDC's hemophilia surveillance program, which comprises both UDC and Community Counts. Data generated from these surveillance systems have been used in the development of public health and clinical guidelines and practices to improve the safety of U.S. blood products and either prevent hemophilia-related complications or identify complications early. Several factors have played a role in the effectiveness of the UDC and Community Counts systems, including 1) a stable data collection design that was developed and is continually reviewed in close partnership with HTC regional leaders and providers to ensure surveillance activities are focused on maximizing the scientific and clinical impact; 2) flexibility to respond to emerging health priorities through periodic updates to data collection elements and special studies; 3) high data quality for many clinical indicators and state-of-the-art laboratory testing methods for hemophilia treatment product inhibitors (developed and refined in part based on CDC research); 4) timely data and specimen collection and submission, laboratory specimen testing, analysis, and reporting; and 5) the largest and most representative sample of persons with hemophilia in the United States and one of the largest and most comprehensive data collection systems on hemophilia worldwide. Interpretation: CDC has successfully developed, implemented, and maintained a surveillance system for hemophilia. The program can serve as an example of how to conduct surveillance for a complex chronic disease by involving stakeholders, improving and building new infrastructure, expanding data collection (e.g., new diagnostic assays), providing testing guidance, establishing a registry with specimen collection, and integrating laboratory findings in clinical practice for the individual patient. Public Health Action: Hemophilia is associated with substantial lifelong morbidity, excess premature deaths, and extensive health care needs throughout life. Through monitoring data from Community Counts, CDC will continue to characterize the benefits and adverse events associated with existing or new hemophilia treatment products, thereby contributing to maximizing the health and longevity of persons with hemophilia.

There are limited observational studies among children diagnosed with von Willebrand Disease (VWD). We analyzed differences in bleeding characteristics by sex and type of VWD using the largest reported surveillance database of children with VWD (n = 2712), ages 2 to 12 years old. We found that the mean ages of first bleed and diagnosis were lowest among children with type 3 VWD. It was even lower among boys than girls among all VWD types, with statistically significant difference among children with type 1 or type 3 VWD. Children with type 3 VWD also reported higher proportions of ever having a bleed compared to other VWD types, with statistically higher proportions of boys compared to girls reporting ever having a bleed with type 1 and type 2 VWD. A similar pattern was observed with the use of treatment product, showing higher usage among type 3 VWD, and among boys than girls with type 1 and type 2 VWD. While there were no differences in life quality or in well-being status by sex, children with type 3 VWD showed a greater need for mobility assistance compared to children with type 1 and type 2 VWD. In an adjusted analysis among children with type 1 VWD, boys showed a significant association of ever bleeding [hazard ratio 1.4; P-value <.001)] compared to girls. Understanding phenotypic bleeding characteristics, well-being status, treatment, and higher risk groups for bleeding among pre-adolescent children with VWD will aid physicians in efforts to educate families about bleeding symptoms.

Background: Continuous prophylaxis, or the routine replacement of deficient clotting factor, is the standard of care therapy for individuals with severe hemophilia A and joint bleeding. In the United States (US), the majority of eligible patients are prescribed continuous prophylaxis, including approximately 75% of children < 20 years of age. However, up to 30% of severe hemophilia A patients develop neutralizing alloantibodies that render factor replacement ineffective requiring inhibitor eradication through induction of immune tolerance (ITI) therapy. Tolerized patients demonstrate successful elimination of inhibitors and normal response to FVIII concentrates. Non-tolerized patients can also be treated on prophylaxis using bypassing agents.

