Social workers have been active members of the multidisciplinary teams of hemophilia treatment centers for many years, but the roles of these social workers may differ greatly from center to center. Social workers are often the advocate for patients and a primary source of assistance, information and referral. In many HTCs, they also provide counseling and therapy services to patients and consultation to staff. Indeed, these social workers appear to provide a wide variety of psychosocial and case management services to patients with bleeding disorders and their families. This research project will attempt to describe the various role tasks of hemophilia treatment center social workers, describe these tasks and identify the influences of the role in each HTC. An online survey will be developed and emailed to the approximately 135 HTC social workers across the nation. Data will be analyzed and shared with the social worker community through sessions and posters and the NHF annual meeting.
Objective:
The ongoing rFVIIIFc extension study, ASPIRE (clinicaltrials.gov #NCT01454739), evaluates the long-term safety and efficacy of rFVIIIFc in adults, adolescents, and children with severe hemophilia A. Here we report interim outcomes for United States (US) subjects in ASPIRE.
Methods:
Eligible subjects could enroll in ASPIRE upon completing A-LONG or Kids A-LONG. There were 4 treatment groups: individualized prophylaxis (25-65 IU/kg every 3-5 days, or 20-65 IU/kg on D1, 40-65 IU/kg on D4 if twice weekly); weekly prophylaxis (65 IU/kg every 7 days); modified prophylaxis (to further personalize and optimize treatment when needed); or episodic treatment. Subjects could change treatment groups at any time. Subjects <12 yrs participated only in individualized and modified prophylaxis groups. Primary endpoint: development of inhibitors. Secondary outcomes included annualized bleeding rate (ABR) and rFVIIIFc exposure days (EDs).
Summary:
Sixty subjects (49 from A-LONG; 11 from Kids A-LONG) enrolled. As of the interim data cut (6 Jan 2014), the median time on ASPIRE was 80.37 (A-LONG) and 15.94 (Kids A-LONG) wks; 82% (A-LONG) and 27% (Kids A-LONG) of subjects had ≥100 cumulative rFVIIIFc EDs. 7/49 A-LONG subjects changed treatment groups upon enrollment into or during ASPIRE; 2 Kids A-LONG subjects switched from individualized to modified prophylaxis upon enrollment into ASPIRE. Median ABRs were low with rFVIIIFc prophylaxis (Table). Overall, most subjects treated prophylactically during the parent study did not experience changes to their total weekly prophylactic dose or dosing interval during ASPIRE. For subjects who enrolled from A-LONG and Kids A-LONG, 94% and 100% of all bleeding episodes during ASPIRE, respectively, were controlled with 1 infusion. In the overall study population, no inhibitors were observed during ASPIRE; adverse events were typical of the general adult and pediatric hemophilia A populations.
Conclusion:
Interim data from US subjects in ASPIRE are consistent with those of the phase 3 parent studies and the overall ASPIRE interim analysis. Results from ASPIRE confirm the longer-term safety of rFVIIIFc and the maintenance of a low ABR with extended interval prophylactic dosing in individuals with severe hemophilia A.
Objective:
Personalizing treatment to a patient’s lifestyle and promoting overall health and wellness in persons with hemophilia (PWH) is essential to optimizing outcomes. There is limited evidence that correlates how activity and infusions impact bleeding episodes and further data on this relationship is needed. The research objective of SPACE is to prospectively explore the association between activity level, timing of infusion, and occurrence of a bleeding episode in PWH using novel technology.
Methods:
This six-month prospective, observational study includes PWH A or B in the United States currently receiving ADVATE or RIXUBIS between the ages of 13 and 65 years. Enrolled PWH use a smartphone eDiary application to log information on activities, infusions, and bleeding episodes. As an additional measurement of activity, enrollees are given a FitBit, a consumer-based activity tracker that measures steps taken and calories burned. Activity types are assessed based on their level of perceived risk for collision, according to the NHF “Playing It Safe” brochure. We report here current study status and descriptive analysis of baseline data.
