Research Studies

Objective:

Haemophilia A is an X-linked recessive bleeding disorder that affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers, and more haemophilia carriers are seeking care in Haemophilia Treatment Centers. Given that data regarding the effect of increased bleeding on health related quality of life (HR-QOL) in haemophilia A carriers is sparse, we tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms.

Methods:

We conducted a cross-sectional, case-control study at Vanderbilt University in Nashville, Tennessee. Case subjects were obligate or genetically verified haemophilia A carriers age 18 to 60 years. Control subjects were recruited from mothers of children with cancer who receive care at the Vanderbilt pediatric hematology oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. The score for each of the eight health domains ranges from 0 to 100 with a lower score indicating poorer HR-QOL. Mann-Whitney U tests were used to compare median scores for the eight health domains between the case and control groups.

Summary:

Forty-two haemophilia A carriers and 36 control subjects completed the Rand 36- Item Health Survey 1.0 and were included in analyses. All but one participant had normal factor VIII activity. Haemophilia A carriers had significantly lower median factor VIII activity (75% versus 138.5%, p-value <0.001 by Mann-Whitney U test) and significantly higher Tosetto bleeding scores (5 versus 1, p<0.001 by Mann-Whitney U test) compared with controls. Haemophilia A carriers had a significantly lower median score for the domain of “Pain” compared to control subjects (73.75 versus 90; p= 0.02). In the domain of “General health”, haemophilia A carriers had a significantly lower median score compared to the control group (75 versus 85; p= 0.01).

Conclusion:

Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey in the domains of “Pain” and “General Health” compared to women in the control group. Our findings highlight the need for further investigation of bleeding in haemophilia A carriers and the effect of bleeding on HR-QOL in this population.

Objective:

Joint status was assessed in the 3-year SPINART study, which compared routine prophylaxis versus on-demand treatment in adults with severe hemophilia A. We report joint outcomes at year 3 obtained using magnetic resonance imaging (MRI).

Methods:

The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled males aged 12–50 years with severe hemophilia A who had ≥150 exposure days with any factor VIII (FVIII) product, no inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. Patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation by 5 IU/kg permitted once per year). MRI was performed at baseline and year 3 to evaluate the structure of 6 index joints. Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the extended MRI (eMRI) scale; higher eMRI scores indicate greater joint structure damage. The score for each joint was based on the readers’ median change score for each of the 45 eMRI scale items when comparing MRIs from different timepoints. Total patient score was derived; change from baseline in total patient score was prespecified as the first in a hierarchy of 2 secondary endpoints. Between- group comparison was made using constrained longitudinal data analysis. Data are presented for the intent-to-treat population.

Summary:

Of 84 patients enrolled (42 per treatment group), MRI data were available for 38 on-demand and 41 prophylaxis patients. Least squares (LS) mean change from baseline to year 3 on the eMRI scale total score was 0.96 for on demand and 0.79 for prophylaxis (LS mean difference, –0.17; 95% CI, –0.92 to 0.59; P=0.66). LS mean change from baseline to year 3 for on demand and prophylaxis was 0.06 and 0.01 for the eMRI soft-tissue domain (LS mean difference, –0.04; 95% CI, –0.18 to 0.10; P=0.53) and 0.90 and 0.78 for the eMRI osteochondral domain (LS mean difference, –0.12; 95% CI, –0.82 to 0.58; P=0.74).

Conclusions:

In adults with severe hemophilia A, progression of structural joint damage was not significantly different between patients using rFVIII prophylactically or on demand over a 3-year follow-up period, although less progression was seen with prophylaxis.

Objective:

In the 3-year SPINART study, routine prophylaxis and on-demand treatment were compared in adults with severe hemophilia A. We report final SPINART efficacy and safety results after 3 study years.

