Research Studies

Knowing the importance of including the consumers voice in the future of research, the National Hemophilia Foundation (NHF) partnered with the software healthcare analytics company; ArborMetrix, to develop a cloud-based platform; NHF’s Community Voices in Research (CVR), formerly known as MyBDC.

Through CVR, NHF will be able to send out longitudinal surveys and follow participants for a minimum of 5 years.
 

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The objective of this study is to assess the relationship between self-reported physical activity, treatment regimen, mental health, and pain in persons with hemophilia (PWH) enrolled in CVR.
 

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Objective:

PUPs A-LONG aimed to evaluate the safety, including inhibitor development, and efficacy of extended half-life (EHL) recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A.

Methods:

This open-label, multicenter, Phase 3 study (NCT02234323) enrolled male PUPs aged <6 years with severe hemophilia A (<1 IU/dL endogenous FVIII) to receive rFVIIIFc. Primary endpoint was inhibitor development (incidence rate=number of patients with inhibitors/number of patients reaching ≥10 exposure days [ED] milestone or with inhibitors). A secondary endpoint was annualized bleed rate.

Summary:

Of 103 patients receiving ≥1 dose, 80 (77.7%) were <1 year old, 20 (19.4%) had a family history of inhibitors, and 82 (79.6%) had a high-risk hemophilia genotype. Eighty-one patients started on episodic treatment; of these, 69 switched to prophylaxis. Twenty patients started on prophylaxis, and 2 were not assigned a regimen. Eighty-seven (84.5%) patients completed the study. Eighty-seven (84.5%), 85 (82.5%), and 81 (78.6%) patients had ≥10, ≥20, and ≥50 EDs to rFVIIIFc, respectively. Total and high-titer (≥5.00 BU/mL) inhibitor rate was 31.1% (28/90) and 15.6% (14/90), respectively, for patients with ≥10 EDs (3 patients with inhibitors and <10 EDs included). Median time to inhibitor development was 9 EDs (range: 1–53). rFVIIIFc dosing and efficacy data are in Table 1. Twenty-eight (27.2%) patients had 32 rFVIIIFc adverse events assessed as related by the investigator (FVIII inhibition, n=28; soft tissue hemorrhage, n=1; deep vein thrombosis, n=1; device-related thrombosis, n=1; papular rash, n=1). There was 1 non–treatment-related death due to intracranial hemorrhage (onset during screening period before first rFVIIIFc dose).

Conclusions:

This was the first prospective study of an EHL, rFVIIIFc, as treatment for PUPs with severe hemophilia A. Overall inhibitor development was within the expected range, although high-titer incidence was lower than that reported in the literature. The data demonstrate that rFVIIIFc was well tolerated and effective in this pediatric patient population.

Objectives:

While publications have reported on mortality in PwcHA, a contemporary evidence-based understanding of mortality in congenital hemophilia A (HA) is absent. This systematic review aims to establish a benchmark of mortality rate and causes of death in PwcHA to enable comparisons and monitoring of mortality in a rapidly evolving treatment landscape.

Methods:

We conducted a systematic literature review of observational studies by searching Medline, Embase, and clinical trials registries for articles published January 2010 through March 2020, using the search terms: HA, mortality, cause of death. Interventional studies, studies not reporting fatalities, and those reporting only on hemophilia B, acquired HA, or mixed other coagulopathies were excluded. References of the included studies and literature reviews were checked.

Summary:

Overall, 7,818 unique records were identified; 1,144 manuscripts passed screening and 20 were included (Figure). In these 20 records, 6 reported mortality rates, 5 reported mortality ratios, and 16 reported cause of death. All studies reporting mortality rates and ratios were population-based; their data collection periods spanned 1961–2018, and most focused on the developed world.

Only four reports provided crude mortality rates (unadjusted for age) in the overall HA population, ranging from 0.38–0.75/100 person-years; two reported age-specific mortality rates. Age-adjusted mortality ratios generally decreased over time as life expectancies of PwcHA approached the general population. Mortality was strongly correlated with age and increased hemophilia severity. Comparisons of the risk of death in PwcHA to that of the general male population (standardized mortality or hazard ratios, adjusted for differing age distributions) ranged from 1.1–2.2 in the overall HA population (five articles) and from 2.4–6.6 in the severe HA population (three articles), indicating a raised mortality risk, particularly in severe HA. Two articles provided inconsistent mortality rates by factor VIII inhibitor status. HIV/HCV infection and liver disease were risk factors for mortality. Studies describing mortality from 1980–2000 reported a higher proportion of deaths from human immunodeficiency virus (HIV)/ hepatitis C virus (HCV).

