Physical Sciences and Mathematics Commons^™

Structural And Thermodynamic Studies Of Antibody Binding To Blood Coagulation Factor Viii, Jordan Vaughan

WWU Graduate School Collection

Blood coagulation factor VIII (FVIII) is a 2332 residue glycoprotein expressed in endothelial cells and plays a significant role in the formation of blood clots. Structurally, FVIII’s domains are organized as A1-A2-B-A3-C1-C2. The absence or deficiency of FVIII in the bloodstream gives rise to Hemophilia A; an X-linked bleeding disorder affecting 1 in 5000 males worldwide. To combat this deficiency, patients undergo FVIII replacement therapy which involves frequent injections of FVIII into the bloodstream in the form of blood, plasma, or protein concentrates. Although effective, this treatment commonly results in the development of anti-FVIII inhibitory antibodies in approximately 20-30% of …

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 Studies Of The Von Willebrand Factor D’ Domain And Its Binding Mechanism To Factor Viii, Ap Wang

WWU Graduate School Collection

Hemophilia A is an X-linked disorder that results in uncontrolled bleeding, which is caused by a lack of activity for blood coagulation factor VIII, an essential protein cofactor in the clotting cascade. Factor VIII consists of multiple domains, and binding disruptions between factor VIII and its circulatory partner, von Willebrand Factor, may cause von Willebrand disease. Von Willebrand Disease type 2N is an autosomal recessive disease, and it is caused by binding disruptions between the D’ domain (also known as TIL’E’) of von Willebrand Factor and a3 domain of factor VIII. A 2.9Å Cryoelectron microscopy structure of the FVIII:vWF complex …

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 Studies Of Complexes Of Blood Coagulation Factor Viii, Joseph S. Gish

WWU Graduate School Collection

Factor VIII (FVIII) is a 2332 amino acid glycoprotein with domain organization of A1-A2-B-A3-C1-C2 which is a crucial component of the blood coagulation cascade. After secretion, FVIII circulates in the bloodstream at a concentration of one nanomolar bound to von Willebrand Factor (vWF) which protects FVIII from clearance. In the event of an injury to the bloodstream, FVIII is proteolytically cleaved, releases from vWF and binds to both activated platelet surfaces and activated Factor IX with nanomolar affinity. These interactions increase the rate of blood clot formation 100,000 fold. Hemophilia A is an x-linked recessive disease affecting 1 in 5000 …

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 …