Research Studies

Klaus Bonazza received his Ph.D. in chemistry from Vienna University of Technology. He is currently a postdoctoral researcher at Boston Children's Hospital and appointed at Harvard Medical School, mentored by Dr. Timothy Springer. His field of interest is the ultra-large concatemeric protein von Willebrand factor (VWF), which accounts for the adaptability of hemostasis to different flow conditions in the blood vessels.

At moderate, physiological flow VWF has a packed, "bird nest's" shape whereas strong elongational flow conditions, occurring downstream of vascular restrictions or injuries, induce a transition to a threat-like, elongated state. On top of this overall unpacking, tensile forces, which are exerted on the chain and transmitted by its A1 domain, cause local conformational changes which activate binding of thrombocyte receptor Glycoprotein Ib (GPIbα) to initiate coagulation. With his JGP fellowship award, Dr. Bonazza will pioneer a new method to obtain structural insights into force dependent VWF unpacking, A1 deformation and GPIbα binding based on hydrogendeuterium exchange under elongational flow conditions.

Objective:

The purpose of this study is to explore the bivariate and linear relationships between and among self-compassion, hope, and quality of life (QOL) among individuals with bleeding disorders. It is expected that these findings will guide the development of positive psychological interventions for this population.

Methods:

The final sample included 86 participants (61.6% male) with a mean age of 29.7 years (SD = 14.42). The majority of participants were diagnosed with hemophilia A (44.2%) or von Willebrand disease (44.2%). Participants completed a demographic questionnaire, and 3 self-report measures: the Self-Compassion Scale (SCS; Neff, 2003), the Adult Hope Scale (AHS; Snyder et al., 1991), and the PedsQL Inventory – Core Generic (Varni et al., 1999). The SCS is a 26-item scale with 6 subscales. Three subscales assess positive components (self-kindness, common humanity, and mindfulness) and three subscales assess negative components (self-judgment, isolation, and over-identification). The AHS is a 12 item instrument comprised of two scales: agency (the ability to identify goals for the future) and pathways (the ability to identify means to achieve those identified goals). The PedsQL assesses physical, mental, social, and school/work domains of QOL, in addition to total QOL, assessing all subscales.

Summary:

There was a significant and positive relationship between overall Quality of Life (QOL) and Overall Self-Compassion (r = .39, p < .001). There were significant and inverse bivariate relationships between Overall Quality of Life and each of the negative Self-Compassion components including Self-Judgement (r = -.44, p < .001), Isolation (r = -.35, p < .001), and Over-Identification (r = -.45, p < .001). A multiple regression analysis was conducted to explore the linear relationship of self-compassion and hope with QOL. Self-Compassion and hope were found to be significant concurrent predictors of QOL, F (2, 83) = 11.45, p < .001. Examination of the standardized beta weights revealed that hope (β = .31, t = 2.54, p < .05) was the only significant individual contributor to QOL.

Conclusions:

Hope and self-compassion were identified as variables that contribute to QOL among individuals with bleeding disorders. Hope, defined as the ability to identify and work toward identified goals, was the strongest predictor of QOL in the model. These findings provide implications for the use of hope-increasing interventions as a means to improve QOL. These findings provide further evidence for the use of strengths-based strategies to enhance well-being within the bleeding disorder population. Future studies could evaluate the effectiveness of specific interventions to improve hope and QOL among various subsets of the bleeding disorder community.

Introduction and Objectives:

The National Hemophilia Foundation (NHF) has offered the Inhibitor Education Summits (also known as the summits), a live consumer education conference, annually for more than ten years. The summits are for people with hemophilia A or B with an active or tolerized inhibitor and their support network. In 2017, NHF introduced a new component to the conference: Inhibitor Teams.

Materials and Methods:

NHF met with the National Inhibitor Summit Steering Committee in 2016 and developed the idea of Inhibitor Teams as a way to better engage participants by connecting them with other members of the inhibitor community that they might not otherwise meet. Inhibitor Teams are small groups of randomly assigned participants that meet three times throughout the conference. Some Inhibitor Summit faculty and NHF staff moderated their pre-assigned group’s discussions as Inhibitor Team Leaders. Inhibitor Team Leaders were trained prior to each summit. Each participant’s badge included their Inhibitor Team name on it as a way for participants to easily identify their team members. The conference app was adapted to foster team member connection.

