Abnormal fibrinogens IJmuiden (B beta Arg sub(14) arrow right Cys) and Nijmegen (B beta Arg sub(44) arrow right Cys) form disulfide-linked fibrinogen-albumin complexes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 8; pp. 3478 - 3482
• Main Authors: Koopman, J, Haverkate, F, Grimbergen, J, Engesser, L, Novakova, I, Kerst, AFJA, Lord, ST
• Format: Journal Article
• Language: English
• Published: 01.01.1992
• Subjects: disulfide bonds; thrombophilia
• ISSN: 0027-8424

The molecular defects in two congenital abnormal fibrinogens, IJmuiden and Nijmegen, were determined by sequence analysis of genomic DNA amplified by the polymerase chain reaction. Both fibrinogens were heterozygous, IJmuiden having a B beta Arg sub(14) arrow right Cys substitution and Nijmegen having a B beta Arg sub(44) arrow right Cys substitution. Clotting induced by thrombin or Reptilase was impaired in both fibrinogens, indicating defective fibrin polymerization. Immunoblot analysis of both purified fibrinogens demonstrated that some of the abnormal molecules were linked by disulfide bonds to albumin. In addition, abnormal high molecular weight fibrinogen complexes in with M sub(r)s between 600,000 and 700,000 were present. Fibrinogen-albumin and high molecular weight complexes were also detected in the patients' plasmas. Quantative analysis demonstrated that of the total plasma fibrinogen in the IJmuiden patient, 20% was linked to albumin and 10% was present as high molecular weight complexes. We also found that a significant fraction of the abnormal fibrinogen molecules contained free sulfhydryl groups.