Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AαIVS4 + 1 G>T mutation and an AαGln328 truncation (fibrinogen Keokuk)

Phil Lefebvre, Pauline T. Velasco, Amy Dear, Karim C. Lounes, Susan T. Lord, Stephen O. Brennan, David Green*, Laszlo Lorand

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2571-2576
Number of pages6
JournalBlood
Volume103
Issue number7
DOIs
StatePublished - Apr 1 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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