FIBRINOGEN OTAGO - A MAJOR ALPHA-CHAIN TRUNCATION ASSOCIATED WITH SEVERE HYPOFIBRINOGENEMIA AND RECURRENT MISCARRIAGE

A woman with a preliminary diagnosis of afibrinogenaemia was later fou nd to have a functional fibrinogen of 0.06 mg/ml and markedly prolonge d thrombin and reptilase times. The stoichiometry of fibrinopeptide re lease was normal but there was a gross delay in the polymerization of purified fibrin. Plasma protein electrophoresis showed an absence of n ormal fibrinogen and a novel anodal component which was confirmed as f ibrinogen by immunofixation. Western blots of non-reducing SDS-PAGE ge ls indicated a molecular weight of 270 kD, compared to 340 kD for norm al fibrinogen and similar analysis of reducing gels showed that the ex pected 67 kD A alpha chain was missing and replaced by a 30 kD band. T his aberrant chain was not detected by the monoclonal antibody F-103, which recognizes the epitope formed by residues 259-276 of the A alpha chain. Cycle sequencing of the DNA encoding the F-103 epitope reveale d the homozygous insertion of cytosine at position 4133 of the gene se quence. Predictably this translates as three new amino acids ((268)Gln -Glu-Pro) before termination at a new (TAG) stop codon. No abnormal A alpha chains could be detected in plasma from the woman's heterozygous son, The hypofibrinogenaemia observed is likely to be the result of d iminished assembly and/or secretion of the truncated A alpha chains ra ther than enhanced extracellular degradation.