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Prothrombin-Related Thrombophilia

Synonyms: F2-Related Thrombophilia, Factor II-Related Thrombophilia, Prothrombin G20210A Thrombophilia, Prothrombin 20210G>A Thrombophilia, Prothrombin Thrombophilia
, MD
Assistant Professor of Pediatrics and Medicine
Oregon Hemophilia Center
Oregon Health and Science University
Portland, Oregon

Initial Posting: ; Last Update: August 14, 2014.

Summary

Disease characteristics. Prothrombin-related thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin-related thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A (G20210A or c.*97G>A) allele in F2 never develop thrombosis, and while most heterozygotes who develop thrombotic complications remain asymptomatic until adulthood, some have recurrent thromboembolism before age 30 years. The relative risk for DVT in adults heterozygous for the 20210G>A allele is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. 20210G>A heterozygosity has at most a modest effect on recurrence risk after a first episode. Although prothrombin-related thrombophilia may increase the risk for pregnancy loss, its association with preeclampsia and other complications of pregnancy such as intrauterine growth restriction and placental abruption remains controversial. Factors that predispose to thrombosis in prothrombin-related thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after travel.

Diagnosis/testing. The diagnosis of prothrombin-related thrombophilia requires molecular genetic testing of F2, the gene encoding prothrombin, to identify the 20210G>A allele (also known as G20210A or c.*97G>A).

Management. Treatment of manifestations: Management depends on the clinical circumstances. The first acute thrombosis is treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux, and concurrent oral administration of warfarin for at least five days (except in pregnancy). The international-normalized ratio (INR) is used to monitor warfarin anticoagulation. Rivaroxaban, a factor Xa inhibitor, is approved for the treatment of acute VTE and long-term prevention of recurrence. The duration of anticoagulation therapy is determined by assessment of the risks for (1) VTE recurrence and (2) anticoagulant-related bleeding. Individuals with a spontaneous thrombosis with no identifiable provoking factors and those with persistent risk factors are candidates for long-term anticoagulation therapy. Treatment for three months is recommended for individuals with transient (reversible) risk factors such as surgery. Graduated compression stockings should be worn for at least two years following an acute DVT.

Agents/circumstances to avoid: Heterozygous and homozygous women with a history of VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT).

Evaluation of relatives at risk: Because there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis.

Pregnancy management: No consensus exists on the optimal management of prothrombin-related thrombophilia during pregnancy; guidelines for treatment of VTE are derived from studies in non-pregnant individuals.

Genetic counseling. Prothrombin-related thrombophilia is inherited in an autosomal dominant manner: heterozygosity for the 20210G>A allele results in an increased risk for thrombosis; homozygosity for this allele confers a higher risk for thrombosis than heterozygosity. All individuals reported to date with prothrombin-related thrombophilia who are heterozygous for the 20210G>A allele have had an affected parent. Because of the relatively high prevalence of this allele in the general population, occasionally one parent is homozygous or both parents are heterozygous for this allele. If one parent of a heterozygous proband is heterozygous for the 20210G>A allele, the sibs of the proband are at 50% risk of being heterozygous; if one parent is homozygous, the sibs of the proband will be heterozygous. Although technically possible, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are rarely, if ever, performed because the 20210G>A allele only increases the relative risk for thrombophilia and is not predictive of a thrombotic event.

Diagnosis

Suggestive Findings

No clinical features are specific for prothrombin-related thrombophilia. The diagnosis is suspected in probands with at least one of the more specific features [Chalmers et al 2011, McGlennen & Key 2002, Howard & Hughes 2013, Bates et al 2012, Royal College of Obstetricians and Gynaecologists 2009, Chalmers et al 2011, Royal College of Obstetricians and Gynaecologists 2011a, Tait et al 2012, American College of Obstetricians and Gynecologists 2013b]:

  • A first unprovoked venous thromboembolism (VTE) before age 50 years
  • A history of recurrent VTE
  • Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
  • VTE during pregnancy or the puerperium
  • VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)
  • An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years

Prothrombin-related thrombophilia may also be considered in probands who have less specific findings, including the following:

  • A history of unprovoked VTE considering discontinuation of anticoagulation [National Clinical Guideline Centre 2012]
  • Selected women with unexplained second trimester fetal loss
  • A first VTE related to use of tamoxifen or other selective estrogen receptor modulators (SERM)
  • Age greater than 50 years with a first unprovoked VTE
  • Neonates and children with non-catheter related idiopathic VTE or stroke

Testing to Confirm the Diagnosis

The diagnosis of prothrombin-related thrombophilia requires molecular genetic analysis of F2, the gene encoding prothrombin, to identify the common pathogenic variant 20210G>A (see Table 1). Note that because the range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range (see Molecular Genetics, Normal gene product), the plasma prothrombin concentration is not reliable for diagnosis.

The decision to test an individual suspected of having prothrombin-related thrombophilia should be based on the likelihood that test results would influence treatment [Baglin et al 2010, EGAPP Working Group 2011, De Stefano & Rossi 2013].

Note: (1) Clinical guidelines from the UK and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group stress the uncertain benefit of testing for inherited thrombophilia in several accepted circumstances, including in individuals who have some of the more specific findings [Baglin et al 2010, EGAPP Working Group 2011, Tait et al 2012]. See Published Guidelines/Policy Statements. (2) American and British guidelines do not recommend routine testing for thrombophilia in adults or children with VTE [Chalmers et al 2011, Tait et al 2012].

Table 1. Summary of Molecular Genetic Testing Used in Prothrombin-Related Thrombophilia

Gene 1Test MethodMutations Detected Proportion of Probands with a Pathogenic Variant Detectable by This Method
F2Targeted mutation analysis 220210G>A (c.*97G>A) 3100%

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Targeted mutation analysis for the 20210G>A (c.*97G>A) allele is performed by a variety of comparable methods [Spector et al 2005 (full text)].

3. The official designation of the pathogenic variant is c.*97G>A per guidelines at www​.hgvs.org.

Interpretation of test results. Molecular genetic test results are reliable in individuals on warfarin, heparin, or other antithrombotic agents and are independent of thrombotic episodes.

Test results on DNA extracted from peripheral blood leukocytes need to be interpreted with caution in the setting of liver transplantation or hematopoetic stem cell transplantation (HSCT).

  • Diagnosis of prothrombin-related thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis [Mas et al 2003].
  • Diagnosis of prothrombin-related thrombophilia in HSCT recipients requires molecular analysis of non-hematopoietic tissue in the recipient (e.g., buccal cells).

It is important to note that testing for the F2 20210G>A allele is not recommended for the following:

  • General population screening
  • Routine initial testing prior to the use of estrogen-containing contraceptives, hormone replacement therapy (HRT), or SERMs
  • Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma) [Hicks et al 2013]
  • Routine initial testing in adults with arterial thrombosis
  • Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
  • Routine initial testing during pregnancy
  • Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia [Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]
  • Prenatal or newborn testing
  • Neonates and children with asymptomatic central venous catheter-related thrombosis
  • Routine testing in asymptomatic children
  • Routine testing of unselected children with a first episode of VTE [Chalmers et al 2011]

Clinical Description

Natural History

The clinical expression of prothrombin-related thrombophilia is variable. Many individuals who are heterozygous or homozygous for the F2 20210G>A allele never develop thrombosis. While most individuals with prothrombin-related thrombophilia do not experience a first thrombotic event until adulthood, some have recurrent VTE before age 30 years.

Venous Thromboembolism (VTE)

The primary clinical manifestation of prothrombin-related thrombophilia is venous thromboembolism (VTE). Deep-vein thrombosis (DVT) and pulmonary embolism (PE) are the most common VTE. The most common site for deep-vein thrombosis is the legs, but upper-extremity thrombosis also occurs.

Risk for VTE in adults heterozygous for the F2 20210G>A allele

The relative risk for VTE is increased two- to fivefold in 20210G>A heterozygotes [Lijfering et al 2009, Rosendaal & Reitsma 2009]. In a large meta-analysis of 79 studies, 20210G>A heterozygosity was associated with a threefold increased risk for VTE [Gohil et al 2009].

Among individuals with DVT, 20210G>A heterozygotes had a significantly higher rate of PE (32%) than those with the factor V Leiden allele (19%) or without thrombophilia (17%). 20210G>A heterozygotes are also at increased risk of developing isolated pulmonary emboli [Martinelli et al 2006] and may develop VTE at a younger age than individuals without the allele [Bank et al 2004, Martinelli et al 2006].

Upper-extremity thrombosis. The available evidence suggests that heterozygosity for 20210G>A is an independent risk factor for upper-extremity thrombosis [Vaya et al 2003, Martinelli et al 2004, Blom et al 2005a, Linnemann et al 2008a]:

  • The 20210G>A allele was reported in 5%-12% of persons with upper-extremity thrombosis not related to a central venous catheter, suggesting that the allele confers a three- to sixfold increased risk for thrombosis in this location [Vaya et al 2003, Martinelli et al 2004, Blom et al 2005a, Linnemann et al 2008a]. The prevalence of the allele is higher in those with idiopathic (unprovoked) upper-extremity thrombosis than in those with thrombosis related to a central venous catheter [Lechner et al 2008].
  • Heterozygosity for 20210G>A was associated with a fivefold increased risk for idiopathic (unprovoked) upper-extremity thrombosis (not related to malignancy or a central venous catheter) [Martinelli et al 2004]. Women heterozygous for 20210G>A who were using oral contraceptives had a nine- to 14-fold increased risk for idiopathic upper-extremity thrombosis [Martinelli et al 2004, Blom et al 2005a].

Cerebral vein thrombosis

Hepatic thrombosis and portal vein thrombosis are other reported complications in adult 20210G>A heterozygotes [Janssen et al 2000, Amitrano et al 2004, Primignani et al 2005]. A meta-analysis concluded that 20210G>A heterozygosity was associated with a fourfold increased risk for both idiopathic and liver disease-associated portal vein thrombosis [Dentali et al 2008a].

