Research Studies

Objective:

With increasing life expectancy of people with hemophilia (PWH) in developed countries, the number of PWH affected with age-related diseases is also increasing. Atrial fibrillation is a common health problem in the general population, but in PWH, evidence-based guidelines for the management of AF are lacking.

The aim of this cross-sectional pan-European study is to analyze the prevalence of AF and risk factors for stroke in our adult hemophilia population and to document current anticoagulation practice.

Methods:

The ADVANCE Working Group consists of members from 14 European hemophilia centers. Each center retrieved data on the number of PWH with AF in their hemophilia population, as well as their total number of adult PWH. For each person with AF, a case report form was completed.

Summary:

In total, 29 PWH with AF were documented. The mean age was 68.2 years (IQR 62-75.5). Hemophilia was severe in 6 (20.6%), moderate in 6 (20.6%) and mild in 17 (58.6%) patients. The prevalence in the total studied hemophilia population was 0.94% (29/3094) and increased with age; in patients >40 years it was 1.7% (29/1723) and in patients >60 years 3.6% (23/635). The mean CHA2DS2-Vasc score was 1.3 (IQR 0-2). Hypertension was reported in 12 patients (41.4%), diabetes in 3 (10.3%), previous stroke or TIA in 1 (3.4%), peripheral vascular disease in 4 (13.8%). In 11 patients (37.9%), anticoagulation was started of whom 9 low dose aspirin and 2 vitamin K antagonists. Of these 11 patients, 9 had mild hemophilia, 1 moderate and 1 severe with FVIII prophylaxis. During follow-up after diagnosis (mean follow-up 52.9 months), there were no thrombotic events reported, nor increases in bleeding severity.

Conclusions:

In this largest cohort of PWH with AF so far, the prevalence of AF in hemophilia increases with age and is predominantly present in mild hemophilia. Based on the population based CHA2DS2-Vasc risk scores, PWH have a low stroke risk that might be even lower considering the hypocoagulable state. Hemophilia doctors prescribe anticoagulation therapy approximately in half of their mild hemophilia patients and very few in moderate and severe.

This study explores perceptions among adolescent aged patients with inherited bleeding disorders regarding religiosity/spirituality and whether their beliefs have an impact on the pain they experience. Subjects participating will be assessed in regards to the type, frequency and intensity of pain experienced and measures used to cope with the pain. Finally, we will measure patient self reports of disease self efficacy. To further assess the impact of religiosity/spirituality on the family system, we will be measuring parental perceptions of religiosity/spirituality with parents of the participating adolescents.

Objective:

A novel recombinant coagulation factor VIII, rVIII-SingleChain, produced without added animal- or human-derived materials, is currently in a clinical phase I/III program (AFFINITY). The present non-clinical studies were conducted to investigate the pharmacokinetic (PK) profile of rVIII-SingleChain in animals to support assessment of its PK/pharmacodynamic properties for future clinical use.

Methods:

The PK behavior of rVIII-SingleChain was explored in hemophilia A mice, rats, and monkeys. Intravenous doses of 50-250 IU/kg for rVIII-SingleChain or a marketed full-length rFVIII concentrate were given. Systemic FVIII activity or antigen levels were recorded in plasma samples after injection. A thrombin generation assay was conducted to assess coagulation parameters ex vivo after treatment of hemophilia A mice with 250 IU/kg of rVIII- SingleChain or full-length rFVIII.

Summary:

In all animal species, treatment resulted in improved PK properties for rVIII- SingleChain compared to full-length rFVIII. Increased systemic availability and mean residence time were observed for rVIII-SingleChain. Correspondingly, the clearance rate was decreased and the terminal half-life was enhanced in comparison with full-length rFVIII. In vivo recovery and volume of distribution of rVIII-SingleChain were equivalent to full-length rFVIII. Consistent with the PK characteristics, rVIII-SingleChain showed a more favorable thrombin generation potential compared to full-length rFVIII between 2-6 days after treatment of FVIII-deficient mice. Results obtained showed that thrombin peak levels were kept between 50-250 nM for an increased period of time by rVIII-SingleChain compared to full-length rFVIII, with an average extension of 20 hours.

Conclusions:

The current investigations demonstrated favorable PK properties of rVIII- SingleChain in animal species. The presented results support the evidence necessary for conducting human trials to explore whether such favorable non-clinical PK characteristics may translate into clinical benefit.

Objective:

Few data sources contain sufficient patient count to study the real-world efficacy of factor VIII (FVIII) therapy in patients with hemophilia A (HA). Health insurance claims databases offer that opportunity. This study sought to identify patients with HA receiving prophylaxis versus on-demand FVIII regimens and describe their characteristics and treatment patterns utilizing data from Medicaid programs.

