Research Studies

Objectives:

To better understand what symptoms beyond bleeds are experienced, as well as the depth of impact of these symptoms and how they uniquely impact people living with hemophilia on a daily basis. Additionally, the study aims to better understand patients’ satisfaction with current treatments in addressing their hemophilia needs.

Design/Method:

An email invitation was sent to all U.S. members affiliated with hemophilia A of MyHemophiliaTeam, a social network of people diagnosed with or caring for someone with hemophilia. 54 members responded to a 24 question survey between April 19 and May 1, 2017.

Results:

Hemophilia had a significant negative impact on the day-to-day life of adults (72%) and children (52%). Pain was the most broadly and acutely experienced symptom: 60% of adults and 28% of caregivers felt that pain had a major impact on their lives and 33% of adults and 25% of caregivers considered mobility to be significantly impacted by hemophilia.

For adults, both pain and mobility limitations impacted sleep (71% and 45%, respectively), being able to perform chores (71% and 65%), and the ability to work (48% and 45%). For children, these conditions impacted school attendance (61% and 58%) and participation in high impact activities like running or playing soccer (56% and 75%).

Depression and anxiety were also common symptoms that impacted sleep across adults (71%, 61%) and children (60%, 55%). Adults most commonly reported feeling negative ones: stress (38%), fatigue (38%) and annoyance (35%).

81% of adults and 86% of caregivers were extremely or very satisfied with current treatment. However, needs beyond treating bleeds are currently not being met. Few felt their pain was adequately addressed by current therapies (74% of adults and 57% of children reported no relief). Mobility impairment issues were also not being adequately addressed. Time spent on treatment impacted people with hemophilia (39% of adults and 43% of children, respectively were not satisfied with the frequency of treatment).

Background:

While people with hemophilia are known to suffer from bleeding, numerous concomitant symptoms also burden these patients, including pain, mobility impairments, depression, and anxiety. These symptoms can have a significant impact on quality of life, limiting work and school attendance, causing social withdrawal, and encouraging inactivity. Additionally, available treatment options can sometimes fall short in treating the totality of hemophilia symptoms.

Conclusions:

People with hemophilia have many challenges beyond bleeds that are not currently being well addressed. This is particularly true for the pain experienced. As such, a more holistic approach to treating hemophilia beyond bleeds would be beneficial to patients living with hemophilia. Additionally, therapies that reduce the need and frequency for treatment could potentially lower the burden of disease.

Objectives:

The primary aims of this study are to 1) evaluate the prevalence of depression and anxiety among adult persons with hemophilia (PWH) and 2) explore relationships between depression, anxiety, chronic pain, and adherence to clotting-factor treatment.

Method:

This study used a subset of data from the IMPACT QoL II, a one-time, cross-sectional survey of 200 adults (age >18) with self-reported diagnosis of either Hemophilia A or B who were able to read, write, and speak English. The study was approved by the IRB in the primary investigator’s institution. Participants were a convenience sample recruited at bleeding disorders conferences in 2013-2014 and issued a randomly generated identification number to ensure anonymity. The 139-item survey was completed electronically through SurveyMonkeyTM on a study computer tablet. Participants were given $20 upon completion of the survey, which took 15-45 minutes to complete. The subset of variables evaluated for this analysis included the Faces of Pain Scale-Revised (FPS-R) (chronic pain), level of control over pain each participant feels they have, adherence to clotting factor measured by total scores (higher score=lower adherence) on the VERITAS-PRO or VERITAS-PRN, anxiety measured by the GAD- 7, depression measured by the PHQ-9, and self-report of ever receiving a diagnosis of depression and/or anxiety. The cut-off score for presence of moderate to severe depression or anxiety was 10 on both the PHQ-9 and the GAD-7, scores which have been validated by previous literature in other populations. Lower vs. higher adherence was defined by VERITAS scores in the highest and lowest quartile respectively.