Thrombosis in unusual locations in adults who are heterozygous for 20210G>A also occurs more frequently than in the general population. However, these events are much less common than DVT or pulmonary emboli, and there is no evidence that identification of a 20210G>A allele should alter management [Tait et al 2012].

Risk for VTE in family members of probands with the F2 20210G>A allele

Whereas the relative risk for a first episode of VTE in asymptomatic family members with a 20210G>A allele is increased two- to fivefold, the absolute risk is low. In several retrospective family studies the absolute incidence of a first VTE was 0.19%/year to 0.41%/year in asymptomatic 20210G>A heterozygotes, compared to 0.05%/year to 0.18%/year in relatives without the allele [Bank et al 2004, Lijfering et al 2009].

  • A prospective study of asymptomatic relatives of probands with a 20210G>A allele and arterial or venous thromboembolism found similar annual incidences of a first VTE in relatives with (0.37%/year) and without (0.12%/year) the allele [Coppens et al 2006].
  • A large study of family members of probands with thrombophilia found no increased risk of VTE among relatives heterozygous for 20210G>A [Rossi et al 2011].
  • The risk for VTE is higher in asymptomatic 20210G>A heterozygotes from families with a strong history of VTE than in unselected individuals identified by population screening [Bank et al 2004, Couturaud et al 2009]. The increased susceptibility to VTE in thrombosis-prone families results from the coinheritance of other unidentified inherited thrombophilic disorders.
  • In a single large retrospective family study, the annual incidence of a first VTE was 1.10%/year in relatives homozygous for 20210G>A [Bank et al 2004]. In contrast, no VTE events occurred in the small number of homozygous family members included in two other studies [Coppens et al 2006, Lijfering et al 2009]. Relatives heterozygous for 20210G>A in combination with other inherited thrombophilic disorders had an annual incidence of first VTEof 0.45%-0.59%/year [Lijfering et al 2009].

Risk for VTE in children heterozygous for the F2 20210G>A allele

A combination of risk factors appears to be necessary to provoke thrombosis in children [Revel-Vilk & Kenet 2006, Raffini 2008, Tuckuviene et al 2011]. VTE in children is usually a complication of one or more medical conditions and/or a central venous catheter. The majority of children reported with VTE had other coexisting inherited and/or circumstantial risk factors [Revel-Vilk et al 2003, Young et al 2008]. An increased prevalence of 20210G>A was found in neonates and children with VTE in some but not all studies. The variation in reported prevalence of the allele likely reflects differences in study design and clinical characteristics of the children included.

The available data summarized below suggest that asymptomatic healthy children who are heterozygotes or homozygotes for 20210G>A are at low risk for thrombosis except in the setting of strong circumstantial risk factors [Tuckuviene et al 2011].

Studies that support an association of 20210G>A heterozygosity with VTE in children:

  • Several retrospective case-control studies found a heterozygous 20210G>A allele in 4%-8% of children with a first VTE compared to 1%-3% of controls, suggesting a three- to fourfold increase in relative risk [Junker et al 1999, Schobess et al 1999].
  • In a retrospective review of 38 symptomatic children heterozygous for the 20210G>A allele, additional circumstantial risk factors were present at the time in 92% of VTE events. Central venous catheters and malignancy were among the most common risk factors identified [Young et al 2003, Young et al 2008].
  • A meta-analysis found that 20210G>A heterozygosity was associated with a two- to threefold increased risk for a first VTE in children. The risk was increased more than ninefold in children with two or more inherited thrombophilic disorders [Young et al 2008]. Other studies also found a higher risk in children doubly heterozygous for the 20210G>A and factor V Leiden alleles or with the 20210G>A allele in combination with other inherited thrombophilic disorders [Junker et al 1999, Young et al 2003].

Studies that do not support an association of 20210G>A heterozygosity with VTE in children:

  • Several studies of unselected children with a history of VTE found a low prevalence of 20210G>A heterozygosity, similar to that in controls or in the general population [Revel-Vilk et al 2003, van Ommen et al 2003, Albisetti et al 2007].
  • In a prospective study of family members of symptomatic probands, asymptomatic children heterozygous or homozygous for 20210G>A had no thrombotic complications during an average follow-up period of five years [Tormene et al 2002].

Cerebral vein thrombosis in children. Although some evidence suggests that 20210G>A heterozygosity may predispose to central nervous system (CNS) thrombosis in children, the evidence is conflicting.

Studies that support an association of 20210G>A heterozygosity with cerebral vein thrombosis in children:

  • The combination of an inherited or acquired thrombophilic disorder (including 20210G>A heterozygosity) and an underlying medical condition conferred a fourfold increased risk for cerebral vein thrombosis, underscoring the multifactorial etiology of this thrombotic complication [Heller et al 2003].
  • A meta-analysis found that a 20210G>A allele was associated with a significant twofold increased risk for the combined outcome of first cerebral vein thrombosis or acute ischemic stroke in children [Kenet et al 2010].

Studies that do not support an association of 20210G>A heterozygosity with cerebral vein thrombosis in children:

  • In a small case-control study, the prevalence of 20210G>A heterozygosity was similar in children with cerebral vein thrombosis (2.6%) and a group of control children (3.5%) [Kenet et al 2004].
  • Data from a large population-based registry suggest a low prevalence of the 20210G>A allele* among children and neonates with cerebral vein thrombosis [DeVeber et al 2001].

*Note: Throughout this GeneReview, 20210G>A without specification of homo- vs. heterozygosity indicates that the studies described did not specify zygosity.

Hepatic, portal, and retinal vein thromboses in children heterozygous for the 20210G>A allele have also been reported.

Thrombosis in unusual locations (e.g., cerebral vein and hepatic vein) in children heterozygous for 20210G>A occur less commonly than thrombosis of an extremity or pulmonary embolism.

Recurrent Thrombosis

Risk for recurrent thrombosis in adult 20210G>A heterozygotes

Summary. Current evidence suggests that 20210G>A heterozygosity has at most a modest effect on recurrence risk after initial treatment of a first VTE [Kyrle et al 2010]. Although the data are conflicting, the majority of more recent studies found no increase in risk. An evidence review by the EGAPP concluded that 20210G>A heterozygosity is not predictive of VTE recurrence [EGAPP Working Group 2011]. The clinical circumstances of the first event (provoked or unprovoked), individual characteristics such as male sex, and global hemostasis tests (e.g. D-dimer) are more important determinants of recurrence. A case-control study found that testing individuals with a first VTE for thrombophilia did not reduce the incidence of recurrence [Coppens et al 2007]. There are no randomized or controlled trials assessing the effect of thrombophilia testing on VTE recurrence risk [Cohn et al 2012].

Studies that support an association of 20210G>A heterozygosity and increased risk for recurrent VTE in adults:

  • In a prospective long-term follow-up study of persons who stopped anticoagulation after treatment for a first VTE, a thrombophilic defect including 20210G>A was associated with a twofold increased recurrence risk [Prandoni et al 2007].
  • A meta-analysis and a systematic review both concluded that 20210G>A heterozygosity is associated with a modest but statistically significant increased risk for recurrent VTE after a first event (OR = 1.72, OR=1.74, respectively) [Ho et al 2006, Marchiori et al 2007].

Studies that do not support an association of 20210G>A heterozygosity and increased risk for recurrent VTE in adults:

Risk for recurrent thrombosis in 20210G>A homozygotes and in 20210G>A heterozygotes with other risk factors

Summary. The risk for recurrent VTE in 20210G>A homozygotes is not well defined, but presumed to be higher than in 20210G>A heterozygotes. Most studies did not include an adequate number of individuals homozygous for the allele to evaluate the effect on recurrence risk [Segal et al 2009, EGAPP Working Group 2011]. The available evidence suggests that individuals with multiple thrombophilic defects have a higher risk for recurrent VTE.

Studies that support an increased risk for recurrent thrombosis in 20210G>A homozygotes and in 20210G>A heterozygotes with other risk factors:

  • Individuals who are heterozygous for both the 20210G>A and factor V Leiden alleles (i.e., doubly heterozygous) have a three- to ninefold higher recurrence risk than those with neither allele, and a threefold higher risk than individuals heterozygous for the factor V Leiden allele alone [De Stefano et al 1999, Margaglione et al 1999, Meinardi et al 2002].
  • In a prospective study, the annual incidence of recurrent VTE was 12%/year in persons homozygous for the 20210G>A allele or doubly heterozygous for 20210G>A and factor V Leiden, compared to 2.8% in those without either thrombophilia-related allele [González-Porras et al 2006].
  • A systematic review found that individuals doubly heterozygous for 20210G>A and factor V Leiden had a nearly fivefold increased risk for recurrent VTE [Segal et al 2009].

Not all studies found an increased risk for recurrent thrombosis in individuals with multiple thrombophilic alleles:

  • In a family study individuals homozygous for the 20210G>A allele or doubly heterozygous for 20210G>A and factor V Leiden did not have an increased risk for recurrent thrombosis, even when the analysis was restricted to those with a first unprovoked VTE [Lijfering et al 2010].

Risk for recurrent thrombosis in children

Summary. The risk for recurrent VTE is likely higher in children with an initial spontaneous (unprovoked) event, a strong family history of thrombosis, and multiple thrombophilic defects [Revel-Vilk & Kenet 2006, Young et al 2008, Young et al 2009]. Data on the risk for recurrent VTE in children who are 20210G>A heterozygotes are limited and conflicting. Multiple studies were not statistically powered because of small sample size.

Studies that support an increased risk for recurrent thrombosis in children who are 20210G>A heterozygotes:

  • In a prospective cohort study, the incidence of recurrent VTE at a median 12 months after the initial event was 58 VTE events/1000 person-years in children with a 20210G>A allele, compared to 11.8/1000 person-years in children without thrombophilia. VTE recurred in 18% of children with 20210G>A compared to 7.6% of controls, suggesting a two- to threefold increase in recurrence risk [Young et al 2009].
  • In a meta-analysis of 12 observational studies, 20210G>A was associated with a twofold increased risk for recurrent VTE. The risk was increased four- to fivefold in children with multiple thrombophilic defects [Young et al 2008].

