Review article
The protein structure and effect of factor VIII

https://doi.org/10.1016/j.thromres.2005.12.015Get rights and content

Abstract

Factor VIII (FVIII) is a key component of the fluid phase of the blood coagulation system. The proteases efficiently cleave FVIII at three sites, two within the heavy and one within the light chain resulting in alteration of its covalent structure and conformation and yielding the active cofactor, FVIIIa. FVIIIa is a trimer composed of A1, A2 and A3–C1–C2 subunits. The role of FVIIIa is to markedly increase the catalytic efficiency of factor IXa in the activation of factor X. Variants of these factors frequently also lead to severe bleeding disorders.

Section snippets

The protein structure of factor VIII

The primary structure of human FVIII was deduced from its cDNA sequence [6]. It was consistent with partial sequence analysis of tryptic peptides [7]. FVIII is synthesized as a 300 kDa precursor protein, which is a 2332-residue single-chain glycoprotein, composed of three distinct domain types in the arrangement, namely (NH2) A1–A2–B–A3–C1–C2 (COOH) [8] (see Fig. 1). Among species, amino acids are highly homologous except for their B domains. The FVIII protein is secreted as a heterodimer, a

The effect of FVIII

FVIII is a plasma glycoprotein that functions as an essential cofactor in blood coagulation [35]. FVIII binds to and circulates with vWF as an inactive precursor. It is activated by thrombin or FXa, which cleaves FVIII at Arg372, between the A1 and A2 domains; at Arg740, between the A2 and B domains; and at Arg1689, which releases the A2 peptide from the light chain [36]. In vitro, trace amounts of thrombin can markedly enhance apparent FVIII clotting activity [37] and the apparent specific

The hemophilia and mutation of protein structure in factor VIII

Quantitative or qualitative deficiencies of FVIII result in the inherited bleeding disorder hemophilia A [70]. Hemophilia A is a sex-linked disorder that results from a deficiency of functional FVIII. Deficiency of FVIII activity leads to hemophilia A, a congenital bleeding tendency of variable severity that is due to a large number of distinct FVIII gene mutations [71].

The effect of recombinant FVIII protein

Greater understanding of the structure–function relationships in the FVIII gene and protein will continue to guide development of more effective recombinant therapeutics and of gene therapy for patients with disease. The past 10 years of clinical experience have demonstrated the safety and efficacy of recombinant FVIII(rFVIII). Now, insights from our understanding of clotting factor structure and function, mechanisms, gene therapy advances and a worldwide demand for clotting factor concentrates

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