Factor VII Deficiency

Disease Overview

Factor VII (FVII) was identified in1951 as serum prothrombin conversion accelerator or proconvertin,1 after it was shown to interact with tissue factor (TF) to mediate the conversion of prothrombin into thrombin.1 TF is located in the membrane subendothelium of cell types that are not in direct contact with plasma.2

FVII is a vitamin K-dependent glycoprotein. The binding of FVII zymogen to TF results in a cleavage at position 152 in the FVII sequence. This creates the activated form of FVII (FVIIa), which is a double chain disulphuric bridge-linked molecule.3 FVIIa normally circulates in minimal amounts (approximately 1% of the total FVII mass) in a steady state condition with the FVII zymogen.3

The activated form, FVIIa, binds with TF in the extrinsic pathway to play a key role in triggering blood coagulation by activating factor IX and factor X.1,4,5

At sites of tissue damage,6 FVIIa forms an equimolar (1:1) complex with TF. The TF/FVIIa complex activates larger amounts of FVII, factor IX (FIX) and FX and is thereby a powerful activator of coagulation in both the intrinsic and extrinsic pathways.

Human coagulation factor VII (FVII) deficiency is a rare, autosomal recessive trait1 that produces severe deficiency in homozygous individuals and a moderate deficiency, usually without clinical manifestations, in heterozygote individuals.7 Persons with congenital FVII deficiency show a wide range of symptoms, including epistaxis, menorrhagia, spontaneous and posttraumatic bleeding, which sometimes correlate poorly with the extent of the laboratory abnormalities.

Congenital FVII deficiency is characterized by a prolonged prothrombin time (PT) that can be corrected with the use of plasma. Individuals with congenital FVII have a substantial reduction in the total FVII mass and very low levels of circulating FVIIa. When measured with conventional assays, the FVIIa is virtually absent. This results in a range of bleeding symptoms of varying severity. The variation is related to two main issues: first, the minimal FVII levels needed to prevent bleeding in different clinical situations are still unknown, and second, as yet uncharacterized elements may be influencing the clinical picture.

According to available data, inherited FVII deficiency is caused mainly by point mutations, with missense mutations being the most frequent. Other variations are related to frame-shift mutations caused by splicing-site, nonsense and small deletions (<17 nucleotides).8

Exon 8 is the largest exon of the FVII gene and is the site of a substantial proportion of mutations. As with other inherited coagulation defects, such as FIX deficiency (hemophilia B), a high number of mutations in FVII deficiency occur at CpG doublets8. These are commonly known hot spot mutational sites that are affected by multiple situations of similar topological significance. Recently, the use of methods other than the conventional polymerase chain reaction (PCR)-based techniques has identified a large and complex intragenic re-arrangement in the FVII gene. This may possibly account for mutant alleles that previously had not been identified.9

International registries (see section on Registries), such as the retrospective International Registry on Congenital FVII Deficiency (IRF7) and the prospective Seven Treatment Evaluation Registry (STER), have been collecting substantial clinical and mutational data from numerous cohorts of patients worldwide. Analyses from a unified database show that the clinical picture among individuals with congenital FVII deficiency is very variable. The relationship between the clotting phenotype and the clinical phenotype is far from clear. Similarly, the relationship between mutations and the clotting phenotype is highly variable.8

Inherited FVII deficiency is the most frequent among rare congenital bleeding disorders, accounting for one symptomatic individual per 500 000 population.3 The condition apparently affects all racial and ethnic groups equally.8 Although FVII deficiency affects both men and women, more women than men are symptomatic.8 The prevalence of FVII deficiency in the general population is probably higher because of the presence of asymptomatic and mildly symptomatic individuals.10