ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Prothrombin G20210A

Prothrombin G20210A
Literature review current through: May 2024.
This topic last updated: Feb 28, 2023.

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".)

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

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

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

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

Screening:

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

Asymptomatic individuals – (See "Hereditary thrombophilia testing in adults without VTE".)

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-dependent clotting factors: Gamma carboxylation and functions of Gla".)

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 noncoding 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 autosomal dominant, and the risk of venous thromboembolism (VTE) in heterozygous individuals is increased approximately three- to fourfold compared with noncarriers. (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 activity in association with a commensurate increase in prothrombin antigen [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 an increased risk of bleeding; the phenotype depends on whether they ultimately decrease or increase prothrombin activation. The following variants are not part of routine thrombophilia panels:

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].

Pathogenic variants 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 is 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 ratio [OR] 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 [3,23].

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) [24]. 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 a greater thrombotic risk associated with the combination [25,26].

However, not all individuals with multiple thrombophilic variants will develop thrombosis. A multicenter case series of 100 patients with rare compound combinations of homozygous FVL with heterozygous prothrombin G20210A variant or heterozygous FVL with homozygous prothrombin G20210A showed that, even though they have a substantial risk for VTE, 19 individuals remained asymptomatic [23].

Other risk factors for VTE such as estrogen-containing contraceptives and pregnancy also 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 [24]. 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 10.2, 95% CI 4.0-25.9) [27]. Implications for management are discussed below. (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 [28].

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) [29]. 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 increased the risk of BCS (OR 1.8, 95% CI 0.8-4.1), but the increase did not reach statistical significance [30]. In comparison, FVL was associated with an increased risk of BCS (OR 6.2, 95% CI 4.2-9.3).

Cerebral venous sinus thrombosis – Cerebral venous sinus thrombosis (CVST; also called cerebral vein thrombosis) has been reported in individuals with prothrombin G20210A. A 2016 meta-analysis that included 868 cases of CVST and 3981 controls found a highly significant association (OR 5.8, 95% CI 4.0-8.6) [31]. The combination of the variant and other risk factors for VTE such as hormonal contraceptive use further increases this risk [32].

VTE recurrence risk — Numerous studies and systematic reviews have evaluated the risk of recurrent VTE in individuals with prothrombin G20210A and a previous VTE episode, with some studies suggesting a possible increased risk and others not [33-38].

In a 2009 systematic review that included 18 articles addressing VTE recurrence risk, heterozygosity for the variant did not confer a statistically significant increased risk of recurrent VTE (OR 1.45, 95% CI 0.96-2.2); the point estimate of the observed effect was similar to that of FVL [37].

It is widely accepted that heterozygosity for prothrombin G20210A does not confer a clinically relevant increased risk for recurrent VTE among patients with a first unprovoked VTE, and the presence of prothrombin G20210A generally does not alter decision-making regarding the duration of anticoagulation. However, the role of thrombophilia testing (and the decision to test for prothrombin G20210A) is complex when VTE occurs in the setting of pregnancy or hormonal therapy, or when there is a strong family history plus a major transient risk factor. Management implications are discussed below and in separate topic reviews. (See 'Management' below and "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 (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

Obstetric complications – 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. Available data do not support the use of anticoagulation to reduce the risk of obstetric complications in individuals with prothrombin G20210A. 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'.)

VTE – Pregnancy increases VTE risk in individuals 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 relative with the variant, a personal history of VTE at an early age or in an unusual site, or recurrent VTE. Prothrombin G20210A may also contribute to thrombosis risk in older individuals with VTE.

Indications for testing are discussed in separate topic reviews. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

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 "Hereditary thrombophilia testing in adults without VTE".)

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 or buccal swab). The presence of the variant can be detected using restriction enzyme digestion with electrophoresis or an enzyme-based immunoassay [47].

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 [47,48].

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 risk factors for venous thromboembolism and pregnancy loss are presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Inherited thrombophilias in pregnancy".)

MANAGEMENT

Patients with VTE

Initial management – The presence of prothrombin G20210A does not influence the initial management of acute venous thromboembolism (VTE) (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".)

Choice of anticoagulant – Prothrombin G20210A does not alter the agent that is chosen for initial or subsequent anticoagulation. 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'.)

Additional information regarding the anticoagulants and their dosing and monitoring is presented separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management" and "Heparin and LMW heparin: Dosing and adverse effects".)

Duration of anticoagulation – The duration of anticoagulation depends on the risk of recurrent VTE; VTE recurrence was 1.45-fold higher in a systematic review of individuals heterozygous for prothrombin G20210A relative to patients with VTE without prothrombin G20210A [37]. (See 'VTE recurrence risk' above.)

As in all patients with VTE, the duration of anticoagulation is an individualized decision. Similar to the general population, we are more likely to advise indefinite anticoagulation in those whose VTE is unprovoked, life-threatening, at an unusual site such as the mesenteric or portal vein, or with more than one episode of VTE. For individuals with heterozygous prothrombin G20210A and a single episode of VTE provoked by a major transient risk factor, three to six months of anticoagulation is generally used, and indefinite anticoagulation generally is not required.

Factors to be incorporated into the decision regarding the duration of anticoagulation are discussed in more detail separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Specific sites of VTE – Recommendations specific to the site of thromboembolism are also presented in separate topic reviews:

Pulmonary embolism (PE) – (See "Venous thromboembolism: Initiation of anticoagulation".)

