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Prothrombin G20210A

Prothrombin G20210A
Author:
Kenneth A Bauer, MD
Section Editor:
Lawrence LK Leung, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 20, 2021.

INTRODUCTION — Prothrombin G20210A is the second most common inherited thrombophilia after factor V Leiden. Challenging clinical issues include the decisions regarding when to test for prothrombin G20210A and how to manage individuals with this variant, either in the setting of venous thromboembolism (VTE) or in asymptomatic individuals.

This topic reviews the diagnosis of prothrombin G20210A and the management of individuals who carry this variant.

Separate topic reviews discuss other thrombophilias and the role of thrombophilia screening in various populations.

Thrombophilias:

●Factor V Leiden (FVL) – (See "Factor V Leiden and activated protein C resistance".)

●Protein C deficiency – (See "Protein C deficiency".)

●Protein S deficiency – (See "Protein S deficiency".)

●AT deficiency – (See "Antithrombin deficiency".)

●APS – (See "Diagnosis of antiphospholipid syndrome".)

●PNH – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

●MPNs – (See "Overview of the myeloproliferative neoplasms".)

Screening:

●Children – (See "Thrombophilia testing in children and adolescents".)

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

●Pregnancy – (See "Inherited thrombophilias in pregnancy".)

●Individuals with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

●Ischemic stroke – (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Overview of the evaluation of stroke", section on 'Blood tests'.)

PATHOPHYSIOLOGY

Role of prothrombin in coagulation — Prothrombin (factor II; F2) is the precursor of thrombin, the end-product of the coagulation cascade (figure 1 and figure 2). Thrombin in turn proteolytically cleaves fibrinogen to fibrin, which becomes crosslinked to form a fibrin clot [1]. Thrombin also acts on a variety of other hemostatic components including platelets, factor VIII (cofactor for factor X activation by factor IXa), factor V (cofactor for prothrombin activation by factor Xa), factor XIII (crosslinks fibrin), and thrombin-activatable fibrinolysis inhibitor (TAFI; regulates clot lysis). (See "Overview of hemostasis".)

Prothrombin is synthesized in the liver. It is a vitamin K-dependent protein. Vitamin K acts as a cofactor for post-translational gamma-carboxylation of prothrombin that is required for functional activity. The half-life of prothrombin in the circulation is approximately 60 hours. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".)

Biology of the mutation and mechanism of increased thrombosis risk — The G20210A point mutation in the prothrombin (coagulation factor II; F2) gene results from a substitution of adenine (A) for guanine (G) at position 20210 in a non-coding region of the gene (figure 3) [2]. Most individuals with this variant are heterozygous, although homozygosity has been reported in a small percentage [3]. Transmission is considered to be autosomal dominant, and the risk of venous thromboembolism (VTE) in heterozygotes is increased approximately three- to fourfold over controls. (See 'Epidemiology' below and 'Risk of VTE' below.)

The location of the base change is in the terminal nucleotide of the 3’ untranslated region of the gene, corresponding to the messenger RNA (mRNA) sequence responsible for polyadenylation [4]. This is considered a gain-of-function mutation because it causes increased prothrombin function [5]. This may be due to effects on the rate of mRNA processing, the site of 3’ cleavage/polyadenylation, and/or the stability of the mRNA [4,6,7].

Heterozygotes for prothrombin G20210A have approximately 30 percent higher plasma prothrombin levels than controls [2,8]. Homozygotes have even higher levels [8]. However, prothrombin levels cannot be used to make the diagnosis of the variant, because there is overlap with the normal range, and the coefficient of variation in coagulation assays is relatively large. (See 'Diagnosis' below.)

The mechanism by which prothrombin G20210A increases the risk of thrombosis is incompletely understood but is thought primarily to involve an increased concentration of prothrombin in the circulation, possibly by increased efficiency of prothrombin mRNA 3’-end formation and increased prothrombin biosynthesis without affecting the rate of transcription; increased glycosylation that promotes protein stability may also play a role [8-10].

Other prothrombin gene variants — Variants in the prothrombin gene other than G20210A have been described. In some cases, these are prothrombotic, and in others, they are associated with increased risk of bleeding; the phenotype depends on whether they ultimately decrease or increase prothrombin activation. We do not routinely test for these.

