High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis.

Recent findings have indicated the importance of factor V (FV) in causing resistance to activated protein C (APC) in a high proportion of patients with venous thrombosis. This prompted us to investigate whether resistance could be due to defective inactivation of FVa by APC. Consequently, we amplified a 3.2 kb fragment of the FV gene sequence encoding the heavy chain APC cleavage site. DNA analysis showed a guanine to adenine transition at nucleotide 1691 in all affected members of two families with inherited APC resistance associated with thrombosis and confirmed suspected homozygosity in two individuals. The mutation, in heterozygous form, was also found in approximately 3.5% of our normal population (n = 144) and correlated with low APC resistance. The high prevalence of this mutation suggests that it may be a major contributory factor in early thrombosis.