, Volume 186, Issue 1, pp 27–36 | Cite as

Impact of Thrombophilic Genetic Factors on Pulmonary Embolism: Early Onset and Recurrent Incidences

  • Petar Ivanov
  • Regina Komsa-Penkova
  • Katia Kovacheva
  • Yavor Ivanov
  • Angelina Stoyanova
  • Ivan Ivanov
  • Plamen Pavlov
  • Pavlina Glogovska
  • Venzislav Nojarov


The importance of genetic thrombophilic factors in the development of venous thromboembolism has been increasingly recognized. Factor V Leiden (FVL), prothrombin gene mutation G20210A (FII G20210), genetic variant C677T of the methylentetrahydrofolate reductase (MTHFR), as well as the polymorphism A2 (PlA2) in platelet glycoprotein IIb/IIIa were recently discussed. We analyzed the contribution of genetic thrombophilic factors to the pathogenesis of pulmonary embolism (PE) and their association with the early onset and recurrence of PE using DNA analysis methods. In this case control trial we found thrombophilic genetic variants in 58.8% of 51 patients with PE. FVL was found in 23.5% of the patients versus 7.1% of the 98 controls (p = 0.01), PlA2 IIb/IIIa was found in 35.3% vs. 14.3% (p = 0.03), and FII G20210A was found in 5.9% vs. 2.0% (NS). Patients with recurrent PE had a very high prevalence of genetic factors, 70.4%. High prevalence of FVL was found in patients under 45 years of age: 39.3% (OR = 14.23, 95% CI = 1.58–330.03, p = 0.01) as well as in patients with recurrent incidence (37%, OR = 7.647, 95% CI = 2.27–26.44, p = 0.001). FVL was also significantly higher in the subgroup of patients with PE combined with deep venous thrombosis (OR = 6.500, 95% CI = 1.81–23.76, p = 0.002) in comparison with patients with isolated PE (OR = 2.261, 95% CI = 0.50–9.69). The carriers of FVL are at higher risk for early and recurrent PE events. High prevalence of PlA2 in PE patients evidently shows the impact of this polymorphism in PE development. A different treatment should be considered in carriers of thrombophilic defects.


Inherited thrombophilic genetic factors Pulmonary embolism Risk of early and recurrent onset 



This work was supported by a grant for scientific research from the University of Medicine-Pleven, Bulgaria.


