Lower factor VIII coagulant activity in daughters of subjects with hemophilia A compared to other obligate carriers

Studies of factor-VIII-related activities were perfomed in 62 obligate carriers of hemophilia A, comparing 23 daughters of hemophilic men (paternal carriers) with 39 mothers of hemophilic sons whose fathers were normal by history (maternal carriers). Nineteen of the maternal carriers were mothers of at least 2 hemophiliacs and 20 were mothers of one, but from families whose other close male members were known to be affected. Fifty-three control subjects (age range 1-65, the same as the carriers) were also evaluated for factor VIII coagulant (VIII:C), factor-VIII-related antigen (VIII:Ag), and the VIII:C to VIIIR:Ag ratio. As expected, VIII:C was lower and VIIIR:Ag was higher in the carrier group than in control subjects, and the mean of the carrier VIII:C to VIIIR:Ag ratio was about 50% of the mean VIII:C to VIIIR:Ag ratio of the control group (0.47 and 0.97, respectively). Within the carrier group there were statistically significant differences in VIII:C levels; lower values were found in paternal carriers as compared to maternal carriers (p < 0.02). Paternal and maternal carriers had similar mean values of VIIIR:Ag; the differences found in mean VIII:C level between paternal and maternal carriers were reflected in the VIII:C to VIIIR:Ag ratio (p < 0.02). These findings were more pronounced when daughters of severely affected subjects were compared to the mothers of equally severely affected individuals (p < 0.001). No statistically significant differences in VIII:C, VIIIR:Ag, and ratio were found when either paternal or maternal carriers were subclassified according to the severity of hemophilia in their offspring. Similarly, no difference in age, VIII:C, VIIIR:Ag, or the VIII:C to VIIIR:Ag ratio were observed when maternal carriers were subdivided into those who were mothers of more than one hemophilic son and those who were mothers of one hemophilic son and had a family history of this disorder on the maternal side. The difference between paternal and maternal carriers could not be attributed to pubertal status, age of the carrier (although the paternal carrier group was significantly younger than the maternal), or greater number of severe hemophilic families in the paternal group. The lower VIII:C levels in paternal carrier women may indicate dominance of the father's affected X chromosome during X-chromosome selection in embryogenesis.