Seminars in Hematology
Volume 44, Issue 2 , Pages 85-92 , April 2007

Predictive Genetic Variants for Venous Thrombosis: What’s New?

  • Irene D. Bezemer

      Affiliations

    • Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
  • ,
  • Frits R. Rosendaal

      Affiliations

    • Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
    • Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
    • Corresponding Author InformationAddress correspondence to Frits R. Rosendaal, MD, Department of Clinical Epidemiology, C9-P, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

References 

  1. Mannucci PM. Laboratory detection of inherited thrombophilia: A historical perspective. Semin Thromb Hemost. 2005;31:5–10
  2. Austin H, Hooper WC, Lally C, Dilley A, Ellingsen D, Wideman C, et al. Venous thrombosis in relation to fibrinogen and factor VII genes among African-Americans. J Clin Epidemiol. 2000;53:997–1001
  3. Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briet E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis (A case-control study of plasma levels and DNA polymorphisms—The Leiden Thrombophilia Study (LETS)). Thromb Haemost. 1994;71:719–722
  4. Carter AM, Catto AJ, Kohler HP, Ariens RA, Stickland MH, Grant PJ. Alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism. Blood. 2000;96:1177–1179
  5. Ko YL, Hsu LA, Hsu TS, Tsai CT, Teng MS, Wu S, et al. Functional polymorphisms of FGA, encoding alpha fibrinogen, are associated with susceptibility to venous thromboembolism in a Taiwanese population. Hum Genet. 2006;119:84–91
  6. Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ, Rosendaal FR, Vos HL, Bertina RM. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma’ levels. Blood. 2005;106:4176–4183
  7. 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;88:3698–3703
  8. Ceelie H, Spaargaren-van Riel CC, Lyon E, Bertina RM, Vos HL. Functional analysis of two polymorphisms in the 3′-UTR of the human prothrombin gene. J Thromb Haemost. 2005;3:806–808
  9. Ceelie H, Bertina RM, van Hylckama Vlieg A, Rosendaal FR, Vos HL. Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels. Thromb Haemost. 2001;85:1066–1070
  10. Martinelli I, Battaglioli T, Tosetto A, Legnani C, Sottile L, Ghiotto R, et al. Prothrombin 19911 A>G polymorphism and the risk of venous thromboembolism. J Thromb Haemost. 2006;4:2582–2586
  11. Chinthammitr Y, Vos HL, Rosendaal FR, Doggen CJM. The association of prothrombin A19911G polymorphism with plasma prothrombin activity and venous thrombosis: Results of the MEGA study, a large population-based case-control study. J Thromb Haemost. 2006;4:2587–2592
  12. Perez-Ceballos E, Corral J, Alberca I, Vaya A, Llamas P, Montes R, et al. Prothrombin A19911G and G20210A polymorphisms’ role in thrombosis. Br J Haematol. 2002;118:610–614
  13. Vos HL. Inherited defects of coagulation Factor V: The thrombotic side. J Thromb Haemost. 2006;4:35–40
  14. Lunghi B, Iacoviello L, Gemmati D, Dilasio MG, Castoldi E, Pinotti M, et al. Detection of new polymorphic markers in the factor V gene: Association with factor V levels in plasma. Thromb Haemost. 1996;75:45–48
  15. Castaman G, Faioni EM, Tosetto A, Bernardi F. The factor V HR2 haplotype and the risk of venous thrombosis: A meta-analysis. Haematologica. 2003;88:1182–1189
  16. Kamphuisen PW, Eikenboom JC, Rosendaal FR, Koster T, Blann AD, Vos HL, et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol. 2001;115:156–158
  17. Mansvelt EP, Laffan M, McVey JH, Tuddenham EG. Analysis of the F8 gene in individuals with high plasma factor VIII:C levels and associated venous thrombosis. Thromb Haemost. 1998;80:561–565
  18. Roelse JC, Koopman MM, Buller HR, ten Cate JW, Montaruli B, van Mourik JA, et al. Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis. Br J Haematol. 1996;92:740–743
  19. Machiah DK, Viel K, Almasy L, Soria JM, Porter S, Souto JC, et al. A common SNP in the factor VIII (f-VIII) gene encodes a conservative aspartate to glutamate substitution (Asp1241Glu) in the B-domain that influences f-VIII activity levels. Blood. 2003;102:181;(abstr)