Causes of death among PwcHA varied across populations, countries, and time in the 16 identified studies; however, underreporting of long-term outcomes limits evidence on mortality in PwcHA. Hemorrhage, HIV, HCV, and cancer were leading causes, with prevalence of cancer similar to the general population.

Conclusions:

Decreasing mortality ratios in PwcHA were observed across several decades, likely from advancements in detection, treatment and supportive care for hemophilia and related complications. Risk factors such as age and comorbidities should be considered when comparing mortality rates. Reporting of cause of death was highly heterogeneous, limiting practical categorization, hypothesis generation and actionable conclusions. A unified approach to reporting mortality and cause of death is needed to understand mortality in PwcHA and to monitor changes as treatments continue to advance.

Introduction/Background:

Maintenance of oral health is frequently challenging for US adults with a bleeding disorder. Underlying causes are due mainly to (1) lack of dental insurance and (2) lack of knowledge among dentists about how to perform safely either primary dental care or oral surgery. Without regular care, patients are at risk for advanced dental disease, which is associated with chronic inflammatory conditions, including type 2 diabetes and cardiovascular disease. Research indicates that controlling periodontal disease reduces inflammatory markers throughout the body, including synovial joints.

Materials and Methods:

The Gulf States Hemophilia and Thrombophilia Center (GSHTC) in Houston, Texas serves a diverse urban population; historically, about 50% of adult patients receive no dental care. In October 2019, GSHTC added adult dental exams to comprehensive care services. Patients are evaluated by University of Texas School of Dentistry residents and scheduled for routine or specialized dental procedures as needed. To assess the scope of dental needs in the GSHTC patient population, we examined the range of procedures recommended and the proportion of patients reporting oral health care problems. We report here preliminary results from the initial six months of adult dental services, October 2019 – March 2020. 

Results:

In this period, 171 adults with a bleeding disorder received dental evaluations, and 146 completed the Oral Health Impact Profile (OHIP-14). The OHIP-14 is a validated survey instrument consisting of 14 questions measuring seven dimensions of oral health: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability and handicap. Responses are rated on a 5-point Likert scale: 0=never, 1=hardly ever; 2=occasionally, 3=fairly often; 4=very often/every day. Total OHIP-14 scores can range from 0 to 56 and are calculated by summing the values for the 14 items. Higher scores indicate worse and lower scores indicate better health-related quality of life (HRQoL). Scores ranges from 0-52; 80 (55%) individuals had a score of 0-1 (no oral health problems); 48 (33%) scored between 2-9, and 18 (12%) had scores of 10 or greater. Since October 2019, nearly all adult patients seen in clinic have received a dental evaluation; approximately 40 patients in need of dental care have received treatment or a treatment plan. Procedures include deep cleaning, regular/surgical extractions, fillings, scaling, root planing, crowns, bridges and root canal, all of which require infusion of factor concentrate prior to treatment.

Conclusion:

A substantial proportion of patients who completed the OHIP-14 reported reduced HRQoL related to poor oral health; subsequent dental examination confirmed the urgent need for treatment in these individuals. Continued administration of the OHIP-14 will monitor the impact of dental treatment on patient HRQoL. Ultimately, we hope to provide evidence of the need for widespread inclusion of adult dental care among US Hemophilia Treatment Centers.

Objective:

Nonprofit organizations that provide educational programs and financial assistance to the bleeding disorders community often face barriers to sustaining and/or expanding their efforts. To help address these gaps in community programs and clinical care, the Hemophilia Alliance Foundation (HAF) created an annual grant funding mechanism that provides $8,000-$10,000 per applicant to increase the capacity of patient-focused organizations. The aims of this study are to evaluate longitudinal trends in these grant applications and gain critical insight into the perceived needs and interests of the patient communities that these organizations serve.

Methods:

HAF grant applications submitted between 2013 and 2020 were retrospectively assessed. The following variables were extracted and harmonized for use in longitudinal analyses: organization type (local chapter/member organization, hemophilia treatment center (HTC), regional core center, or other national organization), application year, geographic location, collaborators, and project descriptions. For collaborative grants, the organizational type was defined as that of the fiscal applicant. Through secondary analysis of project descriptions, indicator variables were created to identify application types (project-based and/or patient assistance-based) and project objectives.