Results:
The interim analysis included 15 patients with a median age of 19 (Range: 13 to 47). At baseline, 87% of patients were on prophylaxis and 13% treated on-demand treatment. Fifty-three percent of patients had 0 target joints at baseline. Eighty-seven percent of patients indicated that they had discussed activity participation with their physician. Sixty-seven percent of patients considered themselves ‘very satisfied’ or ‘satisfied’ with their level of activity. Data collected from the FitBit indicated that patients in SPACE walked on average 7,367 (SD: 3250) steps per day and burned 979 (SD: 398) calories from their activity. For patients on prophylaxis, the mean number of days per week doing mild, moderate and strenuous activity were 3.57, 2.64, and 1.5 respectively. Of the data reported on bleeding episodes, 40% of patients reported no bleeds at the time of the interim analysis. Forty percent of patients did not report having a bleed at the time of the interim analysis. Of all bleeds reported, 34% were associated with physical activity.
Conclusions:
Current data from SPACE demonstrates that subjects are active and participating in various activities. Continued data will provide better understanding of the types of activities and infusion schedules that may be associated with risk as well as protective effects on bleeding episodes by infusing prior to activity. A personalized approach to treatment based on physical activity levels may minimize bleeding risk in PWH.
Background:
BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor (TFPI) developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst for stable clot formation in hemophilic conditions in vitro.
Aims:
The goal of this study was to elucidate the in vivo prophylactic hemostatic potency of BAY 1093884.
Methods:
The hemophilia A mouse tail vein transection model was used for this study to mimic the venous bleeding characteristics of severe hemophilia. Male hemophilia A mice (n=12/group) were treated prophylactically with escalating doses of BAY 1093884. All treatments were administered as single intravenous (IV) bolus at 4 different time courses prior to injury (1, 3, 5, and 7 days). Bleeding was induced by a 1.2-mm deep incision across the left lateral vein. Following injury, the animals were monitored hourly for moribundity for up to 9 hours and after 24 hours followed by euthanasia.
Results:
Efficacious doses of BAY 1093884 providing 50% protection for survival (ED50) for up to 6 days after IV bolus ranged from 0.6–2 mg/kg. In comparison, only 25% protection was achieved 6 days after the treatment with a very high dose of 1000 IU/kg of recombinant factor VIII (rFVIII). The effect of a single IV dose of 18 mg/kg BAY 1093884 providing 80%–90% survival was maintained over 8 days (ED50 6 mg/kg), whereas a single IV dose of rFVIII failed to provide protection over an 8-day period.
Conclusions:
These studies demonstrate that BAY1093884 prevents bleeding and increases long-term survival to a greater degree than rFVIII in hemophilia A mice and may offer a convenient prophylactic treatment option for hemophilia patients with inhibitors.
Background:
Activity limiting joint disease has greatly decreased with the introduction of prophylactic treatment for people with severe bleeding disorders. Previous research using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2TM), a standardized, normative, age and sex matched test of motor development, suggested motor development of males aged 4-21 years with bleeding disorders may be lower than age-matched peers.
Objective:
The primary purpose of this study was to compare the gross motor proficiency of boys with hemophilia ages 4-21 years followed at the Hemophilia Center at Oregon Health & Science University utilizing the BOT-2. Secondarily, we examined the relationship between joint health and gross motor proficiency.
Methods:
a) Participants and setting: Thirty-four subjects with either hemophilia A or B were recruited
from our center. Data collection occurred during clinic visits or at the patients’ homes.
b) Design and Procedures: A prospective, cross-sectional study design was used. The Upper Limb Coordination, Bilateral Coordination, Balance, Running Speed and Agility, and Strength subtests of the BOT-2 were administered. Body composition, range of motion, presence of an inhibitor, and use of prophylaxis were collected at the time of testing or from chart review.
c) Analyses: Analysis of variance (ANOVA) modeling was used to compare BOT-2 scores of PWH with baseline BOT-2 scores estimated from the general population of comparable age.
