Yonsei Med J.  2012 May;53(3):571-577. 10.3349/ymj.2012.53.3.571.

Hereditary Thrombophilia in Korean Patients with Idiopathic Pulmonary Embolism

• Lee M
• No HJ
• Jang SY
• Kim N
• Choi SH
• Kim H
• Kim SH
• Kim HJ
• Kim DK

• KMID: 1776993
• DOI: http://doi.org/10.3349/ymj.2012.53.3.571

Abstract

PURPOSE
Hereditary thrombophilia (HT) is a major risk factor for idiopathic pulmonary embolism (iPE) and shows different prevalence among ethnic groups. The prevalence and clinical characteristics of HT in Korean patients with iPE were investigated.
MATERIALS AND METHODS
Patients with PE on computed tomography (CT) scan were recruited, and those with malignancy were excluded. Patients were divided into iPE and provoked PE (pPE) groups. The presence of HT in the iPE group was assessed by DNA sequencing of the corresponding gene in patients who had low levels of natural anticoagulants. The clinical characteristics of iPE with HT (iPE/HT+) were compared with those of iPE without HT (iPE/HT-) and pPE.
RESULTS
Out of 161 patients, 84 patients had iPE and 77 patients had pPE. Among 54 patients in the iPE group whose coagulation profiles were tested, 28 patients were diagnosed with HT (51.9%; 28/54). Compared with the iPE/HT- and pPE groups, the iPE/HT+ group showed the highest proportion of male patients (71.4%; p<0.001); the youngest mean age (44+/-14 years; p<0.001); and the highest frequencies for history of venous thromboembolism (64.3%; p<0.001), concurrent deep vein thrombosis (75.0%; p=0.021), and adverse clinical outcomes (42.9%, p<0.001). Protein C deficiency was the most common HT. On molecular genetic tests, causative mutation was identified in 13 patients.
CONCLUSION
In this study of Korean patients, about half of the patients with iPE had HT. Patients with iPE and HT were mostly young males with deep venous thrombosis (DVT), previous venous thromboembolism (VTE), and frequent adverse clinical outcomes. Therefore, Korean patients with iPE should be tested for HT.

Keyword

Pulmonary embolism; hereditary thrombophilia; protein C deficiency; Korea

MeSH Terms

Adolescent
Adult
Aged
Aged, 80 and over
Asian Continental Ancestry Group
Female
Humans
Korea
Male
Middle Aged
Mutation
Pulmonary Embolism/diagnosis/genetics/*radiography
Thrombophilia/diagnosis/genetics/*radiography
Young Adult

Figure

• 

  Fig. 1 Flow diagram of the study population showing the number of patients with each diagnosis. PE, pulmonary embolism; HT, hereditary thrombophilia; PC, protein C; PS, protein S; AT, antithrombin; PLG, plasminogen.

Reference

1. Libby Peter, Bonow Robert O., Mann Douglas L., Zipes Douglas P.. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 2008. 8th ed. Philadelphia, PA: Elsevier Inc.;1863.

2. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008. 358:1037–1052.

3. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004. 117:19–25.

4. Couturaud F, Leroyer C, Julian JA, Kahn SR, Ginsberg JS, Wells PS, et al. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest. 2009. 136:1537–1545.

5. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009. 101:93–99.

6. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997. 277:1305–1307.

7. Simkova M, Batorova A, Dostalova K, Pozgayova S, Simko F, Kovacs L. Factor V Leiden in patients with venous thrombosis in Slovak population. Gen Physiol Biophys. 2004. 23:435–442.

8. Miyata T, Sato Y, Ishikawa J, Okada H, Takeshita S, Sakata T, et al. Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. Thromb Res. 2009. 124:14–18.

9. Shen MC, Lin JS, Tsay W. Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan. Thromb Res. 2000. 99:447–452.

10. Angchaisuksiri P, Atichartakarn V, Aryurachai K, Archararit N, Rachakom B, Atamasirikul K, et al. Risk factors of venous thromboembolism in thai patients. Int J Hematol. 2007. 86:397–402.

11. Altinisik J, Ates O, Ulutin T, Cengiz M, Buyru N. Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients. Clin Appl Thromb Hemost. 2008. 14:415–420.

12. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009. 113:5314–5322.

13. Lim W. Antiphospholipid antibody syndrome. Hematology Am Soc Hematol Educ Program. 2009. 233–239.

14. Choung HS, Kim HJ, Gwak GY, Kim SH, Kim DK. Inherited protein S deficiency as a result of a large duplication mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification. J Thromb Haemost. 2008. 6:1430–1432.

15. Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis. 2001. 12:95–99.

16. Chen TY, Su WC, Tsao CJ. Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis. Ann Hematol. 2003. 82:114–117.

17. Caprini JA, Goldshteyn S, Glase CJ, Hathaway K. Thrombophilia testing in patients with venous thrombosis. Eur J Vasc Endovasc Surg. 2005. 30:550–555.

18. Swiatkiewicz A, Jurkowski P, Kotschy M, Ciecierski M, Jawień A. Level of antithrombin III, protein C, protein S and other selected parameters of coagulation and fibrinolysis in the blood of the patients with recurrent deep venous thrombosis. Med Sci Monit. 2002. 8:CR263–CR268.

19. White RH. The epidemiology of venous thromboembolism. Circulation. 2003. 107:23 Suppl 1. I4–I8.

20. Baglin T, Luddington R, Brown K, Baglin C. High risk of recurrent venous thromboembolism in men. J Thromb Haemost. 2004. 2:2152–2155.

21. Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med. 2004. 350:2558–2563.

22. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet. 2006. 368:371–378.

23. Margaglione M, Brancaccio V, De Lucia D, Martinelli I, Ciampa A, Grandone E, et al. Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism. Chest. 2000. 118:1405–1411.

24. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005. 293:2352–2361.

25. Kim HJ, Kim DK, Koh KC, Kim JY, Kim SH. Severe protein C deficiency from compound heterozygous mutations in the PROC gene in two Korean adult patients. Thromb Res. 2008. 123:412–417.

26. Pintao MC, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, de Visser MC, et al. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum Genet. 2009. 126:449–456.

27. Yoo JH, Kim HJ, Maeng HY, Kim YA, Sun YK, Song JW, et al. Hereditary protein S deficiency from a novel large deletion mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification (MLPA). Thromb Res. 2009. 123:793–795.

28. Song KS, Lee SM, Choi JR. Detection of an Ala601Thr mutation of plasminogen gene in 3 out of 36 Korean patients with deep vein thrombosis. J Korean Med Sci. 2003. 18:167–170.