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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
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Supported by an unrestricted educational grant from AncestryHealth®.
- Kenneth A Bauer, MD
- Section Editor:
- Lawrence LK Leung, MD
- Deputy Editor:
- Jennifer S Tirnauer, MD
INTRODUCTION — This monograph discusses the interpretation and possible interventions based on genetic testing that reveals the G20210A variant in the gene encoding prothrombin (factor II; F2), also called the prothrombin gene mutation (PGM). It does not discuss indications for testing, and it is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately in UpToDate . (See 'UpToDate topics' below.)
OVERVIEW OF CLINICAL IMPLICATIONS
How to read the report — All of the following refer to the same point mutation in the prothrombin (F2) gene :
●Prothrombin gene mutation (PGM)
●F2 G20210A or 20210G>A
●Prothrombin G20210A or 20210G>A
●Factor II c.*97G>A
There is no corresponding protein sequence change because the variant is in a noncoding region of the gene.
The G20210A variant is often the only variant tested in the F2 gene, and its pathogenicity as a risk factor for venous thromboembolism (VTE) is well established. Rarely, other variants in F2 may be identified; their clinical implications are discussed separately. (See "Prothrombin G20210A", section on 'Other prothrombin gene variants'.)
Important caveats related to genetic testing are provided in the checklist (table 1).
Clinical significance (VTE risk) — Prothrombin G20210A is a variant (point mutation) in the 3' untranslated region of the F2 gene, which encodes prothrombin (factor II). In normal clotting, prothrombin is cleaved to thrombin, the final enzyme in the coagulation cascade that converts fibrinogen to fibrin to make the fibrin clot (figure 1). The G20210A variant leads to increased levels of prothrombin and increased prothrombin activity in plasma.
Heterozygosity for prothrombin G20210A confers an increased risk for VTE of approximately three- to fourfold (table 2). Typical sites include deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral vein thrombosis (especially in women taking estrogen-containing contraceptives), and thrombosis in the portal or hepatic veins. Homozygosity for prothrombin G20210A and double heterozygosity (for prothrombin G20210A plus another thrombophilia variant) are infrequent and carry a higher risk. We do not routinely test for other variants in asymptomatic individuals, but many individuals who have had thrombophilia testing following a thrombotic event will have this information available. (See "Prothrombin G20210A", section on 'Risk of VTE'.)
Heterozygosity for prothrombin G20210A is highly prevalent in certain populations (frequency, 1 to 4 percent). The vast majority of these individuals are unaware that they carry the variant, and they will never develop a VTE. (See "Prothrombin G20210A", section on 'Epidemiology'.)
It is important to counsel the tested individual that their risk for VTE may be increased despite a negative test for prothrombin G20201A, as VTE risk depends on a number of other inherited and acquired risk factors.
Other major risk factors include (see "Overview of the causes of venous thrombosis"):
●Prior personal history of VTE
●Other thrombophilic variants (table 2)
●Acquired VTE risk factors (estrogen therapy, pregnancy, immobility, trauma, surgery, acute or chronic medical illnesses)
●Family history of VTE, especially if unprovoked.
An association between prothrombin G20210A and early pregnancy morbidity is controversial. (See 'Women with pregnancy morbidity' below.)
ASYMPTOMATIC INDIVIDUALS (NO PRIOR VTE)
VTE risk reduction — The risk of a first episode of venous thromboembolism (VTE) is determined by many factors besides an individual's F2 genotype. These other factors should be considered when determining the appropriate risk reduction strategy, regardless of whether the individual carries the prothrombin G20210A variant. (See 'Clinical significance (VTE risk)' above.)
Our general approach to VTE risk reduction in prothrombin G20210A heterozygotes is similar to the general population, with the following differences (table 3):
●We are more likely to use prophylactic anticoagulation for certain surgeries. (See 'Surgery' below.)
●We advise avoidance of estrogen-containing contraceptives. We encourage the use of alternative methods if contraception is desired or treatment is indicated for other conditions (such as dysmenorrhea or acne). (See 'Estrogen-containing contraceptives' below.)
●We are more likely to use anticoagulation during pregnancy and postpartum if other risk factors are present. (See 'Pregnancy' below.)
This approach is illustrated in the algorithm (algorithm 1).
For rare individuals who are homozygotes for prothrombin G20210A or double heterozygotes for prothrombin G20210A and another inherited thrombophilia variant, VTE risk is higher (table 4). This still translates to a relatively low overall incidence of VTE (<1 percent per year), and we generally do not chronically anticoagulate these individuals. However, anticoagulation may be considered in those with a very strong family history of VTE and/or who place an especially high value on preventing thrombosis. (See "Prothrombin G20210A", section on 'Biology of the mutation and mechanism of increased thrombosis risk'.)
