RESISTANCE TO ACTIVATED PROTEIN-C AS AN ADDITIONAL GENETIC RISK FACTOR IN HEREDITARY-DEFICIENCY OF PROTEIN-S

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 fac tor for thrombosis. In this study, the prevalence of APC resistance in 18 unrelated thrombosis-prone families with inherited protein S defic iency was investigated to determine its role as additional genetic ris k factor for thrombosis. In addition, a detailed evaluation of the cli nical manifestations in these families was performed. Venous thromboti c events had occurred in 47% of the protein S-deficient patients (64/1 36) and in 7% of relatives without protein S deficiency (14/191). As e stimated from Kaplan-Meier analysis, 50% of protein S-deficient family members and 12% of those without protein S deficiency had had manifes tation of venous thromboembolism at the age of 45 years. The age at th e 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 t o APC resistance was present in 6 (38%) of 16 probands available far t esting; in total, the mutation was found in 7 (39%) of the 18 families . In family members with combined defects, 72% (13/18) had had thrombo sis as compared with 19% (4/21) of those with only protein S deficienc y and 19% (4/21) of those with only the factor V mutation. In conclusi on, APC resistance was found to be highly prevalent in thrombosis-pron e families with protein S deficiency and was an additional genetic ris k factor for thrombosis in these families. The results suggest thrombo sis-prone families with protein S deficiency often to be affected by y et another genetic defect. (C) 1995 by The American Society of Hematol ogy.