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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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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 Medicine, Division of Hematology and Medical Oncology
Oregon Health and Science University
Portland, Oregon

Initial Posting: ; Last Update: March 29, 2011.

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, such as 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 DNA analysis of F2, the gene encoding prothrombin, to identify the common mutation 20210G>A (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, fondaparinux, or intravenous unfractionated heparin. Oral administration of warfarin is started concurrently with heparin or fondaparinux (except in pregnancy), and should be overlapped for at least five days. The international-normalized ratio (INR) is used to monitor warfarin anticoagulation. The duration of anticoagulation therapy should be tailored to the individual, based on an assessment of the risk for VTE recurrence and the risk for anticoagulant-related bleeding. Individuals with a spontaneous thrombosis with no identifiable provoking factors or persistent risk factors require a longer course of anticoagulation than individuals with transient (reversible) risk factors, such as surgery. Graduated compression stockings should be worn for at least two years following an acute DVT. No consensus exists on the optimal management of prothrombin-related thrombophilia during pregnancy; guidelines for treatment of VTE are similar to those for individuals who are not pregnant.

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

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 results in more severe thrombophilia and/or increased risk for thrombosis. 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 have a 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 performed because the 20210G>A allele only increases the relative risk for thrombophilia and is not predictive of a thrombotic event.

Diagnosis

Clinical Diagnosis

No clinical features are specific for prothrombin-related thrombophilia. The diagnosis of prothrombin-related thrombophilia requires DNA analysis of F2, the gene encoding prothrombin, to identify the common mutation 20210G>A (commonly referred to incorrectly as G20210A; the official designation by standard nomenclature rules is c.*97G>A).

Prothrombin-related thrombophilia is suspected in individuals with a history of venous thromboembolism (VTE) manifest as deep-vein thrombosis (DVT) or pulmonary embolism, especially in women with a history of VTE during pregnancy or in association with oral contraceptive use, and in individuals with a personal or family history of recurrent thrombosis at a young age.

There is general consensus that F2 20210G>A testing is appropriate in the circumstances listed below [Manco-Johnson et al 2002, McGlennen & Key 2002, Duhl et al 2007, Bates et al 2008, Royal College of Obstetricians and Gynaecologists 2009, American College of Obstetricians and Gynecologists 2010]. The decision to test an individual should be based on the likelihood that test results would influence treatment [Baglin et al 2010, EGAPP Working Group 2011]. Recently published 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 of these accepted circumstances [Baglin et al 2010, EGAPP Working Group 2011(full text)].

  • A first unprovoked VTE before age 50 years
  • A history of recurrent VTE
  • Venous thrombosis at 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)
  • A first VTE at any age in an individual with a first-degree family member with a VTE before age 50 years

However, it is important to note the following:

Testing for the F2 20210G>A allele may be considered in the following individuals/circumstances:

  • Selected women with unexplained fetal loss after ten weeks' gestation
  • Selected women with unexplained early-onset severe preeclampsia, placental abruption, or severe intrauterine growth restriction
  • A first VTE related to use of tamoxifen or other selective estrogen receptor modulators (SERM)
  • Female smokers under age 50 years with a myocardial infarction or stroke
  • Individuals older than age 50 years with a first unprovoked VTE
  • 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
  • Selected women with recurrent unexplained first-trimester losses with or without second- or third-trimester losses.
  • Neonates and children with non-catheter related idiopathic VTE or stroke.

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, HRT, or SERMs
  • Routine initial testing in adults with arterial thrombosis; however, testing may be considered in individuals younger than age 50 years with unexplained arterial thrombosis (e.g., women with stroke associated with oral contraceptives).
  • Routine initial testing during pregnancy
  • Prenatal or newborn testing
  • Neonates and children with asymptomatic central venous catheter-related thrombosis
  • Routine testing in asymptomatic children

Testing

Prothrombin level. Most 20210G>A heterozygotes have a mildly elevated plasma concentration of prothrombin that is approximately 30% higher than healthy control individuals (see Molecular Genetics). However, values vary widely among individuals [Poort et al 1996, Soria et al 2000]. Because the range of prothrombin concentrations in heterozygotes overlaps significantly with the normal range, the plasma concentration of prothrombin is not reliable for diagnosis of prothrombin-related thrombophilia.