Studies that do not support an increased risk for recurrent thrombosis in children who are 20210G>A heterozygotes:

  • In a series of Dutch children with VTE, VTE recurred in 11%, none of whom had a 20210G>A allele. The presence of one or more inherited thrombophilic disorders was not an independent risk factor for recurrent VTE [Van Ommen et al 2003].
  • In another study 20210G>A heterozygosity was not found among children with recurrent thrombosis, all of whom had other acquired risk factors [Revel-Vilk et al 2003].

Risk for recurrent thrombosis in pregnant women

Summary. Women with a prior history of VTE have an increased recurrence risk during pregnancy; recurrence rates range from 0% to 15% among published studies. The risk is higher in women with a prior unprovoked episode or an estrogen-related VTE, and in those with coexisting genetic or acquired risk factors. Note: No studies have specifically evaluated the risk for recurrent VTE in pregnant women with a 20210G>A allele.

  • Analysis of a large in-patient database found that thrombophilia and a prior history of VTE were the strongest risk factors for pregnancy-related VTE, conferring a 52-fold and 25-fold increase in relative risk, respectively [James et al 2006].
  • The results of several studies suggest that women with a history of VTE provoked by oral contraceptives or related to pregnancy are at higher risk for recurrent thrombosis during a subsequent pregnancy [DeStefano et al 2006, White et al 2008].
  • A prospective study evaluated the safety of withholding anticoagulation during pregnancy in women with a history of a single VTE. In subgroup analysis, women with a previous spontaneous thromboembolic event and thrombophilia had the highest recurrence rate during pregnancy (20%, odds ratio of 10) [Brill-Edwards et al 2000]. Women with either inherited or acquired thrombophilia or with a prior unprovoked VTE (but not both) had recurrence rates of 13% and 7.7%, respectively.

Pregnancy Complications

It is unlikely that 20210G>A heterozygosity is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes. Although multiple retrospective studies have suggested a modest increased risk of fetal loss, most prospective studies have not confirmed an association. The available data suggest that 20210G>A heterozygosity is associated with at most a two- to threefold increased relative risk for pregnancy loss.The association with preeclampsia, fetal growth restriction, and placental abruption is more controversial. A 20210G>A allele is at most one of multiple predisposing factors contributing to these complications. Other genetic and environmental triggers are necessary for the development of pregnancy complications in women heterozygous and homozygous for the 20210G>A allele.

Pregnancy loss

Summary. Some (though not all) evidence suggests that 20210G>A heterozygosity increases the risk for fetal loss [Kujovich 2004b]. However, despite a modest increase in relative risk, the absolute risk for fetal loss is low and the majority of heterozygous women have normal pregnancies.

Studies that show an association between unexplained pregnancy loss and a maternal 20210G>A allele:

Some evidence suggests that women with prothrombin-related thrombophilia have a higher risk for pregnancy loss in the second and third trimesters. Although late fetal loss may reflect thrombosis of placental vessels, the role of thrombophilic disorders including 20210G>A in the complex biologic events predisposing to placental insufficiency is not well defined.

  • An observational study of women with three consecutive miscarriages before ten weeks’ gestation found that 20210G>A heterozygotes had a rate of recurrent early miscarriage similar to that of women without a thromboplhic disorder. However, heterozygous women had a significantly higher rate of late fetal loss during the next pregnancy (8.8% versus 2.3%) [Bouvier et al 2014].
  • Two studies found 20210G>A heterozygosity in 9%-13% of women with a first unexplained third-trimester loss, compared with 2%-3% of controls suggesting a two- to threefold increase in risk [Martinelli et al 2000b, Many et al 2002].
  • A meta-analysis found that 20210G>A heterozygosity is associated with a more than threefold higher risk for fetal loss in the second trimester compared to the first trimester. The allele was also associated with a two- to threefold increased risk for third-trimester loss and the risk increased after 24 weeks’ gestation [Robertson et al 2006].

Studies that found no increased risk for pregnancy loss in women with a 20210G>A allele:

  • Multiple observational and prospective studies found no association between 20210G>A and an increased risk for early or late recurrent pregnancy loss [Bank et al 2004, Kocher et al 2007, Karakantza et al 2008, Pasquier et al 2009, Silver et al 2010].
  • A family cohort study suggested that 20210G>A has no effect on the outcome of a subsequent pregnancy after a first fetal loss. The live birth rate in a second pregnancy was high and similar in women with and without the allele (77% and 76%, respectively) [Coppens et al 2007].
  • In a meta-analysis of prospective cohort studies, 20210G>A was not associated with an increased risk for a composite outcome of placental mediated complications including pregnancy loss. However, the analysis was not powered to detect small differences in risk due to the small number of studies reviewed [Rodger et al 2010].

Limited available evidence indicates that paternal thrombophilia, including 20210G>A heterozygosity, is not associated with an increased risk for fetal loss [Toth et al 2008, Pasquier et al 2009, Yenicesu et al 2010].

Other obstetric complications

Although preeclampsia, fetal growth restriction (FGR), and placental abruption may also involve impaired placental perfusion, their association with inherited thrombophilia is controversial. The conflicting results reported in different studies may reflect the varying diagnostic and selection criteria, different ethnic groups, and small number of cases included [Rodger et al 2008, Funai 2009]. The available evidence does not support an association between 20210G>A heterozygosity and these adverse pregnancy outcomes.

Preeclampsia. Preeclampsia is a heterogeneous disorder and it is unlikely that a single thrombophilic variant such as 20210G>A plays a major causal role. The conflicting results of the following studies suggest that 20210G>A heterozygosity does not significantly increase the risk for preeclampsia.

Studies showing an increased risk for preeclampsia in women with a 20210G>A allele:

  • Multiple case-control studies found a significantly higher prevalence of 20210G>A in women with preeclampsia (7%-11%) than in women with normal pregnancies (1%-4%), suggesting a two- to sevenfold increase in risk [Grandone et al 1998, Kupferminc et al 2000a, Benedetto et al 2002, Mello et al 2005].
  • A recent prospective study found that a 20210G>A allele was associated with threefold higher risk for recurrent preeclampsia which occurred in 50% of heterozygous women [Facchinetti et al 2009].
  • A meta-analysis of eight studies found that 20210G>A heterozygosity was associated with a two- to threefold increased risk for preeclampsia [Robertson et al 2006].

Studies showing no increased risk for preeclampsia in women with a 20210G>A allele:

Fetal growth restriction (FGR). The data on the risk for FGR associated with a 20210G>A allele are more limited and also conflicting. There is no consistent association between 20210G>A heterozygosity and FGR.

Studies showing an increased risk for FGR in women with a 20210G>A allele:

Studies showing no increased risk for FGR in women with a 20210G>A allele:

Placental abruption. The data on the risk for placental abruption in women with prothrombin-related thrombophilia are limited and conflicting. A large prospective study and a meta-analysis found that 29210G>A heterozygosity conferred a nine- to12-fold increased risk for placental abruption [Robertson et al 2006, Said et al 2010]. In contrast, other prospective studies and a meta-analysis found no association [Karakantza et al 2008, Rodger et al 2010, Silver et al 2010]. There is currently no convincing evidence of an association with placental abruption.

Factors that Predispose to Thrombosis

The clinical expression of prothrombin thrombophilia is influenced by: the number of 20210G>A alleles, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors.

Number of 20210G>A Alleles

20210G>A heterozygotes have a relative risk for venous thrombosis that is approximately two- to fivefold increased [Poort et al 1996, Leroyer et al 1998, Middeldorp & Van Hylckama Vlieg 2008].

20210G>A homozygotes are at higher risk, although the magnitude is not well defined. Whereas 20210G>A homozygotes may develop thrombosis more frequently and at a younger age, the risk is much lower than that associated with homozygous protein C deficiency or homozygous protein S deficiency. Numerous reports of asymptomatic 20210G>A homozygotes emphasize the contribution of other genetic and acquired risk factors to thrombosis [Ridker et al 1999, Souto et al 1999].

Coexisting Genetic Abnormalities

Another inherited thrombophilic disorder is present in 8%-14% of 20210G>A heterozygotes, creating supra-additive effect on overall thrombotic risk. Individuals with multiple thrombophilic disorders develop VTE at a younger age and are at higher risk for recurrent thrombosis than those with a single defect [Ferraresi et al 1997, Makris et al 1997].

Factor V Leiden. Heterozygosity for a factor V Leiden allele occurs in 20%-40% of symptomatic 20210G>A heterozygotes [Poort et al 1996, Emmerich et al 2001].

Individuals doubly heterozygous for 20210G>A and factor V Leiden have an increased relative risk for VTE, although estimates of the magnitude of risk vary. In one analysis, the risk was increased 20-fold in individuals heterozygous for both alleles, suggesting a multiplicative effect on overall thrombotic risk [Ehrenforth et al 1999, Emmerich et al 2001]. A more recent systematic review concluded that double heterozygosity for both thrombophilic alleles confers a more modest sevenfold increase in thrombotic risk [Segal et al 2009]. Doubly heterozygous individuals are at a three- to fourfold higher risk than those with a single thrombophilic allele and are more likely to develop thrombosis in unusual locations (e.g., hepatic, mesenteric, or cerebral veins) [De Stefano et al 1999].

Anticoagulant protein deficiency. In one study of families with thrombophilia, the combination of protein S deficiency and 20210G>A heterozygosity was associated with a nearly 13-fold increased risk for VTE, compared to a fourfold increased risk with 20210G>A heterozygosity alone [Tirado et al 2001]. In contrast, coinheritance of a 20210G>A allele did not increase the risk for thrombosis in a large kindred with protein C deficiency [Bovill et al 2000].

