The focus of my research lab is on biochemical and cellular mechanisms governing hemostasis and thrombosis, and approved and/or novel therapeutics for clinical use. Coagulation occurs after cellular proteins are exposed to flowing blood. Exposure of these proteins triggers a series of enzymatic reactions that culminate in the production of thrombin. Thrombin then activates platelets and cleaves the plasma protein, fibrinogen, to fibrin, which polymerizes into a web-like mesh that forms a blood clot. Clot formation is dictated by proteins and cells found in the blood, cells lining the blood vessels, and the flow of blood through the vessels.
Hemophilias A and B (deficiency in factors VIII or IX) are hereditary bleeding disorders. We are examining how these deficiencies modulate thrombin generation, and clot formation, structure and stability. We have observed that hemophilia causes the formation of clots with an abnormal structure that are weak and poorly formed, and have decreased stability in the presence of fibrinolytic enzymes. We hypothesize that hemophilic bleeding results from formation of poorly structured clots and that therapies that stop bleeding do so by normalizing clot structure and stability. We are comparing different strategies to treat hemophilic bleeding, including replacement therapy and bypass therapy with high dose factor VIIa, FEIBA, or novel bioengineered “superenzymes.”
Thrombosis [myocardial infarction (heart attack), cerebral infarction (stroke), and venous thromboembolism (blood clots in the arms and legs that may migrate to the lungs)] is thought to result from abnormalities in blood quality, blood flow, and vascular cells.
Abnormal levels of certain blood proteins are a risk factor for thrombosis. We have identified a potential mechanism for the association of elevated prothrombin with thrombosis: increased prothrombin produces clots with abnormally thin fibrin fibers. Since clots with thin fibers are resistant to fibrinolysis, we hypothesize that these clots are overly stable and prone to thrombosis. We further hypothesize that this mechanism is operant in thrombosis related to abnormal levels of other coagulation proteins. We want to compare the structure and stability of plasma clots from individuals and patients with different clotting protein levels.
We have found that cellular procoagulant activity modulates fibrin structure and stability. Since different cells express different levels of procoagulant, antithrombotic, and fibrinolytic activity, we hypothesize that clot quality reflects the cellular environment in which it is formed. We want to identify the unique cellular determinants of clot structure and characterize their effects on the clot’s mechanical and fibrinolytic stability. We also want to understand the role of cell-derived microparticles in blood clot formation, structure, and stability.
Abnormal blood flow is a risk factor for thrombosis. High flow increases platelet deposition on exposed subendothelium, whereas reduced flow is associated with an increased incidence of venous clots. We want to understand how blood flow modulates the formation, structure, and stability of clots.