Abstract Introduction: An estimated 30% of persons with hemophilia (PWH) in the US do not receive care at federally-funded hemophilia treatment centers (HTCs). These estimates suggest that perhaps 6,000 PWH and an unknown number of persons with other genetic bleeding disorders receive care elsewhere (non-HTC PWBD). Data on non-HTC PWBD are not collected on a regular basis nor maintained in a central database. Consequently, little is known about their characteristics, treatment, or care. CDC partnered with a national non-profit, consumer-focused organization, Hemophilia Federation of America (HFA), on the CHOICE Project to collect information on non-HTC PWBD to better estimate disease burden and inform planning, decision making, and programming. The objective of this analysis is to describe the treatment, sources, and patterns of care for non-HTC PWBD. Methods: From 04/2013-07/2015, HFA recruited US PWBD >/=18 years old (adults) and caregivers of children with bleeding disorders for CHOICE through email, social media, print, and word-of-mouth to take a ~20 minute survey in English or Spanish, online or on paper. Non-HTC PWBD were solicited specifically but others were not excluded from participation. Participants' status as non-HTC PWBD was determined using an algorithm based on responses to specific survey questions. For this analysis, survey elements included demographics, diagnosis, treatment regimen and treatment products used, and health services utilization (usual source of care, frequency of care, barriers to regular care, delay of care, hospital emergency room (ER) utilization, and hospitalizations within the past 12 months). Results: One hundred seventy-seven (22%) participants from 805 eligible surveys were identified as non-HTC PWBD: 52.5% male; 72.7% adult; mean age 33 years (±19). One hundred fifty-six (88.1%) reported a single bleeding disorder diagnosis; 21 reported multiple diagnoses. See Tables 1 and 2: The most commonly used treatments for hemophilia A or B were recombinant clotting factor concentrate (factor) (75.9%), topical or non-plasma products (e.g., desmopressin) (19.5%), and plasma-derived factor (11.5%). Non-plasma or topical products (50.0%), plasma-derived factor VIII (47.1%), and hormonal contraceptives (26.5%) were used to treat von Willebrand disease. Over 77% of those using intravenous product infused at home; 45.3% self-infused. Of those using factor, 47.5% used it to prevent bleeds with 38.2% practicing continuous prophylaxis. Approximately 32% did not visit a healthcare provider regularly for their bleeding disorder; top reasons included no need for regular care (51.9%) and expense (22.2%). One hundred seven (61.5%) respondents had one (38.1%) or more (61.9%) healthcare providers from whom they received care for their bleeding disorder. Nearly 88% (94) visited a hematologist; when a hematologist was not visited, the family practitioner was the next most common provider used (6.6%). The most common places for care were the doctor's office (49.4%), ER (16.1%), and hospital outpatient department (12.1%). In the last 12 months, 33.3% visited an ER and 18.6% were admitted to a hospital due to their bleeding disorder; 32.9% delayed or did without needed care due mostly to expense/lack of insurance (54.4%), lack of healthcare providers (21.7%), or inconvenience (17.4%). Children were more likely than adults to: have a usual healthcare provider (75.0% vs. 56.8%, p=.03); visit a healthcare provider regularly for care of their bleeding disorder (97.9% vs. 57.0%, p Conclusions: The majority of non-HTC PWBD in this project received treatment for their bleeding disorder and reported care from an appropriate health care provider; however, about 16% with needs did not see a healthcare provider regularly and over one-third delayed or did without care. This sample does not necessarily represent all non-HTC PWBD, as affiliation with an HTC was not always clear and targeted outreach by HFA Member Organizations in some regions may have led to over-representation of some participant characteristics. Additional analysis of non-HTC PWBD health outcomes is needed to determine whether those outcomes differ from other PWBD and to understand how best to identify and recruit non-HTC PWBD for surveillance. Disclosures Owens: Haplomics Inc.: Consultancy, Equity Ownership.

The development of an antibody in people with hemophilia to products used in the treatment and prevention of bleeding, also referred to as an inhibitor, is the most serious complication of hemophilia care today. CDC, together with healthcare providers, consumer organizations, hemophilia organizations, and federal partners, has developed a public health agenda to prevent the development of inhibitors. This paper describes a public health approach that combines a national surveillance program with epidemiologic, laboratory, and prevention research to address knowledge gaps in rates and risk factors for inhibitor development, and in knowledge and behaviors of patients and providers, in addition to screening and treatment practices.

