Thromb Haemost 2002; 88(05): 723-728
DOI: 10.1055/s-0037-1613292
Review Article
Schattauer GmbH

Interaction Between Hyperhomocysteinemia, Mutated Methylenetetrahydrofolatereductase (MTHFR) and Inherited Thrombophilic Factors in Recurrent Venous Thrombosis

Miranda B. A. J. Keijzer
1   Department of Endocrinology and Epidemiology and Biostatistics, University Medical Center Nijmegen
,
Martin den Heijer
1   Department of Endocrinology and Epidemiology and Biostatistics, University Medical Center Nijmegen
,
Henk J. Blom
2   Laboratory of Paediatrics and Neurology, University Medical Center Nijmegen
,
Gerard M. J. Bos
3   Department of Hematology, University Hospital Maastricht
,
Huub P. J. Willems
4   Department of Hematology, Leyenburg Hospital, The Hague
,
Wim B. J. Gerrits
4   Department of Hematology, Leyenburg Hospital, The Hague
,
Frits R. Rosendaal
5   Department of Clinical Epidemiology and Department of Hematology, Leiden University Medical Center; The Netherlands
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 05. November 2001

Accepted after resubmission 13. Juli 2002

Publikationsdatum:
08. Dezember 2017 (online)

Summary

Venous thrombosis is a multicausal disease involving acquired and genetic factors. In this study we investigated a possible interaction between hyperhomocysteinemia (fasting or postload) and factor V Leiden or prothrombin G20210A on the risk of recurrent venous thrombosis. We also looked at the risk due to mutations in the MTHFR-gene (C677T and A1298C).

We performed a case-control study in 171 patients with a history of recurrent venous thrombosis and 461 control subjects from the general population. Hyperhomocysteinemia (fasting or 6 h after an oral methionine load) was defined as a homocysteine concentration above the 90th percentile of the distributions in the control group.

The odds ratio (adjusted for age and sex) for recurrent venous thrombosis was 1.8 (95%CI: 1.1 to 3.0) for fasting hyperhomocysteinemia, 5.1 (95%CI: 3.0 to 8.6) for factor V Leiden and 1.8 (95%CI: 0.7 to 4.2) for prothrombin G20210A. We found 14 patients and 3 controls with both hyperhomocysteinemia and factor V Leiden, which yielded an odds ratio of 11.6 (95%CI: 3.2 to 42.5). We found no interaction between hyperhomocysteinemia and prothrombin G20210A. The relative risk for MTHFR 677CT was 1.6 (95%CI: 1.1 to 2.4) and for MTHFR 677TT was 1.4 (95%CI: 0.7 to 2.8). The combined risk for MTHFR 677TT and factor V Leiden was 18.7 (95%CI: 3.3 to 108).

We conclude that hyperhomocysteinemia and factor V Leiden are risk factors for recurrent venous thrombosis. The risk of thrombosis appeared high for individuals who had both risk factors.