Other genetic factors. An F2 20210G>A allele may also interact with other genetic factors, such as normal sequence variants in the following two genes, which independently may not predispose to thrombosis:

  • F8, the gene encoding factor XIII. The effect of the F8 Val34Leu variant has been extensively studied with conflicting results [Undas et al 2009, Bereczky & Muszbek 2011]. Two meta-analyses found a slight overall protective effect of an F8 Val34Leu allele against VTE [Wells et al 2006, Gohil et al 2009].
    Note: The F8 variant in exon 2 (NM_000132.3:c.157G>T) encodes a normal protein variant officially designated NP_000123.1:p.Val53Leu (commonly known as Val34Leu, which does not count the 19 amino-acid signal sequence) [Kohler et al 1998].
  • SERPINE1, the gene encoding PAI1 (plasminogen activator inhibitor type 1). Heterozygosity for the SERPINE1 4G polymorphic allele in combination with 20210G>A heterozygosity was associated with a sixfold increased risk for venous thrombosis. Homozygosity for the SERPINE1 4G polymorphic allele in combination with 20210G>A heterozygosity was associated with a 13-fold increased risk for venous thrombosis [Barcellona et al 2003]. (The risk for 4G/5G was not calculated in this study.)

    Note: The SERPINE1 polymorphism commonly referred to as 4G/5G is a missense substitution (NG_013213.1: g.4328G>T;rs114094261) that is -675 nucleotides from the transcription start. The missense substitution results in either four or five G nucleotides in a row; hence, the common designation of 4G or 5G alleles.

Family history. A family history of thrombosis affecting at least one first-degree relative is a risk factor for VTE even after identification of an inherited thrombophilic disorder (including 20210A heterozygosity) [Bezemer et al 2009]. A positive family history is associated with a three- to fourfold increased risk for VTE among individuals with a 20210G>A or factor V Leiden allele [Noboa et al 2008, Rossi et al 2011]. The risk is higher when multiple members are affected and thrombosis occurs at a young age.

Acquired Thrombophilic Disorders

Hyperhomocysteinemia may increase the thrombotic risk associated with 20210G>A heterozygosity. In one study, the combination of high plasma concentrations of homocysteine (>12 µmol/L) and 20210G>A heterozygosity conferred an estimated 50-fold increase in risk, suggesting a multiplicative effect on overall thrombotic risk [De Stefano et al 2001].

Antiphospholipid antibodies (APLA). The effect of antiphospholipid antibodies on the thrombotic risk associated with a 20210G>A allele is not well defined. One study found that the presence of antiphospholipid antibodies was associated with a fourfold increased risk for thromboembolic events in 20210G>A heterozygotes (OR = 4.4) [DeSancho et al 2010].

Malignancy. Whether inherited thrombophilia increases the risk for VTE in persons with cancer is still controversial [Decousus et al 2007]. Malignancy is associated witha markedly increased risk for VTE, especially during the first few months after diagnosis and in those with distant metastases [Blom et al 2005b]. Because malignancy is such a strong risk factor, it may obscure the effect of mild thrombophilic disorders, including prothrombin thrombophilia. Thrombophilia status was not considered in recent guidelines for prophylaxis and treatment of VTE in patients with cancer [Farge et al 2013].

A few small studies found a similar prevalence of 20210G>A heterozygosity in persons with cancer with and without VTE [Ramacciotti et al 2003, Eroglu et al 2007]. Other evidence suggests that the 20210G>A allele may increase the risk for malignancy-related VTE.

  • A large population-based case-control study found that persons with cancer and 20210G>A heterozygosity had a 17-fold higher risk for VTE than individuals with neither risk factor, and a fourfold higher risk for VTE than those with cancer and without the 20210G>A allele [Blom et al 2005b].
  • Individuals with cancer who are heterozygous for factor V Leiden or 20210G>A have a 20-fold higher risk for developing an upper-extremity thrombosis than individuals with cancer without either thrombophilia-related allele [Blom et al 2005a].
  • A meta-analysis found that a 20210G>A allele is associated with a fivefold increased risk for central venous catheter thrombosis in persons with cancer [Dentali et al 2008b].

Circumstantial Risk Factors

Other predisposing factors include: pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, central venous catheter use, surgery, travel, and minor injury. The 20210G>A allele interacts with these environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with prothrombin-related thrombophilia are provoked by additional predisposing factors, with pregnancy being the most common [Gerhardt et al 2000].

Circumstantial risk factors play a major role in VTE in children. In several studies 62%-97% of children with VTE had coexisting circumstantial risk factors, with central venous catheters, malignancy, and congenital heart disease among the most frequently reported [Junker et al 1999, Revel-Vilk et al 2003, Young et al 2008, Tuckuviene et al 2011].

Pregnancy. Women with thrombophilia are at higher risk for VTE during pregnancy [Kujovich 2004a, James et al 2006].

  • In several studies 20210G>A heterozygotes had a three- to 15-fold higher risk for pregnancy-associated VTE than women without the allele [Gerhardt et al 2000, Martinelli et al 2002, Meglic et al 2003].
  • A population based case-control study found that 20210G>A heterozygotes have a 31-fold increased risk of developing VTE during pregnancy or the postpartum period compared with non-pregnant women without the allele [Pomp et al 2008].
  • A meta-analysis suggested that 20210G>A heterozygotes have a nearly sevenfold higher risk for pregnancy-related VTE than pregnant women without inherited or acquired thrombophilia [Robertson et al 2006].

Although 20210G>A heterozygosity increases the relative risk for pregnancy-associated VTE, the absolute risk in asymptomatic heterozygotes is low in the absence of other predisposing factors. The highest risk occurs during the first six weeks post partum:

  • Several retrospective studies estimated the probability of VTE in the range of one in 200 to 300 pregnancies [Gerhardt et al 2000, Gerhardt et al 2003]. A population study estimated that VTE occurs in approximately one in 111 20210G>A heterozygotes during pregnancy [Jacobsen et al 2010].
  • In a retrospective family study, no VTE events occurred during pregnancy in asymptomatic 20210G>A heterozygotes. Postpartum VTE complicated 1.5% of pregnancies of 20210G>A heterozygotes compared to 0.4% of those in relatives without thrombophilia [Martinelli et al 2008].
  • In two prospective cohort studies of unselected pregnant women, no VTE events occurred during pregnancy or the postpartum period in 20210G>A heterozygotes [Said et al 2010, Silver et al 2010].

Women homozygous for 20210G>A or doubly heterozygous for 20210G>A and factor V Leiden have a higher risk for pregnancy-associated VTE:

  • The risk for pregnancy-associated VTE was increased 26-fold in 20210G>A homozygotes in one study [Robertson et al 2006].
  • The risk for pregnancy-associated VTE was increased 15-fold in 20210G>A heterozygotes, ninefold in those heterozygous for factor V Leiden, and greater than 100-fold in women who were doubly heterozygous for 20210G>A and factor V Leiden [Gerhardt et al 2000].
  • VTE complicated 17.8% of pregnancies in women doubly heterozygous for 20210G>A and factor V Leiden, compared to 6.2% of those in women heterozygous for the 20210G>A allele alone, suggesting that the combination confers a nearly threefold greater risk than 20210G>A heterozygosity alone [Samama et al 2003].

The absolute risk for pregnancy-associated VTE in 20210G>A homozygotes and women doubly heterozygous for 20210G>A and factor V Leiden is less well defined:

  • Women doubly heterozygous for 20210G>A and factor V Leiden have a higher risk for VTE in the range of 1/20 to 1/125 pregnancies [Gerhardt et al 2000, Gerhardt et al 2003, Jacobsen et al 2010]. The estimated absolute risk in 20210G>A homozygotes is approximately 1/40 pregnancies [Robertson et al 2006].
  • A family study found a low risk for pregnancy-associated VTE in asymptomatic doubly heterozygous women. No VTE events occurred during pregnancy; postpartum VTE complicated 1.8% of pregnancies [Martinelli et al 2008].
  • In a large family cohort of women who were heterozygous, doubly heterozygous or homozygous for factor V Leiden or 20210G>A, the absolute risk for pregnancy associated VTE with women with no, a single, or combined defects was 0.73, 1.97, and 7.65 per 100 pregnancy years, respectively [van Vlijmen et al 2011].

Oral contraceptive use. The use of oral contraceptives substantially increases the risk for VTE in women heterozygous for the F2 20210G>A allele. The risk for thrombosis is much higher during the first year of oral contraceptive use than during subsequent years [Bloemenkamp et al 2000].

  • Oral contraceptive use alone and 20210G>A heterozygosity alone are associated with a two- to fourfold and two- to threefold increased risk for VTE, respectively. However, the relative risk for VTE is increased 16- to 59-fold in 20210G>A heterozygotes who use contraceptives, indicating a supra-additive effect [Martinelli et al 1999b, Legnani et al 2002, Wu et al 2005].
  • The risk for VTE is also markedly increased in oral contraceptive users who are doubly heterozygous for 20210G>A and factor V Leiden, with reported odds ratios ranging from 17 to 110 [Emmerich et al 2001, Legnani et al 2002, Mohllajee et al 2006]. Although no studies have estimated the thrombotic risk associated with oral contraceptives in 20210G>A homozygotes, the risk is likely to be substantially higher than in women who are heterozygous.

Despite the marked increase in relative risk, the absolute incidence of VTE may still be low because of the low baseline risk in young healthy women.

  • In a recent family study that assessed the risk of a first VTE during OCP use in women heterozygous, doubly heterozygous, or homozygous for factor V Leiden or 20210G>A, the incidence of VTE in women with a single defect or combined defects was 0.35 and 0.94 per 100 person-years, respectively [van Vlijmen et al 2011].
  • In another family study the absolute incidence of VTE among women with a 20210G>A allele who used oral contraceptives was 0.2%/years of use [Bank et al 2004].
  • A prospective family study found that none of the 84 asymptomatic women with a 20210G>A allele who used oral contraceptives developed VTE during a total of 84 years of use [Coppens et al 2006].

