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.

The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones

“…The analysis of clinical phenotypes in 37 homozygotes for the p.A354V-p.P464Hfs variant significantly extends previous information about variability in bleeding severity in FVII-deficient patients. The small range of FVII:C in a group of patients with the same F7 genotype supports the notion that a large variation in clinical phenotypes is detectable with relatively small variations in FVII activity, a major open question in FVII deficiency [3]. The investigation of FVII:Ag in plasma revealed that the antigen levels were clearly higher than the activity levels, suggesting a Type-II defect.…”

“…Factor (F) VII is a vitamin K-dependent glycoprotein synthesized in the liver that undergoes extensive post-translational modifications prior to secretion [1][2][3]. It is secreted into the blood where it circulates at a concentration of roughly 0.5 µg/mL (10 nM) [4].…”

Factor V11 deficiency: A rare cause of nasal bleeding

“…It can present as type I which is a quantitative defect or type II being the qualitative defect with the latter having normal factor VII antigen while the former presenting with both low FVII:C and FVII:Ag [4]. The factor VII gene is located at chromosome 13q34 and several mutations within this gene lead to low levels of FVII [2,6]. Clinically the symptoms do not tally with the levels of FVII with some patients having mild to moderate deficiency but presenting with severe bleeding.…”

N-Terminomics Strategies for Protease Substrates Profiling

“…Proteases are central to numerous biological pathways and play a vital role in regulating many signaling processes, such as cell-cycle progression [ 5 ], cell proliferation [ 6 ], cell death [ 7 ], DNA replication [ 8 ], tissue remodeling [ 9 ], hemostasis [ 10 ], wound healing [ 11 ], and immune responses [ 11 ]. Consistent with their essential roles, alterations in proteolytic systems result in multiple pathological conditions, including cancer [ 12 ], neurodegenerative disorders [ 13 ], infections [ 13 ], allergies [ 14 ], blood clotting disorders [ 15 ], and cardiovascular diseases [ 16 ]. Given the enormity of proteolytic potential, protease activity must be tightly regulated to prevent inappropriate and frequently destructive proteolysis.…”