ANTITHROMBIN CAMBRIDGE-II (ALA384SER) - CLINICAL, FUNCTIONAL AND HAPLOTYPE ANALYSIS OF 18 FAMILIES

Thirty-one individuals from 18 unrelated families with antithrombin de ficiency have been identified as having a single point mutation within codon 384 (13268 GCA-->TCA) resulting in an alanine to serine substit ution. Six families (11 individuals) were identified by the screening of individuals with thromboembolic disease or with a family history of thromboembolic disease, whilst the remaining 12 families (20 individu als) were identified by screening of asymptomatic blood donors. Four i ndividuals had a history of venous thrombotic disease, a further 2 gav e a history of superficial thrombophlebitis but the remaining 25 indiv iduals were asymptomatic. Affected individuals demonstrated normal imm unological levels of antithrombin but a decrease in anti-IIa activity in the presence of heparin. Haplotype analysis was used to examine the possibility of a founder effect to explain the high frequency of this non-CpG mutation. 29/31 individuals showed a single common ''core'' h aplotype, the only variation existing in the number of copies of an (A TT)n repeat polymorphism -13, 14, 15 or 17. The results suggest that a t most there are four independent origins for this mutation.