●Prothrombin Yukuhashi – The Yukuhashi variant was identified in an 11-year-old Japanese girl with VTE; there was a strong family history of thrombosis during childhood [11]. Prothrombin Yukuhashi is a missense mutation (G1787T) that leads to a substitution of arginine for leucine at amino acid 596 of the protein. Thrombin generated from the abnormal protein was severely impaired in its ability to complex with antithrombin. Its procoagulant activity was impaired, but its reduced binding to antithrombin appeared to be dominant, resulting in prolonged procoagulant activity.

●C20209T – The C20209T polymorphism is adjacent to G20210A in the 3’ untranslated region of the prothrombin gene. It was initially identified in an African individual with VTE who was being evaluated for the G20210A variant [12]. The carrier frequency of this variant is estimated to be approximately 0.4 percent, and it is predominantly found in African individuals [13]. Subsequent analysis of additional C20209T heterozygotes showed a possible association with VTE, although small case-control studies have failed to show an increase in VTE; this suggests that if there is an association, it is very weak [13,14].

●A19911G – The A19911G polymorphism is located in an intron in the prothrombin (F2) gene that has been proposed to modulate the G202010A variant. In a case-control study involving 204 consecutive individuals with deep vein thrombosis (DVT) and 204 matched controls, all of whom had the G202010A mutation, the co-occurrence of A19911G led to an additional slight increase in VTE risk (odds ratio [OR] from 3.3 with the G202010A variant alone to 5.9 with both G20210A and A19911G) [15]. Another case-control study found that A19911G increased the risk of VTE in individuals with factor V Leiden (OR 2.1; 95% CI 1.3-3.4) but not those with prothrombin G20210A [16].

Defects in the prothrombin (F2) gene that reduce prothrombin levels (ie, that cause inherited prothrombin deficiency) are associated with an increased risk of bleeding rather than thrombosis. (See "Rare inherited coagulation disorders", section on 'Factor II (prothrombin) deficiency (F2D)'.)

EPIDEMIOLOGY

●General population – The prothrombin G20210A variant (also called prothrombin gene mutation [PGM]) is predominantly found in White people, in which the prevalence of prothrombin G20210A is approximately 1 to 6 percent, with an overall prevalence of approximately 2 percent (table 1) [17,18]. The variant is infrequent in people with ancestry from Asia or Africa.

Linkage studies have suggested a single founder mutation, followed by wide geographic distribution. The variant is more common in Southern than Northern Europe, whereas factor V Leiden (FVL) follows the opposite pattern (FVL is more common in Northern rather than Southern Europe) [5,17].

●Patients with VTE – Among individuals with VTE, the prevalence of prothrombin G20210A is increased in a similar pattern. The prevalence was 4.6 percent in a series of 366 patients with VTE from France and 17 percent in a series of 116 unrelated individuals with VTE from Spain [19,20]. The original description of the variant, which included analysis of 28 probands from highly thrombophilic families, found it in 18 percent [2].

CLINICAL FEATURES — The major clinical manifestation of prothrombin G20210A is venous thromboembolism (VTE). A slight risk of arterial thrombosis may exist in certain settings. Data on obstetrical complications are contradictory, and evidence regarding an increased risk of other findings such as hearing loss or aseptic necrosis of the hip are not particularly convincing.

Venous thromboembolism — Prothrombin G20210A confers an increased risk of VTE, as do other inherited thrombophilias.

Risk of VTE — The risk of VTE in individuals who are heterozygous for prothrombin G20210A has been estimated to be increased approximately three- to fourfold based on evidence from case-control studies (table 1). As an example, in a series of 281 consecutive patients with VTE compared with 850 controls, the variant was found in approximately 8 percent of cases and 2 percent of controls (adjusted odds [OR] ratio for thrombosis, 3.1; 95% CI 1.9-5.2) [21]. Other case-control series have reported adjusted ORs in the range of 2.8 to 3.8 [2,19-22].

The risk of VTE is likely to be higher in individuals who are homozygous for the variant than in heterozygotes, although there are insufficient data to provide a good estimate of the absolute risk. Even among homozygotes, however, not all patients will develop VTE. In a series of 36 individuals who were homozygous for the prothrombin G20210A, 12 (33 percent) developed VTE in the setting of an acquired prothrombotic risk factor such as pregnancy or surgery [3].

