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Prothrombin (Factor II) 20210G>A Mutation Analysis 
Test Summary
Clinical Use

  • Estimate thrombotic risk

  • Assess risk of obstetrical complications

  • Assess thrombophilia risk in family members of affected individuals

Clinical Background

Prothrombin, or factor II, is the precursor of thrombin; as such, it plays a key role in the balance between procoagulation and anticoagulation. A prothrombin genetic variant known as 20210G>A is associated with elevated levels of prothrombin and with thrombophilia. This variant is located at position 20210 of the 3′ untranslated region of the prothrombin gene on chromosome 11 and leads to substitution of an adenine for a guanine. Found primarily in whites, the prevalence is approximately 2% in healthy individuals, 6% to 8% in venous thrombosis cases (18% in known familial cases1), and 3% to 5% in arterial thrombosis cases (see table). More importantly, the relative risk (RR) in the general population is 2 to 5 for venous thrombosis and 0.9 to 4 for arterial thrombosis. The venous thrombosis risk is even higher in selected populations such as patients with a history of thrombotic episodes during pregnancy or the puerperium (RR = 15).2 Additionally, in patients heterozygous for both the factor V Leiden mutation and the 20210G>A mutation, risk of thrombosis increases synergistically.2 The mutation has also been associated with risk of recurrent miscarriage (RR = 4.6)3 and other obstetric complications. In summary, the prothrombin 20210G>A mutation is well established as a risk factor for venous thrombosis, but much controversy still exists regarding the mutation’s value in assessing arterial thrombotic risk.

Table. Prothrombin 20210G>A Prevalence and Associated Relative Risk

  

Prevalence (%)

in Healthy Individuals

Venous Thrombosis

  

    Arterial Thrombosisa

Prevalence
(%)

RR

Prevalence
(%)

RR

Poort SR, et al1

2.3

6.2

2.8

  

Cumming AM, et al4

1.2

5.5

5.4

  

Hillarp A, et al5

1.8

7.1

4.2

  

Schobess R, et al6

3

8.4

3.0

  

Ridker PM, et al7

3.9

6.4

1.7

  

3.5

0.95

Rosendaal FR, et al8

1.6

 

5.1

4.0

Araujo F, et al9

5

 

3.8b

Not provided

Arruda VR, et al10

0.7

 

3.2c

Not provided

Martinelli I, et al11

3.2

3.8

1.2

RR, relative risk.

a Includes cerebral ischemia, myocardial infarction, unstable angina.

b Not significantly different from healthy individuals.

c Significantly different from healthy individuals (P=0.03).

Individuals Suitable For Testing

  • Symptomatic individuals

  • Individuals with family history of thrombosis or thrombophilia-associated mutations

  • High-risk individuals predisposed by surgery, trauma, immobility, pregnancy, oral contraceptives, etc.

Note: Pregnant women with a personal or family history of thrombosis, recurrent spontaneous abortions, and severe early onset preeclampsia are at high risk.

Specimen Requirements

5 mL room temperature whole blood (EDTA, lavender-top tube); 3 mL minimum

Method

17909X

  • Polymerase chain reaction (PCR) amplification of the gene region, followed by oligonucleotide ligation and hybridization to color-coded microspheres

  • Results reported as no mutation detected, heterozygous positive, or homozygous positive for

the 20210G>A mutation

  • CPT codes*: 83898, 83914, 83912

30326X

  • Allele-specific hybridization, signal amplification, and chemiluminescent detection

  • Results reported as no mutation detected, heterozygous positive, or homozygous positive

  • CPT codes*: 83891, 83892, 83896 x2, 83908, 83912

Interpretive Information

Negative results indicate the absence of the prothrombin 20210G>A mutation but do not rule out the presence of other rare mutations within the prothrombin gene. Heterozygous positive results are associated with a 2- to 5-fold increased risk for venous thrombosis, increased risk for obstetric complications (eg, preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth), and, possibly, premature coronary heart disease. Thrombosis risk increases synergistically in the presence of oral contraceptive use (odds ratio is 149.3 for cerebral vein thrombosis12 and 69 for venous thrombosis2) and the factor V Leiden mutation (estimated odds ratio is 107 for women with a history of venous thromboembolism during pregnancy and the puerperium2). Homozygous positive results are rare. All test results should be interpreted in conjunction with clinical and family data.

References

  1. 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;88:3698-3703.

  2. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342:374-380.

  3. Foka ZJ, Lambropoulos AF, Saravelos H, et al. Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod. 2000;15:458-462.

  4. Cumming AM, Keeney S, Salden A, et al. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol. 1997;98:353-355.

  5. 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;78:990-992.

  6. Schobess R, Junker R, Auberger K, et al. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis – Evidence of an age-dependent thrombotic onset in carriers of factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr. 1999;158(Suppl 3):S105-S108.

  7. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999;99:999-1004.

  8. Rosendaal FR, Siscovick DS, Schwartz SM, et al. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997;90:1747-1750.

  9. Araujo F, Santos A, Araujo V, et al. Genetic risk factors in acute coronary disease. Haemostasis. 1999;29:212-218.

  10. Arruda VR, Siquiera LH, Chiaparini LC, et al. Prevalence of the prothrombin gene variant 20210 G>A among patients with myocardial infarction. Cardiovasc Res. 1998;37:42-45.

  11. Martinelli I, Franchi F, Akwan S, et al. The transition G to A at position 20210 in the 3′-untranslated region of the prothrombin gene is not associated with cerebral ischemia. Blood. 1997;90:3806.

  12. 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;338:1793-1797.

 

*The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payor being billed.

This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.

Content reviewed 11/2009