Familial thrombophilia: Clinical and molecular analysis of Swedish families with inherited resistance to activated protein C or protein S deficiency

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 o...