It is not uncommon for an individual to have both prothrombin G20210A and factor V Leiden (FVL) and for the combination to further increase VTE risk. In a pooled analysis of eight case-control studies involving 2310 individuals with VTE and 3204 controls, 51 of the cases (2 percent) were doubly heterozygous for both variants (none of the controls were doubly heterozygous) [23]. ORs for VTE were as follows:

●Prothrombin G20210A – 3.8 (95% CI 3.0-4.9)

●FVL – 4.9 (95% CI 4.1-5.9)

●Both variants – 20.0 (95% CI 11.1-36.1)

Other studies have also documented an increased incidence of combined prothrombin G20201A and FVL and of greater thrombotic risk associated with the combination [24,25].

Other thrombophilic risk factors such as estrogen-containing contraceptives and pregnancy also may increase risk (table 2). In the pooled analysis mentioned above, the use of oral contraceptives increased the odds of VTE in prothrombin G20210A carriers from 3.8 to 7.1 [23]. In a case-control study of 42 women with VTE during pregnancy or postpartum and 213 controls without VTE, 31 percent of the women with VTE had prothrombin G20201A compared with 4.2 percent of controls (OR of 10.2; 95% CI 4.0-25.9) [26]. This supports our practice of avoiding estrogen-containing contraceptives in individuals with the variant and of having a lower threshold for thromboprophylaxis in certain other high-risk settings. (See 'Management' below.)

Sites of thrombosis — The sites of thrombosis are typically the deep leg veins (deep vein thrombosis [DVT]) with or without the pulmonary arterial circulation (pulmonary embolism [PE]), although other sites have been reported.

●DVT or PE – Individuals with prothrombin G20210A may present with proximal or distal DVT and/or PE. The likelihood of DVT and PE is similar.

•In a 2013 meta-analysis, the variant was present in 234 of 2158 individuals (10.8 percent) with proximal DVT and in 46 of 833 individuals (5.5 percent) with distal DVT [27].

•In a 2012 meta-analysis that included 11,111 patients with DVT or PE, prothrombin G20210A was present in 650 of 7062 individuals with DVT (9.2 percent) and 185 of 2515 individuals with isolated PE (7.4 percent) [28]. This differs from findings with FVL, in which the likelihood of presenting with isolated DVT is more than twofold greater than the likelihood of presenting with isolated PE. Reasons for the difference are unknown and may involve the differing biology of factors IIa and Va in the coagulation cascade.

●Portal, hepatic, or mesenteric vein thrombosis – Thrombosis in sites such as the portal vein or hepatic vein (Budd-Chiari syndrome [BCS]) has also been reported in individuals with prothrombin G20210A. In a 2014 meta-analysis that included nine studies evaluating the association of BCS with the prothrombin G20210A variant, presence of the variant did not significantly increase the risk of BCS (OR 1.8; 95% CI 0.8-4.1) [29]. In comparison, FVL was associated with an increased risk of BCS (OR 6.2; 95% CI 4.2-9.3).

●Cerebral vein thrombosis – Cerebral vein thrombosis (CVT) has been reported in individuals with prothrombin G20210A. A 2016 meta-analysis that included 868 cases of CVT and 3981 controls found a modest association (OR 5.8; 95% CI 4.0-8.6) [30]. The combination of the variant and other acquired risk factors such as hormonal contraceptive use further (greatly) increases this risk [31].

Recurrence risk — It is unclear whether prothrombin G20210A increases the risk of VTE recurrence (ie, second episode of VTE), with some studies suggesting a possible increased risk and others not [32-35]. In a 2009 systematic review that included 18 articles addressing VTE recurrence risk, heterozygosity for the variant did not confer increased risk of recurrent VTE (OR 1.45; 95% CI 0.96-2.2) [36]. Previous systematic reviews reported trends toward an increased risk that did not reach statistical significance [37,38]. Even if there is an increased risk of recurrent VTE, the magnitude of the increase is small, and other factors are more important in determining the duration of anticoagulation, such as whether the initial VTE was provoked or unprovoked. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Arterial thrombosis — Prothrombin G20210A does not appear to be a major risk factor for arterial thrombosis, although meta-analyses have documented slightly increased risks in certain settings.

