Christine Guelcher

Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003

Summary.  Before the mid‐1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV‐1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV‐seropositive patients, age 13–88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross‐sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV‐1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV‐1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV‐1‐positive participants had ≥200 CD4+ cells μL−1, only 59% were on HAART. HIV‐1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti‐HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV‐1‐positive than HIV‐1‐negative participants (85% vs. 70%, P < 0.0001). HIV‐1‐positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV‐negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self‐reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non‐Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV‐1, HCV or both.

Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18–30 years) with hemophilia

The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18–30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on‐demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower‐risk activities and approximately half in intermediate‐risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one‐third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part‐time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood. Am. J. Hematol. 90:S3–S10, 2015.

Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B

Inhibitors are an impediment to the effective management of haemophilia B (HB), but there is limited understanding of the underlying genetic risk factors. In this study we aim to understand the role of F9 gene mutations on inhibitor development in patients with HB. Mutations in the F9 gene were identified and HLA typing performed for five boys with severe HB. Data from the CDC Haemophilia B Mutation Project (CHBMP) database were used to assess association between F9 gene mutation type and inhibitor development. Analysis of the CHBMP database showed that larger disruptions in the F9 gene are associated with a higher life‐time prevalence of inhibitors. We detected the following mutations in the five subjects, including four novel mutations: Nonsense in three patients (c.223 C>T; p.Arg75* in two siblings, c.553 C>T; p.Glu185*); Splice site in two patients (c.723 + 1 G>A, c.278‐27 A>G); Missense in one patient (c.580 A>G, p.Thr194Ala; c.723 G>T; p.Gln241His). Of the two siblings only one responded to immune tolerance induction (ITI). These siblings have identical F9 gene mutations but differ with respect to the HLA alleles. Interestingly, an analysis of peptide‐MHC binding affinities shows a significantly higher (one‐sided unpaired t‐test, P = 0.0018) median affinity for FIX‐derived peptides in the sibling that responded to ITI. We conclude that the nature of the F9 gene mutation may be an important risk factor for the development of inhibitors. In addition, the HLA alleles of the individual patients, in conjunction with the mutation type, could be a predictor for the development of inhibitors as well as the response to ITI.

Haemophilia A: patients’ knowledge level of treatment and sources of treatment-related information

Summary.  There are minimal or no data regarding the extent of patient and/or parent/legal guardian/caregiver knowledge about haemophilia A and its treatment, their sources for this information, or their preferred methods of communication. A pilot study using a survey instrument developed by haemophilia nurse coordinators was conducted at a national meeting to obtain information on these topics. A total of 187 surveys were completed. More than 80% of respondents reported high and high‐medium knowledge levels about how haemophilia A is inherited, types of bleeding, identifying and treating bleeding emergencies, prophylaxis and on‐demand treatment, travel and vacation planning and guidelines for exercise and sports activities. However, a lower proportion of respondents (<65%) reported high and high‐medium knowledge levels for drug‐related topics. The majority of respondents (>55%) consistently ranked healthcare providers as the most useful source of information for most topics related to haemophilia A. This pilot survey of well‐informed respondents identified deficits in knowledge regarding factor concentrates for the treatment of haemophilia A and highlights the need for healthcare providers to provide more information about factor concentrates, insurance coverage for treatments, and community and educational resources. Additional study is necessary to determine the extent of knowledge deficits and how best to address them in the haemophilia A population as a whole. Other areas of study needed are whether information deficits and delivery of information vary by age or by other factors.

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Genetic mutations in the gene encoding FVIII (F8) have been extensively studied. Over a thousand different mutations have been reported in the F8 gene. These span a diverse range of mutation types, namely, missense, splice-site, deletions of single and multiple exons, inversions, etc. There is nonetheless evidence that other molecular mechanisms, in addition to mutations in the gene encoding the FVIII protein, may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-à-vis the role of nc-RNAs in the regulation of F8 expression. These hypotheses have not been exhaustively tested in this study as they require carefully curated clinical samples.

