Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics

Abstract

Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common pathway). Due to this central position, it is an attractive therapeutic target to either enhance or dampen thrombin generation. In this brief review, I will summarize key developments in the molecular understanding of this critical clotting factor and discuss the molecular basis of FX deficiency, highlight difficulties in expressing recombinant factor X, and detail two factor X variants evaluated clinically.

Keywords: Coagulation; Factor X; Factor Xa; Protein therapeutic; Recombinant proteins.

Figure 1.. Timeline of FX research and therapeutic development.

Major developments in the understanding of FX are highlighted. Chronological blocks of significance include discovery/early characterization (red); protein biochemistry/understanding FX/FXa function (blue); molecular biology/genetics/structural biology (grey); mutagenesis/FXa inhibitors/FXa therapeutics (yellow).

Figure 2.. Structural organization of the F10 gene and FX protein.

The F10 gene has 8 exons and 7 introns and 22 kb long. The length of each exon is provided and are color coded for each domain they encode (see protein). Pre-pro-FX and mature FX are shown with domains annotated along with specific cleavage sites by proteases. Specific amino acids are numbered including Ile195 (16c) and Ser379 (195c) which are discussed in the text. The green spheres on the activation peptide (AP) represent N- and O-linked glycosylation sites.