Thrombosis & Atherosclerosis Research Institute (TaARI)

Thrombosis & Atherosclerosis Research Institute (TaARI)

TaARI Research Theme Details

Experimental Thrombosis and Atherosclerosis

The Experimental Thrombosis and Atherosclerosis (ETA) Program, conducts fundamental research on the interplay between thrombosis, atherosclerosis, diabetes, cancer, and inflammation.

Heart attacks and strokes are the number one cause of death and
disability in Canada and world-wide. Most heart attacks and strokes are caused by blood clots that form on top of disrupted atherosclerotic plaques in the heart or brain arteries. Abnormal blood clotting or thrombosis can also occur in the deep veins of the leg. Deep vein thrombosis causes leg pain and swelling. More importantly, pieces of the clot can break off and travel to the lungs where they lodge in the pulmonary arteries as pulmonary emboli. Such emboli can be fatal.

Why does thrombosis occur, how can we prevent it, and if it does occur, how can we best treat it? These are some of the questions that are being addressed at the Thrombosis & Atherosclerosis Research Institute. Using a bench-to-bedside approach, we are exploring the complex interplay among genetic, environmental and stochastic factors that impair vascular health and trigger thrombosis.

  • Specific Areas of Research Include:
    • the biochemistry of the enzymes involved in thrombosis and thrombolysis and their inhibitors with the aim of identifying novel targets for therapeutic use (Dr. Jeffrey Weitz)
    • the molecular biology of vascular disease and thrombosis, specifically the role of endoplasmic reticulum stress in human disease (Dr. Richard Austin)
    • the development of a novel anticoagulant, control of thrombin on the surface of biomaterials, understanding the development of the haemostatic system with specific focus on glycosylation of different coagulation inhibitors and coagulation proteins, and the understanding of coagulation in pediatric patients undergoing cardiopulmonary bypass (Dr. Anthony Chan)
    • the development of a laboratory model to study the optimal use of blood thinners when platelet counts are low (Dr. Howard Chan)
    • the efficacy and safety of antithrombotic therapies, the prognostic importance of bleeding and transfusion, and the mechanisms of variable response to antiplatelet drugs (Dr. John Eikelboom)
    • the role of adhesion molecules, proinflammatory mediators and endogenous anti-inflammatory molecules in systemic inflammation as well as the in vivo responses associated with inflammation, septic shock and fluid resuscitation (Dr. Alison Fox-Robichaud)
    • visualization of intravascular processes in a living animal through the use of intravital microscopy (Dr. Peter Gross)
    • the mechanistic links between blood clotting, inflammation, and the host immune system to better understand why dysregulation of these pathways contributes to morbidity and mortality in a variety of vascular disease states (Dr. Patricia Liaw)
    • the use of Genetic and Molecular Epidemiology, to identify genetic determinants of complex disease including hypertension, coronary artery disease, cerebrovascular disease, dislipidemia and other types of chronic disease (Dr Guillaume ParĂ©)
    • the mechanistic links between dyslipidemias and cardiovascular disease with the aim of the identification of novel biomarkers of cardiovascular disease and the development of novel therapies aimed at normalizing lipoprotein levels and inhibiting atherosclerosis. (Dr. Shirya Rashid)
    • the molecular pathways of HDL, LDL and cholesterol metabolism (Dr. Bernardo Trigatti)
  • Clinical Thromboembolism Program

    The Clinical Thromboembolism Program (CTP), led by Sam Schulman, performs research into optimal prevention, diagnosis and treatment of patients with thrombotic problems, translating current research into clinical practice.

  • Current Research

    The members of the regional Clinical Thromboembolism Program (CTP) of McMaster University are represented at all sites of Hamilton Health Sciences, as well as St. Joseph’s Healthcare. The group is involved in citywide, national and international clinical trials.

    Research conducted includes non-invasive methods for diagnosis of deep vein thrombosis and pulmonary embolism, optimal anti-coagulation treatment in cancer and non-cancer patients, the role of anticoagulants as anticancer agents, the clinical role of testing for hereditary and acquired thrombophilias, counseling of patients at risk for thrombosis, prevention of venous thromboembolism in patients with orthopedic surgery, trauma, artificial heart valves, etc. Research carried out by this group interfaces in many areas; for example, the interaction of cancer and thrombosis; associations between venous and arterial thromboembolism; bleeding complications and survival of patients with cardiac disease, etc.

    In addition to venous thromboembolism, several members of the group are increasingly involved with research into arterial thrombosis. In both the venous and arterial thrombosis areas, research is expanding into gene and environmental links to pathogenesis, led by Dr. Sonia Anand.

    Studies focusing on thrombosis prevention in orthopedic patients, or diagnosis and treatment of thrombosis in cancer patients, primarily involve investigators at the Henderson site. Outcome studies, including those dealing with the risk of recurrent thrombosis or long-term complications of thrombosis, are conducted citywide or as part of national or international trials.

    The health outcomes research has been strengthened by the recruitment of Dr. Frederick Spencer from University of Massachusetts. Dr. Spencer’s research is increasingly focused on the associations between venous and arterial thromboembolism.

    New areas of research that the CTP is about to increase its efforts in are knowledge translation, health outcomes research, application of new diagnostic modalities, strategies to simplify treatment with oral anticoagulants, integration of patient preferences in decisions on anticoagulant therapy, cerebral thrombosis in the developing world, alternatives for prophylaxis against stroke and systemic embolism in patients with mechanical heart valves, association between thrombophilic defects and pregnancy complications, as well as prediction of appropriate duration of anticoagulation in patients with venous thromboembolism.

