THE 1691-G-]A MUTATION IN THE FACTOR-V GENE - RELATIONSHIP TO ACTIVATED PROTEIN-C (APC) RESISTANCE AND THROMBOSIS IN 65 PATIENTS

Four hundred fifty subjects were screened for the 1691 G --> A mutatio n in the factor V gene. Two hundred ninety-seven patients were referre d to us for unexplained thrombosis, 133 were family members of these p atients and 20 were normal subjects. We studied the relationships betw een the mutation, resistance to APC and thrombosis. Among the 450 subj ects tested, 65 belonging to 42 families were found to have the 1691 G --> A mutation in one (n = 61) or both alleles (n = 4). The prevalenc e of the mutation in the thrombotic patients was 13%. Resistance to AP C was tested for in 247 subjects not on anticoagulant treatment (4 hom ozygous and 44 heterozygous for the mutation, and 199 individuals with out the mutation). Incomplete cosegregation of heterozygosity for the 1691 G --> A mutation with APC resistance (APC-SR < 2.4 or n-APC-SR < 0.75) was observed, showing that the functional assay alone is insuffi cient for a firm diagnosis. In patients carrying the mutation, elevate d levels of prothrombin fragment 1 + 2 and D-dimers pointed to increas ed thrombin generation in vivo. Clinical manifestations in the heteroz ygous subjects were very similar to those reported in heterozygous PC or PS deficiencies, but the first thrombotic event occurred later than in PC- or PS-deficient patients. Homozygosity for the factor V gene m utation appears to be a far more benign thrombotic disorder than homoz ygous PC and PS deficiencies.