Molecular Genetic Testing

Gene. The allele 20210G>A (c.*97G>A) in F2, the gene encoding prothrombin, is the allele known to be associated with prothrombin-related thrombophilia and is the subject of this GeneReview.

Clinical testing

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

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
F2Targeted mutation analysis 20210G>A (c.*97G>A) 4100%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. The official designation of the mutation 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).

  • In the recipient of a liver transplant who had hepatic artery thrombosis, the 20210G>A allele was found in DNA from donor liver, but not in DNA from recipient peripheral blood leukocytes [Mas et al 2003]. Diagnosis of prothrombin-related thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis.
  • Diagnosis of prothrombin-related thrombophilia in HSCT recipients requires molecular analysis of non-hematopoietic tissue in the recipient (e.g., buccal cells).

Testing Strategy

To confirm/establish the diagnosis in a proband. When clinical care requires testing for prothrombin-related thrombophilia, molecular genetic testing is required. Note: Because the range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range, the prothrombin concentration is not reliable for diagnosis.

Testing of relatives of individuals known to have prothrombin-related thrombophilia requires molecular genetic testing for the 20210G>A allele.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies are rarely performed: although the 20210G>A allele increases the relative risk for thrombophilia, it is not predictive of a thrombotic event.

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 [Rosendaal & Reitsma 2009, Lijfering et al 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 also had an increased risk of developing isolated pulmonary emboli [Martinelli et al 2006]. The results of several studies suggest that VTE occurs at a younger age in 20210G>A heterozygotes than in individuals without the allele [Bank et al 2004, Martinelli et al 2006].

Evidence from multiple case-control studies suggests that heterozygosity for 20210G>A is an independent risk factor for upper-extremity thrombosis [Bombeli et al 2002, Vaya et al 2003, Martinelli et al 2004, Blom et al 2005, 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 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 2005, Linnemann et al 2008a].
  • Heterozygosity for 20210G>A was found in a similar proportion of individuals with upper- and lower-extremity DVT. 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). Women heterozygous for 20210G>A who were using oral contraceptives had a nearly 14-fold increased risk. The risk for recurrent upper-extremity thrombsis was nearly threefold higher in persons heterozygous for 20210G>A or factor V Leiden [Martinelli et al 2004].
  • Another study also found a higher risk in 20210G>A heterozygotes who used oral contraceptives (odds ratio [OR] = 9) or hormone replacement therapy (OR = 5) [Blom et al 2005].
  • 20210G>A heterozygotes with cancer have a markedly increased risk for upper-extremity thrombosis compared to controls without either risk factor (OR = 177). 20210G>A heterozygotes with cancer have a 20-fold higher risk for upper-extremity thrombosis than persons with cancer without this allele or other inherited thrombophilic disorders [Blom et al 2005].

Thrombosis in unusual locations in adult 20210G>A heterozygotes also occurs more frequently than in the general population. However, these events are much less common than DVT or pulmonary emboli.

Cerebral vein thrombosis in adults

  • The risk for cerebral vein thrombosis is increased tenfold in individuals with prothrombin-related thrombophilia [Martinelli et al 1998, Martinelli et al 2003a].
  • The prevalence of a heterozygous 20210G>A allele was twofold higher among persons with cerebral vein thrombosis (11%) than a control group with DVT (4%) [Wysokinska et al 2008].
  • In a meta-analysis of nine studies, 20210G>A heterozygosity was associated with a ninefold increased risk for cerebral vein thrombosis [Dentali et al 2006].
  • In two case-control studies, women heterozygous for 20210G>A who used oral contraceptives had an 80-fold and 150-fold increased relative risk for cerebral vein thrombosis, respectively [Martinelli et al 1998, Martinelli et al 2003a].

Hepatic and portal vein thrombosis in adults are other reported complications in 20210G>A heterozygotes [Chamouard et al 1999, Janssen et al 2000, Amitrano et al 2004, Primignani et al 2005].

  • 20210G>A heterozygosity was associated with an eightfold increased risk for extrahepatic portal vein thrombosis [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 other unusual locations in adults

Risk for VTE in children heterozygous for the F2 20210G>A allele. Although VTE is far less common in children than in adults, the prevalence of inherited thrombophilic disorders in children with VTE is higher than in a corresponding adult population. A combination of risk factors appears to be necessary to provoke thrombosis in children [Nowak-Gottl et al 2001b, Revel-Vilk & Kenet 2006, Raffini 2008]. 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 [Nowak-Gottl et al 2001b].