Results:

A total of 214 families (727 individuals) attended the summits in 2017. Of these families, 11.21% had never attended summit before, so connecting with fellow participants was particularly meaningful. Likewise, active inhibitors were represented in 56% of the families; through their Inhibitor Teams they could connect with others that have been or are going through the challenge of an active inhibitor. Participants on average agreed (4.19 on a 5 point Likert Scale) that they found value in meeting with their Inhibitor Team. Qualitative evaluation data collected also supports this. For example, one participant said, “teams were a great way to meet folks I otherwise may or may not have met or got [the] chance to talk to. Like meeting others that share same life experiences as myself and my family.”

Conclusions:

Inhibitor Teams were a welcomed addition to the Inhibitor Summit program in 2017 with participants finding value in the time spent with their team.

Objective:

Hepatitis C virus (HCV) infection is a significant health problem for patients with bleeding disorders due to the absence of highly effective HCV screening of blood products prior to the early 1990s. The aim of this analysis was to evaluate the safety and efficacy of the ribavirin-free regimen of glecaprevir/pibrentasvir (G/P) among patients with a history of bleeding disorders.

Methods:

Data from 11 Phase 2 and 3 registrational studies conducted across 18 countries worldwide were included. HCV genotype (GT) 1–6-infected patients with compensated liver disease received G/P for 8, 12 or 16 weeks. The sustained virologic response 12 weeks after end of treatment (SVR12) rate and safety are reported.

Results:

Sixty-two patients with history of bleeding disorders were identified, the most common disorder being hemophilia (37%, [23/62]). The remaining 63% (39/62) of patients had other disorders, including Von Willebrand disease. The cohort was 76% (47/62) male and 89% (54/62) white race with a mean age of 50.5 years (standard deviation ± 12.1). Additionally, 23% (14/62) had compensated cirrhosis. The HCV genotype breakdown among the patients was: GT1, 39%; GT2, 18%; GT3, 21%; GT4, 13%, GT5, 8%; GT6, 2%. In addition to bleeding disorders, a medical history of anemia was reported in 16% (10/62) of patients. SVR12 was achieved in 100% (62/62) of patients. Adverse events (AEs) were reported in 68% (42/62) of patients, and 37% (23/62) of patients experienced an AE assessed as possibly related to study drugs. Serious AEs (SAE) were reported in 3 (5%) patients, none being assessed as related to the study drugs; 2 of these SAEs (1 per patient) were associated with the underlying bleeding disorder. There was 1 (2%) AE leading to discontinuation of study drug (dyspepsia); the patient went on to achieve SVR12. There was 1 (2%) non-treatment emergent death reported, occurring 60 days after the last dose of study drug. Post-baseline grade ≥3 laboratory abnormalities occurred in 3 patients: one each in hemoglobin, aspartate aminotransferase and bilirubin (all n = 1; 2%), without concurrent elevations in alanine aminotransferase.

Conclusions:

G/P achieved a 100% SVR12 rate in patients with a history of bleeding disorders and demonstrated a favorable safety profile, thus providing support for treatment of chronic HCV infection with the G/P regimen in this patient population.

Background:

Emicizumab was approved by the FDA in 2017 for routine prophylaxis in PwHA with inhibitors. HAVEN 1, a phase III study in adolescent and adult PwHA with inhibitors, demonstrated that emicizumab prophylaxis significantly reduced annualized treated bleed rate by 87% (P<0.001) vs no prophylaxis. In this retrospective, post-hoc analysis, we examined the use of BPAs to treat breakthrough bleeds before and after emicizumab initiation in HAVEN 1.

