(Circulation. 1998;97:295-296.)
© 1998 American Heart Association, Inc.
Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism
Marco Cattaneo;
Maria Luisa Monzani;
Ida Martinelli;
Cristina Rosario Falcon;
; Pier Mannuccio Mannucci
A. Bianchi Bonomi Hemophilia and Thrombosis Center,
IRCCS Ospedale Maggiore,
University of Milano,
Milano, Italy
To the Editor:
In their large, prospective cohort study published in the April 1, 1997
issue of Circulation,1 Ridker et al
showed that hyperhomocysteinemia is a risk factor for venous
thromboembolism (VTE) only when it coexists with factor V Leiden, which
is responsible for most cases of resistance to activated
protein C. Hyperhomocysteinemia alone did not increase the risk of any
VTE, although it tended to increase the risk of idiopathic VTE
(P=.06). These important findings are in partial
disagreement with those of previous case-control studies, which
demonstrated an increased prevalence of hyperhomocysteinemia in
patients with any VTE and which demonstrated that the association
between hyperhomocysteinemia and any VTE was independent of the
coexistence of activated protein C
resistance2 or factor V
Leiden.3 There are at least three possible
explanations for these contrasting results: (1) Hyperhomocysteinemia is
a consequence, rather than a risk factor, of VTE. Although this
explanation can account for divergences in results of case-control
studies and prospective cohort studies, it should be rejected, because
Ridker et al showed in their prospective cohort study that
hyperhomocysteinemia increases the risk of VTE in subjects with factor
V Leiden. (2) The association between hyperhomocysteinemia and VTE is
stronger in women than in men, as shown by den Heijer et
al.3 If confirmed by further studies, this sex
difference could account for the negative results of the study by
Ridker et al, which included only men. (3) The inclusion of patients
with cancer, which is a very strong risk factor for VTE, could have
masked the effect of hyperhomocysteinemia, which is a relatively weak
risk factor. Most epidemiological studies of hyperhomocysteinemia as a
risk factor of VTE2 3 4 5 6 did not include cancer
patients.
The demonstration by Ridker et al that the coexistence of
hyperhomocysteinemia and factor V Leiden sharply increases the risk for
future VTEs, particularly those considered idiopathic, agrees with two
reports from our group. In a study of 111 patients with early-onset
VTE,7 we found that the frequency of idiopathic
episodes was higher in patients with hyperhomocysteinemia and
activated protein C resistance combined (71%) than in patients
with either defect alone (30% for activated protein C
resistance, 44% for hyperhomocysteinemia). We consider as idiopathic
those episodes not occurring in association with circumstantial
triggering factors such as surgery, trauma, prolonged immobilization,
pregnancy/puerperium, and use of oral contraceptives. More recently,
we9 showed that the risk of VTE in carriers of
both factor V Leiden and the C677T mutation of
methylenetetrahydrofolate reductase,
which is responsible for mild
hyperhomocysteinemia,8 was greater than the
expected joint effect of the two mutations, calculated by either an
additive or a multiplicative model. Also in that study, the frequency
of idiopathic episodes tended to be higher in doubly affected
individuals than in those with either defect alone.
References
1.
Ridker PM, Hennekens CH, Selhub J, Miletich JP,
Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia,
factor V Leiden, and risk of future venous thromboembolism.
Circulation.. 1997;95:1777–1782.[Abstract/Free Full Text]
2.
Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM.
High prevalence of hyperhomocyst(e)inemia in patients with juvenile
venous thrombosis. Arterioscler Thromb.. 1994;14:1080–1083.[Abstract/Free Full Text]
3.
den Heijer M, Koster T, Blom HJ, Bos GMJ, Briet E, Reitsma PH,
Vandenbrouke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor
for deep-vein thrombosis. N Engl J Med.. 1996;334:759–762.[Abstract/Free Full Text]
4.
Fermo I, Viganó-D'Angelo S, Paroni R, Mazzola G, Calori
G, D'Angelo A. Prevalence of moderate hyperhomocysteinemia in patients
with early-onset venous and arterial occlusive disease. Ann
Intern Med.. 1995;123:747–753.[Abstract/Free Full Text]
5.
Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in
patients with deep venous thrombosis. Arterioscler Thromb Vasc
Biol.. 1995;15:1321–1323.[Abstract/Free Full Text]
6.