Summary:

Participants with lower treatment adherence (VERITAS score >57) were more likely to have PHQ-9 scores >10 (P=0.02). GAD-7 scores >10 also demonstrated a trend to be associated with lower treatment adherence (P=0.15). 28% of participants reported a diagnosis of depression, but 53% with PHQ-9 scores >10 had not been diagnosed with depression. Similarly, 22% reported a diagnosis of anxiety but 52% with GAD-7 scores >10 had not been diagnosed. Participants who reported non-control of pain were more likely to have PHQ-9 scores or GAD-7 scores >10 (P=0.001 and P=0.013 respectively). There were significant correlations between PHQ-9 and GAD-7 (Rho=0.76, P<0.0001), PHQ-9 and FPS-R (chronic pain) (Rho=0.31, P=0.003), and GAD-7 and VERITAS (P=0.005). These data indicate that depression and anxiety are associated with greater severity of chronic pain, and depression is associated with poorer adherence to clotting factor treatment regimen (prophylaxis or other regimen). Both depression and anxiety appear to be under-diagnosed in PWH.

Objective:

To identify sociodemographic, clinical and treatment characteristics associated with the quality of life (QoL) of individuals with hemophilia B (HB) using longitudinal data in the HUGS Vb cohort.

Methods:

Between 2009-2012, 148 persons with HB were enrolled into HUGS Vb, a prospective cohort study examining individuals seen at ten federally supported U.S. hemophilia treatment centers (HTCs). Participants or parents of pediatric enrollees completed periodic surveys; data from 107 individuals with at least three follow-up surveys, clinician charts and dispensing records were included in the analyses. Data were analyzed at baseline and 6-month intervals across 2 years, yielding 5 time points. Periodic QoL assessments (SF-12 for adults and PedsQL for children), self-reported pain, employment and insurance status, time lost from work/school and treatment regimen were collected. Descriptive statistics and Spearman’s correlation coefficient test were used to examine the associations.

Summary:

Forty-six percent of the sample had severe HB; 50% were children (2-17 years). Among those with severe HB, 64% of children and 50% of adults treated prophylactically. 58% of adults were employed full-time. Individuals with mild hemophilia missed more work/school days due to disease-related issues (8 days) than those with moderate hemophilia (2 days) or severe hemophilia (3 days, P=0.03). QoL scores were similar over time among those using prophylactic and on-demand treatment for both adults and children. Median adult Mental Component Scores (MCS) and Physical Component Scores (PCS) measured at 5 time points ranged from 53.0 to 55.1 for MCS and 45.5 to 50.5 for PCS, with no significant changes observed over time. However, adults employed full-time had significantly higher median PCS at each time point than those working less than full-time (all Ps<0.05). Adults who reported pain had significantly lower median PCS than those who reported no pain/pain only when bleeding at each time point (all Ps<0.03). Median MCS remained similar between the two groups. Overall, we observed no longitudinal differences in children’s total PedsQL scores (range of median: 81.2-92.4) or in functioning subscales. However, among 18 children with QoL scores at both baseline and 24 months, missed school days were significantly correlated with decreased social functioning over time (rho=0.73, P<0.001). 8% of children who reported pain had consistently lower median total QoL scores than those reporting no pain/pain only when bleeding, despite having access to insurance and prophylactic treatment.

Conclusions:

Longitudinal data collected by HUGS Vb provide a valuable opportunity to examine the association of HB patient characteristics with measures of QoL in a multi-state sample. These data demonstrate that lower QoL was consistently associated over time with multiple factors, including absence from school, unemployment and pain. Continued analysis of this cohort will increase our understanding of the challenges faced by persons with HB.

Objective:

My Life, Our Future (MLOF) seeks to advance understanding of hemophilia by developing the MLOF Research Repository, a resource for use in scientific study. To strengthen the database and improve clinical care for females, MLOF expanded in 2016 to collect data and samples from potential and confirmed carriers.

