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F. Bernardi and G. Mariani et al.
apparently redundant and irreversible inhibition of FVIIa is also exerted by the serpin antithrombin (AT),33 and a sub- stantial portion of FVIIa may be cleared through this rela- tively stable complex (FVIIa-AT),34 which circulates in plas- ma at a concentration similar to that of FVIIa. FVII and FVIIa also bind the protein C receptor on endothelial cells (EPCR) with relevant affinity, but at present the patho- physiological significance of this interaction is unclear.
Congenital factor VII deficiency
Definition, prevalence and epidemiology
FVII deficiency was first described as a bleeding disorder
by Alexander and colleagues13 and represents a model dis- ease to understand the pathophysiology of recessively inherited coagulation deficiencies. Relevant findings on FVII deficiency are summarized on a historical time scale in Figure 1B, and some of the open issues are summarized in Table 2. Congenital FVII deficiency (OMIM 227500, ORPHA 327) is defined as a bleeding disorder associated with FVII coagulant activity below 50% of normal. However, this threshold includes asymptomatic heterozy- gotes for causative mutations and may comprise individu- als homozygous for frequent FVII lowering single nucleotide polymorphisms (SNP).35 These subgroups sub- stantially contribute to the belief that FVII deficiency is a mild bleeding disorder.36
Figure 3. Schema showing factor VII activation, activity and inhibi- tion (see text for specific informa- tion and references). TF: tissue factor; FIXaα: FIXa cleaved only after Arg226; FIXaβ: FIX cleaved after Arg191 and Arg226 (ref. 24); AT: antithrombin; PS: protein S.
Figure 4. F7 genotype driven dif- ferences in FVIIa, FVIIc and FVIIAg in the European popula- tion. Mean values of FVIIa (mU/mL), FVIIc (% of PNP), and FVIIAg (% of PNP) in genotype groups determined by the promot- er (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 paren- theses. Significant differences, groups 1–6 (P<0.001): FVIIc: 1 vs. 2,4,6;4vs.6;FVIIa:1vs.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 geno- type frequencies between Northern and Southern European Populations”.107 FVII: factor VII; FVIIc: FVII activity; FVIIAg: FVII antigen; PNP: pooled normal plas- ma; ins: insertion; del: deletion
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haematologica | 2021; 106(2)