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 family with a history of bleeding. Plasma from affected family members had prolonged prothrombin times and activated partial thromboplastin times, low to below normal factor X coagulant activity, and normal factor 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 resulting in an amino acid substitution of Asn for Asp at residue 282. This residue corresponds with the active site Asp102 of chymotrypsin. The substitution eliminates a TaqI restriction site and provided the basis for a screening assay to detect the mutation in polymerase chain reaction (PCR) amplified factor X exon VIII DNA. Fourteen additional family members were identified as having the mutation at base 964. Plasma factor X purified from the proposita using an anti-factor X monoclonal antibody immunoadsorbent exhibited an approximately 50% decrease in specific activity compared with factor X purified from a normal individual 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 of this amino acid residue in factor Xa coagulant activity.