●A 2017 meta-analysis of case-control and cohort studies evaluating the correlation between prothrombin G20210A and ischemic stroke in children and young adults found a slightly increased risk of stroke in children (odds ratio [OR] 1.83; 95% CI 1.19-2.80) and a similar but slightly smaller effect in young adults [39].

●A 2006 meta-analysis of case-control studies evaluating the role of inherited thrombophilias in coronary heart disease that included 66,155 patients with coronary artery disease and 91,307 controls found a slightly increased risk associated with prothrombin G20210A (relative risk [RR] 1.31; 95% CI 1.12-1.52) [40].

●A 2003 meta-analysis evaluating the association of inherited thrombophilias with arterial thromboembolic events (myocardial infarction, ischemic stroke, or peripheral vascular disease) reported a slight association between prothrombin G20210A and arterial events (OR 1.32; 95% CI 1.03-1.69) [41].

●In a series of 72 individuals who had a stroke before age 50 and did not have other cardiovascular risk factors, prothrombin G20210A was associated with an increased risk of stroke (OR 5.1; 95% CI 1.6-16.3; the prevalence of the variant was 7.6 in patients with stroke versus 1.2 percent in those without stroke) [42]. Other series have reported similar findings [43,44].

However, other studies have demonstrated no increased risk of myocardial infarction in individuals with prothrombin G20210A [45].

A discussion of thrombophilia testing in patients with stroke is presented separately. (See "Overview of the evaluation of stroke", section on 'Hypercoagulable studies' and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation'.)

Obstetric issues — As discussed separately, there is a large and contradictory body of literature on the association between maternal inherited thrombophilia and obstetric complications such as spontaneous abortion, fetal loss, and stillbirth. If an association exists, it is likely to be small. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk'.)

For women with prothrombin G20210A, available data do not support the use of anticoagulants to reduce the risk of obstetric complications. A review of this issue came to the conclusion that net harms of anticoagulation were likely to exceed net benefits [46]. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of pregnancy complications'.)

As noted above, pregnancy increases VTE risk in women with prothrombin G20210A; our approach to thromboprophylaxis in these individuals is addressed separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)

DIAGNOSIS — Prothrombin G20210A may be suspected in an individual with a strong family history of venous thromboembolism (VTE), a known family member with the variant, a personal history of VTE at an early age or in an unusual site, or recurrent VTE. In contrast, we do not routinely test for the variant in adults with isolated VTE, especially provoked VTE, or their asymptomatic family members. This practice is consistent with of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, which recommends against routine testing [47].

Diagnosis of prothrombin G20210A is straightforward because the variant involves a single base change (point mutation) that can be detected by genetic testing, which is unaffected by intercurrent illness or anticoagulant use.

Measurement of an elevated plasma prothrombin level cannot be used to screen for prothrombin G20210A because there is too great of an overlap between the upper limit of normal and levels in individuals who carry the variant.

Additional information about appropriate settings in which to test for prothrombin G20210A and other thrombophilias is presented separately. (See "Thrombophilia testing in children and adolescents" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Overview of the evaluation of stroke", section on 'Blood tests' and "Screening for inherited thrombophilia in asymptomatic adults".)

Genetic testing — As noted above, diagnosis of prothrombin G20210A is made using genetic testing rather than measurement of plasma prothrombin levels. Results of testing are unaffected by intercurrent illness or anticoagulant use.

Polymerase chain reaction (PCR) is the most straightforward and cost-effective method of genetic testing for the G20210A variant. PCR is performed on nucleated cells (eg, from whole blood). The presence of the variant can be detected using restriction enzyme digestion with electrophoresis or an enzyme-based immunoassay [48].

Some laboratories use multiplex PCR reactions to identify prothrombin G20210A and factor V Leiden (FVL) in the same reaction, although many laboratories use separate PCR assays for each variant [48,49].

When testing is indicated, we only screen for the G20210A variant and not for the other rare F2 variants listed above. (See 'Other prothrombin gene variants' above.)

Differential diagnosis — The differential diagnosis of VTE includes other inherited thrombophilias and acquired risk factors for thrombosis.