Other contraceptives. The risk for VTE associated with transdermal and vaginal ring contraception is at least as high as the risk for VTE associated with oral contraceptives [Cole et al 2007, Jick et al 2007, Dore et al 2010]. The thrombotic risk of these newer forms of contraception in 20210G>A heterozygotes has not been studied, but is likely to be higher than in women without thrombophilia. Unopposed progestin contraception is associated with a much lower risk for thrombosis than estrogen-containing contraception. A retrospective study found that oral progestin alone did not increase the risk for VTE in high-risk women with a history of thrombosis and/or thrombophilia including a small group of 20210G>A heterozygotes and women doubly heterozygous for 20210G>A and factor V Leiden [Conard et al 2004]. However, no prospective studies confirm the safety of progestin-alone contraception in 20210G>A heterozygotes.

Hormone replacement therapy (HRT). Oral HRT is associated with a two- to fourfold increase in relative risk for VTE in healthy postmenopausal users of HRT compared to non-users [Grady et al 2000, Rossouw et al 2002, Canonico et al 2007, Renoux et al 2010]. The risk increases with higher estrogen doses and may differ with the particular estrogen and progestin components [Smith et al 2006, Canonico et al 2010, Renoux et al 2010, Canonico et al 2011].

Limited data suggest that women heterozygous for a 20210G> allele who use HRT have a significantly increased thrombotic risk:

  • A case-control study found that women with a 20210G>A allele or a factor V Leiden allele who used oral estrogen replacement had a 25-fold increased risk for VTE compared with non-users without either thrombophilic allele [Straczek et al 2005].
  • The risk of VTE in postmenopausal HRT users with either a 20210G>A or a factor V Leiden allele was threefold higher than the risk in HRT users without thrombophilia [Roach et al 2013].
  • The risk for VTE may differ with the type of hormonal content. In one study, the risk for VTE was fivefold higher with conjugated equine estrogen use than with esterified estrogen use among women with a 20210G>A allele or factor V Leiden allele [Smith et al 2006].
  • A meta-analysis found that women with either a 20210G>A allele or a factor V Leiden allele who used oral estrogen had an eightfold increased venous thrombotic risk [Canonico et al 2008].

Transdermal hormone replacement therapy. The available evidence suggests that transdermally administered estrogen has minimal or no effect on thrombotic risk [American College of Obstetricians and Gynecologists 2013a].

  • Multiple retrospective studies and a meta-analysis found that current use of low- or high-dose transdermal estrogen replacement with or without a progestin did not increase the risk for VTE. In contrast, oral HRT was associated with a two- to fourfold increase in thrombotic risk [Canonico et al 2007, Canonico et al 2008, Canonico et al 2010, Renoux et al 2010, Laliberté et al 2011].
  • There is also evidence that transdermal estrogen is associated with a lower thrombotic risk than oral estrogen in women with inherited thrombophilic disorders such as prothrombin-related thrombophilia [Canonico et al 2007, Canonico et al 2010].
  • Women with a 20210G>A allele using transdermal estrogen had a risk similar to that of non-users with the allele. Among women with a 20210G>A allele the use of oral estrogen was associated with a fourfold higher risk for VTE than transdermal estrogen [Straczek et al 2005]. However, no prospective randomized trials have confirmed the safety of transdermal HRT in women with inherited or acquired thrombophilia and/or prior VTE.

Selective estrogen receptor modulators (SERMs). Limited data suggest that SERMs such as tamoxifen and raloxifene are associated with a twofold increased risk for VTE, similar to the risk for HRT [Cummings et al 1999, Duggan et al 2003, Abramson et al 2006, Barrett-Connor et al 2006]. The thrombotic risk associated with tamoxifen was higher than raloxifene in trials for primary prevention of breast cancer [Nelson et al 2013]. 20210G>A heterozygosity did not increase the risk for arterial or venous thromboembolism in high-risk healthy women using tamoxifen for breast cancer prevention [Duggan et al 2003, Abramson et al 2006]. However, both studies were limited by the small number of cases included. The risk for VTE in women heterozygous for a 20210G>A allele who use SERMs is uncertain but likely higher than that associated with SERM use alone.

Obesity. Obesity (BMI>30 kg/m2) is associated with a two- to threefold increased risk for VTE. Obese women with a 20210 G>A allele have a nearly sevenfold higher risk for VTE than women with neither risk factor. Overweight women (BMI ≥25 and <30 kg/m2) with the allele have a fivefold increased thrombotic risk [Pomp et al 2007].

Organ transplantation. It is unclear whether 20210G>A heterozygosity contributes to thrombotic and other complications after organ transplantation [Pherwani et al 2003, Kujovich 2004c].

  • A 20210G>A allele was associated with a trend toward a threefold increased risk for thromboembolic complications after renal transplantation which did not reach statistical significance due to the small number of recipients with the allele [Ghisdal et al 2010].
  • 20210G>A heterozygosity was identified in 14% of liver allografts complicated by hepatic artery thrombosis, but not in recipient peripheral blood leukocytes [Mas et al 2003]. However, a recent study found no association with hepatic vascular thrombosis after liver transplantation [Pereboom et al 2011]

Central venous catheters. An indwelling central venous catheter is the strongest risk factor for upper-extremity thrombosis, contributing to up to one third of occurrences [Blom et al 2005a]. The data on the contribution of a 20210G>A allele to catheter-related thrombosis are conflicting:

  • 20210G>A heterozygotes had a two- to threefold increased risk for central venous catheter-related thrombosis [Van Rooden et al 2004].
  • Two other studies reported a low prevalence of the allele in persons with catheter-related thrombosis, similar to controls or the general population [Vaya et al 2003, Linnemann et al 2008a].

Surgery. It is still unclear to what extent the F2 20210G>A allele adds to the overall thrombotic risk in individuals undergoing surgery. Any excess risk conferred by 20210G>A heterozygosity is likely small in comparison to the thrombotic risk associated with surgery:

  • Individuals with a 20210G>A allele or a factor V leiden allele undergoing surgery had a nearly 13-fold increased risk for upper-extremity DVT during a postoperative period of up to three months [Blom et al 2005a].
  • In a large prospective trial, a 20210G>A allele was a risk factor for symptomatic VTE after total hip or knee arthroplasty, conferring a tenfold increase in risk. The allele was associated with a sixfold increased risk for symptomatic postoperative pulmonary embolism [Wåhlander et al 2002].
  • In contrast, several other studies found no association between a 20210 G>A allele and the risk for VTE after orthopedic surgery [Joseph et al 2005, Ringwald et al 2009].

Travel. Some evidence suggests that 20210G>A heterozygotes are more likely to develop VTE after travel. One study found that air travel was a mild risk factor for a first VTE (OR = 2). However, the combination of air travel and any type of thrombophilia (including 20210G>A heterozygosity) was associated with a 17-fold increase in risk, indicating a multiplicative interaction between the two risk factors [Martinelli et al 2003b].

Minor injury. Minor leg injuries are associated with a fivefold increased risk for VTE. The risk is particularly high after muscle or ligament rupture. Individuals with a 20210G>A allele and a minor leg injury had a nine- to 30-fold higher thrombotic risk than those without these risk factors [van Stralen et al 2008].

Thrombosis NOT Convincingly Associated with Prothrombin-Related Thrombophilia

Arterial thrombosis in adults. The role of prothrombin-related thrombophilia in arterial disease is controversial, with conflicting results from different studies. The available evidence indicates that the 20210G>A allele is not a major risk factor for arterial thrombosis. The majority of myocardial infarctions (MIs) and strokes occur in the presence of established cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus, and smoking. The contribution of a single thrombophilic allele to these complex diseases is likely small.

Most studies of unselected or elderly adult populations found no significant association between the presence of one or two 20210G>A alleles and myocardial infarction or stroke [Ridker et al 1999, Smiles et al 2002, Linnemann et al 2008b].

Other studies also found no increase in the annual incidence of stroke, transient ischemic attack (TIA), or MI associated with a 20210G>A allele [Bank et al 2004, Slooter et al 2005, Bolaman et al 2009]. In a prospective study the annual incidence of a first arterial cardiovascular event was 0.56% in family members with the allele compared to 0.73% in those without the allele [Coppens et al 2006]. The annual incidence of ischemic stroke or TIA was also similar in family members with and without the allele (0.33% and 0.23%, respectively).

The results of several meta-analyses suggest at most a weak association with ischemic stroke (pooled OR = 1.4) [Casas et al 2004], and myocardial infarction (per allele relative risk = 1.31) [Ye et al 2006].

The risk for arterial thrombosis in 20210G>A homozygotes is unknown, as very few homozygous individuals have been included in published studies.

Myocardial infarction (MI). Although a 20210G>A allele is not a major risk factor for ischemic heart disease, it may contribute to the risk for MI in selected populations. 20210G>A heterozygosity increased the risk for MI 43-fold in women younger than age 50 years with traditional cardiovascular risk factors, particularly smoking [Rosendaal et al 1997]. The risk may also be increased in heterozygous postmenopausal women who use HRT [Psaty et al 2001, Hindorff et al 2006].

Stroke in adults. Although 20210G>A is not a general risk factor for stroke, it may contribute to the risk for stroke in selected populations: In two case-control studies, 20210G>A heterozygosity conferred a fourfold increased risk for ischemic stroke in individuals younger than age 50 years without established cardiovascular risk factors [De Stefano et al 1998, Aznar et al 2004].

Arterial thromboembolism may also occur “paradoxically” through a patent foramen ovale (PFO) in the heart of individuals with venous thrombosis. A meta-analysis concluded that a 20210G>A allele was significantly associated with PFO-related stroke in comparison with controls (OR = 3.85) and persons with non-PFO associated stroke (OR = 2.31) [Pezzini et al 2009].

