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Circulation. 1998;97:295-296

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(Circulation. 1998;97:295-296.)
© 1998 American Heart Association, Inc.

Correspondence

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]




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