●Other inherited thrombophilias – Other inherited thrombophilias include FVL, protein S deficiency, protein C deficiency, and antithrombin (AT) deficiency; of these, FVL is the most common. Like prothrombin G20210A, patients may present with a positive personal or family history of VTE or other thromboembolic complications. Unlike prothrombin G20210A, individuals with these other inherited thrombophilias will have laboratory evidence of the other specific defect and will have negative genetic testing for prothrombin G20210A. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

●Acquired VTE risk factors – A number of acquired risk factors for VTE have been described, including immobility, surgery, trauma, cancer, myeloproliferative neoplasms (MPN), certain drugs, the antiphospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH), disseminated intravascular coagulation (DIC), and hormonal changes including estrogen-containing contraceptives, pregnancy, and the postpartum period. Like prothrombin G20210A, these patients may have VTE in typical or atypical locations. Unlike prothrombin G20210A, these acquired risk factors are often obvious from the patient history and physical examination, and the family history typically does not reveal thrombophilia. (See "Overview of the causes of venous thrombosis", section on 'Acquired risk factors'.)

MANAGEMENT

Patients with VTE — The initial management of acute venous thromboembolism (VTE) in patients with prothrombin G20210A is not different from that in patients without an inherited thrombophilia and typically includes anticoagulation for at least three to six months (algorithm 1). (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Prothrombin G20210A does not alter the choice between warfarin and a direct oral anticoagulant (DOAC). This choice is based on a number of factors including the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Comparison with heparin and warfarin'.)

We are more likely to use a DOAC for individuals with typical VTE presentations, and we are more likely to use warfarin for individuals with concerns about adherence or those who would benefit from maintaining an international normalized ratio (INR) in the high end of the therapeutic range (eg, submassive or massive pulmonary embolism [PE] with severe clinical presentations such as hypoxemia/shock, or deep vein thrombosis [DVT] with proximal clot burden).

The decision to continue anticoagulation beyond three to six months or indefinitely depends on whether the thrombosis was provoked or unprovoked and other factors. Indefinite anticoagulation is recommended for many patients with an unprovoked thromboembolic event, regardless of whether an inherited thrombophilia is identified [50]. Prothrombin G20210A has not been clearly shown to further increase the risk of VTE recurrence, but the presence of the variant may strengthen the case for indefinite anticoagulation, particularly if there is a strong family history of VTE. Other factors that make us more likely to advise indefinite anticoagulation include recurrent thrombosis, life-threatening thrombosis, thrombosis at an unusual site, or more than one inherited prothrombotic defect. This issue is discussed in more detail separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Asymptomatic individuals — Individuals with prothrombin G20210A who have not had a thromboembolic event are not treated with routine anticoagulation. (See "Screening for inherited thrombophilia in asymptomatic adults".)

However, we generally avoid estrogen-containing contraceptives in women with the G20210A variant. (See "Contraception: Counseling for women with inherited thrombophilias".)

We also provide education regarding conditions that increase thrombotic risk (eg, prolonged immobility). A patient information document has been published and is available for downloading [51].

Individuals with prothrombin G20210A may also benefit from the judicious use of prophylactic anticoagulation in certain settings, especially if they have a strong family history of VTE or other VTE risk factors (algorithm 1). Recommendations for anticoagulation in specific settings are presented in separate topic reviews:

●Pregnancy – (See "Inherited thrombophilias in pregnancy".)

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

●Acute medical illness – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Testing of first-degree relatives — The testing of asymptomatic first-degree relatives can be delayed until after puberty and is generally most helpful in settings in which the risk of thrombosis is increased, such as initiation of an estrogen-containing contraceptive or pregnancy. This subject is discussed in more detail separately. (See "Screening for inherited thrombophilia in asymptomatic adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY AND RECOMMENDATIONS

●Genetics and pathophysiology – Prothrombin (factor II; F2) is the precursor of thrombin, the end-product of the coagulation cascade (figure 1 and figure 2). The G20210A variant is a point mutation in which adenine is substituted for guanine at position 20210 in the 3’ untranslated region of the gene (figure 3), corresponding to the messenger RNA sequence responsible for polyadenylation. Heterozygotes for prothrombin G20210A have approximately 30 percent higher plasma prothrombin levels than controls. (See 'Pathophysiology' above.)

