Current Atherosclerosis Reports

, Volume 3, Issue 3, pp 209–215 | Cite as

The genetics of venous and arterial thromboembolism

  • David Lillicrap


There is substantial evidence to indicate that the pathologic processes of venous and arterial thromboembolism involve both genetic and environmental influences. Scientific progress over the past decade has revealed a growing number of genetic factors, such as factor V Leiden and the prothrombin gene variant, that are present in more than 1% of the population and increase the relative risk of venous thrombosis between two- and sevenfold. Furthermore, several of these factors have been demonstrated to interact adversely with environmental influences, such as oral contraceptives and smoking. Although these traits are present at relatively high prevalence in the population, the magnitude of the increased thrombotic risk associated with these factors is substantially less than that related to inherited deficiency of the natural anticoagulant protein antithrombin, and somewhat less than the elevated risk with protein C and protein S deficiencies. In contrast to the progress that has been made in understanding the genetic contributions to venous thromboembolism, much still remains to be learned about the genetic basis of arterial thrombosis. Despite the documentation of associations between several genetic polymorphisms with plasma procoagulant levels, consistent associations with arterial thrombotic disease have not been found.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Blumenfeld Z, Brenner B: Thrombophilia-associated pregnancy wastage. Fertil Steril 1999, 72:765–774.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosendaal FR: Venous thrombosis: a multicausal disease. Lancet 1999, 353:1167–1173.PubMedCrossRefGoogle Scholar
  3. 3.
    Laffan M, Tuddenham E: Thrombophilia: an expanding group of genetic defects that predispose to thrombosis. Mol Med Today 1997, 3:303–309.PubMedCrossRefGoogle Scholar
  4. 4.
    Dahlback 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 U S A 1993, 90:1004–1008.PubMedCrossRefGoogle Scholar
  5. 5.
    Bertina RM, Koeleman BP, Koster T, et al.: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994, 369:64–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Kalafatis M, Rand MD, Mann KG: The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994, 269:31869–31880.PubMedGoogle Scholar
  7. 7.
    Williamson D, Brown K, Luddington R, et al.: Factor V Cambridge: a new mutation (Arg 306 to Thr) associated with resistance to activated protein C. Blood 1998, 91:1140–1144.PubMedGoogle Scholar
  8. 8.
    Hiyoshi M, Hashimoto S, Tagawa S, et al.: A Thai patient with the mutation of Arg306 of FV gene identical to the Hong Kong but not to the Cambridge type. Thromb Haemost 1999, 82:1553–1554.PubMedGoogle Scholar
  9. 9.
    Rees DC, Cox M, Clegg JB: World distribution of factor V Leiden. Lancet 1995, 346:1133–1134.PubMedCrossRefGoogle Scholar
  10. 10.
    Rosendaal FR, Koster T, Vandenbroucke JP, et al.: High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995, 85:1504–1508.PubMedGoogle Scholar
  11. 11.
    Rosendaal FR, Siscovick DS, Schwartz SM, et al.: Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997, 89:2817–2821.PubMedGoogle Scholar
  12. 12.
    Vandenbroucke JP, Koster T, Briet E, et al.: Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994, 344:1453–1457.PubMedCrossRefGoogle Scholar
  13. 13.
    Bernardi F, Faioni EM, Castoldi E, et al.: A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997, 90:1552–1557.PubMedGoogle Scholar
  14. 14.
    Faioni EM, Franchi F, Bucciarelli P, et al.: Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden). Blood 1999, 94:3062–3066.PubMedGoogle Scholar
  15. 15.
    Middeldorp S, Buller HR: How to decide on the optimal duration of anticoagulant therapy in carriers of the factor V Leiden mutation. Thromb Haemost 2000, 84:740–741.PubMedGoogle Scholar
  16. 16.
    Simioni P, Prandoni P, Lensing AW, et al.: The risk of recurrent venous thromboembolism in patients with an Arg506→Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997, 336:399–403.PubMedCrossRefGoogle Scholar
  17. 17.
    De Stefano V, Martinelli I, Mannucci PM, et al.: The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999, 341:801–806.PubMedCrossRefGoogle Scholar
  18. 18.
    Marchetti M, Pistorio A, Barosi G: Extended anticoagulation for prevention of recurrent venous thromboembolism in carriers of factor V Leiden—cost-effectiveness analysis. Thromb Haemost 2000, 84:752–757.PubMedGoogle Scholar
  19. 19.
    Poort SR, Rosendaal FR, Reitsma PH, et al.: 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.PubMedGoogle Scholar
  20. 20.
    Franco RF, Trip MD, Ten Cate H, et al.: The 20210 G→A mutation in the 3′-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol 1999, 104:50–54.PubMedCrossRefGoogle Scholar
  21. 21.
    Rees DC, Chapman NH, Webster MT, et al.: Born to clot: the European burden. Br J Haematol 1999, 105:564–566.PubMedCrossRefGoogle Scholar
  22. 22.
    Martinelli I, Bucciarelli P, Margaglione M, et al.: The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol 2000, 111:1223–1229.PubMedCrossRefGoogle Scholar
  23. 23.