 
  • References

  • 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
  • 2 Heijboer H, Brandjes DPM, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deepvein thrombosis. N Engl J Med 1990; 323: 1512-6.
  • 3 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
  • 4 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
  • 5 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
  • 6 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Cate JW, Mertens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
  • 7 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-8.
  • 8 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
  • 9 Poort SR, Rosendaal 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 1996; 88: 3698-703.
  • 10 Alhenc-Gelas M, Arnaud E, Nicaud V, Aubry ML, Fiessinger JN, Aiach M, Emmerich J. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999; 81: 506-10.
  • 11 Margaglione M, D’ Andrea G, d’ Addedda M, Giuliani N, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A 20210 mutation. Thromb Haemost 1998; 79: 907-11.
  • 12 Cattaneo M, Chantarangkul V, Taioli E, Santos JH, Tagliabue L. The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: Prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res 1999; 93: 1-8.
  • 13 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: 1080-3.
  • 14 Den Heijer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-5.
  • 15 Fermo I, Vigano SD'Angelo, Paroni R, Mazzola G, Calori G, D’ Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with earlyonset venous and arterial occlusive disease. Ann Intern Med 1995; 123: 747-53.
  • 16 Den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
  • 17 Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocysteinemia and deep-vein thrombosis – a case-control study. Thromb Haemost 1996; 76: 883-6.
  • 18 Den Heijer M, Rosendaal FR, Blom HJ, Gerrits WBJ, Bos GMJ. Hyperhomocysteinemia and venous thrombosis: A meta-analysis. Thromb Haemost 1998; 80: 874-7.
  • 19 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 methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
  • 20 Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677→Val in the methylene tetrahydrofolate reductase gene: A risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-21.
  • 21 Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-8.
  • 22 Gemmati D, Previati M, Serino ML, Moratelli S, Guerra S, Capitani S, Forini E, Ballerini G, Scapoli GL. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocysteinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol 1999; 19: 1761-7.
  • 23 Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol 2000; 109: 870-4.
  • 24 Couturaud F, Oger E, Abalain JH, Chenu E, Guias B, Floch HH, Mercier B, Mottier D, Leroyer C. Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease. Respiration 2000; 67: 657-61.
  • 25 Franco RF, Morelli V, Lourenço D, Maffei FH, Tavella MH, Piccinato CE, Thomazini IA, Zago MA. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol 1999; 105: 556-9.
  • 26 Brown K, Luddington R, Baglin T. Effect of the MTHFRC677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations. Br J Haematol 1998; 103: 42-4.
  • 27 Hessner MJ, Luhm RA, Pearson SL, Endean DJ, Friedman KD, Montgomery RR. Prevalence of prothrombin G20210A, Factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR. Thromb Haemost 1999; 81: 733-8.
  • 28 De Stefano V, Chiusolo P, Paciaroni K, Serra FG, Voso MT, Casorelli I, Rossi E, Leone G. Prevalence of the 677C to T mutation in the methylenetetrahydrofolate reductase gene in Italian patients with venous thrombotic disease. Thromb Haemost 1998; 79: 686-7.
  • 29 Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol 1997; 97: 804-6.
  • 30 Salden A, Keeney S, Hay CRM, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997; 99: 472.
  • 31 Kluijtmans LAJ, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254-8.
  • 32 Den Heijer M, Keijzer MBAJ. Hyperhomocysteinemia as a risk factor for venous thrombosis. Clin Chem Lab Med 2001; 39 (08) 710-3.
  • 33 Akar N, Akar E, Akçay R, Avcu F, Yalcin A, Cin S. Effect of methylenetetrahydrofolate reductase 677 C-T, 1298 A-C, and 1317 T-C on factor V 1691 mutation in Turkish deep vein thrombosis patients. Thromb Res 2000; 97: 163-7.
  • 34 De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000; 26: 305-11.
  • 35 D’ Angelo A, Fermo I, Vigano d’ Angelo S. Thrombophilia, homocystinuria, and mutation of the factor V gene. N Engl J Med 1996; 335: 289.
  • 36 Eichinger S, Stümpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, Schneider B, Pabinger I, Lechner K, Kyrle PA. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566-9.
  • 37 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: 1777-82.
  • 38 De Stefano V, Zappacosta B, Persichilli S, Rossi E, Casorelli I, Paciaroni K, Chiusolo P, Leone AM, Giardina B, Leone G. Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 1999; 106: 564-8.
  • 39 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: 1662-6.
  • 40 Akar N, Akar E, Misirlioglu M, Avcu F, Yalçin A, Cin Ş. Search for genetic factors favoring thrombosis in Turkish population. Thromb Res 1998; 92: 79-82.
  • 41 Fiskerstrand T, Refsum H, Kvalheim G, Ueland PM. Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem 1993; 39: 263-71.
  • 42 Van der Put NMJ, Gabreëls F, Stevens EMB, Smeitink JAM, Trijbels FJM, Eskes TKAB, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am J Hum Genet 1998; 62: 1044-51.
  • 43 Woolf B. On estimating the relationship between blood group and disease. Ann Hum Genet 1955; 251-3.
  • 44 Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7-9.