Physical Sciences and Mathematics Commons^™

Structural Characterization Of Factor Viii-Inhibitor Complexes And Factor Viii Lipid Binding Mechanics, Corbin Mitchell

WWU Graduate School Collection

Blood coagulation factor VIII (FVIII) is a crucial protein cofactor within the blood coagulation cascade and facilitates the proteolytic activation of factor X by activated factor IX. During coagulation FVIII is activated and binds, via its C1 and C2 domains, to activated platelet membranes coordinated by interactions with exposed phosphatidylserine on the membrane surface. A deficiency of functional FVIII within a patient's bloodstream leads to the blood disorder hemophilia A, which results in prolonged bleeding episodes. Current treatment for hemophilia A relies on FVIII replacement therapy via the injection of exogenous FVIII. The main complication which arises from FVIII replacement …

Structural And Mutational Characterization Of The Blood Coagulation Factor Viii C Domain Lipid Binding Interface, Shaun C. Peters

WWU Graduate School Collection

Blood coagulation factor VIII (fVIII) functions as a cofactor in the blood coagulation cascade for proteolytic activation of factor X by factor IXa. During coagulation, fVIII is activated and subsequently binds to activated platelet surfaces by coordination of the fVIII C1 and C2 domains to the exposed phosphatidylserine of activated platelet membranes. Structural and mutational studies have suggested that both hydrophobic and electrostatic interactions occur between the two tandem C domains and activated lipid surfaces, but models of C domain phospholipid binding propose conflicting regions that directly interact with the membrane surface. This thesis reports the determination of the molecular …

Structural Characterization Of A Human/Porcine Chimeric Fviii Construct And An Improved Human Factor Viii Model And Progress Towards Determination Of The Fviii C1 Domain In Complex With Inhibitory Antibodies, Ian Smith

WWU Graduate School Collection

Blood coagulation factor VIII (FVIII) is a non-enzymatic protein cofactor, which plays a crucial role in the formation of a stable blood clot. Absence or deficiency of FVIII results in the blood disorder hemophilia A, with symptoms including internal hemorrhaging and the inability to stop bleeding from open wounds. Treatment of hemophilia A relies on replacement of FVIII with blood, plasma, or protein concentrate infusions. Unfortunately, approximately 30% of patients receiving replacement FVIII generate pathologic anti-FVIII inhibitory antibodies, which both reduce the effectiveness of the FVIII therapeutic and increase the severity of hemophilia A symptoms.

This thesis reports the determination …