title: Familial thrombophilia: clinical and molecular analysis of Swedish families with inherited resistance to activated protein C or protein S deficiency.
abstract: This report describes the characterization of Swedish families with inherited resistance to activated protein C (APC resistance) and/or protein S deficiency, two genetic disorders associated with functional impairment of the protein C anticoagulant pathway. The APC resistance phenotype was linked to the factor V gene locus in a kindred with independent inheritance of APC resistance and protein S deficiency. A point mutation changing Arg506 to a Gln (FV:Q506) in the factor V gene was the cause of APC resistance. In studies of 50 families with hereditary APC resistance, the FV:Q506 mutation was identified in 94% (47/50) of the families, and the thrombotic risk was found to be dependent on the factor V genotype. Moreover, 18 families with hereditary deficiency of free protein S were investigated. Type I protein S deficiency (low free and total protein S) and type III deficiency (low free but normal total protein S) coexisted in 78% (14/18) of the families, suggesting the two types to be phenotypic variants of the same genetic disorder. Deficiency of free protein S was caused by equimolar relationship between protein S and beta-chain containing isoforms of C4BP. Though protein S deficiency was a strong risk factor for thrombosis, the FV:Q506 mutation was identified as an additional genetic risk factor in 39% of the families. Thus, familial thrombophilia is a multiple gene disorder. The thrombophilic tendency associated with APC resistance or protein S deficiency was related to increased levels of prothrombin fragment 1 + 2, reflecting increased activation of the common coagulation pathway.
authors.affiliation: Department of Clinical Chemistry, Lund University, University Hospital, Malmö, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Zöller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001778:Blood Coagulation Disorders / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism*; D018455:Protein S Deficiency / Q000378:metabolism*; D013548:Sweden / Q000453:epidemiology; D013927:Thrombosis / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D011486:Protein C