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Gene test interpretation: Prothrombin G20210A

Gene test interpretation: Prothrombin G20210A
Literature review current through: Sep 2023.
This topic last updated: Feb 23, 2023.

INTRODUCTION — This monograph discusses interpretation and possible interventions for genetic testing that reveals the G20210A variant in the F2 gene, which encodes prothrombin, also called prothrombin gene mutation (PGM). It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately in UpToDate [1]. (See 'UpToDate topics' below.)

OVERVIEW OF CLINICAL IMPLICATIONS

How to read the report — Prothrombin G20210A is a point mutation in the 3' untranslated region of the F2 gene, which encodes prothrombin (factor II).

The variant may also be called [2]:

Prothrombin gene mutation (PGM)

F2 G20210A or 20210G>A

Prothrombin G20210A or 20210G>A

Factor II c.*97G>A

There is no protein sequence change because the variant affects a noncoding region of the gene.

Prothrombin G20210A is often the only variant tested in F2. Rarely, other F2 variants may be identified; clinical implications are discussed separately. (See "Prothrombin G20210A", section on 'Other prothrombin gene variants'.)

The checklist provides important caveats (table 1).

Clinical significance (VTE risk) — In normal clotting, prothrombin (factor II) is cleaved to thrombin, the final enzyme in the enzymatic cascade that converts fibrinogen to fibrin in the fibrin clot (figure 1). The G20210A variant leads to increased prothrombin and prothrombin activity and is a risk factor for venous thromboembolism (VTE).

Heterozygosity – Heterozygosity for prothrombin G20210A confers an approximately three- to fourfold increased risk for VTE (table 2). Typical sites include deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral vein thrombosis (CVT; especially in women taking estrogen-containing contraceptives), and portal or hepatic vein thrombosis.

Heterozygosity for prothrombin G20210A is highly prevalent in certain populations (frequency, 1 to 4 percent). Most of these individuals are unaware they carry the variant and will never develop VTE. (See "Prothrombin G20210A", section on 'Epidemiology'.)

Homozygosity and double heterozygosity – 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'.)

Other VTE risk factors – VTE risk may also be increased by other inherited and acquired risk factors (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.

Pregnancy morbidity – An association between prothrombin G20210A and early pregnancy morbidity is controversial. (See 'Pregnancy morbidity' below.)

ASYMPTOMATIC INDIVIDUALS (NO PRIOR VTE)

VTE risk reduction — The risk of a first venous thromboembolic (VTE) event 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.)

Heterozygous individuals – Our approach to VTE risk reduction in individuals who are heterozygous for prothrombin G20210A is similar to the general population, with a few differences (table 3), as shown in the flowchart (algorithm 1).

We are more likely to use prophylactic anticoagulation for certain surgeries. (See 'Surgery' below.)

We advise avoiding estrogen-containing contraceptives.

We encourage alternative methods if contraception is desired or alternative treatments 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.)

Homozygous/double heterozygous individuals – For rare individuals who are homozygous for prothrombin G20210A or double heterozygous for prothrombin G20210A and another 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 those 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 prothrombin G20210A as a high-risk group when deciding 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 adults undergoing hip fracture repair or hip or knee replacement" 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 individuals with:

Homozygosity for prothrombin G20210A

Double heterozygosity for prothrombin G20210A and another thrombophilic variant (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 heterozygous individuals with a negative family history of VTE. However, they 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 "Contraception: Counseling for women with inherited thrombophilias", section on 'Choice of estrogen-progestin oral contraceptive'.)

Supporting evidence and contraceptive recommendations are presented separately. (See "Contraception: Counseling for women with inherited thrombophilias".)

Similar considerations apply for other uses of estrogen-containing contraceptives such as acne or dysmenorrhea. (See "Acne vulgaris: Management of moderate to severe acne in adolescents and adults", section on 'Oral hormonal therapies' and "Dysmenorrhea in adult females: Treatment".)

Pregnancy — Pregnancy is a hypercoagulable state; VTE risk is highest in the first six weeks postpartum. The risk is increased in individuals with prothrombin G20210A (table 4), although the increase is generally not considered sufficient to justify systemic anticoagulation. Our approach to prophylaxis is summarized in the table (table 5).

For individuals 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 individuals with additional risk factors such as a strong family history of VTE, immobility, or cesarean delivery, or other surgery.

For individuals who are homozygous for prothrombin G20210A or double heterozygotes for prothrombin G20210A plus another thrombophilic variant (table 2), we generally use intermediate-dose or low-dose heparin antepartum and intermediate-dose heparin postpartum.

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'.)

Considerations for individuals with a prior VTE or early pregnancy morbidity are discussed below. (See 'People with VTE' below and 'Pregnancy morbidity' below.)

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. We generally do not recommend prophylactic anticoagulation with low molecular weight heparin or a direct oral anticoagulant. (See "Prevention of venous thromboembolism in adult travelers".)

Some individuals may ask about the value of taking low-dose aspirin. We do not recommend this, given the lack of supporting data for its benefit. (See "Prothrombin G20210A", section on 'Asymptomatic individuals'.)

PEOPLE WITH VTE — For individuals with venous thromboembolism (VTE), heterozygosity for prothrombin G20210A generally does not affect management decisions regarding the use of anticoagulation, choice of anticoagulant, or duration of therapy (algorithm 1). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Overview of acute pulmonary embolism in adults".)

Once someone has an unprovoked VTE, heterozygosity for prothrombin G20210A plays little role in predicting the risk of recurrence, which is already high in those without hereditary thrombophilia; the presence of prothrombin G20210A confers less than a twofold increase in risk relative to someone with a prior VTE without the variant. (See "Prothrombin G20210A", section on 'VTE recurrence risk'.)

An exception is an individual who is homozygous for prothrombin G20210A or double heterozygous for prothrombin G20210A plus another thrombophilic variant (table 2), which are considered high-risk thrombophilias; such patients may warrant indefinite anticoagulation following a first provoked VTE.

PREGNANCY MORBIDITY — It is unclear whether prothrombin G20210A increases the risk of spontaneous abortion, stillbirth, or fetal loss, with most prospective studies not finding an association.

Preeclampsia does not appear to be more common with prothrombin G20210A.

Individuals with pregnancy morbidity who are found to carry prothrombin G20210A 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): Terminology, risk factors, and etiology".)

CONSIDERATIONS FOR RELATIVES — Routine testing of first-degree relatives of an individual with prothrombin G20210A 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 a strong family history of VTE, or if the tested individual is homozygous for the variant or double heterozygous 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".)

RESOURCES

UpToDate topics

Inherited thrombophilias

Clinical implications of prothrombin G20210A – (See "Prothrombin G20210A".)

Screening in asymptomatic individuals – (See "Screening for inherited thrombophilia in asymptomatic adults".)

Contraception – (See "Contraception: 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 adults undergoing hip fracture repair or hip or knee replacement".)

Other surgeries – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Pregnancy – (See "Venous thromboembolism in pregnancy: Prevention".)

Cesarean delivery – (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Thromboembolism prophylaxis'.)

General concepts

Terminology – (See "Genetics: Glossary of terms".)

Genetic testing – (See "Genetic testing".)

Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

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