Methods:

Healthcare claims from Florida, Iowa, Kansas, New Jersey, and Missouri Medicaid programs covering 1996 to 2011 were used. Patients with ≥2 HA diagnoses (ICD-9 286.0), ≥2 dispensings for FVIII after age 2, continuous Medicaid eligibility ≥6 months before (baseline period) and ≥12 months after the first FVIII fill, and no evidence of bypassing agents or desmopressin use were included. Prophylaxis and on-demand regimens were identified using an algorithm calibrated to distinguish the regimens within five age groups based on the annual total units of FVIII dispensed regardless of the severity level: 16,480 IU (2–7 years old); 32,770 IU (8–12); 66,920 IU (12–16); 98,349 IU (17–21); 204,552 IU (≥22). The algorithm was developed using prescription records of 1,311 patients from three U.S. specialty pharmacy databases. FVIII treatment patterns and patient demographic and clinical characteristics were examined.

Summary:

From the approximately 14.8 million covered lives encompassed in the five Medicaid databases, a total of 2,408 (0.016%) patients with ≥2 diagnoses for HA were identified; 448 met the study eligibility criteria with 229 (51.1%) patients receiving prophylaxis FVIII and 219 (48.9%) patients receiving on-demand FVIII. Younger patients were more likely to receive prophylaxis therapy (percent by age group: 61% [2–7]; 70% [8–12]; 63% [12–16]; 51% [17–21]; 20% [22+], mean (SD) age, prophylaxis: 10.8 (9.8) years old; on-demand: 18.7 (14.4) years old). Mean (range) observation period was 5.6 (1.0-15.2) years for prophylaxis patients and 5.6 (1.0-15.2) years for on-demand patients.

Conclusions:

In a population of 448 Medicaid patients with HA, this study found that 51.1% and 48.9% patients received prophylaxis and on-demand FVIII regimens, respectively. With the average observation of patients for more than 5.5 years, this database offers the potential for long-term follow-up to assess the relative efficacy of prophylaxis versus on-demand FVIII regimens in decreasing the incidence of bleeding events. These evidences from claims databases are critical to payers and decision makers as they reflect real-world clinical practice and patterns of FVIII use. Information on HA severity level was not available in the databases used.

Objective:

Adherence to treatment has an important impact on health outcomes in chronic conditions, but the relationship between adherence to prophylactic infusions and outcomes in hemophilia is not well documented. This study was conducted to assess the relationship between adherence to prophylaxis and outcomes, including patient-reported health status and bleeding.

Methods:

Adults with hemophilia and parents of minors with hemophilia were identified through a panel of patients originally recruited from hemophilia treatment centres and associations. Panelists reporting moderate or severe hemophilia completed an on-line questionnaire, which included the Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro) for adherence to prophylactic treatment, a measure of health status (adults: SF-12v2 questionnaire; parents of pediatric patients: SF-10) and items assessing the number of times they experienced clinical outcomes, such as breakthrough bleeds, ER visits, hospital admissions, and missed days from work/school due to bleeding episodes. All measures were through self- or parent-report. Generalized linear models were used to assess the relationship between adherence and outcomes, adjusting for age (adults only). The protocol and questionnaire were approved by an institutional review board and all respondents provided informed consent.

Summary (of results obtained):

A total of 53 adults with hemophilia A (n=43) or B (n=10) treated with prophylaxis completed the survey and provided age information. In analyses combining these groups, lower adherence was associated with more days of work or school missed due to bleeding episodes in the past year (p<0.05), as well as the number of bleeding episodes requiring administration of replacement factor in the past year (p<0.001). The relationship between adherence and bleeding episodes was also significant in analyses separating A and B patients (p<0.01 and p<0.05, respectively), as was the link between adherence and days missed in hemophilia A (p<0.05). Adherence was not significantly associated with physical health status (p=0.91) among adults. Among pediatric patients treated with prophylaxis (n=56), the relationship between adherence and number of bleeding episodes in the past year was not significant (p= 0.95). Adherence was associated with clinical outcomes related to bleeding episodes over the past year, such as infection at the injection site (p<0.05), hospital stay due to bleeding episodes (p<0.001), and missed days from work/school due to bleeding episodes (p<0.01). Furthermore, physical health status was better among more-adherent pediatric patients (p<0.01).

Conclusions:

Though sample sizes were limited, greater adherence to prophylaxis was associated with better self-reported clinical outcomes among both adult and pediatric hemophilia patients.