Methods:

MLOF is a collaboration between the American Thrombosis and Hemostasis Network (ATHN) (educates HCPs, collects and protects genetic data, manages ATHNdataset, manages research review committee), Bloodworks Northwest (BWNW) (performs genetic testing and analysis, manages MLOF Research Repository), National Hemophilia Foundation (educates patients and the community), and Bioverativ (provides scientific collaboration and sponsorship). Patients enrolled in MLOF can contribute their de-identified clinical information and specimens (DNA, RNA, plasma and serum) to the MLOF Research Repository. The patients’ hemophilic genetic data (F8 or F9 variant) and specimens are stored at BWNW and their clinical data in the ATHNdataset. For carrier project participants, an ISTH Bleeding Assessment Tool score is determined, and for confirmed carriers factor levels are obtained and recorded in ATHN Clinical Manager. Upon enrollment of 5,000 participants, the MLOF Research Repository was opened to U.S-based investigators in February 2017. Investigators were encouraged to partner with a participating hemophilia treatment center (HTC) on projects for clinical translational support. An independent, international, multidisciplinary panel of experts was convened to review research proposals, evaluating project feasibility, scientific merit and potential contribution to the bleeding disorders community.

Summary:

To date, 97 HTCs are actively participating in MLOF and have enrolled 8,246 patients. Of those, 83% (6,857), including 723 confirmed carriers, have consented to research. The samples of 427 additional females consenting to research are pending evaluation; 1,643 females have participated in MLOF. The first MLOF Research Repository cycle received 9 Letters of Intent and 7 were chosen for full proposal review. The final selection of studies will be announced to the community in June 2017.

Conclusions:

Combining and analyzing genetic and clinical data via this database may allow researchers to solve unmet needs in patients with hemophilia, including understanding inhibitor development, bleeding severity or aiding in identifying new therapeutic targets. By considering molecular drivers of disease and genetic variability, this approach could lead to more individualized treatment through advancement of precision medicine. Global expansion of the MLOF Research Repository is planned for 2018. Carrier testing may help females manage their bleeding disorder and may aid in family planning. Related to research, females provide a unique control group for males with hemophilia on natural history, modifier genes inside and outside the coagulation system, and epigenetic factors affecting outcomes.

Objective:

Patients with hereditary bleeding disorders have been included in Phase 2 and 3 clinical trials of sofosbuvir (SOF), ledipasvir/sofosbuvir (LDV/SOF), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) as well as in a dedicated study (n = 120) in this patient population. This integrated analysis evaluates the safety and efficacy of SOF-based regimens in HCV-infected patients with hereditary bleeding disorders.

Methods:

HCV-infected patients with a medical history of a hereditary bleeding disorder who participated in a SOF-based Phase 2 or 3 study were included in this pooled analysis. Medical history term(s) used to identify patients with bleeding disorders included variations of Hemophilia A or B, Von Willebrand’s Disease, Factor Deficiencies, or conditions associated with hemophilia.

Summary:

A total of 201 patients (74 GT1, 10% GT2, 14% GT3, 2% GT4, <1% GT5) with bleeding disorders were identified across 19 studies. The majority were male (91%), Caucasian (82%), IL28B non-CC (70%), HCV treatment-naïve (55%), and without cirrhosis (74%). Hemophilia A (65%) and B (26%) were the most common bleeding disorders. SVR12 results are shown in the below table by treatment regimen and genotype. The most frequently reported adverse events (>10%) were fatigue and headache; majority were mild or moderate in severity. One patient (<1%) discontinued LDV/SOF due to an adverse event and 11 patients (5%) experienced a serious adverse event. Hemarthrosis, muscle hemorrhage, epistaxis, hematoma, and hematuria were the only hemorrhagic events that occurred in >1 patient. Grade 3 or 4 laboratory abnormalities were infrequent with anemia and hyperbilirubinemia the most frequent Grade 3 laboratory abnormality consistent with RBV administration.