●Prevalence – The prothrombin G20210A variant is most commonly seen in White people, especially those with ancestry from Southern Europe, where the prevalence is approximately 1 to 6 percent overall and 5 to 8 percent in individuals with venous thromboembolism (VTE) (table 1). (See 'Epidemiology' above.)

●VTE risk – The risk of VTE in prothrombin G20210A heterozygotes has been estimated to be increased approximately three- to fourfold; VTE risk is higher in homozygotes. The likelihood of deep vein thrombosis (DVT) and pulmonary embolism (PE) is similarly increased. Patients may also have VTE at atypical sites such as portal, hepatic, or cerebral veins; and a slightly increased risk of arterial ischemic/thrombotic events. (See 'Clinical features' above.)

●Indications for testing – The role of testing for prothrombin G20210A (and other inherited thrombophilias) in various clinical settings is discussed in separate topic reviews. (See "Thrombophilia testing in children and adolescents" and "Screening for inherited thrombophilia in asymptomatic adults" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Overview of the evaluation of stroke", section on 'Blood tests'.)

●Diagnosis – Diagnosis of prothrombin G20210A is straightforward because the variant involves a single base change (point mutation) that can be detected by genetic testing, which is unaffected by intercurrent illness or anticoagulant use. Polymerase chain reaction (PCR)-based methods are the most straightforward and cost-effective. (See 'Diagnosis' above.)

●Treatment – The initial management of acute VTE in patients with prothrombin G20210A is not different from that in patients without an inherited thrombophilia; anticoagulation is typically given for at least three to six months (algorithm 1). The decision to continue anticoagulation beyond three to six months or indefinitely depends on whether the thrombosis was provoked or unprovoked and other factors. Prothrombin G20210A does not alter the choice of anticoagulant or dosing, which are discussed separately. (See 'Patients with VTE' above and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

●VTE risk reduction – For individuals with prothrombin G20210A who have not had a VTE, we generally avoid estrogen-containing contraceptives and provide education and counseling regarding conditions that may increase VTE risk. Judicious use of prophylactic anticoagulation may be appropriate in certain settings, especially if there is a strong family history of VTE or other VTE risk factors (algorithm 1). (See "Contraception: Counseling for women with inherited thrombophilias" and "Inherited thrombophilias in pregnancy" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

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  24. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341:801.
  25. Ehrenforth S, Ludwig G, Klinke S, et al. The prothrombin 20210 A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gln mutation with venous thrombophilia. Blood 1998; 91:2209.
  26. Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol 1998; 179:1324.
  27. Dentali F, Pomero F, Borretta V, et al. Location of venous thrombosis in patients with FVL or prothrombin G20210A mutations: systematic review and meta-analysis. Thromb Haemost 2013; 110:191.
  28. Dentali F, Ageno W, Bozzato S, et al. Role of factor V Leiden or G20210A prothrombin mutation in patients with symptomatic pulmonary embolism and deep vein thrombosis: a meta-analysis of the literature. J Thromb Haemost 2012; 10:732.
  29. Zhang P, Zhang J, Sun G, et al. Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis. PLoS One 2014; 9:e95719.
  30. Gonzalez JV, Barboza AG, Vazquez FJ, Gándara E. Prevalence and Geographical Variation of Prothrombin G20210A Mutation in Patients with Cerebral Vein Thrombosis: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0151607.
  31. 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.
  32. Simioni P, Prandoni P, Lensing AW, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000; 96:3329.
  33. Lindmarker P, Schulman S, Sten-Linder M, et al. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost 1999; 81:684.
  34. Eichinger S, Minar E, Hirschl M, et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost 1999; 81:14.
  35. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. Br J Haematol 2001; 113:630.
  36. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009; 301:2472.
  37. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166:729.
  38. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92:1107.
  39. Sarecka-Hujar B, Kopyta I, Skrzypek M, Sordyl J. Association Between the 20210G>A Prothrombin Gene Polymorphism and Arterial Ischemic Stroke in Children and Young Adults-Two Meta-analyses of 3586 Cases and 6440 Control Subjects in Total. Pediatr Neurol 2017; 69:93.
  40. Ye Z, Liu EH, Higgins JP, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367:651.
  41. Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J 2003; 146:948.
  42. De Stefano V, Chiusolo P, Paciaroni K, et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91:3562.
  43. Lalouschek W, Schillinger M, Hsieh K, et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke 2005; 36:1405.
  44. Lichy C, Reuner KH, Buggle F, et al. Prothrombin G20210A mutation, but not factor V Leiden, is a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia. Cerebrovasc Dis 2003; 16:83.
  45. Eikelboom JW, Baker RI, Parsons R, et al. No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease. Thromb Haemost 1998; 80:878.
  46. Bradley LA, Palomaki GE, Bienstock J, et al. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med 2012; 14:39.
  47. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 2011; 13:67.
  48. Cooper PC, Rezende SM. An overview of methods for detection of factor V Leiden and the prothrombin G20210A mutations. Int J Lab Hematol 2007; 29:153.
  49. Gomez E, van der Poel SC, Jansen JH, et al. Rapid simultaneous screening of factor V Leiden and G20210A prothrombin variant by multiplex polymerase chain reaction on whole blood. Blood 1998; 91:2208.
  50. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest 2021; 160:e545.
  51. Varga EA, Moll S. Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation). Circulation 2004; 110:e15.
Topic 1359 Version 28.0