Objective:

To assure plasma-derived clotting factor concentrates are pathogen safe, virus inactivation and removal methods are applied to the manufacturing process. The effectiveness of currently used methods and procedures was demonstrated.

Methods:

The virus reduction capacity of the manufacturing process for a specific product was quantitated for selected steps of the manufacturing process. A prerequisite of such virus validation studies is a valid downscaling of the manufacturing process to a laboratory scale. After spiking product intermediates with a panel of viruses the same as or similar to known and emerging pathogens, the manufacturing steps were performed according to the defined procedures and the reduction factors for the different viruses measured. Prion reduction was also studied, employing both a microsomal preparation (membrane-associated prions) and purified prion protein. Methods in the manufacturing process solely for the purpose of pathogen reduction, such as pasteurization, solvent-detergent treatment, dry heat treatment of the final container, and virus (nano) filtration, as well as manufacturing steps for purification and concentration of the desired protein(s) such as partitioning by precipitation or chromatography, were studied. The residual risk of transmitting pathogens was assessed based on the results of these studies and the potential virus load in the plasma pool used to produce these products.

Summary:

For a pasteurized FVIII/vWF concentrate, the overall log reduction factors were ≥10.2 for HIV, ≥11.7 for BVDV, 10.2 for PRV, 7.8 for HAV, and 6.0 for CPV, as well as 6.4 and 7.9 for the 2 prion preparations, respectively. For a FVIII/vWF concentrate using solvent- detergent and dry heat, values were ≥12.5 for HIV, ≥13.1 for BVDV, ≥11.4 for PRV, ≥12.2 for HAV, and 6.7 for parvoviruses, as well as 4.0 and 4.9 for the 2 prion preparations. For a FIX concentrate using affinity chromatography and virus filtration, values were ≥10.2 for HIV, ≥12.6 for BVDV, ≥12.8 for WNV, ≥16.1 for PRV, ≥6.7 for HAV, and ≥14.8 for parvoviruses. For a FXIII concentrate using adsorption, chromatography, heat treatment, and virus filtration, values were ≥10.2 for HIV, ≥12.6 for BVDV, ≥12.8 for WNV, ≥16.1 for PRV, ≥6.7 for HAV, and ≥14.8 for parvoviruses, as well as 9.6 and 9.7 for the 2 prion preparations.

Conclusions:

Pathogen safety is based on the overall pathogen reduction factor considerably exceeding the amount of pathogen potentially entering the manufacturing pool. Validation studies verify that safety is attained for currently manufactured plasma-derived clotting factor concentrates.

Objective:

The present study has been conducted to explore the biodistribution of rIX-FP, a recombinant fusion protein linking the human coagulation factor IX to human albumin (CSL Behring GmbH), which is currently being investigated in clinical phase II/III trials (PROLONG- 9FP) for prophylaxis and on-demand treatment of bleeding in hemophilia B patients.

Methods:

Therefore, [3H]-rIX-FP, [3H]-rFIX, or [3H]-albumin were administered intravenously to male rats at a single radioactive dose of 320-420 μCi/kg. Using whole-body autoradiography, tissue radioactivity was determined up to 240 and 24 h following [3H]-rIX-FP and [3H]-albumin, and [3H]-rFIX administration, respectively. In addition to full body sections, the hind limbs were analyzed separately and plasma, urine, and feces were collected to calculate excretion balance and assess physiological elimination pathways.

Summary:

Overall, the tissue distribution of [3H]-rIX-FP and [3H]-rFIX was comparable; both penetrated predominantly into well-perfused tissues, were rapidly present in synovial and mineralized regions of knee joint sections, and seemed to mostly localize to the zone of calcified cartilage within the growth plate regions of long bones, with the longest retention time observed in the bone marrow and endosteum of long bones. Intriguingly, [3H]-rIX-FP signal was detectable over 72 h, whereas comparable [3H]-rFIX signal could only be detected until 24 h post-dosing. Elimination occurred primarily via the urinary route. For [3H]-rIX-FP, after 240 h, 73% of radioactivity was recovered in urine, ≤5% of radioactivity was eliminated in feces, and approximately 20% of radioactivity was present in tissues.

Conclusions:

The study shows that rIX-FP exhibits equal biodistribution compared to other marketed recombinant FIX products, but clearly distinguishes itself from rFIX (BeneFIX®) by its extended plasma half-life, allowing a reduction in dosing frequency leading to increased therapeutic convenience and compliance.

