A Tyr346-->Cys substitution in the interdomain acidic region a1 of factor VIII in an individual with factor VIII:C assay discrepancy

Br J Haematol. 2002 Aug;118(2):589-94. doi: 10.1046/j.1365-2141.2002.03617.x.


The interdomain acidic region a1 is a unique structural feature of coagulation factor VIII (FVIII) and may mediate the proteolytic activation of FVIII and the inactivation of FVIIIa. We report an individual with a Tyr346-->Cys substitution within region a1, who presented with a one-stage FVIII activity (FVIII:C) of 0.34 iu/ml (normal range 0.5-2.0) but normal two-stage FVIII:C and FVIII antigen values. In a factor Xa (FXa)-generation assay for FVIII in which the activation time with thrombin was varied, the variant plasma showed normal FVIII:C at both short and long activation times. However, at intermediate activation times the FXa generation of the variant plasma was less than that of normal pooled plasma. In a modified one-stage FVIII:C assay in which partially purified FVIII was activated with thrombin at low concentrations, the variant FVIII showed less activation than wild-type FVIII, although this defect corrected with increasing concentrations of thrombin. When partially purified variant FVIII was activated with a large molar excess of thrombin, the subsequent rate of decay of FVIII:C was greater for variant FVIII. The complex defects in activation and inactivation displayed by FVIII Tyr346-->Cys support the hypothesis that the a1 sequence is a key regulator of FVIII activity.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Amino Acid Substitution / genetics*
  • Blotting, Western
  • Factor VIII / chemistry
  • Factor VIII / genetics*
  • Factor VIIIa / genetics
  • Hemophilia A / genetics
  • Humans
  • Male
  • Mutation / genetics
  • Partial Thromboplastin Time
  • Protein Structure, Tertiary / genetics*


  • Factor VIIIa
  • Factor VIII