Fibrinogen New Britain: characterization of an A alpha Arg 16-->His variant human fibrinogen

Routine laboratory screening identified an abnormal fibrinogen in an asymptomatic patient from New Britain, Connecticut. This paper reports the characterization of the abnormal fibrinogen. Clinical clotting studies showed marked prolongation of both the thrombin and Reptilase times. A discrepancy was noted between the fibrinogen concentration as determined by a rate-dependent clotting assay (0.73 milligrams) vs immunological determination (2.27 milligrams). Polymerase chain reaction (PCR) based DNA sequencing was used to identify the underlying molecular defect. Fibrinogen New Britain was found to have a point mutation in exon 2 of the A alpha chain. This mutation results in the amino acid substitution Arg-->His at position 16 of the A alpha chain, the site of thrombin cleavage. The substitution results in delayed polymerization of fibrin clot due to impaired release of fibrinopeptide A by thrombin. Studies of fibrin fibre dimensions and structure showed New Britain fibrin fibres to have a larger mean diameter and an increased mass/length ratio when compared with normal fibrin fibres formed under the same conditions.