Methods:

The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled males aged 12–50 years with severe hemophilia A who had ≥150 exposure days with any factor VIII (FVIII) product, no inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. All patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation by 5 IU/kg permitted once per year). The primary efficacy endpoint, bleeding frequency (number of all bleeding episodes at 1 year), has been previously reported. Endpoints reported here are total and annualized numbers of all bleeding episodes, joint bleeding episodes, spontaneous bleeding episodes, and trauma-related bleeding episodes. Between-group comparisons of bleeding frequency were made within the framework of a negative binomial regression model to account for different follow-up times of patients who discontinued prematurely, with stratification variables (presence of target joints at baseline, number of previous bleeding episodes at baseline) included in the model. Safety variables included adverse events (AEs), serious AEs, and inhibitor development.

Summary:

84 patients (42 prophylaxis, 42 on demand) comprised the intent-to-treat population. The total number of all bleeding episodes during the 3-year study was significantly lower with prophylaxis versus on demand (median, 2.0 vs 96.5, respectively; P<0.0001). Annualized number of all bleeding episodes (median [quartile 1; quartile 3], 0.7 [0; 1.6] vs 37.4 [24.1; 52.6]), total joint bleeding episodes (median, 1.0 vs 67.0), and joint bleeding episodes per year (median, 0.3 vs 27.3) were all lower with prophylaxis versus on demand. The numbers of spontaneous and trauma-related bleeding episodes were also lower with prophylaxis versus on demand. Observed AEs were consistent with the established rFVIII-FS safety profile. No patient developed inhibitors.

Conclusions:

Long-term prophylaxis with Bayer’s rFVIII-FS is efficacious in decreasing bleeding episodes, including joint bleeding episodes, in adults with severe hemophilia A. 75% of prophylaxis patients had <2 bleeding episodes per year during the 3-year study. No inhibitors were reported.

The purpose of this project is to determine if children with hemophilia have gross motor delays. Gross motor skills include, but are not limited to walking, running, jumping, climbing, crawling, balancing, kicking, catching and throwing activities. The large muscles of the body are responsible for performing these types of activities. Strength, balance and coordination are needed to demonstrate and improve these skills. Children with hemophilia may experience internal bleeding in their joints or muscles, which limits their activity. Some children with hemophilia may be restricted from active play or sports for fear of getting an injury that could cause internal bleeding. When activity is restricted, there can be decrease in strength, balance and endurance. If a child has gross motor delays, it puts him at risk for injury when playing with his peers. Physical Therapy evaluations in the Hemophilia Treatment Center help determine changes caused by bleeding episodes. There are specific motor skills children master as they grow, which represent strength, balance and coordination. The comprehensive clinic visits do not allow time to complete an intensive gross motor assessment. Physical Therapists use Manual Muscle Testing, MMT, to grade the strength of each muscle group. MMT strength testing is not appropriate for young children and does not represent strength during functional activities. To accurately determine children's muscle strengths, a standardized gross motor test should be used. The PT at the Comprehensive Care Center for Inherited Blood Disorders will conduct gross motor evaluations in conjunction with the annual visit. The scores will be evaluated to determine which patients have gross motor delays, so they can be referred for therapy services. The BOT 2 is the standardized gross motor test that will be used to determine gross motor levels. The gross motor skills that will be evaluated include bilateral coordination, balance, running speed and agility, upper limb coordination and strength. All patients with hemophilia between the ages of 4 and 12 years will be eligible to be evaluated in the upcoming year with additional PT testing with their annual visit. Patients may be referred to therapy or given a home exercise program depending on the deficits noted during the assessments. The goal is to improve our standard of care at the HTC, by adding gross motor screening for our patients to ensure appropriate referrals are made for therapy services.

Objective:

Kids A-LONG was a global, multi-center, open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFVIIIFc in previously treated patients aged <12 years with severe hemophilia A (<1 IU/dL FVIII activity).

