Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.

Resistance to activated protein C (APC) is the most prevalent inherited cause of venous thrombosis. The APC resistance phenotype is associated with a single point mutation in the factor V gene, changing Arg' in the APC cleavage site to a Gln. We have investigated 50 Swedish families with inherited APC resistance for this mutation and found it to be present in 47 of them. Perfect cosegregation between a low APC ratio and the presence of mutation was seen in 40 families. In seven families, the co-segregation was not perfect as 12 out of 57 APC-resistant family members were found to lack the mutation. Moreover, in three families with APC resistance, the factor V gene mutation was not found, suggesting another still unidentified cause of inherited APC resistance. Of 308 investigated families members, 146 were normal, 144 heterozygotes, and 18 homozygotes for the fac- tor V gene mutation and there were significant differences in thrombosis-free survival curves between these groups. By age 33 yr, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestation of venous thrombo- sis. (J. Clin. Invest. 1994 . 94:2521-2524.) Key words: blood coagulation * thrombophilia -protein C * protein S * fac- tor V recently discovered in a single family (2) and is already recognized as a major cause of venous thrombosis (3-6). Intact factor V was found to correct APC resistance (7) which together with close linkage between APC resistance and the factor V gene (8, 9), suggested the molecular defect to be located in the factor V gene. A single point mutation (G to A at position 1691) has been found in many APC-resistant individuals (8- 11 ). This mutation predicts replacement of Arg5 in the APC cleavage site of factor Va with a Gln, which results in APC- resistant factor Va (8, The prevalence in the European population of APC resistance is between 3 and 7% (3, 5).