Pryzdial, Ed - Research and Publications

Dr. Pryzdial’s research group investigates the regulation of clot formation (coagulation), including the effects of viruses and how clots dissolve (fibrinolysis); the molecular basis of clotting protein deficiency in patients; and the quality of clotting constituents in blood products.

Understanding the complicated processes by which clotting proteins are controlled has led to a novel treatment to “bust clots” with anticipated impact on blood product utilization for cardiac surgery. In patients that bleed, discovery of inherited modes of compensation that curtail their blood-loss may also be utilized to conserve blood products. Expertise in clotting protein biochemistry helps maintain an extremely high standard for the Canadian Blood Services plasma quality assurance program.

Dr. Pryzdial studies “non-traditional” functions of blood clotting proteins and their novel application. Combining biochemistry and molecular engineering, Dr. Pryzdial’s group has discovered new functions for several clotting proteins with possible therapeutic or diagnostic applications to heart disease and stroke. In particular, they are focusing on a previously unknown mechanism of communication between the clotting protein factor Xa and the clot-dissolving pathway. They have shown that, after enzymatic modulation, factor Xa becomes an accelerator of the fibrinolysis enzyme called tissue plasminogen activator which is now an important life-saving therapeutic. However, tissue plasminogen activator is beneficial in less than 10% of possible cases and Dr. Pryzdial’s research has led to the development of derivatives of factor Xa that may improve patient outcome.

As part of a team effort within the Centre for Blood Research (University of British Columbia), Dr. Pryzdial’s lab determines the genetic basis of patients with rare clotting deficiencies. The responsible protein is cloned and expressed containing the identified mutation. In this way, nature provides clues to explain how protein structure impacts protein function, and also helps to understand other differences these exceedingly rare individuals (1:2,000,000) may have been born with to compensate for an otherwise lethal deficiency. These compensatory mechanisms alleviate blood-loss and their delineation will reduce the use of transfusion products not only for these patients, but with anticipated general applicability.

Dr. Pryzdial is also a member of the Canadian Blood Services plasma quality assurance team (led at Canadian Blood Services, McMaster University) and has particular interest in the efficacy of coagulation-related proteins on transfusion outcome. 

Members of Dr. Pryzdial’s laboratory investigate how blood clotting proteins enhance infection by viruses; and the persistence of viruses in blood products.

This research has revealed that clotting constituents are exploited by viruses. Furthermore, platelets and red cell units have been shown to harbour and, surprisingly, replicate a prevalent transfusion-transmissible virus. This combined knowledge may further improve the safety of blood products.

Uniquely combining mutated viruses propagated in host cells with restricted protein expression has enabled Dr. Pryzdial’s group to find that model enveloped viruses from the Herpes family can directly assemble clotting enzyme-cofactor-substrate complexes on their surfaces to generate clots. This bypasses the normal strict inhibition of coagulation enzyme activation imposed by cells except at sites of vascular damage. Virus-initiated clot formation can not only contribute to heart disease, but enhances the susceptibility of infection through cell signaling via protease activated receptors. This model virus work provides general insight into many viruses that have a similar envelope structure and the comparable host cell-derived proteins that are incorporated; as possible examples, West Nile, Hepatitis B and C, Human Immunodeficiency and Dengue viruses.

Dengue virus, a highly transfusion-relevant member of the Flavivirus family, was shown to be bound and replicated by platelets. Platelets are enucleated cells that are essential to clotting. Platelets are a vital transfusion blood product to control bleeding. Therefore this observation has implications during the storage of platelet units for transfusion. As global Dengue virus infection is estimated to approach 400 million annually, with platelet loss as a hallmark, this finding also helps to understand pathology.