  20. Scanavini D, Legnani C, Lunghi B, Mingozzi F, Palareti G, Bernardi F. The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels. Thromb Haemost. 2005;93:453–456
  21. Nossent AY, Eikenboom JC, Vos HL, Bakker E, Tanis BC, Doggen CJM, et al. Haplotypes encoding the factor VIII 1241 Glu variation, factor VIII levels and the risk of venous thrombosis. Thromb Haemost. 2006;95:942–948
  22. Kanaji T, Okamura T, Osaki K, Kuroiwa M, Shimoda K, Hamasaki N, et al. A common genetic polymorphism (46 C to T substitution) in the 5′-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood. 1998;91:2010–2014
  23. Tirado I, Soria JM, Mateo J, Oliver A, Souto JC, Santamaria A, et al. Association after linkage analysis indicates that homozygosity for the 46C→T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis. Thromb Haemost. 2004;91:899–904
  24. Grunbacher G, Marx-Neuhold E, Pilger E, Koppel H, Renner W. The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis. J Thromb Haemost. 2005;3:2815–2817
  25. Bertina RM, Poort SR, Vos HL, Rosendaal FR. The 46C→T polymorphism in the factor XII gene (F12) and the risk of venous thrombosis. J Thromb Haemost. 2005;3:597–599
  26. Franco RF, Reitsma PH, Lourenco D, Maffei FH, Morelli V, Tavella MH, et al. Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost. 1999;81:676–679
  27. Ariens RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood. 2000;96:988–995
  28. Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood. 1999;93:906–908
  29. Wells PS, Anderson JL, Scarvelis DK, Doucette SP, Gagnon F. Factor XIII Val34Leu variant is protective against venous thromboembolism: A HuGE review and meta-analysis. Am J Epidemiol. 2006;164:101–109
  30. Vossen CY, Rosendaal FR. The protective effect of the factor XIII Val34Leu mutation on the risk of deep venous thrombosis is dependent on the fibrinogen level. J Thromb Haemost. 2005;3:1102–1103
  31. Komanasin N, Catto AJ, Futers TS, van Hylckama Vlieg A, Rosendaal FR, Ariens RA. A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis. J Thromb Haemost. 2005;3:2487–2496
  32. Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C, et al. Polymorphisms in the 5′ regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: The ECTIM and PATHROS studies. Etude Cas-Temoins de l’Infarctus du Myocarde. Paris thrombosis case-control study. Arterioscler Thromb Vasc Biol. 2000;20:892–898
  33. Zawadzki C, Preudhomme C, Gaveriaux V, Amouyel P, Jude B. The Arg200Trp mutation in the human tissue factor gene. Thromb Haemost. 2002;87:540–541
  34. Roemisch J, Feussner A, Nerlich C, Stoehr HA, Weimer T. The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP). Blood Coagul Fibrinolysis. 2002;13:433–441
  35. Hoppe B, Tolou F, Radtke H, Kiesewetter H, Dorner T, Salama A. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood. 2005;105:1549–1551
  36. Franchi F, Martinelli I, Biguzzi E, Bucciarelli P, Mannucci PM. Marburg I polymorphism of factor VII-activating protease and risk of venous thromboembolism. Blood. 2006;107:1731
  37. Van Minkelen R, de Visser MC, Vos HL, Bertina RM, Rosendaal FR. The Marburg I polymorphism of factor VII-activating protease is not associated with venous thrombosis. Blood. 2005;105:4898
  38. Jick H, Slone D, Westerholm B, Inman WH, Vessey MP, Shapiro S, et al. Venous thromboembolic disease and ABO blood type (A cooperative study). Lancet. 1969;1:539–542
  39. Morelli VM, de Visser MC, Vos HL, Bertina RM, Rosendaal FR. ABO blood group genotypes and the risk of venous thrombosis: Effect of factor V Leiden. J Thromb Haemost. 2005;3:183–185
  40. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345:152–155
  41. Mercier B, Oger E, Le Gal G, Mottier D, Ferec C. Phenotypic but not allelic ABO blood group association with risk of venous thrombosis. Thromb Haemost. 2005;93:388–389
  42. Schleef M, Strobel E, Dick A, Frank J, Schramm W, Spannagl M. Relationship between ABO and Secretor genotype with plasma levels of factor VIII and von Willebrand factor in thrombosis patients and control individuals. Br J Haematol. 2005;128:100–107
  43. Tirado I, Mateo J, Soria JM, Oliver A, Martinez-Sanchez E, Vallve C, et al. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost. 2005;93:468–474
