Research Studies

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.

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:

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:

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 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.

Objective:

Our hypothesis was that females with FVIII deficiency enrolled in the Universal Data Collection (UDC) project have reduced mean joint range of motion (ROM) compared to historic controls from the Normal Joint Study.

Methods:

We employed a cross-sectional study design utilizing the UDC dataset. The overall joint ROM was the sum of the ROM measurements of the five joints for the females with FVIII deficiency and the normal females. Results were displayed as mean overall joint ROM by age group and factor deficiency with differences between groups assessed using the Wilcoxon- rank-sum test.

Summary:

A total of 513 females were identified with FVIII deficiency; 144 females were removed because of a lack of verification for factor deficiency, one female lacking recorded range of motion data. Of the 368 females, the median age was 26 years (range 0-78). Final analysis was performed on 247 females with FVIII deficiency between the ages of 2-69 (excluding very obese females) for comparison to the control group. The mean overall joint ROM worsened with decreasing FVIII activity and in most cases was lower than that of the controls (see table 1).

Conclusions:

Females with FVIII deficiency enrolled in the UDC project had reduced mean ROM compared to normal females without deficiency.

Table 1. Mean overall joint ROM in females with FVIII deficiency by age and factor activity.