Objective:

Patients with hemophilia have been receiving comprehensive care at Hemophilia Treatment Centers (HTC) for the past 30 years which includes: annual medical and psychosocial assessments, training for home infusions of factor, physical therapy evaluations and treatment.

As many of our patients with Hemophilia now self -infuse, they require less visits to the HTC, Emergency Department and hospitalizations. We have noted over the past few years that many patients are delinquent in keeping yearly comprehensive visits. In an effort to increase attendance at comprehensive clinic, and introduce and assess the success of psychosocial interventions, on increasing compliance with appointments, a standard assessment form was created to identify reasons for non-attendance at comprehensive care visits.

Methods:

Data collection included characteristics of the household such as marital status and family size, last comprehensive re-evaluation and ages of patients (< 18 or >18 years). Assessment of barriers included: drug addiction, school related issues relating to academic success, value of comprehensive clinic during a non-emergent time, DYFS involvement, major psychosocial issues, transportation and work related issues such as financial concerns and concern for using days for non-emergent reasons.

Each identified patient was contacted by the social worker to assess reasons for non- compliance utilizing the standard assessment form. Following the assessment, the social worker created and implemented an individually tailored plan developing interventions and employing education, counseling and supportive services.

Summary:

A total of 26 patients were identified as delinquent in comprehensive care visits. Eight were pediatric patients and eighteen were adult patients. All identified patients were called and assessed for barriers to compliance with clinic visits. The major barrier identified was both parents’ and patients’ value of comprehensive clinic during a non-emergent time (46 % of patients). The second major barrier was work related issues (31% of noncompliance). Major psychosocial issues (15 %) and school issues (8 %) accounted for the remaining causes of non-compliance with clinic appointments. Individual plans to address barriers were made and implemented. Following the psychosocial intervention 46 % of the previously non- compliant patients made comprehensive clinic visits.

Conclusions:

Identification of psychosocial reasons for non-compliance to comprehensive care clinic with the development of individual plans to address needs lead to improved compliance with visits.

Objective:

Treatment of bleeding disorders consists of factor replacement on-demand in response to acute bleeding or prophylactically to prevent bleeding. Venous access is a critical aspect of hemophilia care. Placement of Arteriovenous Fistulae (AVF) has previously been reported (Urgo, J et al 2008). We are reporting the long-term use of the AVF and an additional 3 patients.

Methods:

All patients who received an AVF had their records reviewed and they were evaluated for their AVF usage patterns, perceived appearance, longevity of use, and overall satisfaction. The insertion protocol has been previously reported. Each patient’s AVF was assessed routinely at each clinic visit.

Summary:

There were 17 AVF insertions in 16 patients: two von Willebrand disease, 12 Hemophilia A (3 inhibitor), and 3 Hemophilia B (1 inhibitor). Mean follow-up was 5 years (1- 13 years). 15 patients had excellent results with adequate flow and patients/caregivers were able to easily access the AVF for treatment. 1 patient, who underwent 2 procedures, had a poor surgical result with inadequate blood flow to the AVF. No patients had bleeding complications from AVF creation. No patients have an AVF related infection over 5 years. Patients have not experienced any difficulty accessing the AVF for administration of factor. Four patients have reported dissatisfaction with the appearance of the AVF. All report embarrassment over appearance, self-consciousness, wear clothing to hide the AVF, and limited participation in activities where others may question the AVF. All report the AVF works well, no issues with access, and increased confidence in self-infusion. These patients all had enlarged AVF with increased blood flow as demonstrated by fistulogram. 1 patient had revision with banding that had excellent results as well as improved appearance and continued excellent intravenous (IV) access. Two more patients are scheduled for revision. The 4th patient had removal of the AVF due to increased availability of peripheral access.

Conclusion:

AVF continues to be a viable option in patients who do not have IV access and have had repeated complications with other methods of IV access. The complication rate for insertion is 3/17 (18%). Excellent IV access was achieved in 15/16 (94%) patients. Overall satisfaction is good with 9/13 (69%) patients reporting excellent function, ease of access, and satisfaction of the cosmetic appearance of the AVF.

Objective:

To investigate the effect of modified pull-up exercises on elbow range of motion (ROM) and function for people with arthropathy secondary to hemophilia and recurrent bleeding

Methods:

• A) Participants: Men above age 18 years with hemophilia, and greater than 5 degrees ROM loss due to arthropathy from recurrent joint bleeding

• B)  Design and procedure: This pilot study was a prospective case series. Subjects were asked to perform a home exercise program consisting of modified pull ups three times per week for 8 weeks. Data was collected prior to start of program, at 3-5 weeks and at 8-10 weeks. Outcome measures included elbow ROM, pain, upper arm girth and activities of daily living (ADL) related reaching tasks. Information on how often the exercises were being performed, as well as episodes of bleeding was collected each week.