Nonmalignant blood disorders currently affect millions of Americans, and their prevalence is expected to grow over the next several decades. This is owing to improvements in treatment leading to increased life expectancy of people with hereditary conditions, like sickle cell disease and hemophilia, but also the rising occurrence of risk factors for venous thromboembolism. The lack of adequate surveillance systems to monitor these conditions and their associated health indicators is a significant barrier to successfully assess, inform, and measure prevention efforts and progress toward national health goals. CDC is strengthening surveillance activities for blood disorders by improving and developing new methods that are tailored to best capture and monitor the epidemiologic characteristics unique to each disorder. These activities will provide a robust evidence base for public health action to improve the health of patients affected by or at risk for these disorders.

Abstract 3378 Background: Parvovirus B19 (B19) is a small, non-enveloped virus that causes a typically benign flu-like illness most commonly in childhood. However, B19 has been associated with arthritis and poses a hazard to the fetus of a pregnant woman. Because infection is common and viremia can occur before symptoms develop, about 1% of blood donations can be contaminated with B19 virus. The virus is resistant to current viral inactivation steps used in the manufacture of plasma-derived (P-D) anti-hemophilic factor concentrates and B19 transmission through these products has been documented. Since 2000, manufacturers have used a B19 nucleic acid test (NAT) to screen plasma pools and withhold from fractionation those with B19 DNA exceeding an established threshold. No study of populations using these products has been conducted to assess the impact of the screening on B19 transmission. Methods: Blood specimens obtained from participants of the CDC-sponsored Universal Data Collection (UDC) surveillance system of persons with bleeding disorders conducted by specialized US bleeding disorders clinics were used in a B19 seroprevalence study. Since B19 NAT screening began in 2000, only participants born after January 1, 2001 were eligible for study. Data collected on treatment products used by participants both prior to and after enrolment in UDC were used to categorize lifetime exposure as 1) no products, 2) recombinant (recomb) products only, 3) P-D products only, or 4) both recomb and P-D products. The proportions of participants with B19 IgG antibodies were compared across age and product exposure categories to determine whether users of products were at higher risk of past infection with B19 compared to those exposed to B19 only by the usual respiratory route. Results: A total of 1,643 specimens from 1,043 participants aged 2 – 7 years were tested. Demographic and clinical characteristics of study participants are shown in Table 1. Compared to subjects with no exposure to products, subjects in nearly every age group exposed to either P-D products alone or to both P-D and recomb products had a higher B19 prevalence (Table 2). In a logistic regression analysis that controlled for differences in the distribution of age, sex, bleeding disorder, treatment type, number of bleeds in previous 6 months, hemophilia inhibitor status, and year specimen obtained, participants exposed to P-D products alone were 1.7 times more likely to have B19 antibodies than those unexposed to blood or factor products (p = 0.002). In addition, there was a significant overall trend of increasing B19 prevalence over time. Discussion/Conclusion: P-D factor products are important therapies for people with VWD, hemophilia inhibitors and rarer factor deficiencies. Although we had no data on clinical illness, these serologic data provide evidence for continued transmission of B19 through these products after implementation of B19 NAT screening. Lowering the B19 threshold for plasma pool rejection should be considered. More importantly, effective viral inactivation processes are needed to protect users of these products not only from infection with B19 but from other as yet unidentified or emerging viruses that would not be detected by B19 NAT. Disclosures: Kessler: Novo Nordisk Inc.: Consultancy.