Surgery — Surgery confers an increased risk for VTE independent of other risk factors; prothrombin G20210A may further increase this risk.
We generally treat individuals with the prothrombin G20210A variant as a high-risk group when making decisions about postoperative VTE prophylaxis, and we are more likely to prophylactically anticoagulate rather than use other modalities such as aspirin or intermittent pneumatic compression devices alone for surgeries in which postoperative VTE is considered. The variant does not affect the choice or dosing of the anticoagulant.
Supporting evidence, anticoagulant dosing, and other recommendations are presented separately. (See "Prevention of venous thromboembolism in adult orthopedic surgical patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
Estrogen-containing contraceptives — Estrogen-containing contraceptives carry an increased risk of VTE independent of other risk factors, and the risk is significantly increased by prothrombin G20210A (table 4). However, avoiding estrogen-containing contraceptives must be balanced with the risk of unintended pregnancy, which also increases VTE risk.
●We avoid estrogen-containing contraceptives in women with the following:
•Homozygosity for prothrombin G20210A
•Double heterozygosity for prothrombin G20210A and another thrombophilic defect (table 2)
•Heterozygosity for prothrombin G20210A and a personal history of VTE
•Heterozygosity for prothrombin G20210A and a positive family history of VTE in a family member who also carries prothrombin G20210A
●Alternatives to estrogen-containing contraceptives are also favored for prothrombin G20210A heterozygotes with a negative family history of VTE. However, these women may reasonably choose an estrogen-containing contraceptive if they lack other VTE risk factors. If an oral estrogen-containing contraceptive is used, we use one with a low estrogen dose. (See "Contraceptive counseling for women with inherited thrombophilias", section on 'Choice of estrogen-progestin oral contraceptive'.)
Supporting evidence and contraceptive recommendations are presented separately. (See "Contraceptive counseling for women with inherited thrombophilias".)
Similar considerations apply when estrogen-containing contraceptives are used for other purposes such as acne or menstrual pain. (See "Hormonal therapy for women with acne vulgaris" and "Dysmenorrhea in adult women: Treatment".)
Pregnancy — Pregnancy is a hypercoagulable state, with VTE risk highest in the first six weeks postpartum. The risk is increased in individuals with prothrombin G20210A (table 4), although the increase by itself is generally not considered sufficient to justify systemic anticoagulation. Our approach to prophylaxis is summarized in the table (table 5).
●For pregnant women who have not had a prior VTE and are found to be heterozygous for prothrombin G20210A, management of pregnancy and postpartum is mostly similar to the general population. We do not provide routine prophylactic anticoagulation, but anticoagulation may be appropriate for selected individuals based on additional risk factors such as strong family history of VTE, immobility, cancer, or need for surgery.
●For individuals who are homozygous for prothrombin G20210A or double heterozygotes for prothrombin G20210A plus another thrombophilic defect (table 2), we generally use intermediate-dose anticoagulation starting in the first trimester and continuing postpartum; the decision of whether to start anticoagulation antepartum or postpartum is individualized using shared decision-making with discussion of the benefits and risks.
●For prothrombin G20210A heterozygotes who have a cesarean delivery, we provide two weeks of postpartum prophylactic dose anticoagulation in addition to standard pneumatic compression while in the hospital.
Supporting evidence and further discussion is presented separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)
Airline travel — Airline travel is likely associated with an increased risk of VTE, especially over the course of longer flights (more than four to six hours).
For healthy people who are traveling by airplane for more than four hours, we typically recommend frequent ambulation (eg, every one to two hours) and/or calf and thigh muscle stretching. For those who place a high value on reducing VTE risk, we suggest below-the-knee graduated compression stockings. (See "Prevention of venous thromboembolism in adult travelers".)
Some individuals may ask about the value of taking low-dose aspirin. We neither recommend nor object to this practice, as long as they are aware of the lack of supporting data for benefit. (See "Prothrombin G20210A", section on 'Asymptomatic individuals'.)
PEOPLE WITH VTE — For individuals with venous thromboembolism (VTE), the presence of prothrombin G20210A generally does not affect management decisions regarding the use of anticoagulant, choice of anticoagulant, or duration of therapy (algorithm 1). (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Overview of acute pulmonary embolism in adults".)
Once someone has a VTE, the significance of prothrombin G20210A for predicting the risk of recurrence (having a second VTE) declines, conferring less than a twofold risk relative to someone with a prior VTE who lacks the variant. (See "Prothrombin G20210A", section on 'Recurrence risk'.)
An exception is an individual who is homozygous for prothrombin G20210A or a double heterozygote for prothrombin G20210A plus another thrombophilic defect (table 2), which is considered a high risk thrombophilia and generally is an indication for indefinite anticoagulation following a first unprovoked VTE. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Inherited thrombophilias'.)
