Predisposition to Thrombophilia and Hypofibrinolysis in Pulmonary Embolism: Analysis of Inherited Factors


Pulmonary embolism (PE) is a relatively common cardiovascular emergency, though its exact incidence is difficult to assess. Accurate diagnosis is critical because of the high 30-day mortality in patients in whom the diagnosis is missed on admission. Doubt for PE is often raised by the presence of risk factors for venous thromboembolism (VTE), which are categorized into inherited and acquired. Among these, the importance of inherited/genetic thrombophilic factors is increasingly recognized. The most frequent markers of inherited thrombophilia are Factor V Leiden (FVL) and G2021OA prothrombin gene mutation. Among the inherited factors causal to thrombophilia, the C677T variant in methylentetrahydrofolate reductase (MTHFR) gene as well as factors like P1A1/P1A2 polymorphism in platelet glycoprotein Ilb/IIIa (P1A2) and hypofibrinolytic polymorphism 4G/4G in PAI-1 gene are discussed with controversial results. In our study, thrombophilic and hypofibrinolytic genetic variants were identified in 54.2% of 115 patients with PE. The most common significant genetic defects were FVL- 16.5% in patients versus 6.2% in controls (OR=3.102; p=0.05), G20210A PT 5.7% versus 2.1% (OR=2.983; p>0.05). P1A2 was found in 27.3% patients versus 19.9% in controls (OR= 1.523, p>0.05) and PAM 27.8% versus 22.6% (OR =1.501 p>0.05). MTHFR C677T carriage was inverse: 6.7% in patients versus 13.4% in controls. (OR=0.461 p=0.05). Of all the patients studied, 15.65% had a history of recurrent embolic incidents. The risk of recurrence was higher for the carriers of FVL and G20210A prothrombin gene mutation. The association between carriage of thrombophilic genetic factor and the early onset of the first embolic episode was found in the patients with PE. The awareness of risk factors and risk stratification is a critical issue in treatment and prevention policy. Preventive measures should be taken in particular medical conditions.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Torbicki A, Perrier A, Konstantin ides S, Agnelli G, Galie N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism.The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Eu Heart J. 2008;29:2276-315.

  • 2. Goldhaber SZ. Venous thromboembolism: epidemiology and magnitude of the problem. Best Pract Res Clin Haematol. 2012;25(3):235-42.

  • 3. Anderson FA Jr, Wheeler HB, Goldbeig RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. 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. 1991; 151:933-8.

  • 4. Goldhaber SZ, Hennekens CH, Evans DA, Newton EC, Godleski JJ. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med. 1982;73(6):822-6.

  • 5. Rodger M, Wells PS. Diagnosis of pulmonary embolism. Thromb Res. 2001; 103(6): V225 -3 8.

  • 6. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registiy (ICOPER). Lancet. 1999;353:1386-9.

  • 7. Dulicuek P, Maly J, Pesuavova L, Pecka M. Prevalence of inherited thrombophilia in young thrombosis patients from the East Bohemian region. Blood Coagul Fibrinolysis. 2002; 13(6):569-73.

  • 8. British Thoracic Society Standards of Care Committee. Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax. 2003;5 8:470-84.

  • 9. Rosendaal FR, KosterT, Vandenbrouck JP, Reitsma PH. High risk of thrombosis in patients homozygous for lactor V Leiden (activated protein C resistance). Blood. 1995;85:1504-8.

  • 10. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden andtherisk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004; 140:330-7.

  • 11. Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor VR506Q.JBiolChem. 1995;270:4053-7.

  • 12. De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica. 2002;87:1095-108.

  • 13. 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;8 8( 10):3698-703.

  • 14. Bezemer ID, Doggen CJ, 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(5) :497-501.

  • 15. Castro R, Rivera I, Blom H. J, Jakobs C, De Almeida I. T. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit MetabDis. 2006;29(l):3-20.

  • 16. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. JAMA. 2004 ;291:565-75.

  • 17. Fermo I, D'Angelo SV, 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;123:747-53.

  • 18. De Bree A, Verschuren WM, Bjorke-Monsen AL, Van der Put NM, Heil SG, Trijbels FJ, et al. Effect of the methylenetetrahydrofolate reductase 677C-->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. Am JClinNutr. 2003;77:687-93.

  • 19. Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. P1A1/A2 polymorphism of platelet glycoprotein Ilia and risk of myocardial infarction, stroke and venous thrombosis. Lancet. 1997;349:385-58.

  • 20. Renner W, Winkler M, Hoffinann C, Koppel H, Seinost G, Brodmann M, et al. The P1A1/A2 polymorphism of platelet glycoprotein Ilia is not associated with deep venous thrombosis. Int Angiol. 2001 ;20(2): 148-51.

  • 21. Francis C. Plasminogen activator inhibitor-1 levels and polymorphisms. Association with venous thromboembolism. Arch Pathol Lab Med. 2002; 126(11): 1401-4.