Methods:

HAVEN 1 patients were included from emicizumab-treated Arms A (previously treated with only episodic BPA) and C (previously treated with prophylactic BPA) and who had participated in the non-interventional study (NIS). In both studies, bleed and treatment data collection were comparable. In the study protocol, no guidance for the treatment of bleeds was provided; and hemostatic efficacy was not measured, thus optimal treatment of bleeds cannot be accurately assessed. Additionally, only data before October 7th, 2016 are included in this analysis to better represent treatment patterns before amended BPA guidance was provided. We describe the total number of patients and bleeds, number of infusions per bleed, and the cumulative dose/kg per bleed before and after emicizumab initiation.

Results:

This analysis (48 total patients) included 24 patients each from Arm A and Arm C who participated in the NIS prior to enrollment in the HAVEN 1 trial. On average, patients received numerically fewer activated prothrombin complex concentration (aPCC) infusions with lower cumulative doses while on emicizumab as compared to prior to emicizumab administration. In Arm A, 11 bleeds were treated with aPCC resulting in an average of 1.2 aPCC infusions/ bleed and an average cumulative aPCC dose/ bleed of 95.9 U/kg while on emicizumab as compared to 136 bleeds resulting in an average of 1.7 infusions/ bleed and cumulative dose 134 U/kg prior to emicizumab. Similar findings were seen in Arm C (bleeds, aPCC infusion/cumulative dose numbers: 14,2.3/166.6 U/kg on emicizumab compared to 205, 2.6/189 U/kg prior to emicizumab.) Fewer bleeds were treated with rFVIIa and no clear trend was seen regarding how rFVIIa was used to treat bleeds. In Arm A, 11 bleeds were treated with rFVIIa resulting in an average of 1.5 infusions/ bleed and cumulative dose 212.2 µg/kg on emicizumab, vs 97 bleeds, 1.4 infusions/ bleed and cumulative dose 181.6 µg/kg prior. In Arm C, 14 bleeds were treated with rFVIIa resulting in 4.4 infusions/ bleed and cumulative dose 555.6 µg/kg on emicizumab vs 58 bleeds, 8.6 infusions/ bleed and cumulative dose 1829 µg/kg prior.

Conclusions:

Treatment of bleeds with aPCC in HAVEN 1 resulted in numerically fewer infusions and lower cumulative doses of aPCC per bleed while on emicizumab when compared to bleeds treated prior to emicizumab initiation. Treatment of bleeds with rFVIIa showed no clear trend.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. Efficacy in maintaining hemostasis during major surgery was evaluated in a subset of patients with severe hemophilia A in the phase 2/3 PROTECT VIII study.

Methods:

Patients aged 12–65 years requiring major surgery during PROTECT VIII or its ongoing extension were included in the analysis. Patients with severe hemophilia A undergoing major surgery who were not enrolled in PROTECT VIII but met all study inclusion and exclusion criteria also were eligible to participate. BAY 94-9027 dosing during the perioperative period was based on preoperative pharmacokinetic measurements and adjusted at the physician’s discretion. Types of procedures and duration of surgeries, BAY 94-9027 consumption on the day of surgery, intraoperative blood loss, surgeon assessment of hemostasis during surgery, and need for blood transfusion were evaluated.

Summary:

17 patients (median [range] age, 37 [13–61] years) underwent 20 major surgeries, including 15 orthopedic surgeries (9 joint replacements [hip, n=1; knee, n=6; ankle, n=2], 2 open synovectomies, 3 arthroscopies, and 1 thigh hematoma evacuation), 3 complex dental extractions, 1 penile prosthesis, and 1 inguinal hernia repair at data cutoff (January 2015). Median (range) surgical duration was 102 (17‒217) minutes, and median (range) total dose used on day of surgery, including preoperative, intraoperative, and postoperative infusions on that day, was 72.4 (43‒136) IU/kg. Median (range) number of FVIII infusions on the day of surgery was 2 (1–3), with 40% of procedures requiring only 1 infusion (preoperative) on that day. Following a median (range) presurgical dose of 52.1 (41–64) IU/kg, the median (range) FVIII level (chromogenic assay; measured in a central laboratory) immediately before the second infusion was 71.6 (44–140) IU/dL; median (range) time between the presurgical and second infusions was 12.3 (3.6–50.0) hours. Hemostasis during surgery was good (13/20; 65%) or excellent (7/20; 35%) for all procedures. Intraoperative blood loss was within expected ranges for all surgeries (median [range], 50 [0–1000] mL), and blood transfusions were required in 4 patients undergoing knee surgeries.

Conclusions:

BAY 94-9027 is efficacious in maintaining hemostasis during major surgeries in adolescents and adults with severe hemophilia A. Excellent or good hemostasis with blood loss as expected was achieved in all surgical procedures, which included major orthopedic surgeries (75% of all procedures), with 40% of patients requiring only a single infusion of BAY 94-9027 on the day of surgery.

As a social worker at Gulf States Hemophilia & Thrombophilia Treatment Center, I have the privilege of serving patients across their lifespan. I would like to initiate grass roots education about hemophilia in Houston, Texas, by offering educational programming to specialized health care professionals who work directly with the aging population in nursing homes and assisted living communities. This would include executive directors and administrators of these facilities as well as direct clinical staff.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. In the PROTECT VIII Kids trial, BAY 94-9027 was efficacious for the prevention and treatment of bleeding episodes in previously treated children with severe hemophilia A. We report interim long-term efficacy and safety data from the PROTECT VIII Kids extension study.

Methods:

In PROTECT VIII Kids, previously treated patients (PTPs) aged <12 years with severe hemophilia A received BAY 94-9027 prophylaxis twice weekly (25‒60 IU/kg), every 5 days (45‒60 IU/kg), or every 7 days (60 IU/kg). Patients completing ≥50 exposure days (EDs) and ≥6 months in the main study or a 12-week safety substudy (part 2) that enrolled PTPs aged <6 years could continue in the optional extension for an additional ≥50 EDs.

Summary:

Fifty-nine of 73 patients treated with BAY 94-9027 in PROTECT VIII Kids (main study or part 2) continued in the extension (median [range] age at enrollment in the main study, 5.0 [2–11] years). At data cutoff (January 2018), patients had a median (range) of 1456 (351–1665) days in the trial (main study or part 2 plus extension). Patients in the extension received prophylaxis twice weekly (n=20), every 5 days (n=20), every 7 days (n=8), or switched prophylaxis frequency during the extension (variable frequency; n=11). Median (range) dose/infusion was 52.1 (19–62) IU/kg. Median annualized bleeding rate (ABR) for total bleeds was 1.8 for all patients and 0.8, 1.1, 2.1, and 3.2 for those treated twice weekly, every 5 days, every 7 days, or with varying frequency, respectively. Median ABR for joint bleeds in all patients was 0.7. During the extension, 3 patients (5.1%) experienced treatment-related adverse events (AEs) classified as mild (n=1), moderate (n=1), or severe (n=1). One patient discontinued because of a serious AE that was not related to treatment. No confirmed FVIII inhibitors or anti-PEG antibodies were observed; no patients had sustained levels of detectable PEG in plasma.

Conclusions:

Long-term treatment (up to ~4.5 years) with BAY 94-9027 prophylaxis was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

Dr. Shi is a Professor of Pediatric Hematology at the Medical College of Wisconsin and an Investigator of Blood Research Institute at the BloodCenter of Wisconsin. She earned her MD from Fujian Medical University in China in 1990 and her Ph.D. in 1998. Dr. Shi’s research focus is to formulate innovative therapeutic approaches for the treatment of hemophilia A, a genetic bleeding disorder caused by a lack of the critical blood clotting protein, factor VIII (FVIII). One of her research programs funded by the National Institutes of Health, National Heart, Lung, and Blood Institute, is to develop platelet-specific gene transfer strategies for the treatment of hemophilia A and hemophilia A with neutralizing antibodies. In the project supported by the NHF Bridge Grant, Dr. Shi will investigate the potential effect of the FVIII carrier protein, von Willebrand factor, on FVIII immune responses in hemophilia A. Dr. Shi expects that results from her studies will aid the design of more effective protocols to prevent FVIII immune responses and to induce FVIII immune tolerance in patients with HA.

Objective:

The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.

Methods:

A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.

Summary:

Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.

Conclusions:

HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.