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]. There was a trend toward a higher prevalence of the allele in children with spontaneous VTE (OR = 4.8) [Junker et al 1999].
  • Although 20210G>A heterozygosity may increase the risk for spontaneous VTE, most episodes occur in children with other predisposing factors [Junker 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].
  • A meta-analysis of 17 prospective studies found an eightfold increased risk for thrombosis in children with acute lymphocytic leukemia and at least one of a panel of inherited thrombophilic disorders including 20210G>A heterozygosity [Caruso et al 2006].
  • In another meta-analysis of 14 observational studies, 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 [Bonduel et al 2002, Revel-Vilk et al 2003, van Ommen et al 2003, Albisetti et al 2007].
  • 20210G>A heterozygosity was not associated with an increased risk for umbilical catheter-related thrombosis in neonates [Turebylu 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].

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

Cerebral vein thrombosis in children. Although most thromboses in children occur in the extremities, some evidence suggests that 20210G>A heterozygosity may predispose to central nervous system (CNS) thrombosis. However, the evidence regarding the risk for cerebral vein thrombosis is conflicting.

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

  • In the largest reported series of 20210G>A heterozygous children, 37% of symptomatic children had a history of arterial or venous CNS thrombosis, accounting for 30% of thromboembolic episodes. Cerebral sinus thrombosis occurred in 13% of symptomatic children, all of whom were age two years or older [Young et al 2003].
  • Heterozygosity was found in 4%-5% of children with cerebral vein thrombosis compared to 1%-2% of controls, differences that did not achieve statistical significance because of the small number of cases [Bonduel et al 2003, Heller et al 2003].
  • Underlying illnesses and/or circumstantial risk factors were present in the the majority of children reported with cerebral vein thrombosis [DeVeber et al 2001, Heller et al 2003, Kenet et al 2004]. The combination of an inherited or acquired thrombophilic disorder (including 20210G>A heterozygosity) and an underlying medical condition conferred a fourfold increased risk, underscoring the multifactorial etiology of this thrombotic complication [Heller et al 2003].

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].
  • A meta-analysis found a nonsignificant trend toward a twofold increased risk for cerebral vein thrombosis in children (pooled OR = 1.95); however, 20210G>A was associated with a significant twofold increased risk for the combined outcome of first cerebral vein thrombosis or acute ischemic stroke [Kenet et al 2010].

*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

Recurrent thrombosis

Adults: Risk for recurrent thrombosis in 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. A recent evidence review by the EGAPP concluded that 20210G>A heterozygosity is not predictive of VTE recurrence [EGAPP Working Group 2011].

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

  • In several earlier studies, 20210G>A heterozygotes had a two- to fivefold increased risk for recurrent thrombosis during follow-up periods of seven to ten years [Simioni et al 2000, Miles et al 2001].
  • 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 including 3104 persons with a first VTE 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) [Ho et al 2006].
  • Another systematic review found a marginally significant increased risk for recurrent VTE in 20210G>A heterozygotes without other thrombophilic defects (OR = 1.74) [Marchiori et al 2007].

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

  • Four studies found no significant difference in the rate of recurrent VTE between 20210G>A heterozygotes and individuals without the allele [Eichinger et al 1999, Lindmarker et al 1999, De Stefano et al 2001, González-Porras et al 2006].
  • In a randomized trial comparing the oral anticoagulant ximelagatran with placebo after a standard course of anticoagulation for a first VTE, 20210G>A was not associated with a higher recurrence risk in either treatment group [Wahlander et al 2006].
  • A prospective follow-up study of participants in the Leiden Thrombophilia Study found that 20210G>A heterozygotes did not have a higher risk for recurrent VTE than those without the allele [Christiansen et al 2005].
  • In a large family study, the incidence of recurrent VTE in relatives with 20210G>A heterozygosity was 7% after two years, 11% after five years, and 25% after ten years, rates similar to those reported in the general population [Lijfering et al 2009].
  • In a cohort study of young women with a first VTE, 20210G>A heterozygosity did not increase the risk for recurrent thrombosis [Laczkovics et al 2007].
  • A recent systematic review pooling data from nine studies found that 20210G>A heterozygosity is not predictive of recurrent VTE [Segal et al 2009].