Methods:

All participants had ≥50 prior exposure days (EDs) to FVIII, and no history of FVIII inhibitors. Participants were to be treated with twice-weekly rFVIIIFc prophylactic infusions (Day 1, 25 IU/kg; Day 4, 50 IU/kg), with adjustments to dose (≤80 IU/kg) and dosing interval (≥ every 2 days) as needed by the investigator. A subset of participants (<6 years of age, n=25; 6 to <12 years of age, n=35) underwent sequential PK evaluations with FVIII (50 IU/kg), followed by rFVIIIFc (50 IU/kg). The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included PK, annualized bleeding rate (ABR) and number of infusions required to control a bleed.

Summary:

The study enrolled 71 participants from 23 centers (<6 years, n=36; 6 to <12 years, n=35); 94.4% of participants completed the study. Prestudy, 89% of participants received FVIII prophylaxis, the majority (74.6%) of whom required ≥3 infusions per week. The median time on study for treated subjects (n=69) was 26 weeks; 61 participants had ≥50 EDs to rFVIIIFc. No participant developed inhibitors to rFVIIIFc. Overall, the pattern of adverse events reported on rFVIIIFc treatment was typical of the population studied; no serious adverse events were assessed as treatment-related by the investigator. The terminal half-life (arithmetic mean [95% CI]) in participants aged <6 years and 6 to <12 years was 12.67 (11.23, 14.11) hours and 14.88 (11.98, 17.77) hours, respectively. The relative increase in half-life over prior FVIII therapy was ~1.5-fold, consistent with the increase in half-life seen in the A-LONG study of adults and adolescents. Median (IQR) ABR was 1.96 (0.00, 3.96) overall, and 0.00 (0.00, 0.00) for spontaneous bleeds. Median total weekly dose and dosing interval were 88.1 IU/kg and 3.5 days, respectively. 83.7% and 93.0% of bleeding episodes were controlled with 1 or 1–2 infusions, respectively (median dose per bleeding episode: 54.9 IU/kg).

Conclusions:

rFVIIIFc was well-tolerated, efficacious for prophylaxis and treatment of bleeding, and resulted in low bleeding rates. The extended half-life compared to FVIII and the safety profile were generally consistent with that observed in the Phase 3 study in adults and adolescents. rFVIIIFc offers the potential of prolonged dosing intervals and fewer infusions for children with severe hemophilia A.

Objective:

Using point-of-care musculoskeletal ultrasound (MSKUS), we previously demonstrated that patient and physician assessments were unreliable in determining bleeding during acute painful joint episodes. Here we delineated by MSKUS pathophysiological soft tissue changes that may contribute to pain, and investigated to what extent MSKUS findings and functional or radiographic joint status correlate with markers of inflammation.

Methods:

We used the GE Logiq e BT11 US-module with high frequency 8-13 MHz linear transducer and real time spatial compound imaging capability for grey scale and Power Doppler examinations. We analyzed all MSKUS examinations performed between 05/2012 and 08/2013 in 34 adult hemophilia patients (mean age 39.3 years) seen at our Hemophilia Treatment Center. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson Scores, hsCRP, and von Willebrand Factor (VWF) activity and antigen levels. Spearman correlation coefficient and Wilcoxon Mann-Whitney tests were used. P-values ≤0.05 were considered significant. Acute and persistent pain was defined as lasting ≤7 days and >7 days, respectively.

Results:

Sixty-five examinations were performed. Seventy percent of patients had severe hemophilia. Mean Pettersson scores were 22 of 78 and HJHS were 22 of 124. Joints most commonly examined were knees and ankles (72%), with most examinations (72%) performed for persistent pain. Effusions were present in 48% of painful joints. Of those effusions, 90% were bloody during acute and ~50% during persistent pain episodes. Synovitis (+/-tendinitis, enthesitis or bursitis) was observed in 66% of all MSKUS examinations. Synovitis and hemarthrosis coincided in 20% of examinations. In exams revealing hemarthrosis, synovitis was present in 68%. In acute hemarthrosis, synovitis was present in 55% and, with persistent pain, synovitis was present in 80%. Although total and joint-specific HJHS and Pettersson scores were higher in patients with synovitis, only the joint-specific Pettersson score was significantly higher (mean score 3 vs 6.5). HsCRP, VWF activity and VWF antigen levels correlated significantly with joint-specific Pettersson scores (Cr ~0.4) and total HJHS (Cr ~0.6), but not consistently with synovitis.

