CHS / AHCDC / CSL Behring Hemostasis Fellowship Program

/CHS / AHCDC / CSL Behring Hemostasis Fellowship Program
CHS / AHCDC / CSL Behring Hemostasis Fellowship Program2018-08-17T13:52:19+00:00

The CHS/AHCDC/CSL Behring Hemostasis Fellowship Program, was a fellowship in Congenital and Acquired Bleeding Disorders, that was established in the fall of 2001 as a result of a collaborative effort among Novo Nordisk Canada Inc., the Canadian Hemophilia Society and the Association of Hemophilia Clinic Directors of Canada. Beginning in 2010, the Fellowship continued to be made possible thanks to generous financial support from CSL Behring Canada. The program ended in 2015.

The goal of this program was to provide fellows in Hematology or other relevant fields the opportunity to obtain additional focused clinical or research training relevant to Hemostasis so that they may improve the care, the treatment and the quality of the lives of patients with hemophilia and other congenital or acquired  bleeding disorders. Consideration was given on an individual basis to candidates from allied health professions undertaking post-graduate studies.  The fellowship, valued at $75,000, was used for salary support for outstanding candidates who planned a career in Canada.

No applications received for 2015.

The following 2014 project continued in 2015:

Mechanisms associated with hyper-responsive PLT GPIbα cause alterations in PLT activation and function leading to a bleeding phenotype. 

Dr. Harmanpreet Kaur
Queen’s University – Kingston, Ontario
One year funding. Start: April 30, 2014; to end September 2015.

GPIbα is a protein present on the membrane of platelets and is very important in clotting. It binds to another clotting protein called von Willebrand factor (VWF) and this binding is considered to be the first step of clotting at the site of injury. Hyper-responsive GPIbα characterizes the rare bleeding disorder platelet-type von Willebrand disease (PT-VWD) and results in excessive binding between GPIbα and VWF leading to subsequent removal from the circulation. Patients suffering from this disease have mild to severe bleeding problems which can be life threatening in case of surgery, pregnancy and childbirth if not treated properly.  Mechanisms that explain the bleeding condition are not fully understood and appear to be independent of VWF binding and clearance of VWF-platelet complex. We will look at various aspects of platelet activation and clot formation using a mouse model for PT-VWD. We will also study the effect of inhibiting hyper-response GPIbα on bleeding in these mice. This study is important because it could help us better understand this rare disease and to develop strategies to improve bleeding conditions in PT-VWD patients.

Mechanisms associated with hyper-responsive PLT GPIbα cause alterations in PLT activation and function leading to a bleeding phenotype. 

Dr. Harmanpreet Kaur
Queen’s University – Kingston, Ontario
One year funding. Start: April 30, 2014; to end September 2015.

GPIbα is a protein present on the membrane of platelets and is very important in clotting. It binds to another clotting protein called von Willebrand factor (VWF) and this binding is considered to be the first step of clotting at the site of injury. Hyper-responsive GPIbα characterizes the rare bleeding disorder platelet-type von Willebrand disease (PT-VWD) and results in excessive binding between GPIbα and VWF leading to subsequent removal from the circulation. Patients suffering from this disease have mild to severe bleeding problems which can be life threatening in case of surgery, pregnancy and childbirth if not treated properly.  Mechanisms that explain the bleeding condition are not fully understood and appear to be independent of VWF binding and clearance of VWF-platelet complex. We will look at various aspects of platelet activation and clot formation using a mouse model for PT-VWD. We will also study the effect of inhibiting hyper-response GPIbα on bleeding in these mice. This study is important because it could help us better understand this rare disease and to develop strategies to improve bleeding conditions in PT-VWD patients.

Investigating the contribution of von Willebrand factor (VWF) propeptide mutations to Type 3 von Willebrand disease (VWD) using Blood Outgrowth Endothelial Cells (BOEC)

Mackenzie Bowman
Queen’s University – Kingston, Ontario
One year funding. Start: October 1, 2013; To end September 2014.

