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DOI: 10.1055/s-0037-1616135
Phenotypic APC Resistance in Carriers of the A20210 Prothrombin Mutation Is Associated with an Increased Risk of Venous Thrombosis
Publikationsverlauf
Received
28. Dezember 2000
Accepted after resubmission
10. Mai 2001
Publikationsdatum:
14. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200103/lookinside/thumbnails/10.1055-s-0037-1616135-1.jpg)
Summary
We hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 ± 0.12 vs. 0.95 ± 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 ± 0.08 vs. 1.05 ± 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.
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References
- 1 Poort SR, Rosendaal FR, Reitsma PH, Bertina R. 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: 3698-703.
- 2 Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep vein thrombosis. Thromb Haemost 1997; 78: 990-2.
- 3 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
- 4 Mitchell CA, Jane SM, Salem HH. Inhibition of the anticoagulant activity of protein S by prothrombin. J Clin Invest 1988; 82: 2142-7.
- 5 Smirnov MD, Safa O, Esmon NL, Esmon CT. Inhibition of activated protein C anticoagulant activity by prothrombin. Blood 1999; 94: 3839-46.
- 6 Tripodi A, Chantarangkul V, Mannucci PM. Hyperprothrombinemia may result in acquired activated protein C resistance. Blood 2000; 96: 3295-36.
- 7 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, De Ronde H, Van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
- 8 De Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
- 9 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-50.
- 10 Rodeghiero F, Tosetto A. The epidemiology of inherited thrombophilia: the VITA project. Thromb Haemost 1997; 78: 636-40.
- 11 Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA Project: prothrombin G20210A mutation and venous thromboembolism in the general population. Thromb Haemost 1999; 82: 1395-8.
- 12 Tripodi A, Negri B, Bertina RM, Mannucci PM. Screening for the FV:Q506 mutation - evaluation of thirteen plasma-based methods for their diagnostic efficacy in comparison with DNA analysis. Thromb Haemost 1997; 77: 436-9.
- 13 Rodeghiero F, Tosetto A. The VITA project: population-based distributions of protein C, antithrombin III, heparin-cofactor II and plasminogen – Relationship with physiological variables and establishment of reference ranges. Thromb Haemost 1996; 76: 226-33.
- 14 Tosetto A, Missiaglia E, Gatto E, Rodeghiero F. The VITA Project: phenotypic resistance to activated protein C and FV Leiden mutation in the general population. Thromb Haemost 1997; 78: 859-63.
- 15 Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research. Belmont, CA: Lifetime Learning Publication; 1982
- 16 Bertina RM, Reitsma PH, Rosendaal FR, Vandenbroucke JP. Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. Thromb Haemost 1995; 74: 449-53.
- 17 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (Activated protein C resistance). Blood 1995; 85: 1504-8.
- 18 Soria JM, Almasy L, Souto JC, Tirado I, Borell M, Mateo J, Slifer S, Stone W, Blangero J, Fontcuberta J. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood 2000; 95: 2780-5.
- 19 Bauer KA, Humphries S, Smillie B, Li L, Cooper JA, Barzegar S, Rosenberg RD, Miller GJ. Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations. Thromb Haemost 2000; 84: 396-400.
- 20 Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 73: 797-8.
- 21 Faioni EM, Franchi F, Asti D, Mannucci PM. Acquired resistance to activated protein C develops during pregnancy. Thromb Haemost 1995; 73: 1375.
- 22 Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of the clotting factor VIII in effect of von Willebrand factor on occurrence of deep vein thrombosis. Lancet 1995; 345: 152-155.