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 inBlood, 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 (χ2 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 (Table1). 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 (χ2 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.7The 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.
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.
