Correlation of the prothrombin gene G20210A mutation and cerebral venous thrombosis risk: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

FENG Hongliang ,  LIU Yumin , WANG Meiyao , ZHANG Renwei , YU Qing , NADIRE Aiziretiaili , LI Yan

Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P.R.China;

Corresponding author：

LIU Yumin, Email: lym9381@126.com

Keywords：

Cerebral venous thrombosis; Prothrombin gene; G20210A; Gene mutation; Correlation; Meta-analysis

DOI：

10.7507/1672-2531.201602015

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the association between prothrombin gene G20210A mutation and the risk of cerebral venous thrombosis (CVT). Methods Databases including PubMed, Springer, Google Scholar, The Cochrane Library (Issue 1, 2016), CNKI, WanFang Data and CBM were searched for case-control studies concerning the association between prothrombin gene G20210A mutation and cerebral venous thrombosis risk from inception to January 2016. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software and Stata 12.0 software. Results A total of 26 case-control studies were included, involving 1 361 CVT cases and 6 323 controls. The results of meta-analysis showed that: there was a significant association between prothrombin gene G20210A mutation and CVT risk (OR=4.56, 95% CI 3.51 to 5.93,P<0.000 01). Sensitivity analysis showed no significant publication bias was detected confirmed the stability of results. Subgroup analysis showed that G20210A mutation increased CVT risk in adults (OR=5.02, 95% CI 3.81 to 6.60,P<0.000 01), but not in children (OR=1.99, 95% CI 0.83 to 4.79,P=0.12). Conclusion Prothrombin gene G20210A mutation can significantly increase the CVT risk. Due to the limited quality and quantity of included studies, the above results are needed to be validated by more high quality studies.

Citation： FENG Hongliang, LIU Yumin, WANG Meiyao, ZHANG Renwei, YU Qing, NADIRE Aiziretiaili, LI Yan. Correlation of the prothrombin gene G20210A mutation and cerebral venous thrombosis risk: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2017, 17(3): 276-282. doi: 10.7507/1672-2531.201602015 Copy

