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.

Table 1.

Hfe Gene C292Y Carrier Status in Factor V Leiden-Negative and -Positive Thrombotic Patients

Factor V Genotype  Hfe Genotype  
Normal/ C282Y  Normal/ Normal χ2 Value* 
Normal/Normal  3  102 NS  
Normal/Leiden  16  71 P < .001 
Factor V Genotype  Hfe Genotype  
Normal/ C282Y  Normal/ Normal χ2 Value* 
Normal/Normal  3  102 NS  
Normal/Leiden  16  71 P < .001 

*As compared with a carrier frequency of C282Y in the normal population of 6%.

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.

ACKNOWLEDGMENT

D.P.L. is a recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario. Y.X. is a recipient of an Ontario Ministry of Health Laboratory Genetics Fellowship.

REFERENCES

REFERENCES
1
Dalhback
B
Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thromboembolism.
Blood
85
1995
607
2
Poort
SR
Rosendall
FR
Reitsma
PH
Bertina
RM
A common genetic variation in the 3′ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood
88
1996
3698
3
Rosendaal
FR
Siscovick
DS
Schwartz
SM
Beverly
RK
Psaty
BM
Longstreth WT Jr
Raghunathan
TE
Koepsell
TD
Reistma
PH
Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.
Blood
89
1997
2817
4
Rosendaal
FR
Siscovick
DS
Schwartz
SM
Psaty
BM
Raghunathan
TE
Vos
HL
A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.
Blood
90
1997
1747
5
Feder
JN
Gnirke
A
Thomas
W
Tsuchihashi
Z
Ruddy
DA
Basava
A
Dormishian
F
Domingo
R
Jr
Ellis
MC
Fullan
A
Hinton
LM
Jones
NL
Kimmel
BE
Kronmal
GS
Lauer
P
Lee
VK
Loeb
DB
Mapa
FA
McClellan
E
Meyer
ND
Mintier
GA
Moeller
N
Moore
T
Morikang
E
Prass
CE
Quintana
L
Starnes
SM
Schatzman
RC
Brunke
KJ
Drayna
DT
Risch
N
Bacon
BR
Wolff
RK
A novel MHC class I-like gene is mutated in patients with herediatry hemochromatosis.
Nat Genet
13
1996
399
6
(letter)
Jouanolle
AM
Gandon
G
Jezequel
P
Blayau
M
Campion
ML
Mosser
J
Fergelot
P
Chauvel
B
Bouric
P
Carn
G
Andrieux
N
Gicquel
I
Le Gall
Y-V
David
V
Haemochromatosis and HLA-H.
Nat Genet
14
1996
251
7
Barisani
D
Green
RM
Gollan
JL
Genetic hemochromatosis: Pathogenesis, diagnosis and therapy.
Digestive Dis
14
1996
304
8
Roest M, Tempelman MJ, de Valk B, Schouw YT, de Groot PhG, Sixma JJ, Marx JJM, Banga JD: A mutation in the HLA-H gene, present in hemochromatosis patients, is associated with cerebrovascular and total cardiovascular death in post-menopausal women. Thromb Haemost 375a, 1997 (abstr)
9
Kaysser
TM
Wandersee
NJ
Bronson
RT
Barker
JE
Thrombosis and secondary hemochromatosis play major roles in the pathogenesis of jaundice in spherocytic mice, murine models for hereditary spherocytosis.
Blood
90
1997
4610