Von Willebrand disease (VWD) is a bleeding disorder caused by a lack of or a dysfunction of the clotting protein called von Willebrand factor (VWF). The most severe form of VWD is type 3 VWD, which is caused by a complete absence of VWF. Patients that have this form of the disease have serious bleeding, either as a result of trauma or spontaneously. We have previously identified mutations that affect a critical part of the VWF gene in Type 3 VWD patients in Canada and we have learned how to grow endothelial cells from a peripheral blood sample from patients with VWD. By asking patients with mutations in this critical area to provide us with a blood sample, we can grow endothelial cells (the cells which line our blood vessels) from these patients. These endothelial cells contain the specific VWD defects we are interested in and we can investigate how these defects cause the patients’ VWD. We can also test different treatments on these cells to see if we can lessen or cure the VWD. This project will provide us with a better understanding of what causes Type 3 VWD and may help create personal treatment options for patients.

Determination of the role of candidate receptors STAB-2, CLEC4M and SCARA5 as contributing factors to quantitative athologies involving the accelerated clearance of von Willebrand factor

Dr. Laura Swystun
Queen’s University – Kingston, Ontario
One year funding. Start: July 1, 2012; To end June 2013.

Von Willebrand factor (VWF) is a protein that helps blood clot by helping platelets bind to each other and the blood vessel wall. VWD is due to impaired VWF function. Many patients with VWD show evidence of increased VWF clearance or removal from their plasma. Three cell surface receptors (CLEC4M, STAB2, SCARA5) may facilitate clearance of VWF from the blood. We believe that mutations in these receptors may increase VWF clearance and result in VWD. The purpose of our studies are to:

1. characterize the ability of VWF to bind to CLEC4M, STAB2 and/or SCARA5 receptors;

2. investigate the clearance of VWF in animal or cell models that lack these receptors;

3. determine if VWD patients with evidence of accelerated VWF clearance have variations in the CLEC4M, STAB2 and SCARA5 genes.

These studies are important because they could help us better understand how VWF is cleared from blood, and identify new genetic causes of VWD. This could lead to the development of strategies to prevent increased VWF clearance and improve the health of patients with VWD.

Optimizing hemostasis with DDAVP

Dr. Emily Rimmer
Internal Medicine, Section of Hematology / Oncology
University of Manitoba
One year funding.

Bleeding disorders are a common clinical problem encountered by hematologists. The most common types of bleeding disorders are Von Willebrand Disease (VWD) and Hemophilia A and B. These are caused by deficiencies or defects in clotting factors. DDAVP is a medication that is commonly used to treat VWD and hemophilia A. The way this medication works in these disorders is to raise the levels of Von Willebrand Factor (VWF) and Factor VIII, the factors that are deficient in VWD and hemophilia A respectively. Using basic principles of chemistry, we propose that DDAVP could be used to treat other bleeding disorders such as hemophilia B and factor XI deficiency. These are dependent at least in part, on the concentration of factor VIII. This project will look at the laboratory measures of clotting after DDAVP has been given in these patients with hemophilia B and factor XI deficiency. The ultimate goal by the end of the project is to develop a clinical trial looking at the treatment and prevention of bleeding in these patients.

Specialized care of patients with bleeding disorders / Validation of a clinical history assessment tool for bleeding disorders

Dr. Menaka Pai
Department of Medicine
McMaster University
One year funding.

Bleeding problems are common in the general population but can be challenging to assess. This is because healthy people can experience some types of bleeding (e.g. mild bruises and nosebleeds) and because abnormal bleeding is sometimes mild. To assess patients with possible bleeding problems, doctors traditionally ask many questions about excessive bleeding. Patients often find it difficult to answer so many questions during an appointment and doctors are unsure which questions are most important. A short standardized questionnaire would be helpful to ensure that patients are asked important questions about bleeding using language that is easy to understand. Our research group has collected a large amount of information on the symptoms and laboratory findings for over 300 patients with bleeding problems and a group of 99 healthy people. We analyzed this information to develop a short questionnaire. During my fellowship, I will give this new short questionnaire to a large group of patients and healthy people to fill out to explore what symptoms are common in patients with the most common types of bleeding disorders (undefined bleeding disorders and platelet secretion defects) and what their risks of bleeding are. I am optimistic that the new short questionnaire will help doctors identify patients who probably have blood clotting problems and need to undergo further testing. It will also help us learn more about the most common types of bleeding disorders and how they can impact patient’s lives. This research has the potential to improve patient care by finding the best way to assess bleeding symptoms in different types of bleeding disorders and finding out when bleeding problems need to be treated.

