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CHS Research Grants for 2014

Incorporation of rFVIII into platelets as a potential therapy in patients with inhibitory antibodies to factor VIII

Dr. Walter Kahr
The Hospital for Sick Children – Toronto, Ontario
Second year funding

Current treatment of severe hemophilia A patients in Canada involves regular injections of recombinant factor VIII (rFVIII). This treatment is effective, but rFVIII injections are usually frequent because factor does not stay long in the blood stream and around 25% of patients develop inhibitors that block rFVIII effectiveness. Work is underway to develop longer-lasting forms of rFVIII and limit the effects of inhibitors. One approach involves platelets, the tiny, abundant blood cells that coordinate blood clotting. Platelets normally do not contain FVIII, but genetic engineering has been used to make mouse platelets containing FVIII that have proven to be effective in preventing bleeding in hemophilic mice even when they have inhibitors. We have been working on ways to load platelets with rFVIII that do not involve the risk, expense and uncertainties of genetic engineering. Our preliminary work shows that this is possible, and that rFVIII-loaded platelets can inhibit bleeding in hemophilic mice. The goal of our proposed project is to improve our methods for making rFVIII-loaded platelets and to demonstrate their potential for use in hemophilia patients with inhibitors, who are often difficult to treat with conventional therapies.

Understanding Angiodysplasia in von Willebrand Disease: Studies Using BOEC (Blood Outgrowth Endothelial Cells)

Dr. Paula James
Queen's University, Ontario
First year funding. 

Co-investigator: Dr. Maurice Don, Queen's University  

Von Willebrand disease (VWD) is a common, inherited bleeding disorder that causes excessive bleeding from the skin and mucous membranes.  Patients experience nosebleeds, heavy menstrual periods, easy bruising and abnormal bleeding after dental work, childbirth and surgery.  Bleeding from the GI (gastrointestinal) tract in VWD patients occurs in up to 20% of patients and can be particularly difficult to treat. We do not completely understand what causes angiodysplasia (small vascular malformations like varicose veins on the inside of the bowel), which is a common reason for GI bleeding in VWD patients.  This research project will use endothelial cells that can be cultured from blood samples from VWD patients in order to better understand the factors that lead to angiodysplasia.  We will also study the effect and mechanisms of available treatments, including concentrates of von Willebrand factor, estrogen, thalidomide and atorvastatin. Our objective is to improve treatment for VWD with GI bleeding from angiodysplasia.

Characterization of Common Inherited Platelet Function Disorders

Dr. Catherine Hayward

McMaster University, Ontario
First year funding

Dr. Guillaume Pare, McMaster University
Dr. Andrew Paterson, Hospital for Sick Children (University of Toronto)

Platelets are small blood cells that help stop bleeding. If platelets don’t work, it causes bleeding. Platelet disorders are a common cause of abnormal bleeding. To improve knowledge and patient care, we are studying why platelets don’t work normally in some families with bleeding problems. Our goal is to find the causes of very common platelet problems and learn more about how they affect health. We will study genes to learn why some people have platelet problems and others don’t. Answering why platelets don't work normally in some families with bleeding problems requires tests on samples from many persons with platelet problems. Our testing will include studying why platelets don't work normally in individuals from families with platelets problems. Knowledge on what causes common platelet disorders will be helpful to improve patient care and develop better tests for these conditions.

What are the Short-Term Effects of Physical Activity on the Cartilage of Hemophilic and Age-Matched Boys? Functional Imaging Perspective

Lab work studentship

Humayun Ahmed
Hospital for Sick Children
Under the supervision of Dr. Andrea Doria, the Hospital for Sick Children (Toronto)
Summer 2014 funding
Joint disease affects 90% of hemophiliacs greatly contributing to the cost and morbidity of the disease. Cartilage degeneration is the final unfavourable outcome of non-treated hemophilic patients which can be avoided or minimized with the use of prophylaxis.
Imaging is an appealing tool for diagnosing early cartilage degeneration at a point where changes can potentially be reversible with appropriate therapy. T2 mapping MRI is a non-invasive technique that enables depiction of changes in cartilage microstructure which precede macroscopic cartilage loss.  Few studies have previously investigated the water-cartilage pattern of T2 mapping related to the directionality of collagen fibres in diseases other than hemophilia.

Although there is evidence that physical activity increases risk of bleeds in children with hemophilia, exercise is thought to have a beneficial effect on hemophilic joints. Nevertheless, little is known about the effect of exercise on the cartilage status of hemophiliacs.
We plan to apply a short-term exercise protocol (knee squats) to hemophilic and age-matched healthy boys to determine whether a change in the organization of collagen fibers can be detected in their maturing cartilage pre- and post-exercise. This information is critical for the development of future guidelines on safety and effectiveness of physical activity for hemophiliacs.

Effects of FEIBA on FXa generation in factor VIII and factor IX deficient plasma

Lab work studentship

Alice Kun Yi
McMaster University                    
Under the supervision of Dr. Howard Chan, McMaster University – Hamilton, Ontario
Summer 2014 funding

FEIBA is a plasma product containing some activated clotting proteins. It is an important treatment option for hemophilia patients refractory to regular factor replacement therapy because of the presence of inhibitors. As an off label use, it has also been used to reverse the new generation of blood thinners when non-hemophilic patients develop bleeding complications. However, the plasma in patients with hemophilia misses an important clotting factor, which may alter the ability of FEIBA to form blood clot when comparing with plasma obtained from normal population. Ms. Yi will use an assay in the laboratory to compare the differences in various types of plasma. The results will provide important information regarding the mechanistic actions of FEIBA so that its use can be optimized in various clinical settings.