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 inherite d cause of venous thrombosis. The APC resistance phenotype is associat ed with a single point mutation in the factor V gene, changing Arg(506 ) in the APC cleavage site to a Gin. We have investigated 50 Swedish f amilies with inherited APC resistance for this mutation and found it t o be present in 47 of them. Perfect cosegregation between a low APC ra tio and the presence of mutation was seen in 40 families. In seven fam ilies, the co-segregation was not perfect as 12 out of 57 APC-resistan t family members were found to lack the mutation. Moreover, in three f amilies with APC resistance, the factor V gene mutation was not found, suggesting another still unidentified cause of inherited APC resistan ce. Of 308 investigated families members, 146 were normal, 144 heteroz ygotes, and 18 homozygotes for the factor V gene mutation and there we re significant differences in thrombosis-free survival curves between these groups. By age 33 yr, 8% of normals, 20% of heterozygotes, and 4 0% of homozygotes had had manifestation of venous thrombosis.