Hemostasis, or blood clotting, follows tissue injury and involves the deployment of essential plasma procoagulants (such as prothrombin, and Factors X, IX, V, and VIII) that trigger the blood coagulation cascade. This cascade leads to the formation of insoluble fibrin clots and the promotion of platelet aggregation. Defects in Factor VIII and the coagulation cascade result in hemophilia A, a common recessive X-linked coagulation disorder. This disease is characterized by uncontrolled bleeding into joints, muscles, and soft tissues. Factor VIII is a 2,351 amino acid, non-covalent heterodimer that circulates as an inactive procofactor. When catalyzed by thrombin, Factor VIII is converted to its active form known as Factor VIIIa, which then associates with and is a cofactor for Factor IXa. In the presence of Ca2+ and phospholipids, Factor IXa converts Factor X to the activated form Factor Xa. These events are but small links within the larger coagulation signaling cascade. There are two alternatively spliced Factor VIII transcripts: variant 1 encodes a large glycoprotein (isoform a) that circulates in plasma and associates non-covalently with von Willebrand Factor. Variant 2 encodes a putative small protein (isoform b).
Immunocytochemistry/Immunofluorescence: Factor VIII Antibody
Shetty et al discuss the current challenges and open issues in the management of the related but rare condition of acquired hemophilia A (AHA) in their 2014 review of this difficult disease. In their paper, they present basic management strategies, summarize the efficacy of current hemostatic agents, and outline key difference between AHA and the more commonly found congenital hemophilia (1). Sharma from the University of Kentucky reviews the latest breakthroughs in gene therapy for patients with hemophilia A and/or B (2). Due to the cost and lack of efficiency in current treatment methods (predominantly the administration of clotting factors), gene therapy is being pursued. Zhu et al from the Ludong University relied upon the Factor VIII antibody in their ongoing efforts to develop a gene therapy treatment based on dual-AAV delivery vectors (3). The same group used the Factor VIII antibody in their follow up studies on increasing the efficacy of the dual-vector transgene (4). They determined that engineering an interchain disulfide bond increased protein trans-splicing and circulating Factor VIII protein amounts.
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