  44. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–1346
  45. Dilley A, Austin H, Hooper WC, Lally C, Ribeiro MJ, Wenger NK, et al. Relation of three genetic traits to venous thrombosis in an African-American population. Am J Epidemiol. 1998;147:30–35
  46. Philipp CS, Dilley A, Saidi P, Evatt B, Austin H, Zawadsky J, et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost. 1998;80:869–873
  47. Okumus G, Arseven O. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene: Really a risk factor for venous thromboembolism?. Thromb Haemost. 2003;90:766–767
  48. Ekim N, Oguzulgen IK, Demir N, Altinok B, Akar N. The role of angiotensin-converting enzyme gene polymorphism in pulmonary thromboembolism. Thromb Haemost. 2004;92:432–433
  49. Buddingh EP, van Hylckama Vlieg A, Rosendaal FR. The angiotensin-converting enzyme gene insertion/deletion polymorphism: Insufficient evidence for a role in deep venous thrombosis. J Thromb Haemost. 2005;3:403–404
  50. Amini-Nekoo A, Futers TS, Moia M, Mannucci PM, Grant PJ, Ariens RA. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol. 2001;113:537–543
  51. Miyata T, Sakata T, Kumeda K, Uchida K, Tsushima M, Fujimura H, et al. C-399T polymorphism in the promoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Haemost. 1998;80:345–346
  52. Kleesiek K, Schmidt M, Gotting C, Schwenz B, Lange S, Muller-Berghaus G, et al. The 536C→T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost. 1999;82:1–5
  53. Gonzalez-Conejero R, Lozano ML, Corral J, Martinez C, Vicente V. The TFPI 536C→T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost. 2000;83:787–788
  54. Hessner MJ, Luhm RA. The C536T transition in the tissue factor pathway inhibitor (TFPI) gene does not contribute to risk of venous thrombosis among carriers of factor V Leiden. Thromb Haemost. 2000;84:724–725
  55. Paciaroni K, Rossi E, Bazzan M, Ireland H, De Stefano V. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost. 2001;85:938–939
  56. Moatti D, Seknadji P, Galand C, Poirier O, Fumeron F, Desprez S, et al. Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects: Impact of the V264M substitution on plasma levels of TFPI. Arterioscler Thromb Vasc Biol. 1999;19:862–869
  57. Moatti D, Haidar B, Fumeron F, Gauci L, Boudvillain O, Seknadji P, et al. A new T-287C polymorphism in the 5′ regulatory region of the tissue factor pathway inhibitor gene (Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels). Thromb Haemost. 2000;84:244–249
  58. Arnaud E, Moatti D, Emmerich J, Aiach M, de Prost D. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost. 1999;82:159–160
  59. Ameziane N, Seguin C, Borgel D, Fumeron F, Moatti D, Alhenc-Gelas M, et al. The -33T→C polymorphism in intron 7 of the TFPI gene influences the risk of venous thromboembolism, independently of the factor V Leiden and prothrombin mutations. Thromb Haemost. 2002;88:195–199
  60. Uitte de Willige S, van Marion V, Rosendaal FR, Vos HL, de Visser MC, Bertina RM. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost. 2004;2:1305–1310
  61. Biguzzi E, Merati G, Liaw PC, Bucciarelli P, Oganesyan N, Qu D, et al. A 23bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. Thromb Haemost. 2001;86:945–948
  62. Biguzzi E, Gu JM, Merati G, Esmon NL, Esmon CT. Point mutations in the endothelial protein C receptor (EPCR) promoter. Thromb Haemost. 2002;87:1085–1086
  63. Grossmann R, Schwender S, Geisen U, Schambeck C, Merati G, Walter U. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res. 2002;107:13–15
  64. Poort SR, Vos HL, Rosendaal FR, Bertina RM. The endothelial protein C receptor (EPCR) 23 bp insert mutation and the risk of venous thrombosis. Thromb Haemost. 2002;88:160–162
  65. von Depka M, Czwalinna A, Eisert R, Wermes C, Scharrer I, Ganser A, et al. Prevalence of a 23bp insertion in exon 3 of the endothelial cell protein C receptor gene in venous thrombophilia. Thromb Haemost. 2001;86:1360–1362
  66. España F. A new polymorphism in the 3′UTR region of the endothelial protein C receptor associated with increased levels of circulating activated protein c and decreased risk of venous thrombosis. Thromb Haemost. 2001;1:885;(suppl 1, abstr)