Summary:
Mean Running Speed & Agility scores were greater among boys with hemophilia compared to the control population (p=0.0026). Agility scores were similar between boys with hemophilia A and B (p>0.60), and significantly greater compared to the control group (p=0.0153). No other significant differences were found comparing boys with hemophilia to the control group. Within the boys with hemophilia cohort, age-adjusted ANOVA found no significant differences in BOT-2 scores between subjects of different severities, treatment regimen (prophylaxis or episodic), or diagnoses (Hemophilia A or B).
Conclusion:
Boys with hemophilia have the same or better gross motor proficiency as age matched peers.
Objective:
Kids B-LONG was an open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFIXFc in previously treated children (aged <12 years; ≥50 prior exposure days [EDs] to FIX) with severe hemophilia B (≤2 IU/dL endogenous FIX) and no history of FIX inhibitors.
Methods:
Participants initiated prophylactic treatment with 50–60 IU/kg rFIXFc once-weekly; dose and interval adjustments were based upon PK data and bleeding frequency. The primary endpoint was development of inhibitors (neutralizing antibodies). Key secondary outcomes included PK and annualized bleeding rate (ABR).
Summary:
The study enrolled 30 participants (<6 years of age, n=15; 6 to <12 years of age, n=15); 90% completed the study. Prestudy, all participants received FIX prophylaxis (23/30 were dosing ≥2x/week). The median time on study was 49.4 weeks; 24 participants had ≥50 rFIXFc EDs. No participant developed inhibitors to rFIXFc. The pattern of adverse events reported was typical of the population studied. There were no serious allergic reactions and no thrombotic events. No serious adverse events were assessed by the investigator as related to rFIXFc. The terminal half-life (geometric mean [95% CI]) of rFIXFc was 66.5 (55.9, 79.1) hours in the <6 years cohort (n=11) and 70.3 (61.0, 81.2) hours in the 6 to <12 years cohort (n=13). The geometric mean (95% CI) half-life of prestudy BeneFIX was 18.2 (15.5– 21.3) hours in the <6 years cohort (n=11) and 19.2 (17.6–20.9) hours in the 6 to <12 years cohort (n=9). Median (IQR) ABR was 1.97 (0.00, 3.13) overall, and 0.00 (0.00, 1.16) for spontaneous bleeds; 33.3% of participants reported no bleeds on study. At study end, 97% of participants were dosing once weekly. The median (IQR) total weekly prophylactic dose with rFIXFc was 59.4 (53.0, 64.8) IU/kg and 57.8 (51. 7, 65.0) IU/kg, in the <6 years and 6 to <12 years cohorts, respectively. The prestudy FIX median (IQR) total weekly prophylactic dose was 110.0 (58.0, 188.0) IU/kg and 100.0 (58.0, 120.0) IU/kg in the <6 years and 6 to <12 years cohorts, respectively. 75.0% of bleeding episodes were controlled with 1 infusion; 91.7% with 1 or 2 infusions (median average dose per infusion: 68.22 IU/kg).
Conclusions:
rFIXFc was safe and effective for the prevention and treatment of bleeding in children with severe hemophilia B. Study participants achieved low bleeding rates with extended-interval rFIXFc prophylaxis, while reducing their weekly prophylactic factor consumption compared with their prior FIX regimen.
Objective:
To analyze real world rFVIIIFc patient characteristics and treatment interval patterns in patients with hemophilia A based on specialty pharmacy dispensing records.
Methods:
A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from July 2014 through Mar 2015. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received at least one shipment of rFVIIIFc for a prophylactic treatment regimen. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or pharmacy records did not specify a prescribed infusion dose. Patients were categorized according to their age and dosing interval.
