PlumX Metrics
Embed PlumX Metrics

The Missense Mutation Arg 593 → Cys Is Related to Antibody Formation in a Patient With Mild Hemophilia A

Blood, ISSN: 0006-4971, Vol: 89, Issue: 12, Page: 4371-4377
1997
  • 76
    Citations
  • 0
    Usage
  • 20
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    76
    • Citation Indexes
      76
  • Captures
    20

Article Description

The development of inhibitory antibodies to factor VIII in patients affected by a mild form of hemophilia A (factor VIII < 0.05 IU/mL) is considered a rare event. In this study, we evaluated the relationship between genotype and anti-factor VIII antibody formation in a patient with mild hemophilia A. Mutation analysis showed that a missense mutation in the factor VIII gene leading to replacement of Arg 593 by Cys in the A2 domain of factor VIII was associated with hemophilia A in this patient. The anti-factor VIII antibodies present in the patient's plasma were characterized using metabolically labeled factor VIII fragments expressed in insect cells. The anti-factor VIII antibodies, composed of subclasses IgG2 and IgG4, reacted with both the fragment corresponding to the factor VIII heavy chain and the A2 domain. The Arg 593 → Cys substitution was introduced into the cDNA encoding the A2 domain of factor VIII and the resulting construct was expressed in insect cells. Strikingly, the metabolically labeled A2 domain carrying the Arg 593 → Cys mutation was not recognized by the anti-factor VIII antibodies present in the plasma of the patient. These data indicate that the anti-factor VIII antibodies are exclusively directed against exogenous factor VIII. This strongly suggests that the Arg 593 → Cys substitution results in recognition of wild-type factor VIII as nonself and is thereby related to the formation of anti-factor VIII antibodies after factor VIII replacement therapy in this particular patient.

Bibliographic Details

Karin Fijnvandraat; Ellen A.M. Turenhout; Edward N. van den Brink; Jan W. ten Cate; Jan A. van Mourik; Marjolein Peters; Jan Voorberg

American Society of Hematology

Biochemistry, Genetics and Molecular Biology; Immunology and Microbiology; Medicine

Provide Feedback

Have ideas for a new metric? Would you like to see something else here?Let us know