Search

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

Problem/Condition Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in blood-clotting 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

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. The 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.

BACKGROUND: Parvovirus B19 (B19) is known to cause a variety of human diseases in susceptible individuals by close contact via the respiratory route or by transfusion of contaminated blood or blood products. In this study, whether a case of B19 transmission was causally related to the infusion of implicated lots of a solvent/detergent (S/D)-treated, immunoaffinity-purified factor VIII concentrate (antihemophilic factor [human][AHF]) was investigated. STUDY DESIGN AND METHODS: Anti-B19 (both immunoglobulin M [IgM] and immunoglobulin G [IgG]) and B19 DNA (by a nucleic acid testing [NAT] procedure) were assayed in two implicated product lots, a plasma pool, and a recipient's serum sample. Analysis of the partial B19 sequences obtained from sequencing clones or direct sequencing of the samples was performed. RESULTS: Only one of the two implicated lots was B19 DNA–positive. It contained 1.3 × 103 genome equivalents (geq or international units [IU]) per mL. The negative lot was derived from plasma screened for B19 DNA by NAT in a minipool format to exclude high-titer donations, whereas the positive lot was mostly from unscreened plasma. This high-purity AHF product had no detectable anti-B19 IgG. A 4-week postinfusion serum sample from a recipient, who received both lots and became ill, was positive for the presence of B19 antibodies (both IgM and IgG) as well as B19 DNA. The B19 sequences from the positive lot, its plasma pool, and the recipient's serum sample were closely related. CONCLUSION: These findings and the recipient's clinical history support a causal relationship between the implicated AHF product and B19 infection in this recipient. The seronegative patient became infected after receiving 2 × 104 IU (or geq) of B19 DNA, which was present in this S/D-treated, high-purity AHF product.

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. Aim: This analysis used national surveillance data to compare joint and other outcomes in persons with severe hemophilia A on continuous prophylaxis in three groups: no history of an inhibitor, likely tolerized inhibitor and active (non-tolerized) inhibitor. Methods: The Community Counts bleeding disorders surveillance project is funded by the Centers for Disease Control and Prevention (CDC) through a cooperative agreement awarded to the American Thrombosis and Hemostasis Network (ATHN) in partnership with the US Hemophilia Treatment Center Network (USHTCN). The Registry for Bleeding Disorders Surveillance component collects detailed medical information on patients with bleeding disorders who receive treatment within the USHTCN. Likely tolerized inhibitors were defined as having a history of a previous inhibitor and currently being treated with FVIII concentrate; active inhibitors were defined as having a history of a previous inhibitor and being treated with bypassing agents. Using the Registry component, the following data elements, stratified by age and inhibitor status, were extracted from the initial visit form: demographics, treatment regimen, mobility, cumulative joint bleeding, invasive joint procedures, pain and opioid use. Results: Data on 1,300 persons with severe hemophilia A were analyzed including: 739 with a negative inhibitor history; 410 likely tolerized inhibitor patients; and 151 with an active inhibitor. The 410 patients represented 73% of participants with a positive inhibitor history, similar to the North American Inhibitor Registry (DiMichele D, Haemophilia 2009;15:320-8). Participants with likely tolerized inhibitors were treated using continuous prophylaxis in similar proportion to participants with no history of inhibitor (83% vs 78%, respectively), and more often than participants with active inhibitor (83% vs 65%); however outcomes of participants on continuous prophylaxis were similar in all three groups (Table 1). Patients < 20 years of age had less disability, and fewer joint bleeds, invasive procedures, pain and opioid use compared with adult participants. Conclusions: Improved outcomes on preventive strategies may be best determined prospectively in younger patients due to the lesser degree of established morbidity. Persons with severe hemophilia A on continuous prophylaxis with likely tolerized inhibitors (using FVIII) or with active inhibitors (using bypassing agents) demonstrate outcomes similar to those without inhibitors. However, more age- and treatment regimen- stratified analysis is needed for more precise comparisons. Future findings may contribute to the perspective that prophylaxis should be the standard of care for all hemophilia patients regardless of inhibitor status. Disclosures Manco-Johnson: Bayer: Honoraria, Research Funding; Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; CSL Behring: Honoraria. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Buckner:Novo Nordisk: Consultancy; Genentech: Consultancy; Baxalta: 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 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.

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.