    20210G>A heterozygosity is not associated with a higher risk for recurrent VTE during warfarin therapy [Kearon et al 2008a]. Multiple studies showed that the reduction in risk during oral anticoagulation is similar in individuals with and without the allele [Segal et al 2009].

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].

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, individuals homozygous for the 20210G>A allele or doubly heterozygous for the 20210G>A and factor V Leiden alleles had a significantly increased risk for recurrent VTE. 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]. Other studies found an increased risk for recurrent VTE in individuals with more than one inherited predisposition to thrombophilia, but did not assess specific risk for double heterozygosity for 20210G>A and factor V Leiden because of the small number of cases [Prandoni et al 2007].

Studies that do not support an increased risk for recurrent thrombosis in 20210G>A homozygotes and 20210G>A heterozygotes with other risk factors:

  • 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].

Children: Risk for recurrent thrombosis

The available data suggest that the rate of recurrent VTE ranges from approximately 3% in neonates to 8% in older children, and up to as high as 21% after a first unprovoked VTE [Young et al 2008]. 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]. Persistent thrombosis after a course of anticoagulation may also be a risk factor for recurrence [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:

  • During an average of seven years’ follow up after a first spontaneous VTE, recurrent thrombosis occurred in 18% of children heterozygous for 20210G>A compared to 5% in those without the allele [Nowak-Gottl et al 2001a].
  • 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 controls (children without thrombophilia). Recurrent VTE occurred 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].
  • 20210G>A heterozygosity was identified as an independent risk factor for recurrent VTE in a pediatric cohort with cerebral vein thrombosis, conferring a fivefold increase in relative risk [Kenet et al 2007].
  • 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 (including 3% with 20210G>A), recurrent VTE occurred in 11%, none of whom had the 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 all recurrent VTE in neonates and children occurred in the presence of acquired risk factors including central venous catheters and/or an underlying medical condition. 20210G>A heterozygosity was not found among children with recurrent thrombosis [Revel-Vilk et al 2003].

Pregnant women: Risk for recurrent thrombosis

Summary. Women with a prior history of VTE have an increased recurrence risk during pregnancy although recurrence rates range from 0% to 15% among published studies. The risk is likely higher in women with a prior unprovoked episode and/or coexisting genetic or acquired risk factors. Note: Although none of the studies discussed below specifically evaluated the risk for recurrent VTE in pregnant women with a 20210G>A allele, the data suggest that women with thrombophilia (including a 20210G>A allele) have an increased risk for recurrent VTE.

  • The risk for recurrent VTE was increased three- to fourfold in pregnant women with a prior history of VTE [Pabinger et al 2002]. Analysis of a large nationwide 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 pregnancy-related VTE are at higher risk for recurrent VTE during a subsequent pregnancy [DeStefano et al 2006, White et al 2008]:
    • In a retrospective cohort study, women with a prior pregnancy-related VTE had a 9.8% and 15.5% rate of recurrence during pregnancy and the postpartum period, respectively [DeStefano et al 2006].
    • Women with pregnancy-associated VTE are nearly twofold more likely to have a recurrent event during a subsequent pregnancy than women with an initial unprovoked VTE. Among women with a pregnancy-related VTE, 35% of all recurrent episodes occurred during a subsequent pregnancy [White et al 2008].
  • One prospective study evaluated the safety of withholding anticoagulation during pregnancy in a large group of 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 a prior unprovoked VTE (but not both) had recurrence rates of 13% and 7.7%, respectively.

Pregnancy Complications

Summary. Prothrombin-related thrombophilia may increase the risk for pregnancy loss and other obstetric complications. The available data indicate that 20210G>A heterozygosity is associated with a two- to threefold increased relative risk for pregnancy loss; the precise risk is unknown pending longitudinal studies. The association with preeclampsia, intrauterine growth restriction, and placental abruption is controversial. A 20210G>A allele is at most one of multiple predisposing factors contributing to these complications. Other genetic and environmental triggers are likely necessary for the development of pregnancy complications in women heterozygous and homozygous for the 20210G>A allele. Overall, the probability of a successful pregnancy outcome is high.

Pregnancy loss 

Summary. In addition to the increased risk for venous thromboembolism during pregnancy, 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 vast majority of heterozygous women have normal pregnancies.