Summary:
The analysis included 405 hemophilia A patients that received at least one shipment of rFVIIIFc with a median age of 23 (range: 2-68) and median weight of 70 kg (range: 10-154kg). Eight percent of dispensing records were for patients less than 6 years of age, 29% were between 6 and 17 years of age, and 63% were 18 years or greater. Pharmacy dispensing records represented 179 distinct prescribers across 40 states. Dosing frequency ranged from four times weekly to beyond once-weekly, with every four days as the most common dosing interval, representing 33% of patient records. The median infusion frequency was every four days. Fifty percent of all patients had a dosing frequency of four days or greater. Of the patients receiving rFVIIIFc that had previous rFVIII dispensing records, the most common rFVIII dosing frequency was three times per week. The majority of patients previously on prophylaxis regimen with a rFVIII dosing frequency of three times per week had a decreased number of prophylactic infusions per week on rFVIIIFc; 4% of patients reduced infusion frequency to every 3 days, 44% of patients reduced infusion frequency to twice weekly, 30% of patients reduced infusion frequency to every 4 days, 10% of patients reduced infusion frequency to every 5 days.
Conclusions:
Current SPP dispensing records demonstrate that rFVIIIFc is being used in a broad patient population based on age range and geographical distribution. Patients with hemophilia A in the US may experience reductions in FVIII infusion frequency when they switch to rFVIIIFc, with conversion to an infusion frequency every four days as the most common treatment regimen and the recommended prophylaxis starting dose according to the US Prescribing Information.
Background:
Arthropathy is one of the major complications in hemophilia, leading to functional limitations and poor quality of life. Exercise is recommended as being beneficial for people with hemophilia, yet a lack of exercise-related evidence using exercise and control groups exists in this population, compared to other joint pathologies (i.e. osteoarthritis).
Objective:
To evaluate effects of post-hemarthrosis exercise on: pain; swelling; bone density and joint damage, using an animal model.
Methods:
Twelve Wistar rats were divided into an Exercise Group (EG; n=6) and Control Group (CG; n=6). All rats received eight weekly intraarticular injections in their right knees with 0.1 mL autologous blood, and left knees with 0.1 mL saline solution. The EG performed an 8 wk swimming protocol (during the period of intraarticular injections) of 60 min (5x week) with 5% body weight attached on their tails. Pain status was assessed weekly with a static weight-bearing incapacitance test (SWIT). Joint diameters were measured post-protocol with a digital microcaliper. Bone mineral density was assessed using dual-energy X-ray absorptiometry (whole-body, tibia, femur and knee joint) pre and post-study. Following sacrifice, bilateral knee X-rays were taken and scored with Pettersson’s score. Resting heart rate and heart weight were registered post-study, as markers of physical training.
Results:
CG manifested decreased weight-bearing with SWIT, compared to EG (p<0.001). EG presented reduced joint swelling, compared to CG (p=0.034). Significant increase in bone mineral density variation (BMD∆) was observed at the tibia (p=0.016), and knee (p=0.018) of the EF compared to CG. The EG also showed a tendency of an increase in femoral BMD∆ compared to CG (p=0.09). Pettersson scores demonstrated increased bone destruction in the CG compared to EG (p=0.05).
Conclusion:
This is the first time that beneficial effects of a swimming exercise protocol on pain, swelling, bone density and radiologic changes have been shown in a blood-induced, joint damage animal model. Hopefully this data will provide clues for future study designs in this area.
Objective:
To evaluate efficacy of IB1001 with respect to breakthrough bleeding during prophylaxis and with respect to control of hemorrhaging in prophylaxis and on-demand treatment regimens in previously treated patients (PTPs) with hemophilia B.
Methods:
The efficacy of IB1001 has been evaluated in a prospective, open-label, uncontrolled multicenter international study in which a total of 68 male PTPs between 7 and 64 years of age received IB1001 either as prophylaxis or on-demand treatment. All subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors. There were 61 subjects who received prophylaxis [predominantly secondary or tertiary prophylaxis as defined by World Federation of Hemophilia (WFH) guidelines] and 12 were treated on-demand during the study conduct. Both, the subjects and the study investigators rated the efficacy of IB1001 in management of bleeding episodes.