  1. 1.
    Goldhaber SZ (1994) Epidemiology of pulmonary embolism and deep vein thrombosis. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD (eds) Hemostasis and Thrombosis, 3rd ed. Edinburgh, UK: Churchill Livingstone, pp 1327–1333Google Scholar
  2. 2.
    Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE (1991) A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med 151:933–938PubMedCrossRefGoogle Scholar
  3. 3.
    British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group (2003) British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 58:470–484CrossRefGoogle Scholar
  4. 4.
    Craig W, De Staercke C (2002) The relationship between FV Leiden and pulmonary embolism. Respir Res 3:8CrossRefGoogle Scholar
  5. 5.
    Turkstra F, Karemaker R, Kuijer PM, Prins MH, Buller HR (1999) Is the presence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different? Thromb Haemost 81:345–348 PubMedGoogle Scholar
  6. 6.
    Margaglione M, Brancaccio V, Delucia D, Martinelli I, Ciampa A, Grandone E, Di Mino G (2000) Inherited thrombophilic risk factors and venous thromboembolism. Chest 118(5):1405–1411PubMedCrossRefGoogle Scholar
  7. 7.
    De Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G (1999) The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 341:801–806PubMedCrossRefGoogle Scholar
  8. 8.
    Friedline J, Ahmad E, Garcia D, Blue D, Ceniza N, Mattson JC, Crisan D (2001) Combined factor V Leiden and prothrombin genotyping in patients presenting with thromboembolic episodes. Arch Pathol Lab Med 125:105–111PubMedGoogle Scholar
  9. 9.
    Nizankowska-Mogilnicka E, Adamek L, Grzanka P, Domagala TB, Sanak M, Krzanowski M, Szczeklik A (2003) Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. Eur Respir J 21:25–30PubMedCrossRefGoogle Scholar
  10. 10.
    Simioni P, Prandoni P, Lensing AWA, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A (1997) 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 336:399–403PubMedCrossRefGoogle Scholar
  11. 11.
    Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996) A common genetic variation in the three untranslated regions of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88:3698PubMedGoogle Scholar
  12. 12.
    Margaglione M, D’Andrea G, Colaizzo D, Cappucci G, del Popolo A, Brancaccio V, Ciampa A, Grandone E, Di Minno G (1999) Coexistence of factor V Leiden and factor II A20210 mutations and recurrent thromboembolism. Thromb Haemost 82:1583–1587PubMedGoogle Scholar
  13. 13.
    Fermo I, D’Angelo SV, Paroni R, Mazzola G, Calori G, D’Angelo A (1995) Prevalence of moderate hyperhomocysteinemia in patients with early onset venous and arterial occlusive disease. Ann Intern Med 123:747–753PubMedGoogle Scholar
  14. 14.
    Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR (2007) No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 167(5):497–501PubMedCrossRefGoogle Scholar
  15. 15.
    Feng D, Lindpaintner K, Larson MG, Rao VS, O’Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Silbershatz H, D’Agostino RB, Muller JE, Myers RH, Levy D, Tofler GH (1999) Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 19(4):1142–1147PubMedGoogle Scholar
  16. 16.
    Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K (1997) PlA1/A2 polymorphism of platelet glycoprotein IIIa and risk of myocardial infarction, stroke and venous thrombosis. Lancet 349:385–358PubMedCrossRefGoogle Scholar
  17. 17.
    Renner W, Winkler M, Hoffmann C, Koppel H, Seinost G, Brodmann M, Pilger E (2001) The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with deep venous thrombosis. Int Angiol 20(2):148–151PubMedGoogle Scholar
  18. 18.
    Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (eds) (1989) Current Protocols in Molecular Biology vol 2. One Source 4 Media, Clemmons, NC, pp 11.5.1Google Scholar
  19. 19.
    Mullis KB, Faloona FA (1987) Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Meth Enzymol 155:335–350PubMedCrossRefGoogle Scholar
  20. 20.
    Blanck A, Glück B, Wartbichler R, Bender S, Pöll M, Brandl A (1995) Activity of restriction enzymes in a PCR mix. Biochemica, vol 2. Boehringer Mannheim GmbH, p 14Google Scholar
  21. 21.
    Moller J, Ahola L, Abrahamsson L (2002) Evaluation of the DPC IMMULITE 2000 assay for total homocysteine in plasma. Scand J Clin Lab Invest 62:369–374PubMedCrossRefGoogle Scholar
  22. 22.
    Bland JM, Altman DG (2000) Statistics Notes. The odds ratio. BMJ 320:1468Google Scholar
  23. 23.
    Heit JA (2003) Risk factors for venous thromboembolism. Clin Chest Med 24:1–12PubMedCrossRefGoogle Scholar