WOMEN WITH PREGNANCY MORBIDITY — It is unclear whether prothrombin G20210A increases the risk of pregnancy complications (spontaneous abortion, stillbirth, fetal loss), with most prospective studies not finding an association. Preeclampsia does not appear to be more common with the prothrombin G20210A variant. Women with pregnancy morbidity who are found to have the prothrombin G20210A variant should be evaluated by their obstetrician to determine the likely cause(s) of the pregnancy morbidity. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk' and "Pregnancy loss (miscarriage): Risk factors, etiology, clinical manifestations, and diagnostic evaluation".)
CONSIDERATIONS FOR FAMILY MEMBERS — Routine testing of first-degree relatives of an individual with the prothrombin G20210A variant is controversial and may not be indicated, especially if the family history is negative for venous thromboembolism (VTE). For those with questions, referral to a hematologist or genetic counselor may be helpful.
Individuals with the variant should share this information with their first-degree relatives, who can discuss the risks and benefits of knowing their status with their own clinicians and come to individual decisions about whether to be tested.
We are most likely to find value in testing at-risk relatives if they are considering use of an estrogen-containing contraceptive, if there is strong family history of VTE, or if the tested individual is homozygous for the variant or a double heterozygote for prothrombin G20210A and another inherited thrombophilia (table 2). (See "Prothrombin G20210A", section on 'Testing of first-degree relatives' and "Screening for inherited thrombophilia in asymptomatic adults".)
•Clinical implications of prothrombin G20210A – (See "Prothrombin G20210A".)
•Screening in asymptomatic individuals – (See "Screening for inherited thrombophilia in asymptomatic adults".)
•Contraception – (See "Contraceptive counseling for women with inherited thrombophilias".)
•Pregnancy – (See "Inherited thrombophilias in pregnancy".)
●Venous thromboembolism (VTE) prophylaxis:
•Hospitalization – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
•Orthopedic surgery – (See "Prevention of venous thromboembolism in adult orthopedic surgical patients".)
•Other surgeries – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
•Pregnancy – (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)
•Cesarean delivery – (See "Cesarean delivery: Preoperative planning and patient preparation", section on 'Thromboembolism prophylaxis'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Zhang S, Taylor AK, Huang X, et al. Venous thromboembolism laboratory testing (factor V Leiden and factor II c.*97G>A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2018; 20:1489.
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
In a third pathway (3), thrombin also activates factor XI to XIa, which can lead to further generation of factor IXa; it serves as an amplification pathway required during severe hemostatic challenges.
Coagulation factors are shown as Roman numerals. Only the activated forms (with the suffix "a") are shown in this diagram for simplicity. Thrombin is factor IIa.
|Thrombophilia||Prevalence (%)||Relative risk of a first episode of VTE compared with controls|
|General population||Individuals with VTE|
|AT deficiency||0.02 to 0.2%||1 to 7%||16-fold increased|
|Protein C deficiency||0.2 to 0.5%||2 to 5%||7-fold increased|
|Protein S deficiency||Unknown||1%||5-fold increased|
|Factor V Leiden*||4 to 5%||12 to 18%||4- to 5-fold increased|
|Prothrombin G20210A*||2%||5 to 8%||3- to 4-fold increased|
*Applies to Caucasian populations; prevalence is much lower in other groups.
|Patient population||Intervention(s) that may be appropriate|
|VTE risk reduction for asymptomatic individuals|
|Additional considerations for women||
|First- and second-degree relatives||
* Applies to estrogen-containing contraceptives for prevention of pregnancy or other indications (treatment of menstrual pain, acne). Must be balanced against the risk of unintended pregnancy, which also increases VTE risk. We feel most strongly about avoiding estrogens in individuals with a personal history of VTE and those with a strong family history of VTE. Options for alternative forms of contraception (or alternative treatments for menstrual pain or acne) should be provided. A progesterone-releasing intrauterine device or the mini-pill (progesterone only) do not increase VTE risk.