Objective:

We sought to explore real-world outcomes, such as annualized bleeding rate (ABR) and markers of adherence, in persons with hemophilia A (PwHA) or with hemophilia B (PwHB) who receive standard half-life (SHL) or extended half-life (EHL) factor VIII (FVIII) or factor IX (FIX) replacement products.

Methods:

We analyzed de-identified data from the Adelphi Disease Specific Programme (DSP) database, a patient health record–based survey of hematologists in the US and 5 European countries (France, Germany, Italy, Spain and the UK). Data were collected from May–November 2017 for male patients with moderate or severe HA or HB. Outcomes in the two groups of patients (SHL vs EHL) were compared and descriptive statistics were used to summarize results.

Summary:

A sample of 595 patients with HA or HB met the inclusion criteria (US, n=123; Europe, n=472). Age, weight, and body mass index (BMI) were similar between SHL and EHL groups for PwHA and PwHB on both continents. Higher ABR was noted consistently in Europe vs the US. Hemophilia A: Analysis included 101 patients from the US (SHL, n=64; EHL, n=37) and 360 patients from Europe (SHL, n=340; EHL, n=20). The ABR was similar between both groups on both continents (median: US, 1.0 SHL and 1.0 EHL; Europe, 1.0 SHL and 1.5 EHL; mean: US, 1.3 SHL and 1.2 EHL, P=0.68; Europe, 1.8 SHL and 1.7 EHL, P=0.76). The mean of the physician-reported ‘number of doses missed of the last 10 doses’ appeared to be numerically higher in the EHL vs the SHL group in the US (mean: 0.4 SHL and 1.6 EHL, P=0.13), whereas in Europe, the trend was reversed (mean: 0.7 SHL and 0.0 EHL, P=0.29). Hemophilia B: Analysis included 22 patients from the US (10 SHL; 12 EHL) and 112 patients from Europe (91 SHL; 21 EHL). The median ABR for PwHA and PwHB in the US was 1.0 (SHL) and 1.0 (EHL), and the mean was 1.6 SHL and 0.8 EHL (P=0.25); in Europe, the median ABR was 2.0 SHL and 1.0 EHL, and the mean was 2.2 SHL and 1.6 EHL, P=0.25. The mean of the physician-reported ‘number of doses missed of the last 10 doses’ was 0.8 SHL and 0.5 EHL (P=0.63) in the US and 0.6 SHL and 0.1 EHL (P=0.33) in Europe.

Conclusions:

These preliminary real-world data, unadjusted for treatment regimen and inclusive of US and ex-US sampling, showed no clinically meaningful difference in ABR or adherence markers in PwHA or PwHB who received SHL versus EHL FVIII or FIX products. These observations may challenge assumptions regarding adherence and or clinical outcomes associated with SHL/EHL product selection among PwHA and PwHB. Further analyses should be explored.

Per Dr. Kumar, the JGP Fellowship has enabled him to test his ideas related to factor V biology. It has facilitated his scientific training to become increasingly independent in the planning and execution of his research. Important to note, findings generated from these studies have provided new concepts and tools to target factor V for therapeutic purposes. After the completion of his award in 2018, Dr. Kumar would like to continue his career in the field of hematology.

Dr. Jessica Garcia is currently a pediatric hematology/oncology fellow at the Medical College of Wisconsin/Children's Hospital of Wisconsin. Her clinical mentor is Dr. Joan Gill, Director of the Comprehensive Center for Bleeding Disorders (CCBD) in Milwaukee, Wisconsin.  Dr. Garcia's primary research mentor will be Dr. Veronica Flood, with Dr. Bob Montgomery as her secondary research mentor. Dr. Garcia attended medical school and completed her pediatric residency at the University of Illinois College of Medicine at Peoria/Children's Hospital of Illinois. During her pediatric residency, Dr. Garcia worked with Dr. de Alarcon studying the mechanisms underlying the thrombocytosis seen with iron deficiency anemia in an animal model. As a NHF-Baxalta Clinical Fellow, Dr. Garcia will receive specialized training in hemostasis and thrombosis, available through the Comprehensive Center for Bleeding Disorders (CCBD) and Blood Research Institute (BRI). Her research will focus on the biology of von Willebrand factor.