Conclusions:

SOF-based regimens led to high rates of SVR in genotype 1–5 HCV infected patients with bleeding disorders. SOF-based regimens were safe and well tolerated with no new toxicity specific to patients with bleeding disorders emerging
.

Background:

Hemophilia is an inherited bleeding disorder caused by an impairment in the body’s ability to accomplish the natural clotting process. People with hemophilia experience bleeds because there is an inadequate amount of thrombin due to a deficiency in factor VIII or IX. Thrombin is critical to clotting and sealing the wound by converting fibrinogen into fibrin, reinforcing the primary platelet plug. Thrombin activity is regulated by antithrombin.

Fitusiran is a subcutaneously administered investigational RNA interference (RNAi) therapeutic targeting antithrombin with the goal of improving thrombin generation to promote clotting in people with hemophilia A or B with and without inhibitors. Fitusiran is currently being evaluated as a prophylactic agent for hemophilia A and B with and without inhibitors in an ongoing Phase 2 extension study. Breakthrough bleeds on the study are being managed using replacement factors (non-inhibitor patients) or bypassing agents (BPAs; inhibitor patients). The use of replacement factors or BPAs in the background of fitusiran treatment is of clinical interest and will be described.

Methods:

The Phase 2 extension study (NCT02554773) includes people with hemophilia A or B with and without inhibitors, previously dosed in the Phase 1 (NCT02035605) study. Participants receive monthly, fixed subcutaneous doses of fitusiran, 50 mg or 80 mg. Data on breakthrough bleeds and how they were treated were collected by patient diary.

Results:

As of May 2017, 33 participants were enrolled in the study. Previously reported data demonstrated that fitusiran was generally well tolerated and led to dose-dependent antithrombin lowering, thrombin generation increase, and decrease in bleeding frequency in participants with hemophilia A and B with or without inhibitors. Among those achieving target antithrombin lowering of >75%, few bleed events occurred during the observation period. Bleed events were treated with factor concentrates (FVIII or FIX) or bypassing agents (rFVIIa or aPCC), respectively, in doses according to or lower than recommended by the WFH guidelines. Detailed analyses of the frequency and management of bleed events in the Phase 2 study will be presented.

Conclusions:

Clinical data suggest that fitusiran may be a promising investigational prophylactic therapy to promote appropriate clotting and reduce the frequency of bleeding in people with hemophilia A or B with and without inhibitors. Further, the initial limited experience in treating breakthrough bleeds with replacement factor or BPAs has been encouraging, demonstrating good treatment effect in the absence of identified safety concerns.

Swimming is an important life skill that benefits hemophilia patients medically and psychosocially. The goal of this project is to provide inner city children and teenagers the opportunity to learn how to swim. The swim program will be held at the Detroit Medical Center, where a team of professionals will teach the basics of swimming with the goal of independent swimming by the end of the program. The team will measure the children's progress medically and psychosocially throughout the program. This program will provide children and teenagers at our HTC with an amazing opportunity and also a very important life skill. We will also be using adult hemophilia patients to teach the children how to swim, which will provide them with work experience and community involvement.

Objective:

Limited evidence supports activity-associated bleeding risk assessment for people with hemophilia (PWH), and consumer materials generically describe types of risk and a single activity risk score based on input from a few physical therapist (PT) authors. The aim of AIR was to assess activity-specific risk ranges, bleed-specific risks, and inherent/modifiable factors that increase risk based on survey/consensus of PT experts.

Methods:

Peer- nominated PTs from US hemophilia treatment centers (HTCs) were invited to participate in a survey regarding ~100 sports/recreational activities. For each activity, respondents provided a low (minimum) and high (maximum) risk assessment on a 5-point scale (low=1, high=5). Position-specific assessments were made for some team sports (eg, baseball pitcher, catcher, and field positions). Sports with distinctly different rules for contact were evaluated separately (eg, flag/tackle football, boys/girls lacrosse, Frisbee/ultimate). Drivers of risk were identified from free text comments and explored at a consensus meeting. Drivers of risk were categorized as inherent, modifiable, activity-driven, and patient-driven.