Stroke in children. Arterial ischemic stroke in children usually occurs in the setting of multiple predisposing factors [Barnes & Deveber 2006]. Data on the association of thrombophilia with ischemic stroke are conflicting and mostly limited to small case series and case-control studies. Stroke accounted for 21% of thrombotic events in a highly selected group of symptomatic children with a 20210G>A allele. Children younger than age two years had a significantly higher rate of arterial thrombosis than older children in whom venous thrombosis was far more common [Young et al 2003]. A meta-analysis of 13 studies found that children with a 20210G>A allele had a twofold increased risk for a first stroke. The risk was increased nearly 19-fold in children with multiple thrombophilic defects [Kenet et al 2010]. However, several other small studies and a smaller meta-analysis found no significant association between 20210G>A heterozygostiy and first ischemic stroke in children [Zenz et al 1998, Kenet et al 2000, Bonduel et al 2003, Haywood et al 2005].

Genotype-Phenotype Correlations

Homozygotes for the 20210G>A allele have a greater risk for thrombosis than do heterozygotes for the 20210G>A allele, although the magnitude of risk is not well defined.

The clinical course of an acute thrombotic episode is not more severe or resistant to anticoagulation in 20210G>A homozygotes than in 20210G>A heterozygotes.

Prevalence

F2 20210G>A heterozygosity is the second most common inherited thrombophilia after factor V Leiden. The prevalence of 20210G>A heterozygosity varies by population.

  • 20210G>A heterozygosity occurs in 1.7%-3% of the general US and European populations. The highest heterozygosity rate is found in Europe; the allele is extremely rare in Asian, African, and Native American populations. Within Europe the prevalence varies from 3% in southern Europe to 1.7% in northern countries [Rosendaal et al 1998].
  • In the US, the prevalence of 20210G>A heterozygosity is 2%-5% in whites, 2.2% in Hispanic whites, and 0%- 0.6% in African Americans, reflecting the world distribution of the allele [Dilley et al 1998, Dowling et al 2003, Chang et al 2009].
  • A study of a multiracial American population found 20210G>A heterozygosity in 8.2% of white and 1.1% of African American persons with VTE. The allele was not detected in the African American control population [Dowling et al 2003].

Among adults with VTE, 20210G>A heterozygosity is present in 6%-14% of those with a first VTE, and 18%-21% of those with a personal or family history of recurrent VTE [Poort et al 1996, Margaglione et al 1998, Tosetto et al 1999]. A prospective study identified 20210G>A heterozygosity in 3.7% of children with a first spontaneous VTE [Nowak-Gottl et al 2001].

The prevalence of 20210G>A homozygosity is approximately one in 10,000. 20210G>A homozygosity is found in 1.8%-4.5% of individuals with a history of VTE [Margaglione et al 1999, Barcellona et al 2003].

Double heterozygosity for the 20210G>A and factor V Leiden alleles occurs in approximately one in 1000 individuals in the general population and is found in 1%-5% of persons with VTE [Margaglione et al 1999, Salomon et al 1999, Emmerich et al 2001, Simioni et al 2000].

Differential Diagnosis

The differential diagnosis of venous thromboembolism (VTE) includes several other inherited and acquired thrombophilic disorders. Because these disorders are not clinically distinguishable, laboratory testing is required for diagnosis in each case. (See also Management, Evaluations Following Initial Diagnosis.)

Inherited

Factor V Leiden refers to the specific G-to-A substitution in F5 that predicts a single amino-acid replacement (Arg506Gln) that destroys a cleavage site for activated protein C. The resulting impaired anticoagulant response to activated protein C results in increased thrombin generation and a prothrombotic state [Kujovich 2011]. Factor V Leiden heterozygosity is found in 3%-8% of the general population and 15%-20% of individuals with a first VTE. Factor V Leiden heterozygosity is identified in 20%-40% of symptomatic 20210G>A heterozygotes with VTE [Poort et al 1996, Emmerich et al 2001].

A specific single nucleotide variant (SNV) (677C>T) in MTHFR, encoding methylenetetrahydrofolate reductase, results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Homozygosity for 677C>T (also known as C677T) occurs in 10%-20% of the general population and predisposes to mild hyperhomocysteinemia in the setting of suboptimal folate stores. The MTHFR variant does not confer an increased risk for VTE [Bezemer et al 2007]. The official designation for this MTHFR variant is NM_005957.4:c.665C>T, NP_005948.3:p.Ala222Val, or rs1801133.

Inherited deficiencies of the natural anticoagulant proteins C, S, and antithrombin are approximately tenfold less common than F2 20210G>A heterozygosity with a combined prevalence of less than 1% of the population. Anticoagulant protein deficiencies are found in 1%-3% of individuals with a first VTE.

Elevated levels of lipoprotein(a) are associated with premature atherosclerosis and may also be a risk factor for venous thrombosis.

Hereditary dysfibrinogenemias are rare and infrequently cause thrombophilia and thrombosis.

See Thrombophilia: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.

Acquired

High plasma concentration of homocysteine is present in 10% of individuals with a first VTE. In early studies a high plasma concentration of homocysteine was associated with a twofold increased relative risk for VTE; however, more recent data indicate that a high homocysteine level is a much weaker risk factor for VTE than previously reported [den Heijer et al 2005]. It was not associated with an increased thrombotic risk in children [Joachim et al 2013]. The plasma concentration of homocysteine reflects genetic as well as environmental factors.

Antiphospholipid antibodies comprise a heterogeneous group of autoantibodies directed against proteins bound to phospholipid. Anticardiolipin antibodies and the related anti-beta2 glycoprotein 1 antibodies are detected by solid phase immunoassays. Lupus inhibitors are autoantibodies that interfere with phospholipid-dependent clotting assays. Persistent high titer lupus inhibitors are more strongly associated with arterial and venous thromboembolism than other antiphospholipid antibodies [Galli et al 2003]. Recent evidence indicates that “triple positivity” for all three types of antiphospholipid antibodies confers the highest risk of thrombosis and pregnancy complications [Pengo et al 2010].

An elevated factor VIII level greater than 150% of normal is associated with a four- to fivefold increased risk for a first VTE [Koster et al 1995, Bank et al 2005] and also significantly increases the risk for recurrent thrombosis [Kyrle et al 2000]. Familial clustering of high factor VIII levels occurs although the relative contribution from genetic factors to persistently elevated levels is still unknown. No specific F8 benign variants have been associated with elevaled plasma factor VIII levels [Jenkins et al 2012].

An elevated plasma level of factor IX and factor XI is each associated with a twofold increased risk for VTE [Van Hylckama Vlieg et al 2000, Cushman et al 2009].

Elevated plasma levels of both factor VIII and factor IX are associated with an eightfold increased risk for VTE [Meijers et al 2000, Van Hylckama Vlieg et al 2000].

An elevated plasma prothrombin level greater than 110% -115% of normal is associated with a twofold increased risk for VTE in the absence of F2 20210G>A [Poort et al 1996, Legnani et al 2003]. The combination of oral contraceptives and high levels of prothrombin and factor V or factor XI had a supra-additive effect on thrombotic risk, with odds ratios ranging from ten to 13 [Van Hylckama Vlieg & Rosendaal 2003].

Other

Although thrombosis has been reported in association with defects or deficiencies of other coagulation and fibrinolytic proteins, including heparin cofactor II, PAI-1, tissue factor pathway inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), and protein Z, a causal association has not been established [Meltzer et al 2010].

Other genetic risk factors for thrombosis under investigation include a fibrinogen gamma chain variant (10034T), genetic variants in the protein C promoter region, and several single-nucleotide polymorphisms (SNPs) in coagulation proteins [Smith et al 2007, Bezemer et al 2008]. Genome-wide association analysis has also been used to identify novel susceptibility genes for venous thrombosis [Germain et al 2011].

Several global markers of coagulation such as measurement of thrombin generation show promise in identifying individuals at high risk for thrombosis [Eichinger & Kyrle 2009, Kyrle et al 2010].

Testing for these potential risk factors is not routinely recommended and in many cases, assays are not commercially available.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

Because of the increased incidence of a second thrombophilic defect among symptomatic individuals with inherited thrombophilia [Emmerich et al 2001], individuals heterozygous or homozygous for the F2 20210G>A allele should be tested for other inherited and acquired thrombophilic disorders in order to evaluate the risk for thrombosis. Testing should include:

  • An activated protein C resistance or DNA assay for factor V Leiden;
  • Serologic assays for anticardiolipin antibodies and anti-beta 2 glycoprotein 1 antibodies;
  • Multiple phospholipid-dependent coagulation assays for a lupus inhibitor.
    Note: Testing for antiphospholipid antibodies should include assays for all three antibodies (anticardiolipin antibodies, anti-beta2 glycoprotein 1 antibodies, and lupus inhibitors) since only 50% of individuals with the antiphospholipid antibody syndrome have more than one type of antibody.

Evaluation of high-risk individuals (i.e., those with a history of recurrent VTE especially at a young age, or those with strong family history of VTE at a young age), should also include assays of:

  • Protein C activity;
  • Antithrombin activity;
  • Protein S activity or free protein S antigen.

Note: In an evaluation for thrombophilia: (1) Measurement of plasma concentration of homocysteine is no longer recommended because no data support the use of vitamin supplementation or modification of the duration of anticoagulation in individuals with hyperhomocysteinemia and a history of VTE [den Heijer et al 2007]; (2) there is no clinical rationale for DNA testing for MTHFR variants; and (3) routine measurement of factor VIII and other clotting factor levels is not recommended; however, such testing may be useful in certain instances [Bauer 2010, Jenkins et al 2012]

Treatment of Manifestations

The management of thrombosis in individuals with prothrombin-related thrombophilia depends on the clinical circumstances.

The first acute thrombosis should be treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux (a pentasaccharide) [Kearon et al 2012]. Low molecular-weight heparins and fondaparinux have largely replaced unfractionated heparin because of their many advantages [Garcia et al 2012].

Oral administration of warfarin is started concurrently with LMWH or fondaparinux (except during pregnancy) and monitored with the international-normalized ratio (INR). A target INR of 2.5 (therapeutic range: 2.0-3.0) provides effective anticoagulation, even in F2 20210G>A homozygotes.

Rivaroxaban, a direct factor Xa inhibitor, is also approved for the treatment of acute DVT and PE and secondary prevention of recurrent VTE.