Conclusion:

Inflammation and bleeding were prominent findings in painful hemophilic arthropathy. One-fifth of persistently painful joints were diagnosed with hemarthroses, which were almost always associated with synovitis. Inflammatory markers correlated to some extent with joint findings, but were diagnostically not helpful. We conclude that sensitive imaging technology such as MSKUS is critical to precisely diagnose causes of pain in hemophilic arthropathy with a need for personalized care that includes tailored clotting factor replacement and/or novel anti-inflammatory strategies.

Objective:

To assess quality of life, self-reported comorbidities, health-related quality of life (HRQoL), and impact of hemophilia on activities of young adult (YA) patients with hemophilia (PWH).

Methods:

Analysis of US YA-PWH respondents (aged 18-30) in the international HERO study conducted in 2010-2011. US respondents were recruited through NHF, Facebook, and e-mail. An independent ethics board approved the US survey.

Summary:

Of 189 adult PWH HERO respondents in the United States, 66 were aged 18-30 years, 74 were aged 31-40 years, and 49 were older than 40 years. The median (interquartile range) age of YA-PWH was 26 (22-28), and had hemophilia A (58%), hemophilia B (21%), or hemophilia with inhibitors (21%). Most were Caucasian (77%). Half were on prophylaxis (50%), with the remainder treated on-demand alone (24%) or with occasional short-term prophylaxis (24%). Compared with PWH older than 40 years, YA-PWH less frequently self- reported bone/skeletal/arthritis (41% vs 67%), chronic pain (38% vs 57%), and viral comorbidities (20% vs 65%). On EQ-5D-3L, 62% of YA-PWH reported no difficulties with mobility, 71% no difficulties with usual activities, and 94% no difficulties with self-care. In contrast, 68% reported moderate and 5% extreme pain/discomfort, and 33% reported some/moderate and 8% extreme anxiety/depression. On EQ-5D-VAS, 53% reported VAS scores of 80-90-100 (vs 24% for PWH >40 years). Surprisingly, 89% reported pain interference with daily activities in the past 4 weeks, with 9% reporting it was extreme/a lot. More YA-PWH had pain only with bleeding than PWH older than 40 (42% vs 18%), with 14% citing pain all the time and 39% reporting pain all the time and worse with bleeding. YA-PWH reported seeking psychological treatment in the prior 5 years (26%), frequently related to hemophilia (71%). When asked about specific activities, YA-PWH reported participating in lower-risk (80%), intermediate-risk (61%), and higher-risk activities (27%); older PWH reported 82%, 45%, and 16%, respectively.

Conclusions:

YA-PWH in the United States are less likely than older PWH to report arthritis, chronic pain, or viral diseases; yet, HERO results suggest these remain important problems for this age group. Pain appears to be perhaps the most significant; only 11% did not report pain interference in the past 4 weeks, and only 27% reported no pain/discomfort at the time of the survey. Additionally, 33% reported some/moderate depression. The relationship of intermediate- and high-risk activities to the rates of reported pain and arthritis is unclear.

Objective:

Assaying thrombin generation (TG) in real time using fluorogenic substrates has been a popular approach for developing a true global hemostasis assay. Benefits over other assays include assessment of global hemostasis potential, not just the level of coagulation factor deficiencies. Recent experiments in our laboratory have suggested that adding factor XIa to the assay improves the sensitivity and robustness of this assay approach. Its effects on clot formation and lysis are also being assessed.