Developing a Prediction Tool for Clinically Significant Bleeding in the Pediatric Intensive Care Unit

Dr. Paul Moorehead
Dept. of Pediatrics, Division of Hematology / Oncology
Children’s Hospital of Eastern Ontario – Ottawa, Ontario
One year funding

Bleeding is a danger for many patients in the Pediatric Intensive Care Unit (PICU), because they may have had major surgery, traumatic injury, or disease that may cause bleeding. In this project, we will look at several different kinds of information (information about patients such as age and weight, information about why patients are admitted at PICU, and information from blood tests) to find the information that best predicts which patients in the PICU will have problems with bleeding. This project will give doctors a way to know which patients in the PICU are at higher risk of bleeding. Knowing which patients are at higher risk will help doctors find ways to prevent bleeding before it occurs and to stop bleeding when it happens.

RNA splicing mediated therapies for Hemophilia

Dr. Kelly Aukema
Postdoctoral Fellow, 
Michael Smith Foundation for Health Research
University of Northern British Columbia
Prince George, British Columbia

Hemophilia, an inherited bleeding disorder caused by defects in a clotting factor, affects roughly 1 in 10,000 Canadians. Alternative treatments for Hemophilia are desirable as current therapies, consisting of clotting factor replacement injections, are extremely expensive, totaling up to $1 million per person annually. Furthermore, the effectiveness of clotting factor injection is limited by immune response as up to 35% of patients treated develop antibodies to the injected factor.

RNA splicing offers a viable alternative treatment. Hemophilic mice have been successfully treated by repairing the genetic defect at the level of the messenger RNA. Taking advantage of a rare side reaction of the existing cellular RNA splicing machinery, a corrective RNA fragment can be spliced into a defective clotting factor messenger RNA by a mechanism called trans-splicing.

Mammalian RNA splicing is coupled to DNA transcription, and this coupling may be a mechanism employed by the cell to deter trans-splicing, as uncontrolled trans-splicing in a normal context is likely detrimental to the cell. This raises the possibility that the efficiency of trans-splicing, and therefore splicing-based therapies, may be improved if splicing could be slowed to allow transcription to finish before splicing begins.

As a CHS fellow working towards improving splicing-based therapies for hemophilia, I will investigate the function of the U6 RNA, considered one of the most important components of the splicing machinery because of its location in the catalytic core, as effective means for slowing pre-mRNA splicing. Specifically, I propose to investigate the incorporation of U6 into the splicing complex as potential rate adjustable step in splicing. I propose to determine the timing of the conformational change in U6 that precedes its incorporation into the catalytically active splicing complex, and I will test our extensive collection of mutations in Prp24, the protein that catalyzes the conformational change in U6, for their ability to alter the rate of U6 conformational change.

Quality assurance of special coagulation laboratory practices 

Dr. Elianna Saidenberg
Chief Resident in Hematology
McMaster University – Hamilton, Ontario
One year funding

It is a pleasure for me to have this opportunity to introduce myself to the hemophilia community of Canada. I am presently in my sixth postgraduate year of medical training and am enrolled in a transfusion medicine fellowship at the University of Ottawa. Concurrent with this training I am working in the coagulation laboratory and with the clinical hemophilia and bleeding disorders service. Given the necessity of treating many haemostatic defects with human and recombinant blood products, the connection between transfusion medicine and hemostasis medicine feels very natural. 

This year I am the very fortunate and grateful recipient of the Novo-Nordisk- Canadian Hemophilia Society- Association of Hemophilia Clinic Directors of Canada Fellowship in Hemophilia. I aim to use the opportunities afforded to me by this fellowship to gain the skills needed to effectively manage a coagulation laboratory. Availability of prompt, precise and accurate measurements of hemostatic parameters is vitally important in the provision of medical care to patients with bleeding disorders. To further my knowledge and understanding of procedures and process in the coagulation lab I am planning several quality assurance projects. 

The first project I have undertaken relates to creation of normal ranges for platelet aggregation and secretion tests done at our site. These tests are very important in the diagnosis of congenital and acquired disorders of platelet function as well as other disorders of coagulation such as von Willebrand disease. The testing machines used are called aggregometers. They provide a visual representation of the test results as a graph and also provide measurements of the slope and amplitude of the curve. Interpretation of these tests relies heavily on the interpreting physician’s reading of the curve. Thus, the results could vary based on the eye of the interpreter. To improve the accuracy of these test results it is recommended by the Clinical Laboratory Standards Institute that every laboratory calculate normal ranges for their own aggregometers. To comply with these recommendations I have begun the task of compiling data on aggregation test results done on healthy volunteers at our centre. This information will then be evaluated by a statistician who will apply the necessary mathematical processes to determine the normal ranges. 