References

1 : Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment.

2 : 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.

3 : Homozygous patients with the 20210 G to A prothrombin polymorphism remain often asymptomatic in spite of the presence of associated risk factors.

4 : Increased efficiency of mRNA 3' end formation: a new genetic mechanism contributing to hereditary thrombophilia.

5 : Classic thrombophilic gene variants.

6 : Prothrombin G20210A is a bifunctional gene polymorphism.

7 : The G20210A mutation does not affect the stability of prothrombin mRNA in vivo.

8 : Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis.

9 : A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation.

10 : G20210A is a functional mutation in the prothrombin gene; effect on protein levels and 3'-end formation.

11 : Thrombosis from a prothrombin mutation conveying antithrombin resistance.

12 : Abnormal melt curve profile during prothrombin 20210G -->A analysis due to the 20209C -->T variant.

13 : Characterization of a novel prothrombin variant, Prothrombin C20209T, as a modifier of thrombotic risk among African-Americans.

14 : The prevalence of the prothrombin gene variant C20209T in African-Americans and Caucasians and lack of association with venous thromboembolism.

15 : Prothrombin A19911G and G20210A polymorphisms' role in thrombosis.

16 : Prothrombin A19911G polymorphism and the risk of venous thromboembolism.

17 : Geographic distribution of the 20210 G to A prothrombin variant.

18 : A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.

19 : Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients.

20 : The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population.

21 : Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant.

22 : The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis.

23 : Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.

24 : The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.

25 : The prothrombin 20210 A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gln mutation with venous thrombophilia.

26 : Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.

27 : Location of venous thrombosis in patients with FVL or prothrombin G20210A mutations: systematic review and meta-analysis.

28 : Role of factor V Leiden or G20210A prothrombin mutation in patients with symptomatic pulmonary embolism and deep vein thrombosis: a meta-analysis of the literature.

29 : Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis.

30 : Prevalence and Geographical Variation of Prothrombin G20210A Mutation in Patients with Cerebral Vein Thrombosis: A Systematic Review and Meta-Analysis.

31 : High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.

32 : Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis.

33 : The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.

34 : The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene.

35 : The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation.

36 : Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.

37 : Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review.

38 : The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies.

39 : Association Between the 20210G>A Prothrombin Gene Polymorphism and Arterial Ischemic Stroke in Children and Young Adults-Two Meta-analyses of 3586 Cases and 6440 Control Subjects in Total.

40 : Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls.

41 : Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies.

42 : Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients.

43 : Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years.

44 : Prothrombin G20210A mutation, but not factor V Leiden, is a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia.

45 : No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease.

46 : Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review.

47 : Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members.

48 : An overview of methods for detection of factor V Leiden and the prothrombin G20210A mutations.

49 : Rapid simultaneous screening of factor V Leiden and G20210A prothrombin variant by multiplex polymerase chain reaction on whole blood.

50 : Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report.

51 : Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation).