Prothrombin G20210A:

DEFECT: A G to A transition at position 20210 in the 3' untranslated region of the prothrombin gene. Frequency: 2%-3% in the general population; 6% in patients with venous thrombosis.

ASSOCIATED RISK: Heterozygous carriers have ~3 to 5 fold increased risk for venous thrombosis.

MODE OF ACTION: Conversion of prothrombin to thrombin is a central event in fibrin clot formation and platelet activation. The mutation acts synergistically with Factor V Leiden G1691A gene mutation in the development of venous thrombosis.

METHOD OF DETECTION: Allele-specific PCR on DNA isolated from leukocytes found in whole blood.

POSSIBLE CLINICAL UTILITY: Tests for Prothrombin G20210A should be done on:

• People with multiple thrombotic events, family history of thrombotic events, thrombotic events at younger age (under 40-45), thrombosis at an unusual anatomical site: outside the veins of legs, pelvis, or lungs.
• Immediate family members of patients carrying the mutation.
• Women who are at increased risk for venous thrombosis, especially if they are taking oral contraceptives or are pregnant or have had fetal loss should also be screened for this risk factor.

Finding the mutation represents a permanent risk factor and could influence the length of therapy to prevent future events.

NOTE: Numerous studies have found no association between heart disease and the Prothrombin G20210A polymorphism. We have not included these studies in the list of references. If you would like to review these publications, please and we will send you copies of these articles.

References:

1. Doggen CJ, Cats VM, Bertina RM, Rosendaal FR.; Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998 Mar 24;97(11):1037-41

The risk of myocardial infarction in the presence of the Prothrombin 20210 mutation (AG genotype) was increased by 50% (odds ratio, 1.5; 95% confidence interval [95% CI], 0.6 to 3.8). The risk of myocardial infarction for carriership of factor V Leiden mutation was increased by 40% (odds ratio, 1.4; 95% CI, 0.8 to 2.2). When a coagulation defect was present (ie, the 20210 AG prothrombin genotype or the factor V Leiden mutation), the risk of myocardial infarction for carriers versus noncarriers was 1.4 (95% CI, 0.9 to 2.2). This risk was substantially increased when one of the major cardiovascular risk factors of smoking, hypertension, diabetes mellitus, or obesity also was present, with odds ratios varying between 3 and 6. These risks exceeded those of the single effects of the cardiovascular risk factors (ie, in the absence of the coagulation defect). CONCLUSIONS: We conclude that in men the 20210 G-->A variant of prothrombin is associated with an increased risk of myocardial infarction. The combined presence of major cardiovascular risk factors and carriership of a coagulation defect increases the risk considerably.

2. Arruda VR, Siquiera LH, Chiaparini LC, Coelho OR, Mansur AP, Ramires A, Annichino-Bizzacchi JM.; Prevalence of the prothrombin gene variant 20210 G --> A among patients with myocardial infarction. Cardiovasc Res 1998 Jan;37(1):42-5.

They suggest that being heterozygote for the allele variant 20210A of the prothrombin gene could be a genetic risk factor for developing myocardial infarction. The prevalence of heterozygotes for the prothrombin mutated allele was 3% among patients with myocardial infarction and 0.7% in the general population (P = 0.03). For individuals over 45 years old the prevalence among females was higher than among males (5% vs. 0%).

3. Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, Costa FF.; Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997 Dec;78(6):1430-3

These data support the hypothesis that the prothrombin variant is a risk factor for venous thrombosis and suggest that it may also be a risk factor for arterial disease. The prevalence of 0.7% for 20210A allele in the control group increased to 4.3% (P = 0.021) among patients with venous thrombosis. There was also a high prevalence of the mutated allele in a selected arterial disease group (5.7%) without hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to the controls (P = 0.013).

4. 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 Nov 15;88(10):3698-703.

18% percent of the patients had the 20210 AG genotype, as compared with 1% of a group of healthy controls (100 subjects). The 20210 A allele was identified as a common allele (allele frequency, 1.2%; 95% confidence interval, 0.5% to 1.8%), which increased the risk of venous thrombosis almost threefold odds ratio, 2.8; 95% confidence interval, 1.4 to 5.6. The risk of thrombosis increased for all ages and both sexes. An association was found between the presence of the 20210 A allele and elevated prothrombin levels. Most individuals (87%) with the 20210 A allele are in the highest quartile of plasma prothrombin levels (> 1.15 U/mL). Elevated prothrombin itself also was found to be a risk factor for venous thrombosis.


5. Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR.; The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997 Aug;98(2):353-5

5.5% were found to be heterozygous carriers of the 20210A allele vs. 1.2% in the control (allele frequency 0.61%, 95% CI 0.08-2.19). When patients with a known alternative hereditary risk factor for venous thrombosis (factor V Leiden mutation or deficiency of antithrombin, protein C or protein S) were excluded, the G20210A variant was found to increase the risk for venous thrombosis by approximately 5-fold (odds ratio 5.4, 95% CI 1.16-25.0). Patient size= 219

6. Hessner MJ, Dinauer DM, Luhm RA, Endres JL, Montgomery RR, Friedman KD.; Contribution of the glycoprotein Ia 807TT, methylene tetrahydrofolate reductase 677TT and prothrombin 20210GA genotypes to prothrombotic risk among factor V 1691GA (Leiden) carriers. Br J Haematol 1999 Jul;106(1):237-9

The prothrombin 20210GA genotype was nearly 5 times as prevalent (19/156 v 2/77; P < 0.02) in the symptomatic FVL carriers (odds ratio 5.21; 95% confidence interval 1.20-47.62), demonstrating that this important prothrombotic risk factor acts synergistically with FVL.

 

7. Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ.; Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997 Dec;78(6):1426-9.

They have demonstrated that the prevalence of the PT 20210A allele is significantly greater in subjects with venous thrombosis and characterised heritable thrombophilia than in normal control subjects and that the additional inheritance of PT 20210A is associated with an increased risk of venous thromboembolism. They also confirmed that plasma prothrombin levels are significantly greater in subjects possessing the PT 20210A compared with those who do not. 8% of patients were heterozygous for the PT 20210A allele compared with 0.7% in the control subjects (p = 0.005). After exclusion of patients on warfarin, the mean plasma prothrombin of 113 subjects without 20210A was 1.09 U/ml, vs. 1.32 U/ml in 8 with the allele (p = 0.0002). Among the 101 patients with other risk factors (either factor V Leiden, protein S deficiency, protein C deficiency or antithrombin deficiency), the age adjusted mean number of venous thromboembolic episodes at diagnosis was 3.7 in those with the PT 20210A allele, as compared with 1.9 in those without (p = 0.0001).

8. Hillarp A, Zoller B, Svensson PJ, Dahlback B.; The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997 Sep;78(3):990-2

Their results confirm the 20210 A allele of the prothrombin gene to be an important risk factor for venous thrombosis. The prevalence of the 20210 A allele was 7.1% (7/99) in the patient group, and 1.8% (5/282) in the healthy control group (p = 0.0095). The relative risk of venous thrombosis was calculated to be 4.2 (95% CI, 1.3 to 13.6), and was still significant when adjustment was made for age, sex and the factor V:R506Q mutation causing APC resistance [odds ratio 3.8 (95% CI, 1.1 to 13.2)]. 28% of the patients were carriers of the factor V:R506Q mutation. 34% (one patient carried both traits) of unselected patients with deep venous thrombosis were carriers of an inherited prothrombotic disorder.

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