¶ Other risk factors include bedrest for preeclampsia, surgery, or cesarean delivery.
|Thrombophilia||Prevalence||Relative (absolute annualized) risk of initial VTE*||Relative risk of recurrent VTE||Relative (absolute annualized) risk of initial VTE, OCP users*¶||Relative (absolute annualized) risk of initial VTE, HRT users*¶Δ||Absolute risk of VTE in pregnancy*|
|FVL heterozygous||2-7%||3.48-5.51 (0.05-0.2%)||1.1-1.8||2.47-15.04 (0.1-0.6%)||1.4-13.16 (1.6-5.97%)||0.5 percent at age <35, 0.7 percent at age ≥35|
|FVL homozygous||0.06-0.25%||6.79-19.29 (0.8%)||1.8||Uncertain||Uncertain||2.2 percent at age <35, 3.4 percent at age ≥35|
|PGM heterozygous||1-2%||2.25-3.48 (0.13%)||0.7-2.3||3.60-8.63||(2.85%)||0.4 percent at age <35, 0.6 percent at age ≥35|
|PGM homozygous||Rare||2.19-20.72||Uncertain||Uncertain||Uncertain||Not available|
|Compound FVL and PGM heterozygosity||0.1%||1.13-5.04 (0.42%)||2.7||3.79-76.47 (0.17%)||Uncertain||5.5 percent at age <35, 8.2 percent at age ≥35|
|PC deficiency||0.2-0.5%||10 (0.4-2.3%)||1.8||1.7-23.9 (1.7-7.1%)||(2.96%)||0.7 percent at age <35, 1.1 percent at age ≥35|
|PS deficiency||0.1-0.7%||9.6 (0.7-3.2%)||1.0||1.4-17.1 (1.3-2.4%)||(2.3%)||0.7 percent at age <35, 1.0 percent at age ≥35|
|AT deficiency||0.02%||10-30 (1.2-4.4%)||2.6||1.4-115.8 (2.5-5.1%)||(5.73%)||6.1 percent at age <35, 9.0 percent at age ≥35|
* Data are taken from reference 14; therefore, absolute rates may differ from the other sources since calculations are based on prevalence and relative risk.[1-13]
¶ Relative risks are compared with nonusers without thrombophilia.
Δ With the exception of heterozygous FVL, estimates are based on modeling rather than epidemiologic studies.
- Christiansen SC, Cannegieter SC, Koster T, et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293:2352.
- Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med 2008; 121:458.
- Simone B, De Stefano V, Leoncini E, et al. Risk of venous thromboembolism associated with single and combined effects of factor V Leiden, prothrombin 20210A and methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28:621.
- Mahmoodi BK, Brouwer JL, Ten Kate MK, et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 2010; 8:1193.
- Pernod G, Biron-Andreani C, Morange PE, et al. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline. J Mal Vasc 2009; 34:156.
- Merriman L, Greaves M. Testing for thrombophilia: an evidence-based approach. Postgrad Med J 2006; 82:699.
- Wu O, Robertson L, Twaddle S, et al. Screening for thrombophilia in high-risk situations: a meta-analysis and cost effectiveness analysis. Br J Haematol 2005; 131:80.
- Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy. Chest 2012; 141:e691S.
- Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia screening. Vasa 2008; 37:19.
- Cohen W, Castelli C, Suchon P, et al. Risk assessment of venous thrombosis in families with known hereditary thrombophilia: the MARseilles-NImes prediction model. J Thromb Haemost 2014; 12:138.
- Davis SM, Branch DW. Thromboprophylaxis in pregnancy: who and how? Obstet Gynecol Clin North Am 2010; 37:333.
- Culwell KR, Curtis KM, del Carmen Cravioto M. Safety of contraceptive method use among women with systemic lupus erythematosus: a systematic review. Obstet Gynecol 2009; 114:341.
- Wu O, Robertson L, Langhorne P, et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The thrombosis: risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94:17.
- Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors of thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016; 128:2343.
|Clinical setting||Antepartum management||Postpartum management|
Lower-risk thrombophilia* with personal history of previous VTE
Higher-risk thrombophilia¶ without personal history of previous VTE
|Anticoagulation therapy (intermediate dose)||Anticoagulation therapy (intermediate dose)|
|Lower-risk thrombophilia* without personal history of VTE||Surveillance for VTE without anticoagulation therapy. Anticoagulation may be warranted for individual patients with additional factors that place them at greater risk of thrombosis (eg, prolonged immobility, first-degree relative with unprovoked VTE at age <50 years).||Anticoagulation therapy (prophylactic dose) for women who deliver by cesarean|
|Higher-risk thrombophilia¶ with previous VTE on chronic anticoagulation||Anticoagulation therapy (therapeutic dose)||Anticoagulation therapy (therapeutic dose)|
* Lower-risk thrombophilias include women who are heterozygotes for factor V Leiden (FVL) or prothrombin G20210A gene mutation (PGM) and women with deficiencies of protein C or protein S.
¶ Higher-risk thrombophilias include women with antithrombin (AT) deficiency, homozygotes for the FVL mutation, homozygotes for the PGM mutation, double heterozygotes for FVL and PGM.
Contributor DisclosuresKenneth A Bauer, MDConsultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation].Lawrence LK Leung, MDNothing to discloseJennifer S Tirnauer, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.