Note: LMWH and warfarin are both safe in women who are breast-feeding. Rivaroxaban is contraindicated during pregnancy and breast-feeding because animal studies showed reproductive toxicity, and evidence that the drug crosses the placenta and is secreted in milk [Ageno et al 2012].

The duration of oral anticoagulation therapy should be based on an individualized assessment of the risks of VTE recurrence and anticoagulant-related bleeding. Approximately 30% of individuals with VTE experience recurrent thrombosis within the subsequent five years [Prandoni et al 2007]. Recurrence risk is determined by the clinical circumstances of the first event (provoked or unprovoked), adequacy of early treatment, and individual risk factors (see Natural History, Recurrent Thrombosis, Risk for recurrent thrombosis in adult 20210G>A heterozygotes.

20210G>A heterozygosity is generally not an indication for long-term anticoagulation in the absence of other risk factors. The presence of a hereditary thrombophilia was not a factor determining the duration of anticoagulation in the 2012 American College of Chest Physicians Guidelines on Antithrombotic Therapy and Prevention of Thrombosis based on evidence that inherited thrombophilic disorders are not major determinants of VTE recurrence risk [Kearon et al 2012 (full text)]. Other clinical guidelines and expert opinion also conclude that identification of 20210G>A heterozygosity should not affect clinical decision making [Baglin et al 2010, Bauer 2010, Kyrle et al 2010, Heleen van Ommen & Middeldorp 2011, Monagle et al 2012, National Clinical Guideline Centre 2012]. See Published Guidelines/Consensus Statements.

Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [Kearon et al 2012].

Long-term oral anticoagulation is recommended for individuals with a first or recurrent unprovoked (i.e., idiopathic) VTE and no risk factors for bleeding with good anticoagulation monitoring [Kearon et al 2012]. The decision should be based on an assessment of potential risks and benefits regardless of 20210G>A status [EGAPP Working Group 2011]. Long-term anticoagulation is considered in selected individuals homozygous for the 20210G>A allele or with multiple inherited or acquired thrombophilic disorders [De Stefano & Rossi 2013]. In these individuals at higher risk for recurrence, the potential benefits of long-term anticoagulation may outweigh the bleeding risks.

LMWH, fondaparinux, warfarin, and rivaroxaban are the primary antithrombotic agents used for the acute and long-term treatment of VTE. Several direct thrombin inhibitors (lepirudin, argatroban, and dabigatran), and apixaban, a direct factor Xa inhibitor, are approved for use in specific circumstances [Schulman 2014].

Graduated compression stockings should be worn for at least two years following an acute DVT.

Treatment of thrombosis in children. Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that a 20210G>A allele should influence decisions about the intensity or duration of anticoagulation in children [Monagle et al 2012, Chalmers et al 2011, Heleen van Ommen & Middeldorp 2011, Monagle et al 2012]. British guidelines for antithrombotic therapy in children do not consider inherited thrombophilia as a determinant of either the intensity or duration of therapy.

Children with a first VTE should receive initial treatment with either unfractionated heparin (UFH) or LMWH for at least five days. LMWH is favored over warfarin for continued therapy, especially in very young children and those with complex medical problems. Recommendations on the duration of antithrombotic therapy are based on the nature of the thrombotic event (e.g., spontaneous or provoked) [Chalmers et al 2011, Monagle et al 2012, Chalmers et al 2011] (see Published Guidelines/Consensus Statements).

Anticoagulation is recommended:

  • For at least three months after a VTE provoked by a clinical risk factor that has resolved.
  • Beyond three months until the risk factor has resolved in children with ongoing but potentially reversible risk factors.
  • For six to 12 months after a first idiopathic (unprovoked) VTE.
  • Indefinitely for those with recurrent idiopathic VTE

Expert opinion emphasizes the importance of a careful risk/benefit assessment in each individual [Raffini & Thornburg 2009, Heleen van Ommen & Middeldorp 2011].

Consensus guidelines are also available for management of stroke in infants and children [Monagle et al 2012].

Prevention of Primary Manifestations

In the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes, since the 1%-3% yearly risk for major bleeding from warfarin is greater than the estimated (<1%) yearly risk for thrombosis [Martinelli et al 2000a, Middeldorp & Van Hylckama Vlieg 2008, EGAPP Working Group 2011].

Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the 2012 American College of Chest Physicians consensus guidelines [Guyatt et al 2012 (full text)].

Surveillance

Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the bleeding risk.

Selected 20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. (See Prevention of Primary Manifestations.)

Agents/Circumstances to Avoid

F2 20210G>A heterozygotes:

  • With a history of VTE should avoid estrogen contraception and HRT; asymptomatic women should be counseled on the risks of estrogen-containing contraception and HRT and should consider alternative forms of contraception and strategies for control of menopausal symptoms.
  • Who are asymptomatic and elect to use oral contraceptives should avoid formulations with third-generation and other progestins with a higher thrombotic risk;
  • Who elect short-term hormone replacement therapy for severe menopausal symptoms should use low-dose transdermal preparations, which have a lower thrombotic risk than oral formulations [Straczek et al 2005, Canonico et al 2007, Renoux et al 2010].

F2 20210G>A homozygous women with or without prior VTE should avoid estrogen-containing contraception and HRT.

Evaluation of Relatives at Risk

The genetic status of asymptomatic at-risk family members can be established using molecular genetic testing. However, as there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis [Segal et al 2009].

Clarification of 20210G>A allele status may be useful in:

  • Asymptomatic adult family members of probands with one or two known 20210G>A alleles, especially those with a strong family history of VTE at a young age;
  • Asymptomatic female family members of probands with known prothrombin-related thrombophilia who are pregnant or considering estrogen contraception or pregnancy.

There is no clinical evidence to support testing asymptomatic children with a family history of thrombosis and/or inherited thrombophilia. Guidelines suggest delaying testing until children are able to understand the implications of the results and (optimally) can give informed consent for testing [Chalmers et al 2011].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals [Kujovich 2004a, Royal College of Obstetricians and Gynaecologists 2009, Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]; see Published Guidelines/Consensus Statements. LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. All women with inherited thrombophilia should undergo individualized risk assessment. Decisions about anticoagulation should be based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis [Bates et al 2012, American College of Obstetricians and Gynecologists 2013b].

Prophylactic anticoagulation during pregnancy:

A six-week course of postpartum prophylactic anticoagulation is recommended for:

Prevention of pregnancy loss. It is still unkown if prophylactic antithrombotic therapy improves pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss. The available evidence consists of predominantly uncontrolled trials, observational studies, and a few randomized trials with important methodologic limitations. There are no prospective randomized trials that include an untreated control group that confirms the benefit of LMWH for preventing pregnancy loss in women with inherited thrombophilia. Of note, the ALIFE2 study, a multicenter randomized trial of LMWH versus standard surveillance in women with inherited thrombophilia and a history of recurrent miscarriage, began recruitment in December 2012 (www.trialregister.nl, NTR 3361).

Current consensus guidelines and expert opinion recommend against the use of antithrombotic therapy in women with inherited thrombophilia and unexplained recurrent pregnancy loss outside of clinical trials because of the absence of high quality evidence confirming benefit [Baglin et al 2010, Royal College of Obstetricians and Gynaecologists 2011a, Royal College of Obstetricians and Gynaecologists 2011b, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b, Middeldorp 2013].

Studies suggesting that prophylactic anticoagulation improves pregnancy outcome:

  • The results of several observational studies suggested that prophylactic antithrombotic therapy may improve pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss [Brenner et al 2000, Carp et al 2003].
  • A recent study of women with a history of unexplained pregnancy loss compared the frequency of obstetric complications in women with factor V Leiden or 20210G>A alleles and women without thrombophilia. Women with a thrombophilic disorder with a prior fetal loss after ten weeks’ gestation who received enoxaparin during their next pregnancy had a significantly lower rate of fetal loss and severe preeclampsia and a higher rate of live births compared to women without a thrombophilic disorder with the same obstetric history who did not receive prophylaxis [Bouvier et al 2014].
  • A prospective randomized trial compared prophylactic-dose enoxaparin and low-dose aspirin in women heterozygous for 20210G>A, factor V Leiden, or protein S deficiency, and a history of a single unexplained fetal loss after ten weeks’ gestation. Enoxaparin prophylaxis was associated with a significantly higher live birth rate of 86% compared to 29% with aspirin. However, there were methodologic problems with this study and the results have not been confirmed in other trials.

Studies suggesting that prophylactic anticoagulation does not improve pregnancy outcome:

  • Several studies found no benefit with LMWH on pregnancy outcome in women with inherited thrombophilia [Laskin et al 2009, Warren et al 2009, Visser et al 2011].
  • Two recent randomized trials compared the efficacy of LMWH and aspirin to no antithrombotic therapy or placebo in women with unexplained recurrent pregnancy loss. Combined LMWH and low-dose aspirin did not increase the live birth rate in either study [Clark et al 2010, Kaandorp et al 2010]. Because only a small proportion of the study populations had inherited thrombophilia (3.5% and 15.7%), subgroup analyses were insufficiently powered to assess the effect of antithrombotic therapy.
  • In the recent Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) multinational randomized trial, antepartum prophylactic LMWH did not reduce the incidence of pregnancy loss or placenta-mediated complications in pregnant women with thrombophilia (22% with a 20210G>A allele) who are at high risk for these complications [Rodger et al 2014].

Other pregnancy complications. Data supporting the benefit of antithrombotic therapy in women with inherited thrombophilia and other pregnancy complications are considerably more limited and also conflicting [Gris et al 2011, De Vries et al 2012, Martinelli et al 2012]. There is insufficient evidence that LMWH (with or without aspirin) reduces the risk for preeclampsia, placental abruption, or other obstetric complications in women with or without inherited thrombophilia. Current guidelines recommend against antithrombotic prophylaxis for women with inherited thrombophilia and a history of pregnancy complications [Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b].