1.	Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med, 2005, 352(17): 1791-1798.
2.	Dentali F, Poli D, Scoditti U, et al. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study. J Thromb Haemost, 2012, 10(7): 1297-1302.
3.	Miranda B, Ferro JM, Canhao P, et al. Venous thromboembolic events after cerebral vein thrombosis. Stroke, 2010, 41(9): 1901-1906.
4.	Tufano A, Guida A, Coppola A, et al. Risk factors and recurrent thrombotic episodes in patients with cerebral venous thrombosis. Blood Transfus, 2014, 12(Suppl 1): s337-s342.
5.	Voetsch B, Jin RC, Bierl C, et al. Role of promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene as a risk factor for cerebral venous thrombosis. Stroke, 2008, 39(2): 303-307.
6.	Madonna P, De Stefano V, Coppola A, et al. G20210A PRTH gene mutation and other trombophilic polymorphisms in patients with cerebral vein thrombosis. Stroke, 2000, 31(7): 1787-1788.
7.	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(10): 3698-3703.
8.	常建华, 马越, 张广森. 中国壮族人群凝血酶原基因 G20210A 突变频率研究. 中华医学遗传学杂志, 2005, 12(03): 341-343.
9.	Bank I, Libourel EJ, Middeldorp S, et al. Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study. Arch Intern Med, 2004, 164(17): 1932-1937.
10.	Haywood S, Liesner R, Pindora S, et al. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child, 2005, 90(4): 402-405.
11.	Cosmi B, Legnani C, Pengo V, et al. The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs. Thromb Haemost, 2013, 109(3): 510-516.
12.	Margaglione M, Brancaccio V, De Lucia D, et al. Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism. Chest, 2000, 118(5): 1405-1411.
13.	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(11): 801-806.
14.	Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120 000 cases and 180 000 controls. Thromb Haemost, 2009, 102(2): 360-370.
15.	Jiang B, Ryan KA, Hamedani A, et al. Prothrombin G20210A mutation is associated with young-onset stroke: the genetics of early-onset stroke study and meta-analysis. Stroke, 2014, 45(4): 961-967.
16.	Altinisik J, Ates O, Ulutin T, et al. Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients. Clin Appl Thromb Hemost, 2008, 14(4): 415-420.
17.	Ben SO, Fekih-Mrissa N, N’Siri B, et al. Thrombophilic polymorphisms-factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T - in Tunisian patients with cerebral venous thrombosis. J Clin Neurosci, 2012, 19(9): 1326-1327.
18.	Bombeli T, Basic A, Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol, 2002, 70(2): 126-132.
19.	Boncoraglio G, Carriero MR, Chiapparini L, et al. Hyperhomocysteinemia and other thrombophilic risk factors in 26 patients with cerebral venous thrombosis. Eur J Neurol, 2004, 11(6): 405-409.
20.	Bonduel M, Sciuccati G, Hepner M, et al. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. Acta Haematol, 2006, 115(3-4): 180-185.
21.	Colaizzo D, Amitrano L, Iannaccone L, et al. Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings. J Med Genet, 2007, 44(6): 412-416.
22.	Heller C, Heinecke A, Junker R, et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation, 2003, 108(11): 1362-1367.
23.	Kenet G, Waldman D, Lubetsky A, et al. Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study. Thromb Haemost, 2004, 92(4): 713-718.
24.	Klai S, Fekih-Mrissa N, Mrissa R, et al. Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities. Blood Coagul Fibrinolysis, 2013, 24(3): 269-272.
25.	Le Cam-Duchez V, Bagan-Triquenot A, Menard JF, et al. Association of the protein C promoter CG haplotype and the factor II G20210A mutation is a risk factor for cerebral venous thrombosis. Blood Coagul Fibrinolysis, 2005, 16(7): 495-500.
26.	Le Cam-Duchez V, Bagan-Triquenot A, Barbay V, et al. The G79A polymorphism of protein Z gene is an independent risk factor for cerebral venous thrombosis. J Neurol, 2008, 255(10): 1521-1525.
27.	Lichy C, Dong-Si T, Reuner K, et al. Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems. J Neurol, 2006, 253(3): 316-320.
28.	Lichy C, Kloss M, Reismann P, et al. No evidence for plasminogen activator inhibitor 1 4G/4G genotype as risk factor for cerebral venous thrombosis. J Neurol, 2007, 254(8): 1124-1125.
29.	Madonna P, De Stefano V, Coppola A, et al. G20210A PRTH gene mutation and other trombophilic polymorphisms in patients with cerebral vein thrombosis. Stroke, 2000, 31(7): 1787-1788.
30.	Margaglione M, Brancaccio V, Ciampa A, et al. Inherited thrombophilic risk factors in a large cohort of individuals referred to Italian thrombophilia centers: distinct roles in different clinical settings. Haematologica, 2001, 86(6): 634-639.
31.	Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med, 1998, 338(25): 1793-1797.
32.	Miller SP, Wu YW, Lee J, et al. Candidate gene polymorphisms do not differ between newborns with stroke and normal controls. Stroke, 2006, 37(11): 2678-2683.
33.	Ozyurek E, Balta G, Degerliyurt A, et al. Significance of factor V, prothrombin, MTHFR, and PAI-1 genotypes in childhood cerebral thrombosis. Clin Appl Thromb Hemost, 2007, 13(2): 154-160.
34.	Rahimi Z, Mozafari H, Bigvand AH, et al. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: association with factor V Leiden. Clin Appl Thromb Hemost, 2010, 16(4): 430-434.
35.	Reuner KH, Ruf A, Grau A, et al. Prothrombin gene G20210-->A transition is a risk factor for cerebral venous thrombosis. Stroke, 1998, 29(9): 1765-1769.
36.	Ringelstein M, Jung A, Berger K, et al. Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. J Neurol, 2012, 259(11): 2287-2292.
37.	Romero A, Marco P, Verdu J, et al. Genetic thrombophilia and cerebral venous thrombosis. Med Clin Barc, 2007, 128(17): 655-656.
38.	Stolz E, Valdueza JM, Grebe M, et al. Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study. J Neurol, 2007, 254(6): 729-734.
39.	Tufano A, Coppola A, Varricchione N, et al. Predisposing factors in patients with early-onset cerebral vein thrombosis. Thromb Res, 2005, 115(5): 439-440.
40.	Tufano A, Guida A, Coppola A, et al. Risk factors and recurrent thrombotic episodes in patients with cerebral venous thrombosis. Blood Transfus, 2014, 12(Suppl 1): s337-s342.
41.	Ventura P, Cobelli M, Marietta M, et al. Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis. Cerebrovasc Dis, 2004, 17(2-3): 153-159.
42.	孟强. 脑静脉血栓形成的病因学研究. 北京: 军医进修学院, 2001.
43.	白春梅, 潘家绮, 李秀荣, 等. 静脉血栓患者和正常人凝血因子 V Leiden 和凝血酶原基因 G20210A 变异的研究. 中华医学杂志, 1999, 79(12): 19-21.
44.	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
45.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
46.	Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials, 1986, 7(3): 177-188.
47.	Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol, 2007, 6(2): 162-170.
48.	林雪, 陈军, 赵益林. 脑静脉窦血栓形成的临床和影像学表现. 中华临床医师杂志(电子版), 2012, 6(20): 6325-6329.
49.	Saposnik G, Barinagarrementeria F, Brown RJ, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2011, 42(4): 1158-1192.
50.	Aznar J, Mira Y, Vaya A, et al. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke. Thromb Haemost, 2004, 91(5): 1031-1034.
51.	Lopaciuk S, Bykowska K, Kwiecinski H, et al. Factor V Leiden, prothrombin gene G20210A variant, and methylenetetra-hydrofolate reductase C677T genotype in young adults with ischemic stroke. Clin Appl Thromb Hemost, 2001, 7(4): 346-350.
52.	周荣富, 王鸿利. 凝血因子与静脉血栓形成. 国外医学, 输血及血液学分册, 2004, 8(6): 508-512.
53.	郑红, 连建华, 贺颖, 等. 中国人群凝血酶原FⅡG20210A 和 FVLeiden的分布. 郑州大学学报(医学版), 2006, 24(1): 102-104.
54.	Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost, 1998, 79(4): 706-708.

1. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med, 2005, 352(17): 1791-1798.
2. Dentali F, Poli D, Scoditti U, et al. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study. J Thromb Haemost, 2012, 10(7): 1297-1302.
3. Miranda B, Ferro JM, Canhao P, et al. Venous thromboembolic events after cerebral vein thrombosis. Stroke, 2010, 41(9): 1901-1906.
4. Tufano A, Guida A, Coppola A, et al. Risk factors and recurrent thrombotic episodes in patients with cerebral venous thrombosis. Blood Transfus, 2014, 12(Suppl 1): s337-s342.
5. Voetsch B, Jin RC, Bierl C, et al. Role of promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene as a risk factor for cerebral venous thrombosis. Stroke, 2008, 39(2): 303-307.
6. Madonna P, De Stefano V, Coppola A, et al. G20210A PRTH gene mutation and other trombophilic polymorphisms in patients with cerebral vein thrombosis. Stroke, 2000, 31(7): 1787-1788.
7. 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(10): 3698-3703.
8. 常建华, 马越, 张广森. 中国壮族人群凝血酶原基因 G20210A 突变频率研究. 中华医学遗传学杂志, 2005, 12(03): 341-343.
9. Bank I, Libourel EJ, Middeldorp S, et al. Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study. Arch Intern Med, 2004, 164(17): 1932-1937.
10. Haywood S, Liesner R, Pindora S, et al. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child, 2005, 90(4): 402-405.
11. Cosmi B, Legnani C, Pengo V, et al. The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs. Thromb Haemost, 2013, 109(3): 510-516.
12. Margaglione M, Brancaccio V, De Lucia D, et al. Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism. Chest, 2000, 118(5): 1405-1411.
13. 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(11): 801-806.
14. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120 000 cases and 180 000 controls. Thromb Haemost, 2009, 102(2): 360-370.
15. Jiang B, Ryan KA, Hamedani A, et al. Prothrombin G20210A mutation is associated with young-onset stroke: the genetics of early-onset stroke study and meta-analysis. Stroke, 2014, 45(4): 961-967.
16. Altinisik J, Ates O, Ulutin T, et al. Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients. Clin Appl Thromb Hemost, 2008, 14(4): 415-420.
17. Ben SO, Fekih-Mrissa N, N’Siri B, et al. Thrombophilic polymorphisms-factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T - in Tunisian patients with cerebral venous thrombosis. J Clin Neurosci, 2012, 19(9): 1326-1327.
18. Bombeli T, Basic A, Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol, 2002, 70(2): 126-132.
19. Boncoraglio G, Carriero MR, Chiapparini L, et al. Hyperhomocysteinemia and other thrombophilic risk factors in 26 patients with cerebral venous thrombosis. Eur J Neurol, 2004, 11(6): 405-409.
20. Bonduel M, Sciuccati G, Hepner M, et al. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. Acta Haematol, 2006, 115(3-4): 180-185.
21. Colaizzo D, Amitrano L, Iannaccone L, et al. Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings. J Med Genet, 2007, 44(6): 412-416.
22. Heller C, Heinecke A, Junker R, et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation, 2003, 108(11): 1362-1367.
23. Kenet G, Waldman D, Lubetsky A, et al. Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study. Thromb Haemost, 2004, 92(4): 713-718.
24. Klai S, Fekih-Mrissa N, Mrissa R, et al. Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities. Blood Coagul Fibrinolysis, 2013, 24(3): 269-272.
25. Le Cam-Duchez V, Bagan-Triquenot A, Menard JF, et al. Association of the protein C promoter CG haplotype and the factor II G20210A mutation is a risk factor for cerebral venous thrombosis. Blood Coagul Fibrinolysis, 2005, 16(7): 495-500.
26. Le Cam-Duchez V, Bagan-Triquenot A, Barbay V, et al. The G79A polymorphism of protein Z gene is an independent risk factor for cerebral venous thrombosis. J Neurol, 2008, 255(10): 1521-1525.
