PHENOTYPIC HOMOZYGOUS ACTIVATED PROTEIN-C RESISTANCE-ASSOCIATED WITH COMPOUND HETEROZYGOSITY FOR ARG506GLN (FACTOR-V-LEIDEN) AND HIS1299ARGSUBSTITUTIONS IN FACTOR-V

Two patients from two unrelated families with a history of thrombosis showed severe plasma activated protein C (APC) resistance. However, ge notypic analysis demonstrated that the patients were heterozygous for factor V (FV) Leiden mutation. Coagulation studies revealed that FV cl otting activity and antigen were similarly reduced at about 50% of nor mal in the patients. One brother of propositus A also showed the same abnormalities. Genetic analysis showed that, in addition to FV Leiden mutation in exon 10 of the FV gene (G1691A), these patients had a tran sition in exon 13 of the FV gene (A4070G; R2 allele) predicting His129 9Arg substitution in the mature FV. Study by RT-PCR of platelet FV mRN A indicated that the mRNA produced by the FV gene, marked by the R2 al lele, was reduced in amount in both pseudohomozygous patients of famil y A. The R2 allele has previously been demonstrated to be significantl y associated with plasma FV deficiency in the Italian population. The presence of FV deficiency did not protect the propositi from thrombosi s. These data confirm that genotypic analysis is mandatory in patients with phenotypic severe APC resistance before these patients are defin itely classified as homozygotes for FV Leiden and that further genotyp ic analysis is advisable.