Summary:
The mean number of exposure days (ED) was 138.2 (median: 127.5 ED), including 55 subjects with ≥ 50 ED and 45 subjects with ≥ 100 ED. Subjects on prophylaxis received a mean intravenous dose of 55.0 ± 12.8 IU/kg IB1001 twice weekly, while subjects in the on- demand regimen received a mean dose of 60.0 ± 18.2 IU/kg IB1001. In the prophylaxis group, median annualized bleed rate (ABR) was 1.52, and in the on-demand group, median ABR was 16.39. There were 19/61 (31.1%) subjects on IB1001 prophylaxis who reported no bleeding episodes. A total of 508 bleeding episodes were treated with IB1001; 286 bleeds were recorded for patients on prophylaxis and 222 in the on-demand regimen. Majority of the bleeds (70.9%) resolved after a single IB1001 infusion, while 13% of the bleeds required two infusions. A minority of the bleeds (4.7%) required 5 or more infusions; these bleeds were predominantly related to trauma, target joints and/or muscle bleeds. Subjects rated efficacy of IB1001 as ‘excellent’ or ‘good’ in 84% of all treated bleeding episodes. Of 414 subject visits where the efficacy of IB1001 was evaluated by the study investigators, 92% were rated as ‘effective’ in prevention and treatment of bleeding by IB1001.
Conclusions:
IB1001 is effective for the treatment of hemophilia B either as secondary or tertiary prophylaxis or on an episodic (on-demand) basis. Based on clinical trial data, IB1001 is effective in controlling breakthrough or episodic bleeding episodes.
Introduction:
Since the emergence of community-acquired methicillin-resistant S. aureus (MRSA), severe manifestations of infection are encountered more frequently. Venous thrombosis (VT) has been previously reported in children with S. aureus infections. This study reviews our institutional experience and outcomes of children with VT and staphylococcal infections.
Methods:
A retrospective analysis of 15 pediatric patients (≤ 18 years) treated for VT and staphylococcal infections at Children’s Memorial Hermann Hospital between January 1, 2010 and December 31, 2014 was performed.
Results:
Fifteen patients were included (10 males, 5 females) with a median age at diagnosis of 8 years (range 2 mo-17yrs). Underlying infections included: osteomyelitis (n=7), soft tissue infection (n=3), aortitis (n=1), meningitis (n=1), septic arthritis (n=1), central line infection (n=1), septicemia (n=1). Primary presentation included: swelling (n=12), pain (n=11), tenderness (n= 8), and color changes (n=3). One patient had prior history of VT. Family history was positive for VT in one patient. Isolated organisms included: MRSA (n=9), MSSA (n=3), polymicrobial (n=2), and Staphylococcus non- aureus (n=1). Eight patients had central venous catheters (CVC) and 5 of them had thrombosis at the CVC site. VT sites identified by Doppler US (DUS) included: upper extremity (n= 5), lower extremity (n= 8), and neck (n=2). All thrombophilia work up was negative. The median D-dimer at diagnosis was 3 ug/ml (range: 0.31- 6.54 ug/ml). Median time elapsed between infection and VT diagnosis was 5.5 days (range: 0-35 days). All patients received anticoagulation using LMWH (1mg/kg/dose) except one who had superficial thrombophlebitis and was managed conservatively. Median time to achieve therapeutic anti- factor Xa level was 2.5 days (range 1- 6 days). Median duration of anticoagulation was 3 months. Three out of 13 patients (23%) had resolution of thrombosis within one week of anticoagulation. Four other patients had thrombus resolution by DUS at 3-6 months. Five patients did not have DUS at 3-6 months. None of the 15 patients required hospital re- admission for bleeding or thrombotic complications.
Discussion:
Staphylococcal infections may increase the risk of VT in children. Nine out of 15 patients (60%) with VT had a documented MRSA infection, which appears to confer an even higher risk for development of VT. Over half of the patients responded favorably to anticoagulation with resolution of VT within 6 months.
Conclusions:
A high index of suspicion for VT is warranted in children with Staphyloccoccal infections (particularly MRSA) to promptly diagnose and treat. This approach may improve outcomes and minimize complications including septic emboli and post-thrombotic syndrome. Prophylactic anticoagulation in presence of MRSA infection could be considered in future studies.
Keywords: Children, staphylococcal infection, venous thrombosis