Management of US men, women, and children with hemophilia and methods and demographics of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study

The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B‐HERO‐S) initiative was launched in an effort to address specific gaps in the understanding of the psychosocial impact of mild‐moderate‐severe hemophilia B. The original Hemophilia Experiences, Results and Opportunities (HERO) qualitative study evaluated the needs of people with hemophilia A or B in multiple countries; however, a majority of participants had the more common moderate‐severe hemophilia A. The B‐HERO‐S study was designed in collaboration with the hemophilia community to evaluate the needs of adults with hemophilia B and caregivers of children with hemophilia B, including affected women and caregivers of girls with hemophilia. The report presented here describes participant demographics and comorbidities, as well as treatment regimens and access to treatment. Bleeding symptoms were reported by 27% of mothers of children with hemophilia B who participated. Women were more likely than men to self‐report arthritis and depression/anxiety as comorbidities associated with hemophilia B. More adults and children with hemophilia B were on routine treatment than on on‐demand treatment, and a high percentage of adults with moderate hemophilia B received routine treatment (86%). Many adults with hemophilia B (78%) and caregivers (69%) expressed concern about access to factor in the next 5 years, and of adults with hemophilia B, women more commonly experienced issues with access to factor in the past than did men (72% vs 44%). The findings of the B‐HERO‐S study reveal potential unmet needs of some patients with mild‐moderate hemophilia B, and the results may be leveraged to inform patient outreach by hemophilia treatment centers and education initiatives.

Impact of mild to severe hemophilia on engagement in recreational activities by US men, women, and children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study

The psychosocial impact of hemophilia on activities was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study (675 people with hemophilia and 561 caregivers of children with hemophilia in 10 countries). The impact of hemophilia B may not be accurately reflected in the HERO results, as ~75% of respondents described issues affecting males with hemophilia A. To address the needs of this population, the Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B‐HERO‐S) was developed as a pilot study in the United States in collaboration with the hemophilia community. The analysis reported here assessed engagement in recreational activities and changes to treatment regimens around activities as reported by 299 adults with hemophilia B and 150 caregivers of children with hemophilia B. Nearly all adults with hemophilia B (98%) experienced a negative impact on their participation in recreational activities due to hemophilia‐related issues, and most caregivers (90%) reported that hemophilia B had a negative impact on their childs engagement in recreational activities. One of the main reasons identified for discontinuing past activities was the risk of bruising or bleeding (adults/children with hemophilia B, 49%/41%). In particular, adults with hemophilia B reported a history of activity‐related bleeding, and most adults decreased their participation in high‐risk activities as they aged. Substantial percentages of adults and children with hemophilia B (including mild/moderate severity) altered their treatment regimens to accommodate planned activities. These findings may help inform guidelines for individualizing treatment regimens around participation in recreational activities based on hemophilia severity, baseline factor level, and activity risk and intensity.

Impact of hemophilia B on quality of life in affected men, women, and caregivers-Assessment of patient-reported outcomes in the B-HERO-S study

Health‐related quality of life (HRQoL) is impaired in patients with hemophilia; however, the impact in mild/moderate hemophilia B and affected women is not well characterized.

US haemophilia centre nurses and advanced practice providers: Demographics, roles/responsibilities, training, educational barriers and employment benefits

Abstract Introduction As the focus on personalised treatment is refined, more products are brought to market and the life expectancy of persons with haemophilia increases, there will be an expanded need of experienced and expert healthcare providers to ensure optimal patient outcomes. Aim This survey describes the demographics, roles/ responsibilities, practice patterns, educational opportunities/barriers and employment benefits of nurses and advanced practices providers (APPs), including advanced practice registered nurses (APRNs) and physician assistants (PAs) employed by haemophilia treatment centres (HTCs) across the United States. Methods This one-time convenience online survey was approved by the Munson Medical Center Institutional Review Board. A survey of this type had never been attempted in the HTC nursing community; therefore. there was no opportunity to utilise a previous tool. Data was analysed using statistical tools through SurveyMonkey. Results Gaps were identified in provider age distribution, research opportunities, and standardised educational opportunities for APPs. An aging but highly educated HTC nursing population is revealed: over 50% of respondents were over the age of 50; the majority held at least a baccalaureate degree and almost half had national board certification; most were experienced in healthcare but newer to the field of bleeding disorders. Conclusion Development of an APP fellowship program would standardise the care and treatment of those with bleeding and clotting disorders across the United States. This fellowship should include a didactic portion, advocacy within the community, mentorship with experienced APPs and regular webinar-based case studies to review current trends in care. This survey is a call to action to begin standardised education programs for the advanced practice role.