Subsequent projects I have planned will evaluate the quality of other tests done in the coagulation lab to help ensure their quality. Through assessment of these procedures I will gain vital skills in laboratory management which will hopefully help me ensure that I can provide the best possible care for my patients with bleeding disorders.

Evaluation of thromboelastography (TEG) as a tool in monitoring the effect of recombinant factor VIIa in hemophilia A animal models

Dr Maha Ahmed Othman
Université Queen’s, Kingston, Ontario

Despite similar factor levels, hemophiliacs often display variable tendencies for bleeding and heterogenous responses to FVIII therapy. To date, no routinely used coagulation assay has proven ideal in predicting the bleeding pattern in hemophilia or reflecting the individual patient’s response to therapy. Conventional assays typically use clot formation as the end point and underestimate the impact of other components of the hemostatic process. Thromboelastography (TEG) is a global assay that assesses the quality of the blood clot and monitors different aspects of the hemostatic process. It provides information about the kinetics of the blood clot and thus a more comprehensive picture of coagulation than standard tests. Recombinant coagulation factor VIIa (rFVIIa) (Novoseven)TM is a safe and effective treatment for hemophilia A and B patients with inhibitors. However, laboratory monitoring of the therapeutic efficacy of this product is still a problem. Bleeding risk does not correlate well with the standard clotting tests and the treatment response also cannot be adequately monitored.

In this study, we have two major goals:1) to investigate the TEG pattern in hemophilia A animal models with and without inhibitors and evaluate the sensitivity of this test to variations in clinical phenotype.2) to evaluate changes in the TEG pattern following administration of rFVIIa in therapeutic doses to these animals and to correlate this to clinical phenotype correction.

These studies have the potential to significantly improve our understanding of the clinical heterogeneity among hemophiliacs. This may help predict individual bleeding risks and improve the laboratory monitoring of rFVIIa therapy.

 

Approaches to investigate the cause and management of acute toxicities associated with adenovirus-mediated gene therapy in Hemophilia A

Dr. Maha Ahmed Othman
Queen’s University, Kingston, Ontario

Gene therapy is an attractive potential treatment for hemophilia A. The condition is due to mutations in a single, identified gene, the clinical picture is dramatically improved with a small increment of plasma FVIII levels and excellent animal models are available for preclinical testing. Replication deficient adenovirus is an efficient vehicle for liver-directed gene delivery. However, a major obstacle to the successful application of these vectors in humans has been the activation of the host immune and inflammatory response. These responses limit the efficiency of transduction, prevent readministration of the vector and cause adverse effects to the host such as acute liver injury and thrombocytopenia (reduction of the platelet count).

We have evaluated three approaches to reduce the early host immune responses to adenovirus-mediated gene delivery. These three strategies, the infusion of chilled (and thus structurally altered) platelets, intravenous immunoglobulin (IVIG) and the macrophage depleting drug Clodronate have been evaluated in a mouse model of hemophilia A. We have shown that while the transfusion of chilled platelets did not benefit the outcome of the adenoviral gene therapy protocol, there is a potential for using clodronate since it not only enhances the subsequent expression of FVIII but also significantly reduces the development of an antibody response to FVIII. Two other major advantages that we observed were that the acute thrombocytopenia that normally follows adenovirus administration was not encountered in each of the clodronate and IVIG treatment groups and acute liver injury was minimal.

In continuing with this project, we are beginning to investigate the mechanisms responsible for the acute fall in the platelet count following adenovirus-mediated gene therapy. Preliminary studies have shown that adenovirus is capable of “activating” platelets and that this event may subsequently trigger other responses in the hemostatic system. The experimental plan will be focused on studying adenovirus platelet interactions, which will involve in vitro as well as studies in laboratory mice. These studies have the potential to significantly improve our understanding of the mechanism responsible for adenovirus-induced thrombocytopenia and may provide opportunities to prevent this effect.

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