An Association Between the Common Hereditary Hemochromatosis Mutation and the Factor V Leiden Allele in a Population With Thrombosis

To the Editor:

It is now generally accepted that the occurrence of clinical thromboembolic events represent the pathological consequence of a combination of genetic and environmental prothombotic factors. In the past 5 years, substantial progress has been made in identifying some of the more common genetic hypercoagulable traits, with the factor V Leiden (R506Q) and the prothrombin (G20210A) variants being associated with an increased relative risk of venous thrombosis of sevenfold1 and threefold,2 respectively. Furthermore, recent subgroup analysis indicates that these genetic variants may also enhance the relative risk of arterial thrombosis in some populations.3 4 In addition, there are likely many as yet undefined genetic influences that contribute small but significant effects to the prothrombotic state and determine why the factor V Leiden and prothrombin variant traits show such marked variability of clinical expression.

In this preliminary report, we describe the results of a genetic study that may have identified a trait that contributes to the hypercoagulability associated with the factor V Leiden variant. We have documented the prevalence of the recently described common hereditary hemochromatosis (HH) mutation of the Hfe gene (C282Y)5 in a population of unscreened patients with thrombosis referred for molecular genetic studies of hypercoagulability. Eighty-seven of these patients (all unrelated) were heterozygous for the factor V Leiden mutation. In this population, the carrier frequency for the Hfe C282Y mutation was 18.7% (Table 1). In contrast, in 105 unrelated patients who were negative for the factor V Leiden mutation, the frequency of Hfe gene C282Y heterozygotes was only 3%. The results obtained for these two groups were compared with each other and with normal control populations in which the frequency of C282Y heterozygotes is approximately 6%.5 6 It was found that the frequency of C282Y heterozygotes was significantly higher in the factor V Leiden carriers (χ², P < .001) than that observed in either the factor V Leiden-negative patients or in control populations (Table 1). In contrast, the frequency of C282Y heterozygotes in the factor V Leiden-negative patients was not significantly different from that observed in control populations.

This small preliminary study has documented a highly significant and biologically interesting association between the heterozygous states for the factor V Leiden and the Hfe gene C282Y mutations in an unscreened population of patients referred for hypercoagulable testing. Is there a biologically plausible association between the thrombotic events in these patients and the doubly heterozygous state for factor V Leiden and HH? This is unclear at present and, indeed, neither the heterozygous nor homozygous state for HH has been reported to be complicated by an increase in thrombotic events.7 However, a preliminary association between the heterozygous state for HH and total cardiovascular death has recently been reported,8 and an interesting association of thrombosis and secondary hemochromatosis has been documented in a mouse model of hereditary spherocytosis.9 We speculate that perhaps even minor dysregulation of iron metabolism may, under certain circumstances, such as when the heterozygous state for factor V Leiden is also present, contribute to the enhanced risk of a clinical thrombotic event. In contrast, the thrombotic population testing negative for both factor V Leiden and HH may have an increased thrombotic risk that is the result of distinct and independent metabolic defects.

We propose that this preliminary observation deserves further evaluation in larger and more stringently defined populations.