Summary:

Of 32 invited PTs, 17 responded to the survey with median 26.5 years as a PT and 15.5 years at an HTC; 8 participated in the full-day consensus meeting. Of the survey participants, majorities reported treating adults (94%) and treating children (88%), and most worked in the HTC full- time (29%) or nearly full-time (41%). Overall, few activities had low and high risk assessments both fall within the lower (1) or upper (5) end of the response range. For example, swimming is associated with low risk scores, even when including maximum risk with year-round competitive teams (median low 1, high 2), and tackle football had consistently high scores (median low 5, high 5). Risk scores (median low, high) for some common sports were as follows: baseball pitcher (3,4), catcher (3,4) or other position (2,3); basketball (2,4); hockey (4,5); skiing-downhill (2,4); soccer goalie (2,4) or other position (2,4); snowboarding (3,5). Risks for joint injuries were consistent with position and motion requirements for each sport, while head and muscle bleeds were associated with contact. Key drivers of risk that were identified included progression from seasonal participation to year-round play, overtraining, competitive level, participation in tournaments, and improper body mechanics. Inherent risks included impact with surface/ball/equipment (eg, soccer goalie), impact with players (eg, football), or falls (eg, horseback riding). Modifiable risks included tricks/stunts (eg, skateboarding) and use of safety equipment when not required.

Conclusion:

AIR provides insights into activity-specific risk for PWH including types of bleeding risk and drivers of increased risk. The results may provide a broader framework for assessing activities with respect to bleed site-specific risks and for recognizing how certain activities may be modified to decrease risk or to identify those with non-modifiable inherent risks for injury.

Objective:

The B-HERO-S study evaluated the impact of mild-severe hemophilia B on the lives of affected adults and children. Here we assess the impact of hemophilia B on relationships.

Methods:

US adults with hemophilia B and caregivers of affected children completed separate 1-hour online surveys that included questions regarding impact on interpersonal relationships.

Summary:

Most (88%) of the 299 adults completing the survey had mild-moderate hemophilia B. Of those, 54% were married or in a long-term relationship, and 44% were single. Most adults (87%) reported that hemophilia impacted their ability to form close relationships with partners or prospective partners; 35% were very/quite dissatisfied with the support received from a previous partner. Ninety percent reported that their experiences in a prior relationship, including satisfaction with support from their previous partner, impacted their decision to enter a relationship with their current partner. Nearly all participants (98%) were very/quite satisfied with the support received from their current partner. The top reason for satisfaction was “my partner takes the lead in providing financial security” (45%). Most were very/quite satisfied with the support from family (87%) and friends (96%). Most participants reported a negative reaction or experience as a result of disclosing their hemophilia (friend/colleague/employer, 76%/80%/82%); some reported having felt bullied by peers/colleagues (69%/66%). Majorities reported that past experiences impacted which friends/colleagues they told about their hemophilia, and how or when they disclosed their hemophilia status to these individuals (97%/95%). Seventy-four percent of participants indicated that hemophilia has affected the quality of their sex life; only 54% were extremely/moderately satisfied with their overall sexual relationship. Many reported having had a bleed during sex (40%). Of 150 caregivers of children with mostly mild-moderate hemophilia (74%), 89% were married or in a long-term relationship, and most felt very/quite supported by their partner (98%) and family (87%). Impact on unaffected siblings was more often mixed (49%) than negative (18%). Most felt very/quite satisfied with support of teachers (91%), children at school (80%), and other adults in regular contact (72%). Most caregivers reported negative experiences telling a friend (76%) or having their child tell a friend (69%) about the child’s hemophilia; 43% reported that their child was bullied as a result of having hemophilia.