Therapies Under Investigation

Several new oral anticoagulants (which have not been specifically studied in individuals with inherited thrombophilia) are alternatives to warfarin in specific clinical settings.

Dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (two new factor Xa inhibitors) are approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation [Weitz et al 2012].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Prothrombin-related thrombophilia and an associated risk for thrombosis are inherited in an autosomal dominant manner. Individuals with one mutant allele will have thrombophilia (a disorder of blood clottiing that predisposes to thrombosis) and an increased risk for thrombosis. Individuals with two mutant alleles will have thrombophilia and a higher risk of thrombosis than heterozygotes.

Risk to Family Members — Proband Heterozygous for the F2 20210G>A Allele

Parents of a proband

  • All individuals reported to date with prothrombin-related thrombophilia have had a parent who is heterozygous or homozygous for the F2 20210G>A allele.
  • Prothrombin-related thrombophilia as the result of de novo mutation has not been reported.
  • Because of the relatively high prevalence of the 20210G>A allele in the general population, occasionally one parent is homozygous or both parents are heterozygous for this allele.

Note: Although most individuals diagnosed with prothrombin-related thrombophilia have a parent who is heterozygous or homozygous for the 20210G>A allele, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If one parent of a heterozygous proband is heterozygous, each sib of the proband has a 50% chance of being heterozygous for a 20210G>A allele.
  • If one parent is homozygous, all sibs of the proband will be heterozygous for a 20210G>A allele.
  • If both parents are heterozygous, each sib of the proband has a 25% chance of being homozygous for the 20210G>A allele, a 50% chance of being heterozygous, and a 25% chance of inheriting both normal F2 alleles.

Offspring of a proband

  • Each child of an individual heterozygous for a 20210G>A allele has a 50% chance of inheriting the allele.
  • If the proband's reproductive partner is heterozygous for the F2 20210G>A allele, each offspring has a 25% chance of being homozygous for the 20210G>A allele, a 50% chance of being heterozygous for the 20210G>A allele, and a 25% chance of inheriting both normal F2 alleles.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. The family members of a person who is heterozygous or homozygous for F2 20210G>A allele are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the F2 20210G>A allele, possible non-medical explanations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Testing of at-risk asymptomatic adults. The presence of one or two 20210G>A alleles can be identified in asymptomatic at-risk family members using molecular genetic testing. However, the indications for testing at-risk family members are unresolved (see Evaluation of Relatives at Risk).

Testing of at-risk individuals during childhood. Asymptomatic at-risk individuals younger than age 18 years are not usually tested because thrombosis rarely occurs before young adulthood, even in homozygous individuals.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Prenatal Testing

Prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for F2 20210G>A allele or custom prenatal testing.

Prenatal testing for the 20210G>A allele is requested rarely, if ever, as the disorder may never cause thrombosis and effective treatment is available. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the F2 20210G>A allele has been identified. However, PGD for prothrombin-related thrombophilia is rarely requested as the disorder may never cause thrombosis and effective treatment is available.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Lifeblood: The Thrombosis Charity
    c/o The Thrombosis & Haemostasis Centre
    St Thomas' Hospital
    Level 1 North Wing
    London SE1 7EH
    United Kingdom
    Phone: 0207 633 9937
    Email: information@thrombosis-charity.org.uk
  • National Blood Clot Alliance
    120 White Plains Road
    Suite 100
    Tarrytown NY 10591
    Phone: 877-466-2568 (toll-free); 914-220-5040
    Email: info@stoptheclot.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Prothrombin-Related Thrombophilia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
F211p11​.2ProthrombinF2 homepage - Mendelian genesF2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Prothrombin-Related Thrombophilia (View All in OMIM)

176930COAGULATION FACTOR II; F2
188050THROMBOPHILIA DUE TO THROMBIN DEFECT; THPH1

Gene structure. F2 has 14 exons (NM_000506.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Variants of uncertain significance. Three allelic variants have uncertain clinical significance. Larger studies are needed to determine if they increase the risk for thrombosis in individuals with and without inherited thrombophilic disorders. Genetic testing for these variants is not routinely recommended.

Table 2. Selected F2 Variants of Uncertain Significance

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
Alias 1Standard Nomenclature
c.1787G>Tp.Arg596LeuNM_000506​.3
NP_000497​.1
20209C>Tc.*96C>T 2None
19911A>Gc.1726-59G>ANone

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. * indicates that the variant is in the 3’ untranslated region of F2; 96 indicates that the variant is the 96th nucleotide 3’ of the translation stop codon. (Nucleotides are numbered *1, *2, etc.)

Pathogenic allelic variant. The 20210G>A pathogenic allelic variant is located in the 3' untranslated region of F2 where it increases the efficiency and accuracy of processing of the 3' end of the mRNA (see Abnormal gene product).

Haplotype analysis of F2 strongly suggests that the 20210G>A allele was a single event that occurred 20,000 to 30,000 years ago, after the evolutionary separation of whites from Asians and Africans [Zivelin et al 1998]. A more recent analysis of single nucleotide polymorphisms (SNPs) and microsatellites flanking F2 suggests that the variant arose 21,000-24,000 years ago in whites toward the end of the last glaciation [Zivelin et al 2006].

Although the high prevalence of the 20210G>A allele among whites suggests a balanced nucleotide variant with some type of survival advantage associated with the heterozygous state, no such advantage has been confirmed. Some investigators speculate that the mild hypercoagulable state conferred by the allele may have had a beneficial effect in reducing mortality from bleeding associated with childbirth or trauma in premodern times [Corral et al 2001, McGlennen & Key 2002, Zivelin et al 2006].

Table 3. F2 Pathogenic Allelic Variant Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
Alias 1Standard Nomenclature
20210G>A or G20210Ac.*97G>A 2NoneNM_000506​.3
NP_000497​.1

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. * indicates that the variant is in the 3’ untranslated region of F2; 97 indicates that the variant is the 97th nucleotide 3’ of the translation stop codon. (Nucleotides are numbered *1, *2, etc.)

Normal gene product. Coagulation factor II (prothrombin) has 622 amino acids.

Abnormal gene product. The 20210G>A allele is associated with elevated plasma levels of prothrombin [Poort et al 1996, Kyrle et al 1998, Simioni et al 1998, Soria et al 2000]. Experimental evidence suggests that the G>A transition increases the efficiency and accuracy of processing of the 3' end of the mRNA, resulting in an accumulation of mRNA and increased synthesis of the protein prothrombin. The observation that elevated prothrombin levels independently increase the risk for thrombosis suggests that the allele may act through this mechanism [Poort et al 1996, Legnani et al 2003]. The results of several experimental and clinical studies suggest that elevated prothrombin levels contribute to increased thrombin generation and a prothrombotic state, although other mechanisms may also be involved [Kyrle et al 1998, Butenas et al 1999, Lavigne-Lissalde et al 2010].

Most 20210G>A heterozygotes have a mildly elevated plasma concentration of prothrombin that is approximately 30% higher than healthy controls [Poort et al 1996, Soria et al 2000]. However, because the range of prothrombin concentrations in heterozygotes varies widely and overlaps significantly with the normal range, the plasma concentration of prothrombin is not reliable for diagnosis of prothrombin-related thrombophilia.

Individuals with one or two 20210G>A alleles often have elevated plasma levels of the prothrombin fragment F1+2, and other coagulation activation markers, reflecting the resulting mild hypercoagulable state [Eikelboom et al 1999, Franco et al 1999, Gouin-Thibault et al 2002].

References

Published Guidelines/Consensus Statements

  1. American College of Obstetricians and Gynecologists. Practice Bulletin No.138: Inherited thrombophilias in pregnancy. 2013. Available online (registration or institutional access required). 2013. Accessed 8-7-14.
  2. Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Available online. 2010. Accessed 8-6-14. [PubMed: 20128794]
  3. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO; American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 8-7-14. [PMC free article: PMC3278054] [PubMed: 22315276]
  4. Chalmers E, Ganesen V, Liesner R, Maroo S, Nokes T, Saunders D, Williams M; British Committee for Standards in Haematology. Guideline on the investigation, management and prevention of venous thrombosis in children. Available online. 2011. Accessed 8-7-14. [PubMed: 21595646]
  5. 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 VTE and their adult family members. Available online. 2011. Accessed 8-6-14. [PubMed: 21150787]
  6. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 8-8-14. [PMC free article: PMC3278060] [PubMed: 22315257]
  7. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis. 9 ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 8-7-14. [PMC free article: PMC3278049] [PubMed: 22315268]
  8. Monagle P, Chan AK, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, Vesely SK; American College of Chest Physicians. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141:e737S-801S. Available online. Accessed 8-7-14. [PMC free article: PMC3278066] [PubMed: 22315277]
  9. National Clinical Guideline Centre. Venous Thromboembolic Diseases: The Management of Venous Thromboembolic Diseases and the Role of Thrombophilia Testing. National Institute for Health and Care Excellence Clinical Guidelines. Available online. 2012. Accessed 8-7-14.
  10. Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline 37a. Available online. 2009. Accessed 8-7-14.
  11. Spector EB, Grody WW, Matteson CJ, Palomaki GE, Bellissimo DB, Wolff DJ, Bradley LA, Prior TW, Feldman G, Popovich BW, Watson MS, Richards CS. Technical standards and guidelines: venous thromboembolism (Factor V Leiden and prothrombin 20210G>A testing): a disease-specific supplement to the standards and guidelines for clinical genetics laboratories. Available online. 2005. Accessed 8-6-14. [PubMed: 16024978]
  12. Tait C, Baglin T, Watson H, Laffan M, Makris M, Perry D, Keeling D; British Committee for Standards in Haematology. Guidelines on the investigation and management of venous thrombosis at unusual sites. Available online. 2012. Accessed 8-6-14. [PubMed: 22881455]

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Chapter Notes

Revision History

  • 14 August 2014 (me) Comprehensive update posted live
  • 29 March 2011 (me) Comprehensive update posted live
  • 25 July 2006 (me) Review posted to live Web site
  • 25 April 2005 (jk) Original submission
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