Summary:

A total of 131 organizations submitted 585 grant applications from 46 U.S. states and territories from 2013-20. Among 562 (96%) approved applications, 331 (59%) were from chapter/member organizations, 131 (23%) were from HTCs, 58 (10%) were from regional centers, and 42 (7%) were from national organizations. By application type, 493 (88%) applications allocated funding to projects and 274 (49%) applications allocated funding to patient-assistance programs. The HAF has seen a consistent growth in both the number of applications (59 in 2013; 81 in 2020) and states represented (32 in 2013; 38 in 2020) per year, signaling an identified need for this additional funding source within the community. There has been a positive trend in the number of organizations submitting collaborative applications (17 in 2014; 38 in 2020), many of which have promoted increased visibility of and communication between local chapters and HTCs. In exploratory cross-sectional analyses of 67 chapters/member organizations and HTCs in 2019, 45% of applications allocated funding for hosting local events, 33% for attending national meetings (e.g. the National Hemophilia Foundation’s Bleeding Disorders Conference), 33% for capacity-building (e.g. office equipment, staff training), and 9% for developing new programs.

Conclusions:

This study provides unique insight into the perceived and persistent gaps facing bleeding disorders organizations at the local and national levels that have submitted grant applications to the HAF over an 8-year period. With organizations continuing to demonstrate a need for additional funding for patient-focused projects and assistance programs, further research into the increasing trend toward collaborative grant applications may offer an opportunity for more effective and efficient care in the bleeding disorders community.

Objective:

Women with Severe Von Willebrand disease (VWD), including Type 3 VWD, Severe Type 1/1C VWD (VWF ristocetin cofactor and antigen ≤10%), and Severe Type 2A (VWF ristocetin cofactor and antigen ≤10%) are at high risk for bleeding-related complications, including gynecological and obstetrical bleeding, however the prevalence of these complications in this population is unknown, as are optimum management strategies.

Methods:

Participants who attended the VWD Connect Foundation Annual meeting were given an Audience Response System to be used for the duration of the meeting. During the half-day Period Symposium, participants were surveyed, their responses were recorded and analyzed using basic statistical methods.

Summary:

22 patients and/or caregivers participated in the period symposium, 21 of which had demographic information. Participants were 100% female.  38% of participants were patients or caregivers of patients under 18, 14% were 18-29 years, 38% 30-45 years, 9.5% over age 45. The diagnoses of participants included 15 Type 3 VWD (71%), 1 Type 1/1C VWD (5%), 4 Type 2A VWD (19%), 1 other VWD (5%).

Women experienced high rates of complications related to gynecological bleeding including emergency department evaluation for heavy menstrual bleeding (HMB) in 53% (n=20), hospitalization for HMB in 50% (n=22), blood transfusion for HMB in 48% (including >2 times in 7/10), iron deficiency anemia in 76% (n=21), and hemorrhagic ovarian cyst requiring treatment in 44% (n=13). At menarche, 63% of women experienced prolonged menses >15 days (n=22), and at the current time 18% of women reported menses lasting >9 days (n=22). 78% of participants (n=14) reported starting hormonal therapy within 2 years of starting their period. Management practices varied, with most effective methods in managing periods reported as hormonal pills/patch/ring or medroxyprogesterone injection by 6, intrauterine device by 3, VWF infusions by 3 (n=15). For women on oral contraceptives, 6/7 were prescribed extended cycle oral contraceptives. Rates of surgical procedures to manage HMB were low in this young cohort, including hysterectomy (0%), dilation and curettage (n=1) or ablation (n=1).

HMB continues to have a negative impact on school and work functioning, with 66% of respondents (n =22) missing at least 1 day of school/work in the past year. Other challenges identified include improving access to knowledgeable OB/GYN providers with expertise in management of bleeding disorders.

Conclusions:

Women with Severe VWD have significant morbidity from HMB including high rates of hospitalization, high rates of blood transfusion, and hemorrhagic ovarian cyst rupture requiring medical treatment. Women should consider establishing care with a gynecologist prior to menarche to help prepare for menarche and to decrease the negative impact on school/work.  Ongoing prospective studies with a larger cohort are needed to better understand treatment effectiveness, impact on quality of life and inform practice guidelines.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans, but there are numerous barriers to accurate and timely diagnosis. In January 2021, new evidence-based guidelines were released by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) (James et al., 2021). The guidelines were designed to support patients, clinicians, and other health care professionals in promptly, accurately, and efficiently diagnosing VWD. Key recommendations in the guidelines include the use of bleeding-assessment tools when unusual bleeding is present and/or VWD is suspected; diagnostic assays; and the role of genetic vs. phenotypic testing for some types of VWD. Nurse practitioners can aid in identifying potential symptoms of VWD to help shorten the time from onset of symptoms to diagnosis.
 

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