title: Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency.
abstract: We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing-over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co-segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia.
authors.affiliation: Department of Clinical Epidemiology, University Hospital Leiden, The Netherlands.
authors.forename: H H
authors.initials: HH
authors.lastname: van Boven
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: T A
authors.initials: TA
authors.lastname: Bayston
authors.forename: V
authors.initials: V
authors.lastname: Chowdhury
authors.forename: K A
authors.initials: KA
authors.lastname: Bauer
authors.forename: I
authors.initials: I
authors.lastname: Scharrer
authors.forename: J
authors.initials: J
authors.lastname: Conard
authors.forename: D A
authors.initials: DA
authors.lastname: Lane
mesh_terms: D000293:Adolescent; D000328:Adult; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency; D005165:Factor V / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012307:Risk Factors; D013927:Thrombosis / Q000235:genetics*
chemical_list: C095381:factor V Leiden; D000990:Antithrombin III; D005165:Factor V