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Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):351-362
Francesco Bernardi1 and Guglielmo Mariani2
1Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy and 2Department of Science and Technology, University of Westminster, London, UK
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 clini- cal findings associated to low or elevated FVII activity (FVIIc). Congenital FVII deficiency, the most frequent among the recessively inherited bleed- ing 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 lev- els 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 extensive- ly investigated in humans. Genome-wide analyses extended association to numerous loci that, together with F7, explain >50% of FVII level plas- ma 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 dis- orders and ii) the impact exerted by genetically predicted FVII level vari- ation on bleeding as well as on the thrombotic states.
Introduction
Blood coagulation is initiated by the formation of a complex between tissue fac- tor (TF), a single-pass transmembrane glycoprotein, and activated factor VII (FVIIa), a serine protease highly dependent for its procoagulant activity on TF.1-4 The absence of either of these components is incompatible with life.5 However, small amounts of these proteins, interacting in the FVIIa-TF complex, are sufficient to ini- tiate a number of reactions6 on membrane surfaces.4 The FVIIa-TF complex might also possess non-hemostatic, signaling properties.7
Detailed knowledge of the physiological and biochemical properties of FVIIa has enabled its pharmacological application as recombinant FVIIa (rFVIIa), a landmark in the management of bleeding disorders.8 Genetic9 and clinical studies have defined the heterogeneous molecular basis10-12 of FVII deficiency13 and could lay the foundations for gene therapy.
Extensive plasma studies and genetic investigations14 have defined the impor- tance of the F7 gene variation in determining the large FVII variance in plasma con- centration,15 with implications in predisposition to thrombosis16-18 in both individu- als and the population as a whole.
A comprehensive review on FVII is complex because of the wealth of informa- tion available both in the field of hemostasis and thrombosis (Figure 1). The main aim of this review is to provide an integrated and balanced perspective of the bio-
Correspondence:
FRANCESCO BERNARDI
ber@unife.it
Received: July 3, 2020. Accepted: October 29, 2020. Pre-published: January 7, 2021.
https://doi.org/10.3324/haematol.2020.248542
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