    Several investigators in the group (Jeff Ginsberg, Shannon Bates, Clive Kearon) have a solid background in studies on diagnostic strategies in venous thromboembolism. We plan for expanding research into new diagnostic modalities that come as a result of better access to new imaging technology including 64-slice CTs and MRI and highly qualified professionals in the field of diagnostic imaging with expertise with these techniques.

    Cerebral vein thrombosis is particularly common in the developing world but poorly investigated. With the global network of PHRI, it is now feasible to investigate etiology, diagnosis and treatment of CVT in this population.

    Patients with mechanical heart valves are traditionally treated with vitamin K antagonists for prophylaxis against valve thrombosis, stroke and systemic embolism. The initial “bridging” treatment after open-heart surgery before warfarin becomes fully therapeutic is poorly evaluated. Together with Dr. Richard Whitlock and the Cardiac Surgery Department, we are involved in a multicenter evaluation of the safety of different options. The Thrombosis Service at Hamilton General site will also be an important hub for the first study on an alternative to warfarin— dabigatran—for patients with mechanical heart valves.

    Treatment with vitamin K antagonists is complicated and for some patients very demanding. Current and planned trials aim at demonstrating regimens that reduce resource utilization and often are easier and more convenient for patients. The planned studies are phase II trials, but if successful, phase III trials will require larger networks and strong methodological support. Studies addressing the optimal management of warfarin after major bleeding are crucial to respond to frequently posed questions by clinicians. One study addressing the optimal interval until resumption after intracranial hemorrhage has been completed, and other similar topics are currently being addressed.

    Several of the CTP members (Sam Schulman, Clive Kearon, Jeff Ginsberg) have played a leading role in the research on optimal duration of anticoagulant treatment after venous thromboembolism. There are still many unresolved questions here and the general practitioner finds it very difficult to make appropriate decisions regarding when to discontinue therapy. A large management study with the use of a marker of activation of coagulation (D-dimer) is currently being performed, involving Canadian, US, and also European centers.

    The group serves as a model for mentoring, with established investigators providing expertise, time and resources to ensure the success of more junior colleagues. The success of these ventures is evidenced by the large number of faculty and trainees who have career support from external granting agencies or from local sources and the number of mentoring awards from the Canadian Institutes of Health Research.

    The members of the CTP have several national and international networks, and at least half of the studies include centers outside of Hamilton. Within Canada, the closest co-operation is with Jewish Hospital in Montreal and Sunnybrook Hospital in Toronto. Another network includes several centers in the US. There is also collaboration with Australian and European centers (e.g. Brest [France], Palermo and Varese [both in Italy] and Stockholm [Sweden]). For studies on arterial thromboembolism the group has increasing cooperation with the Population Health Research Institute (PHRI), directed by Dr. Salim Yusuf.

  • Comparative Medicine

    Comparative Medicine supports the research activities of TaARI and McMaster faculty, postdoctoral fellows, residents and students by fostering a comprehensive program of quality animal care. CM ensures humane care and use of all laboratory animals, provides technical information and training in conjunction with the Central Animal Facility at McMaster University.

  • Responsibilities and Services provided by CM include:
    • Provision of a Canadian Council on Animal Care Good Animal Practice accredited facility
    • Consultation and collaboration with research personnel to assist in research project planning and model development
    • Training programs in conjunction with the McMaster Central Animal Facility
    • Animal procurement
    • Provision of daily animal husbandry
    • Provision of animal health surveillance
    • Provision of veterinary care and technical support

    Please see www.taaricm.ca for more information.

  • Neonatal Trials Group

    The Neonatal Trials Group (NTG) conducts randomized controlled trials on aspects of neonatal care in babies. Originally part of the Clinical Trials Methodology Group, NTG was established as a separate entity in 2006 when it joined the Thrombosis and Hemostasis Program, and subsequently became part of TaARI with the move to the new research facility at the David Braley Research Institute. NTG’s academic home is in the department of Clinical Epidemiology and Biostatistics in the Faculty of Health Sciences.

    Typically, NTG studies assess the efficacy and safety of common, but insufficiently evaluated, neonatal therapies in very small babies born prematurely who spend their first few months in a neonatal intensive care unit (NICU). The group strives to determine the relative merits of competing care strategies both in terms of medical outcome in the short-term (to initial discharge from the NICU) but, more importantly, in longer term mental and physical outcomes. By the standards of the pediatric research community, the trials conducted by NTG are large, with sample sizes of up to 2000 babies. All NTG trials are multi-centered in that eligible babies are recruited from participating Canadian and international NICUs.

    The members of the NTG include a biostatistician (Robin Roberts), pediatricians/neonatal specialists (Drs. Barbara Schmidt and Haresh Kirpalani), research manager (Lorrie Costantini), research assistant (Wendy Yacura), research nurse/consultant/specialist (Judy D’Ilario, Joanne Dix), IT/database consultant (Harvey Nelson), and various undergraduate and graduate students.

  • Current Research

    The majority of our trials have been funded primarily by the Canadian Institutes of Health Research (CIHR). Although a Canadian-based funding agency, CIHR has recognized that these neonatal trials require an international scope partly to facilitate timely recruitment, but also to foster international collaboration. We are currently conducting two international, randomized controlled trials each involving more than 1000 babies recruited from up to 40 clinical sites worldwide. In addition, we are continuing extended follow-up at age 11-12 years of participants in our earlier trial of caffeine in 2000 babies. We recently completed and published the results of assessment at 5 years of age for this trial. NTG is also involved in analyzing data from previously conducted follow-up trials. Our group has successfully completed three large randomized trials; the results of all three trials were reported in high-impact journals and have led to a variety of subsidiary publications.

    Please see www.fhs.mcmaster.ca/ceb/ntg for more information.