Since 1998, the CDC has coordinated a national public health surveillance project-the Universal Data Collection (UDC) program-on chronic, rare, inherited bleeding disorders. In this program, uniform data are gathered through a network of 130 hemophilia treatment centers (HTCs) throughout the U.S. and its territories. Initially, the program was designed to address two primary goals: (1) establishment of a blood-safety monitoring system among people with bleeding disorders, and (2) collection of a uniform set of clinical outcomes data that could be used to monitor trends in the prevalence of infectious diseases and joint complications among this population. To this end, the program has been acquiring useful longitudinal data to monitor complications of bleeding disorders. For example, with the establishment of range-of-motion measurements for joints as required data elements, a large database has been developed for studies examining risk factors for joint-disease progression. The UDC program data have been used to provide evidence for a national prevention campaign to promote the need for patients with hemophilia to establish or maintain a healthy weight to help prevent joint disease. Risk factors leading to complications such as joint infection have also been identified. The application of geographic information systems technology to UDC program data has helped identify needs for outreach and availability of blood products and sources of care. Future analyses of data collected on babies, women, and individuals with rarer bleeding disorders than hemophilia will provide further information, leading to improved public health prevention strategies.

To determine mortality rates and risk factors among males with hemophilia who receive care in federally supported HTCs, we analyzed mortality data on the 85% of HTC patients voluntarily enrolled in UDC. Demographic, diagnostic, clinical, and treatment data were collected for all UDC patients on a standard form at annual comprehensive care visits. Proportion of expected annual UDC visits for each patient was the number of visits attended divided by the number of years between UDC enrollment and the end of the study. Blood specimens were tested centrally for markers of hepatitis and HIV infection. Data on mortality including date and causes of death was submitted by HTC staff using a standard form. Follow-up began at initial UDC visit and continued until date of death or December 31, 2006, whichever came first. Mortality rates were calculated as the number of deaths divided by person time and multiplied by 10,000 (deaths /104 person years PY). Univariate associations used the relative risk and multivariate analysis used Cox proportional hazards regression. Over the study period, 12,883 males with hemophilia ≥2 years old were enrolled in UDC and followed for a total of 68,060 PY. Among UDC participants there were 451 deaths for an overall mortality rate of 66.3 /104 PY. Hemophilia (14.2%), HIV (17.5%), and liver (29.1%) related causes of death were most commonly specified. As expected, mortality was strongly associated with age and ranged from 2.5 /104 PY for 2–10 year olds to 270 /104 PY for those >60 years. Also significantly associated with higher mortality in univariate analyses were Native American (NA) race vs. white, hemophilia A vs. B, severe vs. non-severe disease, HIV infection, hepatitis B active and past infection, hepatitis C infection, any restriction in activity level vs. none, increasing body mass index (BMI), history of intracranial hemorrhage (ICH), alcohol abuse, and any sign of liver disease including jaundice, ascites, varices, or elevated ALT/AST or PT. On the other hand, patients who attended from 1/3 to 2/3 of their expected UDC visits were 60% less likely to die and those who attended more than 2/3 of expected UDC visits were 90% less likely to die than those patients who attended less than 1/3 of their expected UDC visits. The distribution of patients attending <1/3, 1/3 to 2/3 and >2/3 of expected visits was 15.3%, 31.3% and 53.4%, respectively. A multivariate model including all risk factors indicated that NA race RR=2.6 (95% CI: 1.2, 5.6), HIV infection RR=3.3 (2.6, 4.3), severe disease RR=1.8 (1.4, 2.3), alcohol abuse RR=1.3 (1.0, 1.7), jaundice RR=2.0 (1.4, 3.0), ascites RR=1.5 (1.0, 2.4), varices RR=2.0 (1.3, 3.1), elevated ALT/AST RR=1.4 (1.1, 1.8), and elevated PT RR=1.5 (1.1, 2.1) increased risk for mortality. Whereas attending 1/3 to 2/3 expected visits RR=0.36 (0.29, 0.44), attending >2/3 expected visits RR=0.07 (0.05, 0.10) and 10 unit increase in BMI RR=0.72 (0.58, 0.90) were protective against mortality. Hemophilia type, activity restriction, history of ICH, and hepatitis B and C infection were no longer significantly associated with death in the multivariate model. Our finding that patients enrolled in the UDC project who returned regularly to HTCs for comprehensive care were much less likely to die, even after adjusting for other mortality risk factors, supports results of previous studies that showed lower mortality among patients receiving comprehensive care in HTCs.