Conclusion:

While the impact of severe hemophilia on relationships has been reported in HERO and other studies, B-HERO-S suggests that mild-moderate hemophilia B also significantly impacts relationships of affected men/women and boys/girls, especially in terms of disclosure, intimacy, and feeling bullied by peers/colleagues. Opportunities may be explored to more proactively counsel individuals with mild-moderate hemophilia B and families in the setting of comprehensive care to better navigate interpersonal relationships and improve quality of life.

The purpose of this project is to request support for the development of a Virtual Reality Environment (VRE) study program for pediatric patients diagnosed with hemophilia. The VRE program proposed was developed and created for children and includes interactive imagery, character avatars and colorful visual environments. This VRE program will be deployed by the child in a clinical setting and is proposed to help decrease, anxiety and needle phobia during intravenous factor infusions. Outcome measures will include an anxiety scale before and after each infusion, collection of biophysiologic data, pain score and visual analogue evaluation. The expected result of this nursing project is to monitor the use of a VRE in the pediatric population with a reduction of fear, anxiety and pain experienced with intravenous factor infusions.

Dr. Parthasarathy's research will tackle two important biological issues in coagulation - namely how procofactor FVIII converts to the active cofactor form (FVIIIa) and binds to IX and X, and the location of FVIII in generating the active Xase complex. Results from this study will provide molecular and biochemical insights into the role of FVIIIa in regulating hemostasis and further elucidate the interactions between coagulation complexes. Dr. Parthasarathy obtained his Masters in Biotechnology from Jawaharlal Nehru University in New Delhi, India and received his Ph.D. in Biochemistry from the University of Kansas in 2011. He has been a postdoctoral researcher in the lab of Dr. Rodney Camire at The Children's Hospital of Philadelphia since July 2011. This award has been made possible through a generous donation from Hemophilia of Georgia, Inc.

It is unknown if there are differences in attitudes and behaviors between mothers of sons with hemophilia who have a known family history of hemophilia compared to mothers without a known family history. To capture these differences, this study will measure mothers' perceived vulnerability of their sons, protective behaviors toward their sons and reported stress in the mother-son relationship. Sixty mothers will complete the following surveys: Parent Protection Scale, Child Vulnerability Scale and Parenting Stress Index/Short Form. The results of this data will influence clinic social work practice in the comprehensive care model at hemophilia treatment centers.

Dr. von Drygalski's research focuses on better understanding the mechanisms operating the anti-fibrinolytic system and how this process works in patients with hemophilia and specifically with joint bleeding. Accelerated fibrinolysis and clot instability are becoming increasingly recognized as contributing factors to bleeding in hemophilia. One important molecule that prevents fibrinolysis is called TAFI (Thrombin Activatable Fibrinolysis Inhibitor). Dr. von Drygalski will be studying the dual anti-fibrinolytic and anti-inflammatory functions of TAFI in hemophilia arthropathy and develop a therapeutic TAFI-based approach to improving the efficacy of FVIIa based bypassing strategies for acute bleeding and joint protection. Her mentors and collaborators are John H. Griffin, PhD, Laurent O. Mosnier, PhD and Martin Lotz, MD, distinguished researchers at UCSD -The Scripps Research Institute. Dr. von Drygalski received her M.D. from the Universities of Erlangen/Nurnberg and Munich in 1995 and her Pharm.D. from the University of Munich in 1988. She joined the faculty in July 2011 as Assistant Clinical Professor at UCSD and Director of the Adult Hemophilia and Thrombosis Treatment Center, Division of Hematology/Oncology, Department of Medicine. She also has an appointment as Adjunct Assistant Professor at the Scripps Research Institute (TSRI). The funding for this award is made possible thanks to a generous grant from Novo Nordisk.

Per Dr. Fu, the JGP provided her with the opportunity to work on hemophilia, as well as von Willebrand disease. After the completion of her JGP project, Dr. Fu remained in the bleeding disorder field.