27. Lichy C, Dong-Si T, Reuner K, et al. Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems. J Neurol, 2006, 253(3): 316-320.
28. Lichy C, Kloss M, Reismann P, et al. No evidence for plasminogen activator inhibitor 1 4G/4G genotype as risk factor for cerebral venous thrombosis. J Neurol, 2007, 254(8): 1124-1125.
29. Madonna P, De Stefano V, Coppola A, et al. G20210A PRTH gene mutation and other trombophilic polymorphisms in patients with cerebral vein thrombosis. Stroke, 2000, 31(7): 1787-1788.
30. Margaglione M, Brancaccio V, Ciampa A, et al. Inherited thrombophilic risk factors in a large cohort of individuals referred to Italian thrombophilia centers: distinct roles in different clinical settings. Haematologica, 2001, 86(6): 634-639.
31. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med, 1998, 338(25): 1793-1797.
32. Miller SP, Wu YW, Lee J, et al. Candidate gene polymorphisms do not differ between newborns with stroke and normal controls. Stroke, 2006, 37(11): 2678-2683.
33. Ozyurek E, Balta G, Degerliyurt A, et al. Significance of factor V, prothrombin, MTHFR, and PAI-1 genotypes in childhood cerebral thrombosis. Clin Appl Thromb Hemost, 2007, 13(2): 154-160.
34. Rahimi Z, Mozafari H, Bigvand AH, et al. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: association with factor V Leiden. Clin Appl Thromb Hemost, 2010, 16(4): 430-434.
35. Reuner KH, Ruf A, Grau A, et al. Prothrombin gene G20210-->A transition is a risk factor for cerebral venous thrombosis. Stroke, 1998, 29(9): 1765-1769.
36. Ringelstein M, Jung A, Berger K, et al. Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. J Neurol, 2012, 259(11): 2287-2292.
37. Romero A, Marco P, Verdu J, et al. Genetic thrombophilia and cerebral venous thrombosis. Med Clin Barc, 2007, 128(17): 655-656.
38. Stolz E, Valdueza JM, Grebe M, et al. Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study. J Neurol, 2007, 254(6): 729-734.
39. Tufano A, Coppola A, Varricchione N, et al. Predisposing factors in patients with early-onset cerebral vein thrombosis. Thromb Res, 2005, 115(5): 439-440.
40. Tufano A, Guida A, Coppola A, et al. Risk factors and recurrent thrombotic episodes in patients with cerebral venous thrombosis. Blood Transfus, 2014, 12(Suppl 1): s337-s342.
41. Ventura P, Cobelli M, Marietta M, et al. Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis. Cerebrovasc Dis, 2004, 17(2-3): 153-159.
42. 孟强. 脑静脉血栓形成的病因学研究. 北京: 军医进修学院, 2001.
43. 白春梅, 潘家绮, 李秀荣, 等. 静脉血栓患者和正常人凝血因子 V Leiden 和凝血酶原基因 G20210A 变异的研究. 中华医学杂志, 1999, 79(12): 19-21.
44. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
45. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
46. Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials, 1986, 7(3): 177-188.
47. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol, 2007, 6(2): 162-170.
48. 林雪, 陈军, 赵益林. 脑静脉窦血栓形成的临床和影像学表现. 中华临床医师杂志(电子版), 2012, 6(20): 6325-6329.
49. Saposnik G, Barinagarrementeria F, Brown RJ, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2011, 42(4): 1158-1192.
50. Aznar J, Mira Y, Vaya A, et al. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke. Thromb Haemost, 2004, 91(5): 1031-1034.
51. Lopaciuk S, Bykowska K, Kwiecinski H, et al. Factor V Leiden, prothrombin gene G20210A variant, and methylenetetra-hydrofolate reductase C677T genotype in young adults with ischemic stroke. Clin Appl Thromb Hemost, 2001, 7(4): 346-350.
52. 周荣富, 王鸿利. 凝血因子与静脉血栓形成. 国外医学, 输血及血液学分册, 2004, 8(6): 508-512.
53. 郑红, 连建华, 贺颖, 等. 中国人群凝血酶原FⅡG20210A 和 FVLeiden的分布. 郑州大学学报(医学版), 2006, 24(1): 102-104.
54. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost, 1998, 79(4): 706-708.

Chinese Journal of Evidence-Based Medicine

Correlation of the prothrombin gene G20210A mutation and cerebral venous thrombosis risk: a meta-analysis

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