  • 22. Tsantes AE,Nikolopoulos GK, BagosPG,RaptiE, Mantzios G, Kapsimali V, et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost 2007;97(6):907-13.

  • 23. Komsa-Penkova R,Kovacheva- Kotseva K, Angelova S, SavovA, Scmionova M. Selected methods of DN A analysis and clinical applications. Pleven: MU-Pleven; 2004.

  • 24. Ivanov P, Komsa-Penkova R, Ivanov Y, Ivanov I, Matkov O, Beshev L [4G/5G polymorphism in the gene for plasminogen activator inhibitor-1 in patients it may be a deep vein thrombosis]. Modcma Medicina. 2009;60(l-2):35-9. [in Bulgarian].

  • 25. Kwok S, Higuchi R. Avoiding false-positives with PCR. Nature. 1989;339:237-8.

  • 26. Ivanov P, Komsa-Penkova R, Kovacheva K, Ivanov Y, Stoyanova A, Ivanov I, Pavlov P, Glogovska P, Nojarov V. Impact of genetic factors on pulmonary embolism - early onset and recurrent incidences. Lung. 2008;186(1)^7-36.

  • 27. Ridker PM, Miletich JP, Stampfcr MJ, Goldhabcr SZ, Lindpaintncr K, Hennekeas CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation. 1995;92:2800-2.

  • 28. Perry SL, Ortel TL. Clinical and laboratory evaluation of thrombophilia Clin Chest Med 2003;24:153-70.

  • 29. Nizankowska-Mogilnicka E, Adamek L, Grzanka P, Domagala T.B, Sanak M , Krzanowski M, Szczcklik A. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. EurRespir J. 2003 ;21(1 ):25-30.

  • 30. Ogzulgcn IK, Eim NN , Akar N, Dcmircl K, Ki-tapei M. The role of thrombophilic risk factors in the severity of pulmonary embolism. Eur Respir J. 2002; 19(4):705-11.

  • 31. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166(7):729-36.

  • 32. Roscndaal FR, Doggen CJ,ZivelinA, Arruda VR, Aiach M, Siscovick DS, ct al. Geographic distribution of the 20210 G to A prothrombin variant. Thro mb Haemost. 1998;79(4):706-70.

  • 33. De Stefano V, Martinclli I, Mannucci PM, Pacia-roni K, Rossi E, Chiusolo P, et al. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. Br J Haematol. 2001; 113(3 ):630-5.

  • 34. Kwak SH, Wang XQ, He Q, Fang WF, Mitra S, Bdcir K, et al. Plasminogen activator inhibitor-1 potentiates LPS-inducod neutrophil activation through a JNK-mediated pathway. Thromb Haemost. 2006;95(5):829-35.

  • 35. Pcdroja BS, Kang LE, Imas AO, Carmeliet P, Bernstein AM. Plasminogen activator inhibitor-1 regulates integrin alpha v bcta3 expression and autocrine transforming growth factor beta signaling. J Biol Chem. 2009 ^ 84(31):20708-17.

  • 36. Abboud N, Ghazouani L, Saidi S, Ben-Hadj-Kha-lifa S, Addad F, Almawi WY, ctal. Association of PAI-1 4G/5G and - 844G/Agcne poly-morphlsms and changes in PAI -1 /tissue plasminogen activator levels in myocardial infarction: a case-control study. Genet Test Mol Biomarkers. 2010;14( 1):23-7.

  • 37. Saidi S, Slamia LB, Mahjoub T, Ammou SB, Almawi WY. Association of PAI-1 4G/5G and -844G/A gene polymorphism and changes in PAI-1A PA levels in stroke: a case-control study. Stroke Ccrebrovasc Dis. 2007;16(4): 153-9.

  • 38. Tsantes AE, Nikolopoulos GK, Bagos PG, Bono-vas S, Koptcridcs P, Vaiopoulos G. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res. 2008;122(6):736-42.

  • 39. Eichingcr S, Pabingcr I, Stiimpflcn A, Hirschl M, Bialonczyk C, Schneider B, et al. The risk of recurrent venous thromboembolism in patients with and without factorV Leiden. Thromb Haemost. 1997;77:624-8.

  • 40. Lindmarkcr P, Schulman S, Sten-Linder M, Wiman B, Egbcrg N, Johnsson H., et al. 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. 1999;81:684-9.

  • 41. Simioni P, Prandoni P, Lensing AW, Scudcllcr A, Sardclla C, Prias MH, 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.

  • 42. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Research Committee of the British Thoracic Society. Lancet 1992;340:873-6.

  • 43. Prandoni P, Leasing AW, Cogo A, Cuppini S, Villalta S, Carta M,Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinicalcourse of acute deep venous thrombosis. AnnlntcrnMod. 1996;125:1-7.

  • 44. Geno J. Merli. Pathophysiology of venous thrombosis, thrombophilia, and the diagnosis of deep vein thrombosis-pulmonarycmbolism in the elderly. Clin Geriatr Med. 2006;22:75-92.


Journal + Issues