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CHS Research Grants for 2012

Novel imaging techniques for assessment of early cartilage and soft tissue changes in haemophilic ankles

Dr. Andrea Doria
The Hospital for Sick Children – Toronto, Ontario
First year funding continued in 2012 due to late start.

Co-investigators: Dr. Aaron Fenster; Dr. Marshall Sussman; Dr. Victor Blanchette

Hemophilia is an inherited bleeding disorder characterized by the lack of coagulation factors which results in an inability to control bleeding into joints, leading to long-term joint damage. Prophylaxis, reduces the joint symptoms and avoids further degeneration of the joints, however it should be started prior to the development of cartilage lesions. Repeated extravazation of blood into the joint cavity is the factor responsible for cartilage degeneration in hemophilic arthropathy. Microstructural cartilage changes are thought to precede macroscopic cartilage lesions [8] which are responsible for most of the morbidity of hemophilic arthropathy. Conventional imaging techniques are unable to visualize early soft tissue and cartilage changes. Evaluation of soft tissue changes and microstructural cartilage changes with sensitive imaging tools may direct clinical management and prophylaxis towards avoiding further irreversible macroscopic osteochondral damage. New functional MRI techniques and 3DUS anatomic imaging may be able to diagnose early joint changes at a time where treatment is still effective to avoid further degeneration of the joint. No prior studies have investigated the imaging of very early structural and physiologic events in hemophilic joints. We will pioneer the development of novel imaging techniques for assessment of early soft tissue and cartilage changes in hemophiliacs.

Oral administration of FVIII DNA to modulate inhibitors in hemophilia mice

Dr. Gonzalo Hortelano
McMaster University – Hamilton, Ontario
First year funding

The delivery of genes as therapeutic drugs is still facing numerous challenges, particularly how to effectively deliver a therapeutic gene to the desired target cells, and the immune responses generated by the immune system to foreign DNA and to foreign or new proteins. Viruses are the most popular vehicle to deliver therapeutic genes, since they are very efficient at infecting cells. However, some human trials have revealed some safety concerns that need to be addressed. Additional and novel ways to deliver therapeutic genes would be desirable.
Ingestion of therapeutic genes would allow the intestine to produce a therapeutic protein for distribution throughout the body. However, DNA is degraded in the acidic stomach environment and by DNA-degrading proteins in the intestine. Our laboratory has shown that DNA formulated with chitosan into nanoparticles can withstand degradation under those conditions. Interestingly, we have not observed antibodies against the therapeutic protein encoded by ingested DNA. Further, we have evidence suggesting that this strategy can modulate the immune response to FVIII. The overall goal of this proposal is to understand the effect of ingested DNA on the immune system and to evaluate the potential of oral DNA in preventing and/or reducing FVIII inhibitors.

Platelet–type von Willebrand disease: Novel studies in the PT-VWD mouse model

Dr. Maha Othman
Queen’s University – Kingston, Ontario
First year funding.

PT-VWD is a rare inherited bleeding disorder .Only 55 patients are described worldwide. The disease results from a hyper-responsive platelet protein known as GP Ib alpha due to genetic defect in the platelet GP1BA gene. The disease is characterized by low plasma VWF and platelet count. The latter can be aggravated in response to stress, infection and during pregnancy. Patients can have life threatening bleeding if not diagnosed and treated properly.
Currently the standard test for evaluating bleeding pattern is VWF:RCo (ristocetin cofactor assay) which has shown problems in relation to sensitivity and ristocetin binding. We hypothesize that the thromboelastography (TEG); a global hemostatic test is useful in evaluating hemostasis in PT-VWD and would potentially help monitor patients during pregnancy, at times of infection and following treatment. We plan to carry out novel studies in the PT-VWD
mouse model carrying a common human mutation G233V and exhibiting a similar phenotype to the human disease. We will investigate the utility of TEG in PT-VWD, evaluate the mouse model during early and late pregnancy and in response to infection and evaluate the effect of GP1b alpha inhibitors in improving the bleeding phenotype in these mice. These studies have not been previously done and are likely to improve our understanding of the PT-VWD disease and help diagnosis and follow up of patients.

Effects of anticoagulants on clot formation in factor VIII deficient plasma

Lab work studentship

Frank Lee
McMaster University

Under the supervision of Dr Howard Chan
McMaster University
Summer 2012 funding

Hemophilia patients have bleeding tendency. Yet, in certain situations, these patients are also subject to high risk of clotting. Blood thinner (anticoagulant) is used to prevent or treat blood clot. However, anticoagulants also carry the risk of bleeding. The optimal use of anticoagulant in these conditions has not been well studied. Mr. Lee has set up an assay system in the laboratory mimicking the clotting system in hemophilia patients. He will use this assay to determine the effects of anticoagulants on blood clot formation. His work will provide important information to guide the safe use of anticoagulants in hemophilia patients.

Determinants of health-related quality of life among patients with von Willebrand disease

Lab work studentship

Yan Xu
Queen’s University

Under the supervision of Dr Paula James
Queen’s University
Summer 2012 funding

von Willebrand disease (VWD) is a common bleeding disorder. Among its patients, there is a significant health burden associated with the bleeding symptoms from the disease. While methods of numerically determining patients’ bleeding symptoms have recently been developed and tested, very little research has gone into investigating the quality of life among those afflicted with this disease, especially in the Canadian patient population. This project aims to determine the quality of life among patients with mild, moderate and severe forms of VWD. Further, we hope to find out whether a patient’s quality of life can be predicted by his or her levels of bleeding symptoms, social support and geographical access to treatment. By understanding the relative contributions of these 3 factors on quality of life, we hope to inform better ways to ensure that day-today living for all VWD patients can be improved.

Treatment adherence on the Canadian Hemophilia Prophylaxis Study

Lab work studentship

Daniel Kazandjian
Carleton University

Under the supervision of Dr Brian Feldman
The Hospital for Sick Children
Summer 2012 funding

Research Question: How does treatment adherence affect outcomes?
The Canadian Hemophilia Prophylaxis Study is on ongoing prospective cohort study. The first subject was enrolled in 1997. We have followed 56 boys for a median of 106 months. With this large data set we would like to examine adherence with various aspects of the protocol. Last summer we performed some preliminary analysis of adherence with the protocol in regards to treatment, escalation and prescribed infusions. This preliminary work led to this proposal in which we are looking at adherence in much great details. We will first look at adherence with all aspects of the protocol including infusion, visits, escalations and treatment of joint bleeds. After this early analysis is complete we will look at some more interesting questions that will include the following: how does adherence with the protocol affect outcomes? How does adherence with infusions (per protocol) relate to bleeding, physiotherapy scores and other outcomes? We will also look at adherence related to the time on study as well as adherence within each of the steps of the protocol.

Factor XIII deficiency in Canada

Lab work studentship

Jodie Odame

University of Western Ontario

Under the supervision of Dr. Vicky Breakey
Summer 2012 funding

Factor XIII deficiency is a rare, but important bleeding disorder. The Rare Inherited Bleeding Disorder Registry in Canada shows that there are approximately 50 Canadians with factor XIII deficiency. Although individuals with severe factor XIII deficiency often receive prophylaxis, little is known about compliance with prophylaxis and any breakthrough bleeding that may occur. A survey will be completed to document the current management of this bleeding disorder and to better understand the impact of factor XIII deficiency for patients in Canada. Although factor XIII deficiency is uncommon, it is important that pediatricians are knowledgeable about this condition, as it often presents with intracranial bleeding in the neonatal period.In addition, women with factor XIII deficiency need special care to maintain pregnancy. An educational module will enrich the current education of medical students, residents and fellows, with the goal of increasing awareness of rare bleeding disorders.