title: Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S.
abstract: Inherited resistance to activated protein C (APC), which is caused by a single point mutation in the gene for factor V, is a common risk factor for thrombosis. In this study, the prevalence of APC resistance in 18 unrelated thrombosis-prone families with inherited protein S deficiency was investigated to determine its role as additional genetic risk factor for thrombosis. In addition, a detailed evaluation of the clinical manifestations in these families was performed. Venous thrombotic events had occurred in 47% of the protein S-deficient patients (64/136) and in 7% of relatives without protein S deficiency (14/191). As estimated from Kaplan-Meier analysis, 50% of protein S-deficient family members and 12% of those without protein S deficiency had had manifestation of venous thromboembolism at the age of 45 years. The age at the first thrombotic event ranged from 10 to 81 years (mean, 32.5 years) and a large intrafamilial and interfamilial variability in expression of thrombotic symptoms was seen. The factor V gene mutation related to APC resistance was present in 6 (38%) of 16 probands available for testing; in total, the mutation was found in 7 (39%) of the 18 families. In family members with combined defects, 72% (13/18) had had thrombosis as compared with 19% (4/21) of those with only protein S deficiency and 19% (4/21) of those with only the factor V mutation. In conclusion, APC resistance was found to be highly prevalent in thrombosis-prone families with protein S deficiency and was an additional genetic risk factor for thrombosis in these families. The results suggest thrombosis-prone families with protein S deficiency often to be affected by yet another genetic defect.
authors.affiliation: Department of Clinical Chemistry, University of Lund, Malmö General Hospital, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Zöller
authors.forename: A
authors.initials: A
authors.lastname: Berntsdotter
authors.forename: P
authors.initials: P
authors.lastname: García de Frutos
authors.forename: B
authors.initials: B
authors.lastname: Dahlbäck
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D015995:Prevalence; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D018455:Protein S Deficiency / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013927:Thrombosis / Q000209:etiology / Q000235:genetics
chemical_list: D011486:Protein C