Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis

Abstract

Activated factor VII (FVIIa), the first protease of clotting, expresses its physiological procoagulant potential only after complexing with tissue factor (TF) exposed to blood. Deep knowledge of the FVIIa-TF complex and F7 gene helps to understand the Janus-faced clinical findings associated to low or elevated FVII activity (FVIIc). Congenital FVII deficiency, the most frequent among the recessively inherited bleeding disorders, is caused by heterogeneous mutations in the F7 gene. Complete FVII deficiency causes perinatal lethality. A wide range of bleeding symptoms, from life-threatening intracranial hemorrhage to mild mucosal bleeding, is observed in patients with apparently modest differences in FVIIc levels. Though clinically relevant FVIIc threshold levels are still uncertain, effective management, including prophylaxis, has been devised, substantially improving the quality of life of patients. The exposure of TF in diseased arteries fostered investigation on the role of FVII in cardiovascular disease. FVIIc levels were found to be predictors of cardiovascular death and to be markedly associated to F7 gene variation. These genotype-phenotype relationships are among the most extensively investigated in humans. Genome-wide analyses extended association to numerous loci that, together with F7, explain >50% of FVII level plasma variance. However, the ability of F7 variation to predict thrombosis was not consistently evidenced in the numerous population studies. Main aims of this review are to highlight i) the biological and clinical information that distinguishes FVII deficiency from the other clotting disorders and ii) the impact exerted by genetically predicted FVII level variation on bleeding as well as on the thrombotic states.

Figure 1.

Publications over 70 years and some key achievements related to coagulation factor VII. (A) Coagulation factor VII (FVII) biochemistry and F7 genetics. (B) FVII deficiency, FVII level associated cardiovascular disease, FVII levels and F7 gene: N: number of publications reported in Pubmed. Only some of the discoveries are referenced in the text due to space constraints. A complete list is available on request. GWAS: Genome Wide Analysis Study; NGS: next-generation sequencing.

Figure 2.

Schematic diagram of the F7 gene and factor VII protein expression. Upper part: Exons are numbered (1-9) and colored in accordance with the encoded protein domains (lower part). Exon 2 is in parenthesis because it is not included in the most abundant mature mRNA. FVII: factor VII; F7: factor VII gene; KB: kilobase. In addition to the complete nuclear transcript the most represented FVII mRNA is indicated. Lower part: Protein domains are indicated with different colors. GLA, triangle, γ-carboxyglutamic acid-containing domain. EGF, trapezium, epidermal growth factor-like domain. Green box, promoter. The complete intracellular protein, and the circulating forms are depicted. The numbers of residues in the pre-pro-leader sequence (n=60), in the circulating forms (n=406) and in the light (n=152) and heavy (n=254) chains are indicated. The interchain disulphide bridge is also depicted (yellow bracket).

Figure 3.

Schema showing factor VII activation, activity and inhibition (see text for specific information and references). TF: tissue factor; FIXaα: FIXa cleaved only after Arg226; FIXab: FIX cleaved after Arg191 and Arg226 (ref. ); AT: antithrombin; PS: protein S.

Figure 4.

F7 genotype driven differences in FVIIa, FVIIc and FVIIAg in the European population. Mean values of FVIIa (mU/mL), FVIIc (% of PNP), and FVIIAg (% of PNP) in genotype groups determined by the promoter (5′F7 ins del) and missense 353(413)Arg/Gln polymorphisms. Standard deviation is reported above each column. The number of subjects is reported in parentheses. Significant differences, groups 1–6 (P<0.001): FVIIc: 1 vs. 2, 4, 6; 4 vs. 6; FVIIa: 1 vs. 4, 6; 2 vs. 6; 4 vs. 6; and FVIIag 1 vs. 4, 6. Adapted from “Contribution of factor VII genotype to activated FVII levels. Differences in genotype frequencies between Northern and Southern European Populations”. FVII: factor VII; FVIIc: FVII activity; FVIIAg: FVII antigen; PNP: pooled normal plasma; ins: insertion; del: deletion