Methods:

To expand the utility of the TG test, we optimized the reaction mixture and protocol. We add FXIa to the substrate/calcium mixture as previous experiments in our laboratory have shown FXIa needs to be added during or after plasma recalcification in order to maintain activity. We are also observing, concurrently with TG by fluorescence, absorbance as a direct measurement of fibrin generation (FG). Congenitally FV, FVII, FVIII, and FIX-deficient plasma were supplemented with their respective purified factors to give known level of factor deficiency. Tissue plasminogen activator (tPA) and thrombomodulin (TM) are also added to our assay to induce and allow observation of clot lysis and thrombin-dependent lysis inhibition. We run equivalent samples on Thrombinoscope’s Calibrated Automated Thrombinography (CAT, Stago USA) platform to assess our variations from the current standard protocol.

Summary of results:

Adding FXIa improves the robustness and sensitive range of the TGT as applied to clotting factor deficiencies. For FVIII deficiency, adding FXIa results in thrombin peak heights begin rising at lower factor concentrationsand increases in thrombin peak heights. For FIX deficiency, the addition of FXIa gives a dose-dependent thrombin maximum response that would otherwise be absent or weak. However, FV deficiency showed dose- dependent TG trends with or without FXIa, while the addition of FXIa eliminates dose- dependent TG trends in FVII deficiencies. These trends are seen both using our in-house TGT and CAT. The addition of tPA and TM do not appear to produce additional factor- dependent TG or FG responses under conditions tested, while they diminished the factor- dependent time to peak thrombin trend for FIX-deficient plasma.

Conclusions:

The addition of FXIa to the TGT gives us a more sensitive assessment of global hemostasis in intrinsic pathway deficiencies and reveals patterns not seen using current standard protocols.

Disclaimer. The authors are employees of the US Food and Drug Administration (FDA). This presentation is an informal communication and represents authors’ own best judgment. These comments do not bind or obligate FDA.

Dr. Jonathan Roberts is currently a pediatric hematology and oncology fellow with the Medical College of Wisconsin and the Children's Hospital of Wisconsin. His fellowship mentor will be Joan Gill, MD, Professor of Pediatrics at the Medical College of Wisconsin and Director of the Comprehensive Center for Bleeding Disorders (CCBD) at the BloodCenter of Wisconsin. Roberts graduated with honors from Greenville College, Illinois, and received his MD from Southern Illinois University School of Medicine. He did his residency in Pediatrics at the University of Illinois at Peoria and Children's Hospital of Illinois, where he also distinguished himself, receiving awards of excellence for critical care and research. During his pediatric residency, Roberts worked with Dr. Michael Tarantino to initiate a clinical research trial to assess the role of FXIII on intraventricular hemorrhage in premature, low birth weight infants. As a NHF-Baxter Clinical Fellow, Roberts will receive focused training and gain clinical experience through the hemostasis clinics at CCBD and further develop his research skills in a project to develop a new ELISA-based assay for assigning VWF phenotype. Roberts has plans to pursue a Master's Degree in Clinical and Translational Science. His goal is to become an expert physician/scientist with a long-term career focus on hemophilia, and other bleeding and clotting disorders.

As technology advances and provides electronic tools for enhancing communication by phone and computer, health care providers are finding ways to adapt these tools into patient care. Telehealth is the use of electronic information and telecommunications technologies to support long-distance clinical health care. For patients with hemophilia who experience a bleed in the home setting, telehealth has the potential to help the patient, family, and health care provider assess what is going on and develop the best plan of care, all while the patient stays in the home setting. In this clinical project, we will use the telehealth resources available at our institution to partner with patients and families with severe hemophilia with a high risk of bleeding episode who also have a home computer with a camera and internet access. We want to find out more about how many patients have these home resources, how to use video-conferencing when managing a bleed and what patients, families, and health care staff think about using video conferencing. This will help us plan future research using telehealth video-conferencing for a larger group of hemophilia patients.