Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of cross-linked γ-γ fibrin chain dimers without high polymers of αn. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aα-chain residues 241-476 but not by antibodies to Aα219-348 or Aα349-406. DNA analysis revealed a heterozygous CAA → TAA mutation at the codon for amino acid 328 of the Aα gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aα chain. Analysis of purified fibrinogen revealed expression of the abnormal Aα chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aα mutation, a GT → TT splice site mutation in intron 4 (IVS4 + 1 G>T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms.
ASJC Scopus subject areas
- Cell Biology