Cattaneo M, Martinelli I, Mannucci I. Hyperhomocysteinemia as a
risk factor for deep-vein thrombosis. N Engl J Med.. 1996;335:974–975.[Free Full Text]
7.
Monzani ML, Cattaneo M, Falcon CR, Martinelli I, Faioni E,
Braga M, Mannucci PM. Association between activated protein C
resistance and hyperhomocyst(e)inemia in juvenile venous
thromboembolism. Thromb Haemost.. 1995;73:1368. Abstract.
8.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews
RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen
R. A candidate genetic risk factor for vascular disease: a common
mutation in the methylenetetrahydrofolate reductase. Nat
Genet.. 1995;10:111–113.[Medline]
[Order article via Infotrieve]
9.
Cattaneo M, Tsai MY, Bucciarelli P, Taioli E. Zighetti ML,
Bignell M, Mannucci PM. A common mutation in the
methylenetetrahydrofolate reductase gene (C677T) increases the risk for
deep-vein thrombosis in patients with mutant factor V (Factor V:Q506).
Arterioscler Thromb Vasc Biol.. 1997;17:1662–1666.[Abstract/Free Full Text]
Response
Paul M. Ridker, MD
Brigham and Women's' Hospital,
Harvard Medical School,
Boston, Mass
My coauthors and I appreciate the kind words from Dr Cattaneo
and colleagues concerning our finding of a marked increase in risk of
venous thromboembolism among patients affected by both factor V Leiden
and hyperhomocystinemia compared with patients with either of these
abnormalities alone.1 In our prospective data,
dietary-induced hyperhomocystinemia appears to be at least as important
as the presence of homozygosity for the
methylenetetrahydrofolate reductase
(MTHFR) polymorphism. As noted in the "Discussion" section of
our article, the majority of patients in our study who had
hyperhomocystinemia did not carry the abnormal polymorphism.
We disagree somewhat with the view that there was no association in our
data between hyperhomocystinemia and venous thrombosis when
hyperhomocystinemia was considered in isolation. As described in the
original manuscript, those with hyperhomocystinemia were at
significantly increased risk of developing future idiopathic venous
thromboembolic events (relative risk=3.4, P=.002). However,
no such increase in risk was found for venous thromboemboli associated
with cancer, surgery, or trauma, which we defined on an a priori
basis as secondary events. Indeed, this difference between primary and
secondary venous thromboembolic events may explain why
some2 3 4 but not all5 6
prior studies evaluating hyperhomocystinemia and venous thrombosis
reported significant relationships. This distinction is additionally
relevant with regard to factor V Leiden because the risk of recurrent
events associated with this mutation also appears limited to idiopathic
events.7 Thus, our data and those forthcoming
from Cattaneo and colleagues suggest that patients with idiopathic
venous thromboses who carry factor V Leiden may require additional
screening for other concomitant abnormalities of hemostasis, such as
hyperhomocystinemia.
References
1.
Ridker PM, Hennekens CH, Selhub J,
Miletich JP, Malinow MR, Stampfer MJ. Interrelation of
hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous
thromboembolism. Circulation. 1997;95:1777–1782.
2.
Den Heijer M, Blom HJ, Gerrits WJ, Rosendaal FR, Haak
HL, Wijermans PW, Bos GM. Is hyperhomocystinemia a risk factor for
recurrent venous thrombosis? Lancet. 1995;345:882–885.[Medline]
[Order article via Infotrieve]
3.
Den Heijer M, Koster T, Blom HJ, Bos GM, Briet E,
Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocystinemia as a
risk factor for deep-vein thrombosis. N Engl J
Med. 1996;334:759–762.
4.
Falcon CR, Cattaneo M, Panzeri D, Martinelli I,
Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with
juvenile venous thrombosis. Arterioscler Thromb. 1994;14:1080–1083.
5.
Brattstrom L, Tengborn L, Lagerstedt C, Israelsson B,
Hultberg B. Plasma homocysteine in venous thromboembolism.
Haemostasis. 1991;21:51–57.[Medline]
[Order article via Infotrieve]
6.
Amundsen T, Ueland PM, Waage A. Plasma homocysteine
levels in patients with deep venous thrombosis. Arterioscler
Thromb Vasc Biol. 1995;15:1321–1323.
7.
Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ,
Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent
idiopathic venous thromboembolism. Circulation. 1995;92:2800–2802.[Abstract/Free Full Text]