Challenges in transition to adulthood for young adult patients with hemophilia: Quantifying the psychosocial issues and developing solutions

Congenital hemophilia is a rare bleeding disorder resulting from a deficiency of coagulation factor VIII in patients with hemophilia A (classic hemophilia) or of factor IX in patients with hemophilia B (Christmas disease) [1]. Approximately 20,000 individuals in the United States have been diagnosed with congenital hemophilia [2]. Severity of bleeding symptoms is related to the residual amount of factor activity present, with less than 1% representing severe deficiency, 1–5% moderate deficiency, and more than 5% up to 40% mild deficiency. Whereas those with mild disease may only have bleeding with major trauma or surgery, those with severe disease suffer from spontaneous bleeding, most typically in the joints, which results in joint arthropathy, pain, and disability over time. Until the late 1980s and early 1990s, viral contamination of early blood-derived products in the US resulted in a majority of patients becoming infected with human immunodeficiency virus (HIV) and Hepatitis B and C [3,4]. With the development of recombinant factor products, treatment has progressed from treating bleeding episodes acutely (on-demand therapy) to routine administration with a goal of preventing bleeding, known as primary prophylaxis if started early in childhood with normal joints or secondary prophylaxis if initiated after joint bleeding. Improvements in care were also disseminated through a nationwide regional network of hemophilia treatment centers (HTCs), which treat children, adults, or both [5]. Psychosocial issues affect the ability of people with hemophilia (PWH) to lead the lives that they desire [6]. The Hemophilia Experiences, Results and Opportunities (HERO) initiative was developed to address the need for increased understanding of the psychosocial issues facing PWH and was led in part by a multidisciplinary International Advisory Board of health care professionals (hematologists, nurses, physical therapists, psychologists), patients, and caregivers. Following a systematic literature review [6], qualitative interviews of 150 healthcare professionals, patients, and caregivers in seven countries led to a quantitative survey of 675 adult PWH and 561 caregivers representing 10 countries. Overall results of HERO demonstrated issues with access to treatment and treatment centers even in developed countries, arthropathy-associated pain, and significant impacts of hemophilia on both employment and relationships [7–9]. Traditionally, HTCs and recommendations of national organizations have focused on comprehensive care approaches to the transitions associated with childhood development, and a new emphasis at the other end of the spectrum on issues associated with PWH reaching middle-age and advanced years. However, the transition from childhood to adulthood, with increased independence in living situations and financial responsibilities and engagement in adult relationships, may be particularly challenging for young adult PWH (YA-PWH). Little is known specifically on this group between ages 18–30 that spans the pediatric and adult HTC. This supplement provides a quantitative look at the psychosocial issues and quality of life in YA-PWH. Witkop et al. [10] and Curtis et al. [11] present data from the HERO study and Hemophilia Utilization Group Studies (HUGS). Quon et al. [12] then presents a comprehensive approach toward defining the key issues to be addressed by comprehensive care to address this transition group and results of roundtable discussions around solutions. In HERO, the 66 YA-PWH of 189 US adult respondents were more likely to receive prophylaxis than on-demand treatment, with a quarter of US respondents reporting issues with access to factor replacement [10]. Many YA-PWH reported comorbidities, including arthritis, chronic pain, and viral infections, and nearly half reported anxiety/depression. Roughly one third reported that hemophilia affected their ability to develop close relationships with a partner, and while nearly four in five US YA-PWH were employed, most reported that hemophilia has had a negative impact on employment [10].