  24. 24.
    Perry SL, Ortel TL (2003) Clinical and laboratory evaluation of thrombophilia. Clin Chest Med 24:153–170 PubMedCrossRefGoogle Scholar
  25. 25.
    Ogzulgen IK, NN Eim N Akar K Demirel M Kitapci (2002) The role of thrombophilic risk factors in the severity of pulmonary embolism. Eur Respir J 19:705–711Google Scholar
  26. 26.
    Van der Meer FJM, Koster T, Vandenbroucke JP, Briet E, Rosendaal FR (1997) The Leiden Thrombophilia Study (LETS). Thromb Haemost 78:631–635PubMedGoogle Scholar
  27. 27.
    Boyanovski B, Russeva M, Ganev V, Penev M, Baleva M (2001) Prevalence of factor V Leiden and prothrombin 20210 A variant in Bulgarian patients with pulmonary thromboembolism and deep venous thrombosis. Blood Coagul Fibrinolysis 12(8):639–642CrossRefGoogle Scholar
  28. 28.
    Isotalo PA, Donnely JG (2000) Prevalence of methylenetetrahydrofolatereductase mutations in patients with venous thrombosis. Mol Diagn 5:59–66 PubMedGoogle Scholar
  29. 29.
    Perrier A (2000) Deep vein thrombosis and pulmonary embolism. Chest 118(5):1234–1236PubMedCrossRefGoogle Scholar
  30. 30.
    Bounameaux H (2000) Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 356:182–183PubMedCrossRefGoogle Scholar
  31. 31.
    De Moerloose P, Reber G, Perrier A, Perneger T, Bounameaux H (2000) Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 110:125–129PubMedCrossRefGoogle Scholar
  32. 32.
    Bauer K (2001) The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 135:367–373PubMedGoogle Scholar
  33. 33.
    Manten B, Westendorp RGJ, Koster T, Reistma PH, Rosendaal FR (1996) Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: A focus on the factor V Leiden mutation. Thromb Haemost 76:510–513PubMedGoogle Scholar
  34. 34.
    Ho KW, Hankey GJ, Quinlan DJ, Eikelboom JW (2006) Risk of recurrent venous thromboembolism in patients with common thrombophilia. Arch Intern Med 166:729–736PubMedCrossRefGoogle Scholar
  35. 35.
    Eichinger S, Pabinger I, Stümpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA (1997) The risk of recurrent venous thromboembolism in patients with and without factorV Leiden. Thromb Haemost 77:624–628PubMedGoogle Scholar
  36. 36.
    Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H (1999) The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost 81:684–689PubMedGoogle Scholar
  37. 37.
    Mansilha A, Arau F, Severo M, Sampaio S, Toledo T, Albuquerque R (2005) Genetic polymorphisms and risk of recurrent deep venous.thrombosis in young people: prospective cohort study. Eur J Vasc Endovasc Surg 30:545–549PubMedCrossRefGoogle Scholar
  38. 38.
    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 (1999) Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 19:511–518PubMedGoogle Scholar
  39. 39.
    Ehrenforth S, von Depka Prondsinski M, Aygoren-Pursun E, Nowak-Gottl U, Scharrer I, Ganser A (1999) Study of the prothrombin gene 20210 GA variant in FV: Q506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vasc Biol 19:276–280PubMedGoogle Scholar
  40. 40.
    Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM (1997) A common mutation in the methylenetetrahydrofolatereductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol 17:1662–1666PubMedGoogle Scholar
  41. 41.
    Bertina R, Koeleman B, Koster T (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67PubMedCrossRefGoogle Scholar
  42. 42.
    Ridker P, Glynn RJ, Miletich J,Goldhaber Z, Stampfer M, Hennekens C (1997) Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med 126:528–531PubMedGoogle Scholar
  43. 43.
    Stein P, Hull R, Kayali F, Ghali W, Alshab A, Olson R (2004) Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 164:2260–2265PubMedCrossRefGoogle Scholar
  44. 44.
    Folsom AR, Cushman M, Tsai MY, Aleksic N, Heckbert SR, Boland LL, Tsai AW, Yanez ND, Rosamond WD (2002) A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 99(8):2720–2725PubMedCrossRefGoogle Scholar
  45. 45.
    Goldhaber SZ, Visani L, De Rosa M (1999) Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 353:1386–1389PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Petar Ivanov
    • 1
  • Regina Komsa-Penkova
    • 1
  • Katia Kovacheva
    • 2
  • Yavor Ivanov
    • 3
  • Angelina Stoyanova
    • 1
  • Ivan Ivanov
    • 1
  • Plamen Pavlov
    • 3
  • Pavlina Glogovska
    • 3
  • Venzislav Nojarov
    • 3
  1. 1.Department of BiochemistryUniversity of MedicinePlevenBulgaria
  2. 2.Medical GeneticsUniversity of MedicinePlevenBulgaria
  3. 3.University Lung Diseases Hospital, University of MedicinePlevenBulgaria

Personalised recommendations