Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2135-2136
CORRESPONDENCE
C282Y Hemochromatosis Mutation Does Not Contribute to
Hypercoagulability in a Factor V Leiden Population Referred for Venous
Thrombosis
 |
LETTER |
To the Editor:
Factor V Leiden (R506Q mutation) is the most common hereditary risk
factor for venous thrombosis, with a prevalence of heterozygous carriers of 20%1 (normal carrier frequency, 3% to
5%2). Recently, the presence of homozygous mutation C282Y
in HLA-HFE gene has been shown in almost all patients with hereditary
hemochromatosis (HH).3,4 In a recently published letter in
Blood, Xie et al5 reported data about a possible
association between C282Y mutation and factor V Leiden mutation in a
population of patients with thrombosis. To see if heterozygous C282Y
mutation is a trait that may enhance thrombotic risk in a patient with
factor V Leiden mutation, they described a genetic analysis of these
two variants in 192 patients with venous thrombosis. They found 18.7%
to carry the heterozygous C282Y mutation among 87 patients
heterozygous for factor V Leiden mutation and only 3% to
carry the mutation among 105 patients negative for factor
V Leiden mutation (
2 test, P < .001).
We report here 246 patients referred for genetic study after deep vein
thrombosis. Fifty-five (22%) patients were heterozygous for factor V
Leiden mutation and 45 (18%) were heterozygous (n = 43) or
homozygous (n = 2) for C282Y mutation (Table
1). Among the 55 patients heterozygous for
factor V Leiden mutation, 14 (25%) carried C282Y mutation and, among
191 patients negative for factor V Leiden mutation, 31 (16%) were
positive for C282Y mutation (2 test, P = .158;
odds ratio, 1.69 [0.76 to 3.73]).
In our study, we found no significant association between C282Y
mutation and factor V Leiden mutation in a population observed for
history of venous thrombosis. We are not surprised, because HH has not
been reported as being a prothrombotic state.6 The speculation of Xie et al5 is based in part on the
observation of high incidence of thrombosis in a mouse model of
hereditary spherocytosis with secondary hemochromatosis.7
The first remark is that patients with hemolytic anemias are at risk
for venous thrombosis because of platelet activation (probably due in
part to release of ADP).8 Another observation is that, in
Xie et al's study,5 the incidence of factor V Leiden
variant is much higher (45%) than usually observed in patients with
usual deep venous thrombosis (we retrieved 22%). In our study, we have
shown a very high incidence of C282Y mutation (18%) that is in
agreement with the previously described very high frequency of HH in
the southwest region of Brittany (Finistère sud).9 In
conclusion, our results cannot support the hypothesis that the
heterozygous state for C282Y mutation enhances the risk of venous
thrombosis even in patients with another genetic influence such
as factor V Leiden trait. A hypothesis of such an association should be used very cautiously before drawing any conclusion.
Franck Lellouche
Service d'Hématologie
Ian Dorval
Jean Marc Corvisier
Service de Biochemie
Hôpital Laennec
Quimper, France
Pascal Jézéquel
Laboratoire de Biologie
Moléculaire
Loïc Campion
Unité de
Bio-Statistiques
Centre René Gauducheau
Nantes,
France
| |
REFERENCES |
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An association between the common hereditary hemochromatosis mutation and the factor V Leiden allele in a population with thrombosis.
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Response
We appreciate the comments made by Lellouche et al about our
preliminary report concerning a potential association between the
common C282Y hemochromatosis mutation and factor V Leiden in producing
thrombosis. As we had suggested in this report, our preliminary
observation should now be evaluated in larger and more stringently
defined populations, such as that assembled by Lellouche et al. We have
two points of clarification with regards to the letter by Lellouche et
al. First, our study population differed from the group studied by
Lellouche et al in that it represented an unselected population with a
history of both venous and arterial thrombosis. Second, the information
relating to our positive rate for factor V Leiden heterozygosity has
been misinterpreted from the presentation of what amounted to a
subgroup study. Overall, after testing 1,424 thrombotic patients in the
past 4 years, we have found a 14% rate of heterozygosity for factor V
Leiden in this group.
Finally, we have recently submitted a second report addressing
this potential association in a case control study of 481 venous thromboembolism patients. In this population, our findings agree with
those of Lellouche et al and show no association between the C282Y
hemochromatosis mutation, factor V Leiden, and thrombosis.
S.A.M. Taylor
D. Lillicrap
Department of
Pathology
Queen's University
Kingston, Ontario, Canada
T.P. Baglin
Department of Haematology
Addenbrooke's NHS
Trust
Cambridge, UK