    Koster T, Blann AD, Briet E, et al.: Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995, 345:152–155.PubMedCrossRefGoogle Scholar
  24. 24.
    Kamphuisen PW, Eikenboom JC, Vos HL, et al.: Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemostas 1999, 81:680–683.Google Scholar
  25. 25.
    Kamphuisen PW, Houwing-Duistermaat JJ, van H, et al.: Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemostas 1998, 79:323–327.Google Scholar
  26. 26.
    Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ, et al.: Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000, 109:519–522.PubMedCrossRefGoogle Scholar
  27. 27.
    Gill JC, Endres-Brooks J, Bauer PJ, et al.: The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987, 69:1691.PubMedGoogle Scholar
  28. 28.
    Rozen R: Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemostas 1997, 78:523–526.Google Scholar
  29. 29.
    Rosenberg RD, Baur KA: Thrombosis in inherited deficiencies of antithrombin, protein C, and protein S. Hum Pathol 1987, 18:253–262.PubMedCrossRefGoogle Scholar
  30. 30.
    Manson HE, Austin RC, Fernandez-Rachubinski F, et al.: The molecular pathology of inherited human antithrombin III deficiency. Transfusion Med Rev 1989, 3:264–281.Google Scholar
  31. 31.
    Lane DA, Olds RJ, Thein SL: Antithrombin III: summary of first database update. Nucleic Acids Res 1994, 22:3556–3559.PubMedGoogle Scholar
  32. 32.
    Griffin JH, Evatt B, Zimmerman TS, et al.: Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981, 68:1370–1373.PubMedGoogle Scholar
  33. 33.
    Marlar RA, Montgomery RR, Broekmans AW: Report on the diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the ICTH-Subcommittee on Protein C and Protein S. Thromb Haemost 1989, 61:529–531.PubMedGoogle Scholar
  34. 34.
    Reitsma PH: Protein C deficiency: summary of the 1995 database update. Nucleic Acids Res 1996, 24:157–159.PubMedCrossRefGoogle Scholar
  35. 35.
    Spek CA, Lannoy VJ, Lemaigre FP, et al.: Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein C gene promoter. J Biol Chem 1998, 273:10168–10173.PubMedCrossRefGoogle Scholar
  36. 36.
    Spek CA, Greengard JS, Griffin JH, et al.: Two mutations in the promoter region of the human protein C gene both cause type I protein C deficiency by disruption of two HNF-3 binding sites. J Biol Chem 1995, 270:24216–24221.PubMedCrossRefGoogle Scholar
  37. 37.
    Spek CA, Koster T, Rosendaal FR, et al.: Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1995, 15:214–218.PubMedGoogle Scholar
  38. 38.
    Comp PC, Nixon RR, Cooper MR, et al.: Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984, 74:2082–2088.PubMedGoogle Scholar
  39. 39.
    Mahasandana C, Suvatte V, Chuansumrit A, et al.: Homozygous protein S deficiency in an infant with purpura fulminans. J Pediatr 1990, 117:750–753.PubMedCrossRefGoogle Scholar
  40. 40.
    Makris M, Leach M, Beauchamp NJ, et al.: Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000, 95:1935–1941.PubMedGoogle Scholar
  41. 41.
    Ploos van Amstel HK, Reitsma PH, Bertina RM: The human protein S locus: identification of the PS alpha gene as a site of liver protein S messenger RNA synthesis. Biochem Biophys Res Commun 1988, 157:1033–1038.PubMedCrossRefGoogle Scholar
  42. 42.
    Catto AJ, Kohler HP, Coore J, et al.: Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999, 93:906–908.PubMedGoogle Scholar
  43. 43.
    Franco RF, Reitsma PH, Lourenco D, et al.: Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost 1999, 81:676–679.PubMedGoogle Scholar
  44. 44.
    von Depka M, Nowak-Gottl U, Eisert R, et al.: Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000, 96:3364–3368.Google Scholar
  45. 45.
    Humphries SE, Cook M, Dubowitz M, et al.: Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987, 1:1452–1455.PubMedCrossRefGoogle Scholar
  46. 46.
    Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, et al.: A common mutation (G-455→ A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest 1997, 99:3034–3039.PubMedCrossRefGoogle Scholar
  47. 47.
    Gardemann A, Schwartz O, Haberbosch W, et al.: Positive association of the beta fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction. Thromb Haemost 1997, 77:1120–1126.PubMedGoogle Scholar
  48. 48.
    Green F, Kelleher C, Wilkes H, et al.: A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb 1991, 11:540–546.PubMedGoogle Scholar
  49. 49.
    Ye S, Green FR, Scarabin PY, et al.: The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude Cas Temoins de I’nfarctus du Mycocarde. Thromb Haemostas 1995, 74:837–841.Google Scholar
  50. 50.
    Lacquemant C, Gaucher C, Delorme C, et al.: Association between high von Willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group. Kidney Int 2000, 57:1437–1443.PubMedCrossRefGoogle Scholar
  51. 51.
    Keightley AM, Lam YM, Brady JN, et al.: Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: Identification of three novel single nucleotide polymorphisms in the vWF gene promoter. Blood, 93:4277–4283.Google Scholar
  52. 52.
    Weiss EJ, Bray PF, Tayback M, et al.: A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996, 334:1090–1094.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • David Lillicrap
    • 1
  1. 1.Departments of Pathology and MedicineQueen’s UniversityKingstonCanada

Personalised recommendations