• C) Analyses: A paired t-test was used to compare pre and post intervention measurements.

Summary:

Ten subjects have been recruited with ages ranging from 26-45 years. All have severe hemophilia A. Six subjects have completed the 8 week program to date. Those who completed the program demonstrated a mean increase of 5.3° of elbow flexion ROM (p=0.007). There was a trend toward increase in supination ROM between the two time points (p=0.058). No significant difference was seen in pre and post measurements for extension and pronation ROM. The only ADL related reaching task that demonstrated change between the two time points was palm of hand to occiput. Distance between the palm of hand to the occiput decreased 2.2 inches (p=0.009). Only 2 of the 6 subjects reported having pain in their elbow prior to the start of the program and it was unchanged during the course of the study. Arm girth data only existed for 5 of the 6 subjects and was measured at 3-5 week and 8-10 weeks. There was a trend toward increase in upper arm girth (p=0.078). There have been three reported episodes of elbow bleeding; only one was attributed to the exercises according to subject’s report.

Conclusion:

Preliminary results suggest that an eight week exercise program consisting of modified pull- ups may increase elbow flexion ROM in men with elbow joint contracture due to recurrent joint bleeding from hemophilia. Continuation of this study as well as development of others is needed to further determine if strength training is beneficial to improving elbow movement and function in those with hemophilic arthropathy.

Objective:

To examine the causes for spontaneous bleeds in severe hemophilia A patients on prophylaxis in an effort to increase care collaboration, decrease these incidents and optimize care.

Methods:

From our company’s bleeding disorders patients’ prescriptions and assessment records databases between April 1,2011 and March 31, 2012 (12 months period), prescriptions and assessment records were analyzed for prophylaxis (factor VIII) patients with severe hemophilia A who did not have inhibitors and who had at least one bleed (self- reported) requiring extra factor in the last 12 months. Due to limitations related to data retrieval from different databases, we eliminated all the patients where accuracy of match was doubtful resulting in a reduced “N”. Out of the 52 patients, 17 were identified with at least one spontaneous bleed. To identify details of psychosocial environment that might have contributed to the bleeds, chart reviews were done on five among them who reported two or more spontaneous bleeds.

Results:

Patients with four bleeds:

Patient A developed a left ankle target joint. Patient has not consistently reported bleeds to HTC. Specialty RPh notified HTC for evaluation of dose and to report bleed pattern.

Patient B frequently missed doses resulting in spontaneous bleeds.

Patients with three bleeds:

Patient C communicated well with home care and HTC. This collaboration contributed to care plan personalization and an increase in dose and frequency resulting in cessation of spontaneous bleeds.

Patients with two bleeds:

Patient D is a toddler making it difficult to identify spontaneous versus trauma induced bleeding. Homecare nurse communicated frequently with HTC leading to dosing adjustments resulting in rare spontaneous bleeds.

Patient E is a non-compliant teen and at times does not adhere to his prophy regimen.

Conclusion:

The goal of prophylaxis should be zero spontaneous bleeds. There are a variety of factors that might contribute to the bleeds such as lack of compliance, development of target joints, age, growth spurts, or improper dosing frequency and amount. Collaborating with a home infusion company or specialty pharmacy can afford an opportunity to identify and address some of these factors to take corrective actions wherever possible and hence to optimize outcomes.

Objective:

To assess the dental experiences of patients with von Willebrand disease for the purpose of developing guidelines for screening and dental management.

Methods:

A 13-question survey was administered to individuals at the National Outreach von Willebrand Conference, held in Phoenix, AZ in February 2012. A total of 55 respondents answered questions regarding oral hygiene habits, frequency and types of prior dental visits, dentists’ attitudes and knowledge of the disease, adverse bleeding events and quality of communication between dentist and haematologist.

Results:

Eighteen percent of respondents reported being refused dental treatment upon disclosure of von Willebrand disease history, while 81% of respondents reported that their dentist did not consult their haematologist prior to rendering treatment. More than half of those surveyed (56%) reported adverse bleeding events following dental procedures. Finally, 37 respondents reported gingival bleeding and 21 had not visited a dentist in the past six months.

Conclusions:

The results of this pilot study indicate that there is a need to educate the dental profession about von Willebrand Disease, especially its oral manifestations. Simultaneously, patients with von Willebrand Disease need to be educated as to the importance of maintaining oral health. Much more research needs to be done on the effects of poor oral health on the severity of bleeding disorders.