FACTOR-X STOCKTON - A MILD BLEEDING DIATHESIS ASSOCIATED WITH AN ACTIVE-SITE MUTATION IN FACTOR-X

A unique blood coagulation factor X variant has been identified in a f amily with a history of bleeding. Plasma from affected family members had prolonged prothrombin times and activated partial thromboplastin t imes, low to below normal factor X coagulant activity, and normal fact or X antigen levels. Sequencing of DNA from the propositus revealed a single G to A substitution in one allele of factor X at base 964 resul ting in an amino acid substitution of Asn for Asp at residue 282. This residue corresponds with the active site Asp(102) of chymotrypsin. Th e substitution eliminates a TaqI restriction site and provided the bas is for a screening assay to detect the mutation in polymerase chain re action (PCR) amplified factor X exon VIII DNA. Fourteen additional fam ily members were identified as having the mutation at base 964. Plasma factor X purified from the proposita using an anti-factor X monoclona l antibody immunoadsorbent exhibited an approximately 50% decrease in specific activity compared with factor X purified from a normal indivi dual in a similar manner. Bleeding in family members with the mutation , termed factor X Stockton, appears to be due to disruption of normal hemostasis by the presence in plasma of circulating abnormal factor X Factor X Stockton is the first naturally occurring substitution,at the active site Asp of a serine protease and underscores the importance o f this amino acid residue in factor Xa coagulant activity.