Deep vein thrombosis (DVT) – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Portal vein thrombosis (PVT) – (See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)

Cerebral vein thrombosis (CVT) – (See "Cerebral venous thrombosis: Treatment and prognosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

Asymptomatic individuals — Individuals with prothrombin G20210A who have not had a thromboembolic event do not require anticoagulation unless there is a clinical indication such as an acute medical illness or surgery for which routine thromboprophylaxis is indicated. However, unlike the general population, we are more likely to use anticoagulation for certain surgeries. (See 'Surgery/pregnancy/acute medical illness' below.)

Contraceptives — When contraception is appropriate, we advise use of non-estrogen-containing methods. (See "Contraception: Counseling for women with inherited thrombophilias".)

Airline travel — A common question that arises is the prevention of VTE during airline travel or other situations with prolonged sitting. We generally suggest ambulating and performing leg exercises while seated. Compression stockings may be appropriate for individuals with leg edema. There are no high-quality data that aspirin or an anticoagulant reduces the risk of VTE. (See "Prevention of venous thromboembolism in adult travelers".)

Additional evaluations — We do not perform screening for other inherited thrombophilias in asymptomatic individuals with prothrombin G20210A as a way to estimate their risk of VTE because there are no data to support this practice. (See "Hereditary thrombophilia testing in adults without VTE".)

Counseling — A patient information document has been published and is available for downloading [49].

Surgery/pregnancy/acute medical illness — 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 — If testing of asymptomatic first-degree relatives is considered, this 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 "Hereditary thrombophilia testing in adults without VTE".)

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 F2 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. (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 "Hereditary thrombophilia testing in adults without VTE" 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.)

VTE treatment – The presence of prothrombin G20210A does not influence the initial management of acute VTE (algorithm 1). We individualize the duration of anticoagulation according to features such as whether the VTE was provoked, life-threatening, and/or at an unusual site, as done for the general population, rather than a more aggressive approach. After a first episode of VTE provoked by a hormonal risk factor such as oral contraceptives, pregnancy, or the postpartum period, presence of prothrombin G20210A may justify considering indefinite duration anticoagulation. (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 asymptomatic individuals who are heterozygous for prothrombin G20210A, routine anticoagulation is not required. Additional issues such as possible avoidance of estrogen-containing contraceptives are discussed above. (See 'Asymptomatic individuals' above and "Contraception: Counseling for women with inherited thrombophilias".)

Population screening – Screening for prothrombin G20210A in asymptomatic individuals is discouraged. (See "Hereditary thrombophilia testing in adults without VTE".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.

  1. Meeks SL, Abshire TC. Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment. Haemophilia 2008; 14:1159.
  2. 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.
  3. Girolami A, Scarano L, Tormene D, Cella G. Homozygous patients with the 20210 G to A prothrombin polymorphism remain often asymptomatic in spite of the presence of associated risk factors. Clin Appl Thromb Hemost 2001; 7:122.
  4. Gehring NH, Frede U, Neu-Yilik G, et al. Increased efficiency of mRNA 3' end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 2001; 28:389.
  5. Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114:885.
  6. Carter AM, Sachchithananthan M, Stasinopoulos S, et al. Prothrombin G20210A is a bifunctional gene polymorphism. Thromb Haemost 2002; 87:846.
  7. Pollak ES, Lam HS, Russell JE. The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood 2002; 100:359.
  8. Soria JM, Almasy L, Souto JC, et al. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood 2000; 95:2780.
  9. Gelfi C, Viganò A, Ripamonti M, et al. A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation. Proteomics 2004; 4:2151.
  10. Ceelie H, Spaargaren-van Riel CC, Bertina RM, Vos HL. G20210A is a functional mutation in the prothrombin gene; effect on protein levels and 3'-end formation. J Thromb Haemost 2004; 2:119.
  11. Miyawaki Y, Suzuki A, Fujita J, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med 2012; 366:2390.
  12. Dunn ST, Allen RA, Bates F, et al. Abnormal melt curve profile during prothrombin 20210G --> A analysis due to the 20209C --> T variant. Blood Coagul Fibrinolysis 2006; 17:599.
  13. Itakura H, Telen MJ, Hoppe CC, et al. Characterization of a novel prothrombin variant, Prothrombin C20209T, as a modifier of thrombotic risk among African-Americans. J Thromb Haemost 2005; 3:2357.
  14. Hooper WC, Roberts S, Dowling N, et al. The prevalence of the prothrombin gene variant C20209T in African-Americans and Caucasians and lack of association with venous thromboembolism. Thromb Res 2006; 118:767.
  15. Pérez-Ceballos E, Corral J, Alberca I, et al. Prothrombin A19911G and G20210A polymorphisms' role in thrombosis. Br J Haematol 2002; 118:610.
  16. Martinelli I, Battaglioli T, Tosetto A, et al. Prothrombin A19911G polymorphism and the risk of venous thromboembolism. J Thromb Haemost 2006; 4:2582.
  17. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79:706.
  18. Zivelin A, Rosenberg N, Faier S, et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood 1998; 92:1119.
  19. Leroyer C, Mercier B, Oger E, et al. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80:49.
  20. Souto JC, Coll I, Llobet D, et al. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80:366.
  21. Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. Ann Intern Med 1998; 129:89.
  22. Hillarp A, Zöller B, Svensson PJ, Dahlbäck 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.
  23. Lim MY, Deal AM, Kim S, et al. Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: an international case series of 100 individuals. Eur J Haematol 2016; 97:353.
  24. Emmerich J, Rosendaal FR, Cattaneo M, et al. 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. Thromb Haemost 2001; 86:809.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  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. 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.
  48. 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.
  49. Varga EA, Moll S. Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation). Circulation 2004; 110:e15.
Topic 1359 Version 30.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