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CHS Research Grants for 2017

VWF in megakaryocytes and the role of platelet-VWF in VWD

Dr. Walter Khar
Hospital for Sick Children – Toronto
First year funding

People with severe von Willebrand disease (VWD) have bleeding problems caused by a lack of von Willebrand factor (VWF), typically missing in their plasma and platelets. We have found, however, that patients with a particular mutation have some VWF in their platelets. They have less severe bleeding problems than most severe VWD patients, possibly owing to this platelet VWF.

Our study addresses two key knowledge gaps: 1) How is VWF packaged by megakaryocytes into platelets? 2) What is the role of platelet VWF in reducing bleeding symptoms in some severe VWD patients? We will address these questions using methods we have successfully employed in my laboratory involving platelet development and function, including high resolution microscopy and genetic manipulation of megakaryocytes.

The role of FVIII glycans on the immunogenic potential of FVIII concentrates

Dr. David Lillicrap
Queen’s University – Kingston, Ontario
Second year funding

The aim of the studies described in this research proposal are to investigate possible causes for the increased risk of factor VIII inhibitor development that has been documented with one particular form of recombinant factor VIII concentrate. The theory being tested in these experiments is that the recombinant factor VIII in question is “decorated” with a different pattern of sugar molecules that trigger a response from the early, innate arm of the immune defense system. The studies that ate proposed will first determine the pattern of sugars associated with the surface of different forms of recombinant factor VIII. We will then examine the effect of the various recombinant concentrates on the immune cells that cleat factor VIII from blood and provide the initial response to the protein. These experiments will test whether the immune cells are excessively “activated” by any of the factor VIII concentrates. We will also be able change the sugar content of the factor VIII proteins through chemical means, to see whether this alters the effect on the immune cells. Finally, we will test the potential of the different factor VIII products to produce inhibitors in a novel “humanized” mouse model of hemophilia.

Role of Gfi1b in the formation of platelets and in inherited bleeding disorders

Dr. Tarik Möröy
Institut de recherches cliniques de Montréal (IRCM)
Department of Hematopoiesis and Cancer
Third year funding

Platelets are essential for blood clotting and are formed in the bone marrow by large cells, so-called 'megakaryocytes', which form long protrusions that penetrate into blood vessels, where the shear forces of the blood stream detach small pieces, which form the platelets. Low platelet numbers can be caused by different diseases or can be the result of an inherited disorder that leaves megakaryocytes unable to produce platelets. These heritable diseases are of clinical importance since low platelet numbers can cause excessive bleeding, which can create severe complications for instance during surgery. A better understanding which factors regulate platelet production is therefore needed to develop new treatments for platelet deficiencies. Recently, mutations in a gene called 'Gfi1b' have been identified in patients with a bleeding disorder caused by low platelet numbers. We have generated mice deficient for this gene and have observed that they show most of the typical symptoms of the human disease associated with the mutated Gfi1b, suggesting that the Gfi1b gene is a critical element in platelet formation. We propose therefore to investigate how this gene functions and regulates platelet formation to gain new insight on how to treat patients with bleeding disorders and platelet deficiencies.

The link between the gut microbiome and inhibitor development in hemophilia A mice.

Lab work studentship

Matt Cormier
Queen’s University – Kingston, Ontario
Under the supervision of Dr. David Lillicrap and Julie Tarrant, Queen’s University

Hemophilia A is a genetic disorder that manifests itself through an inability to form blood clots within the body. Since this is due to the absence of a clotting protein (factor VIII), the gold-standard treatment is to inject the protein that is missing into the patient’s circulation to make up for the deficiency. Unfortunately, about 30% of hemophilia A patients develop inhibitors against this infused protein and render the treatment ineffective. The interaction between factor VIII and the body’s white blood cells are important for inhibitor generation as well as the tolerance to factor VIII, which is the absence of inhibitor generation to the protein. The gut harbours a vast population of microbes that have been shown to influence the immune response. Since different compositions of bacteria are linked to altered immune states, we are deciding to test whether different bacterial gut compositions have an affect on the development of inhibitors to factor VIII in mouse models. To do this, we are giving the hemophiliac mice antibiotics to alter their gut composition and measure many factors to determine if the presence of certain types of bacteria actually do influence the development of inhibitors.

Developing an evidence-based training program for mentors for a virtual peer-to-peer hemophilia mentoring program for teens.

Lab work studentship

Claudia Nguyen
Ryerson University – Toronto, Ontario
Under the supervision of Dr. Vicky Breakey, McMaster University – Hamilton, Ontario

Hemophilia is a rare bleeding disorder that can be complicated to manage. While the child and family share management of hemophilia; teens are expected to take on a greater role in managing their hemophilia as they mature. Yet, most teens with hemophilia do not receive comprehensive education on how to manage hemophilia on their own. Peer mentoring is proposed as one solution to address this gap in clinical care. Peer mentoring can provide meaningful social support and has also been associated with improved health outcomes. An online Skype-based peer mentoring program (Virtual Peer-to-Peer Support Mentoring Program [VP2P]) exists for teens with arthritis and chronic pain. However, these diseases are different and the groups are primarily female therefore making changes to this program necessary for the male teens with hemophilia. Recently, we have completed interviews in 25 young people with hemophilia to identify their peer mentoring wants and needs of youth with hemophilia in order to determine necessary changes to the VP2P for youth with hemophilia. This information will be used to develop a tailored peer mentoring program for youth with hemophilia. Our summer student’s project will involve developing the tailored mentoring program based on the information collected from teens and young adults. This program will later be studied to determine if it is an effective approach to improving transition of care from pediatrics to adult-based clinics.

A study of the clot ultrastructure when factor VIII deficient-plasma is coagulated in the presence of anticoagulants.

Lab work studentship

Rachelle Li
University of Western Ontario – London, Ontario
Under the supervision of Dr. Anthony Chan, Dr. Howard Chan and Jorell Gantioqui, McMaster University – Hamilton, Ontario

Hemophilia patients may develop life-threatening bleeding problems but they may paradoxically develop blood clot issues when the missing clotting protein in the blood is being replaced. Whereas blood thinner is usually needed to treat the blood clot, this treatment imposes a high risk of bleeding in hemophilia patients because of their inherited risk of bleeding. This is a very challenging situation for the managing clinicians. Therefore, we are proposing a study using electron microscopy to investigate the changes of blood clot structure. The information of this study will provide some fundamental information regarding the blood clot in hemophilia patients if they also receive blood thinner treatment. The findings of the current proposed study will look at the clotting process from another angle that can help the researchers to understand how blood thinner affects the blood clot in hemophilia patient who has already been deficient in a clotting protein.