title: Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis.
abstract: The antithrombin A384S mutation has a relatively high frequency in the British population but has not been identified in other populations. This variant has been associated with cases of thrombotic disease, but its clinical relevance in venous thrombosis remained unclear. We have conducted a secondary analysis of the prevalence of the mutation in a large case-control study, including 1018 consecutive Spanish patients with venous thromboembolism. In addition, we evaluated its functional consequences in 20 carriers (4 homozygous). This mutation, even in the homozygous state, did not affect anti-Xa activity or antigen levels, and it only slightly impaired anti-IIa activity. Thus, routine clinical methods cannot detect this anomaly, and, accordingly, this alteration could have been underestimated. We identified this mutation in 0.2% of Spanish controls. Among patients, this variant represented the first cause of antithrombin anomalies. Indeed, 1.7% patients carried the A384S mutation, but 0.6% had any other antithrombin deficiency. The mutated allele was associated with an increased risk of venous thrombosis with an adjusted OR of 9.75 (95% CI, 2.2-42.5). This is the first study supporting that antithrombin A384S mutation is a prevalent genetic risk factor for venous thrombosis and is the most frequent cause of antithrombin deficiency in white populations.
authors.affiliation: Centro Regional de Hemodonación, Universidad de Murcia, Murcia, Spain. javier.corral@carm.es
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: David
authors.initials: D
authors.lastname: Hernandez-Espinosa
authors.forename: Jose Manual
authors.initials: JM
authors.lastname: Soria
authors.forename: Rocio
authors.initials: R
authors.lastname: Gonzalez-Conejero
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordonez
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Gonzalez-Porras
authors.forename: Elena
authors.initials: E
authors.lastname: Perez-Ceballos
authors.forename: Ramon
authors.initials: R
authors.lastname: Lecumberri
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sanchez
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldan
authors.forename: Jose
authors.initials: J
authors.lastname: Mateo
authors.forename: Antonia
authors.initials: A
authors.lastname: Minano
authors.forename: Marcos
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Alberca
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000328:Adult; D000409:Alanine / Q000235:genetics; D000990:Antithrombin III / Q000032:analysis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D012307:Risk Factors; D012694:Serine / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics*
chemical_list: C069998:antithrombin Cambridge II; D012694:Serine; D000990:Antithrombin III; D000409:Alanine