Recently, we found that high levels of clotting factor VIII (> 150 IU/
dl) are common and make an important contribution to thrombotic risk.
The determinants of high factor VIII:C are unclear and might be partly
genetic. Therefore, we tested the influence of age, blood group and v
on Willebrand factor (VWF) levels on factor VIII:C levels, and investi
gated whether factor VIII:C levels are genetically determined. We perf
ormed an analysis of 564 female relatives of hemophilia A patients, wh
o had visited our center for genetic counseling. In univariate analysi
s, AB0 blood group, age and VWF antigen (VWF:Ag) levels all. influence
d factor VIII:C levels. After adjustment for the effect of VWF:Ag leve
ls, both blood group and age still had an effect on factor VIII:C leve
ls. In sister pairs, the Pearson correlation coefficient between facto
r VIII:C levels was 0.17 (p = 0.024) and this correlation remained pos
itive (0.15, p = 0.046) after correction for the influence of VWF:Ag.
In mother-daughter pairs, no correlation of factor VIII:C levels was f
ound. The correlation of VWF:Ag levels in sisterpairs was 0.41 (p <0.0
01) and in mother-daughter pairs 0.44 (p <0.001), in line with the ass
umption that VWF:Ag levels are under control of autosomal genes. Famil
ial influence on plasma factor VIII:C and VWF:Ag levels was investigat
ed with a recently developed familial aggregation lest. This test veri
fies whether familial aggregation of a particular parameter exists in
a set of pedigrees. In 435 women from 168 families, factor VIII:C as w
ell as VWF:Ag levels correlated significantly within families, which s
uggests a familial influence. The familial aggregation was more promin
ent for VWF:Ag levels than for factor VIII:C levels, possibly because
the genetic effect on VWF:Ag levels is larger than on factor VIII:C le
vels. Our results support the presence of a familial influence on fact
or VIII:C as well as on VWF:Ag levels.