  67. Galligan L, Powell C, Livingstone W, Mynett-Johnston L, Smith OP. The G7763C endothelial protein C receptor (EPCR) gene mutation: Prevalence and association with DVT in the Irish population. Thromb Haemost. 2002;88:163–165
  68. Medina P, Navarro S, Estelles A, Vaya A, Bertina RM, España F. Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of factor V Leiden. Thromb Haemost. 2005;94:389–394
  69. Medina P, Navarro S, Estelles A, Vaya A, Woodhams B, Mira Y, et al. Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, thrombotic risk. Thromb Haemost. 2004;91:905–911
  70. Saposnik B, Reny JL, Gaussem P, Emmerich J, Aiach M, Gandrille S. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood. 2004;103:1311–1318
  71. Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med. 2002;126:1401–1404
  72. Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb. 1991;11:183–190
  73. Segui R, Estelles A, Mira Y, España F, Villa P, Falco C, et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol. 2000;111:122–128
  74. Barcellona D, Fenu L, Cauli C, Pisu G, Marongiu F. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost. 2003;90:1061–1064
  75. Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb Haemost. 1998;80:949–955
  76. Martini CH, Brandts A, de Bruijne EL, van Hylckama Vlieg A, Leebeek FW, Lisman T, et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol. 2006;134:92–94
  77. Henry M, Aubert H, Morange PE, Nanni I, Alessi MC, Tiret L, et al. Identification of polymorphisms in the promoter and the 3′ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood. 2001;97:2053–2058
  78. den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: A meta-analysis of published epidemiological studies. J Thromb Haemost. 2005;3:292–299
  79. Bezemer ID, Doggen CJM, Vos HL, Rosendaal FR. No association between the common MTHFR 677C→T polymorphism and venous thrombosis: Results from the MEGA study. Arch Intern Med. 2007;167:497–501
  80. Water N, Tan T, Ashton F, O’grady A, Day T, Browett P, et al. Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: A new form of thrombophilia. Br J Haematol. 2004;127:190–194
  81. Al Shanqeeti A, van Hylckama Vlieg A, Berntorp E, Rosendaal FR, Broze GJ. Protein Z and protein Z-dependent protease inhibitor (Determinants of levels and risk of venous thrombosis). Thromb Haemost. 2005;93:411–413
  82. Gonzalez-Conejero R, Perez-Ceballos E, Vicente V, Corral J. Protein Z-dependent protease inhibitor W303X mutation in venous thrombosis. Br J Haematol. 2005;129:561–562
  83. Razzari C, Martinelli I, Bucciarelli P, Viscardi Y, Biguzzi E. Polymorphisms of the protein Z-dependent protease inhibitor (ZPI) gene and the risk of venous thromboembolism. Thromb Haemost. 2006;95:909–910
  84. Corral J, Gonzalez-Conejero R, Soria JM, Gonzalez-Porras JR, Perez-Ceballos E, Lecumberri R, et al. A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis. Blood. 2006;108:177–183
  85. Tarumi T, Kravtsov DV, Moore JH, Williams SM, Gailani D. Common single nucleotide polymorphisms in the promoter region of the human factor XI gene. J Thromb Haemost. 2003;1:1854–1856
  86. De Visser MC, Poort SR, Vos HL, Rosendaal FR, Bertina RM. Factor X levels, polymorphisms in the promoter region of factor X, the risk of venous thrombosis. Thromb Haemost. 2001;85:1011–1017
  87. Le Flem L, Picard V, Emmerich J, Gandrille S, Fiessinger JN, Aiach M, et al. Mutations in promoter region of thrombomodulin and venous thromboembolic disease. Arterioscler Thromb Vasc Biol. 1999;19:1098–1104
  88. Le Flem L, Mennen L, Aubry ML, Aiach M, Scarabin PY, Emmerich J, et al. Thrombomodulin promoter mutations, venous thrombosis, and varicose veins. Arterioscler Thromb Vasc Biol. 2001;21:445–451
  89. Thude H, Wilkens A, Anders O, Barz D. Analysis of the thrombomodulin gene in patients with venous thrombosis. Thromb Res. 2002;107:109–114
  90. Heit JA, Petterson TM, Owen WG, Burke JP, de Andrade M, Melton LJ. Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: A population-based case-control study. J Thromb Haemost. 2005;3:710–717

PII: S0037-1963(07)00008-X

doi: 10.1053/j.seminhematol.2007.01.007

Seminars in Hematology
Volume 44, Issue 2 , Pages 85-92 , April 2007