F. Bernardi et al., A FACTOR-V GENETIC COMPONENT DIFFERING FROM FACTOR-V R506Q CONTRIBUTES TO THE ACTIVATED PROTEIN-C RESISTANCE PHENOTYPE, Blood, 90(4), 1997, pp. 1552-1557
Factor V gene polymorphisms were investigated to detect components tha
t may contribute to the activated protein C (APC) resistance phenotype
in patients with venous thromboembolism. A specific factor V gene hap
lotype (HR2) was defined by six polymorphisms and its frequency was fo
und to be similar in normal subjects coming from Italy (0.08), India (
0.1), and Somalia (0.08), indicating that it was originated by ancestr
al mutational events, The relationship between the distribution of nor
malized APC ratios obtained with the functional assay and haplotype fr
equency was analyzed in patients heterozygous for factor V R506Q (fact
or V Leiden), The HR2 haplotype was significantly more frequent in pat
ients with ratios below the 15th percentile than in those with higher
ratios or in normal controls. Moreover, the study of 10 patients with
APC resistance in the absence of the factor V R506Q mutation showed a
50-fold higher frequency of HR2 homozygotes, The HR2 haplotype was ass
ociated with significantly lower APC ratios both in patients with veno
us thromboembolism and in age-and sex-matched controls, However, the t
wo groups showed similar HR2 haplotype frequencies, plasma mixing expe
riments showed that an artificially created double heterozygote for th
e factor V R506Q mutation and the HR2 haplotype had an APC ratio lower
than that expected for a simple R506Q heterozygote. Time-course exper
iments evaluating the decay of factor V in plasma showed the normal st
ability of the molecule encoded by the factor V gene marked by the HR2
haplotype, which ruled out the presence of a pseudo-homozygous APC re
sistance mechanism, Our results provide new insights into the presence
of factor V genetic components other than the factor V R506Q that are
able to contribute to the APC resistance phenotype in patients with v
enous thromboembolism. (C) 1997 by The American Society of Hematology.