title: Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation.
abstract: We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. e.castoldi@bioch.unimaas.nl
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Castoldi
authors.forename: Jose W P
authors.initials: JW
authors.lastname: Govers-Riemslag
authors.forename: Mirko
authors.initials: M
authors.lastname: Pinotti
authors.forename: Debora
authors.initials: D
authors.lastname: Bindini
authors.forename: Guido
authors.initials: G
authors.lastname: Tans
authors.forename: Mauro
authors.initials: M
authors.lastname: Berrettini
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Mazzucconi
authors.forename: Francesco
authors.initials: F
authors.lastname: Bernardi
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
mesh_terms: D000328:Adult; D001780:Blood Coagulation Tests; D005165:Factor V / Q000235:genetics*; D005167:Factor VII / Q000235:genetics; D005168:Factor VII Deficiency / Q000235:genetics*; D015951:Factor Xa / Q000096:biosynthesis; D005260:Female; D006470:Hemorrhage / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D011486:Protein C / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*
chemical_list: D011486:Protein C; C095381:factor V Leiden; D005165:Factor V; D005167:Factor VII; D013917:Thrombin; D015951:Factor Xa