Research Studies

Hemophilia causes repetitive bleeding episodes throughout the musculoskeletal system, primarily into joints, such as knees and ankles. This leads to significant joint damage resulting in increased pain reproduction, decreased functional abilities, such as walking, and negatively impacts quality of life. Traditionally the extend of joint damage has been examined via clinical assessments, such as the Hemophilia Joint Health Scores, x-rays, MRIs, and more recently musculoskeletal ultrasound (MSKUS). However, these modalities fail to establish the global impact of joint damage on the entire body of a person with hemophilia and their functional abilities. Analyzing joint motion and forces acting upon the joint during walking has been a widely established technique to gain understanding of abnormal three-dimensional movements and is a key factor in clinical decision making-processes. With the overall goal of establishing better treatment approaches for persons with hemophilia it is vital to understand the underlying functional joint limitations. Therefore, the purpose of this study is to investigate characteristics of damaged joints, joint motion and control as well as forces acting upon the joint during walking in persons with hemophilia.

Objective:

Persons with bleeding disorders experience pain in association with needle pokes, joint and muscle bleeds and permanent tissue damage.  The impact of this pain on patients can include time off school or work, a change in career, income, stress, mental health concerns and change in relationships.  Comprehensive pain management includes strategies from the “Four P’s of Pain Management” which include pharmacological, physical, psychological and prevention.

The aim of the project was to examine current psychological knowledge and management of pain within our patient population.  This study asked the following research questions: 1) What is currently understood about pain and bleeding disorder care among social workers (CSWHC)? 2) What specific pain knowledge and training is prioritized by social workers in Hemophilia Treatment Centres?

A scoping review was conducted concurrently with the qualitative study.  Medline and SocIndex were searched with the terms “social work” and “pain management” and a second search was conducted with the term “social work and hemophilia/von willebrand's or platelet disorders”.  A total of 105 articles were examined by three independent reviewers. Eleven articles have been included for the purpose of examining the role of social work in pain management.

Methods:

Qualitative interviews were conducted and recorded with 12 social workers from the CSWHC between September 2018 and February 2019.  Five provinces were represented. Social work participants were deployed within paediatric, adult or within combined clinics. The interviews were approximately 20-45 minutes.  Transcribed interviews were coded with NVivo by two independent reviewers with Thematic Analysis.

Summary:

Social workers identified the roles of social work to include completion of psychosocial assessments and meeting the practical needs of patients, while supporting patients in medical decisions.  Barriers to pain management and the impact of pain on patients were described as having an impact on individuals and families. Social workers also discussed their understanding of acute and chronic pain in patients, which has indicated an increase of knowledge is required.  Skills development in multi-dimensional nature of pain and pain assessment were determined to be most likely to produce positive impact on practice outcomes. Initial themes include hope, relationship of trust, stigma (diagnosis vs. pain), defining multidisciplinary roles.

Conclusion:

Study results, first, will contribute to the literature supporting the need for social work education for those practicing in bleeding disorder care.  Secondly, they will provide recommendations for an educational pain curriculum for social workers in bleeding disorder care. This education will reflect the need for pain knowledge in acute and chronic pain dimensions which will facilitate dialog with other professionals in pain management.  Pain assessment will also be a focus in order for social workers to be able to support and provide appropriate referrals for pain management.

Objective:

PAI-1 is a serine protease inhibitor (SERPIN) whose function in vivo is to downregulate fibrinolysis by inhibiting urokinase- and tissue-type plasminogen activators (uPA and tPA). The goal of this research is to use PAI-1 as a prototypical SERPIN scaffold from which to develop “designer” PAI-1 variants with altered specificity and inhibitory kinetics.

Methods:

PAI-1 variants of interest were identified using a molecular evolution approach in which traditional phage-display technology was coupled with next generation high throughput DNA sequencing. Filamentous phage displaying PAI-1 fused to the p3 coat protein were randomly mutagenized through error prone PCR, reacted with uPA, and selected with an anti-uPA polyclonal antibody in two sets of complimentary experiments to (1) determine the stable half-life of PAI-1 or (2) the rate at which PAI-1 inhibits uPA. At selected time points in each of the described experiments, the PAI-1 encoding portion of the phage genome was analyzed by next- generation sequencing. Evaluation of 7-10 million sequencing reads per time point facilitated massively parallel kinetic analyses to determine the effect of amino acid substitutions at every residue in PAI-1 simultaneously with respect to both half-life and rate of uPA inhibition.

Summary of Results:

This analysis generated data for 74% of all possible single amino acid substitutions, identifying 492 mutations that extended the functional half-life of PAI-1, as well as 1509 destabilizing mutations. These results were validated for representative single amino acid substitutions expressed as individual, purified recombinant proteins.

Conclusions:

These data provide a useful resource for interpreting human mutations identified by future large scale clinical human genome sequencing. In addition, these findings provide new insight into structure-function relationships in PAI-1. Finally, these tools lay the groundwork for future studies aimed at developing novel SERPINs based on the PAI-1 scaffold with altered target protease specific potentially applicable to treatment for a number of disorders of hemostasis and thrombosis, as well as various other SERPIN disorders (eg alpha-1-antitrypsin and C1-inhibitor deficiency).

Objective:

Immune tolerance induction (ITI) is the standard of care for inhibitor eradication and restoration of factor VIII (FVIII) responsiveness in subjects with severe hemophilia who develop high-titer inhibitors. Retrospective data support the use of recombinant FVIII Fc fusion protein (rFVIIIFc) in ITI (Carcao et al. Haemophilia. 2018) but this has yet to be confirmed in prospective studies. This study presents preplanned interim results of verITI-8 (NCT03093480).

Methods:

VerITI-8 is a single-arm, nonrandomized, open‐label, ethics-approved study of rFVIIIFc (200 IU/kg/day) for first-time ITI. Eligible subjects had a history of high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL) and provided informed consent. The primary endpoint is time to tolerization, defined by negative inhibitor titer (<0.6 BU/mL) at two consecutive visits; incremental recovery ≥66% of expected at two consecutive visits; and rFVIIIFc half‐life ≥7 hours. ITI failure is defined as not meeting the above criteria by Week 48. This interim analysis was planned when ≥10 subjects had received ≥6 months of rFVIIIFc ITI.

Summary:

Fifteen subjects were screened as of the December 5, 2018 cutoff, while 14 subjects enrolled and had received ≥1 dose of rFVIIIFc for ITI. The median (range) age at start of ITI was 2.6 (0.8–16.0) years and historical peak inhibitor titer was 29.6 (6.2–256.0) BU/mL. Six subjects have been successfully tolerized, with a median (range) time to first negative titer, normal incremental recovery, and tolerization of 2.3 (1.7–15.6), 6.0 (4.3–28.1), and 11.7 (8.1–32.0) weeks, respectively. Seven subjects continue to receive rFVIIIFc ITI (median [range] time on ITI: 16.0 [0.1–35.6] weeks) and 1 subject has failed. No adverse events related to rFVIIIFc have been reported.

Conclusions:

Early results from this prospective/ongoing study of first-time ITI indicate that rFVIIIFc may offer rapid time to tolerization in some subjects with severe hemophilia A and high-titer inhibitors. Achieving tolerance faster can improve quality of life and reduce costs.