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

  • 20210G>A heterozygosity was found in 4%-9% of women with recurrent pregnancy loss (the majority in the first trimester), compared with 1%-2% of those with uncomplicated pregnancies, with odds ratios ranging from two to nine [Souza et al 1999, Foka et al 2000, Pihusch et al 2001, Raziel et al 2001, Reznikoff-Etievan et al 2001].
  • 20210G>A heterozygosity was associated with a six- to sevenfold increased risk for first-trimester recurrent fetal loss [Ivanov et al 2009].
  • 20210G>A heterozygosity also increased the risk for early first-trimester recurrent fetal loss among Turkish women [Yenicesu et al 2010].
  • In a large prospective cohort study of healthy nulliparous women, 20210G>A heterozygosity was associated with a two- to threefold increased risk for a composite outcome of pregnancy complications including stillbirth. There was a nonsignificant trend toward an increased risk for stillbirth alone [Said et al 2010].
  • Several meta-analyses concluded that 20210G>A heterozygosity was associated with a two- to threefold increased risk for recurrent first and second-trimester fetal loss and non-recurrent late fetal loss [Rey et al 2003, Kovalevsky et al 2004].
  • A more recent meta-analysis found a similar two- to threefold increased risk for pregnancy loss during all three trimesters. 20210G>A heterozygosity was associated with a nearly threefold increased risk fof recurrent first trimester loss and a nearly ninefold increased risk for non-recurrent second trimester loss [Robertson et al 2006].

Some evidence suggests that women with prothrombin-related thrombophilia have a higher risk for pregnancy loss in the second and third trimesters. One possible explanation is that late pregnancy losses reflect thrombosis of the placental vessels, in contrast to first-trimester losses, which more commonly have other causes. However, the role of thrombophilic disorders including 20210G>A in the complex biologic events predisposing to placental insufficiency is not well defined.

  • A large case-control study identified 20210G>A as an independent risk factor for a first unexplained fetal loss after ten weeks’ gestation (OR = 2) [Lissalde-Lavigne et al 2005].
  • 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].

Other evidence suggests that women with prothrombin-related thrombophilia also have a higher risk for pregnancy loss in the first trimester. The prothrombotic consequences of inflammation at the maternal-fetal interface may be exacerbated in women with inherited thrombophilia and thus interfere with implantation [Branch 2010].

Several case-control studies and three meta-analyses found an increased risk for first-trimester pregnancy loss in women with a 20210G>A allele [Rey et al 2003, Kovalevsky et al 2004, Robertson et al 2006, Ivanov et al 2009, Yenicesu et al 2010].

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

  • Three case-control studies found no association between 20210G>A and an increased risk for early or late recurrent pregnancy loss [Jivraj et al 2006, Kocher et al 2007, Pasquier et al 2009].
  • Several other earlier studies also found no significant association between 20210G>A and fetal loss [Brenner et al 1999, Gris et al 1999].
  • In a large retrospective family study, first-degree relatives with a 20210G>A allele did not have a higher risk for miscarriage or recurrent fetal loss than family members without the allele [Bank et al 2004].
  • 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].
  • Two prospective studies of unselected pregnant women found no association between 20210G>A heterozygosity and pregnancy loss [Karakantza et al 2008, Silver et al 2010].
  • 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 [Rodger et al 2010].

Although less well-studied, the 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, intrauterine growth restriction (IUGR), 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. Many studies of these complications were retrospective and underpowered to detect a significant association. 20210G>A heterozygosity is more likely to be present in women with unexplained severe and/or recurrent adverse pregnancy outcomes [Rodger et al 2008, Funai 2009].

Preeclampsia. Preeclampsia is a heterogeneous disorder and it is unlikely that a single thrombophilic mutation such as 20210G>A plays a major causal role. The conflicting results of the following studies suggest that 20210G>A heterozygosity has at most a weak effect on 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].
  • In a large prospective study of unselected pregnant women, 20210G>A heterozygosity was associated with a more than threefold increased risk for a composite outcome of complications including severe preeclampsia. The study was underpowered to detect associations between the mutation and individual obstetric complications [Said et al 2010].
  • 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].
  • In a case-control study 20210G>A heterozygosity did not increase the risk for severe preeclampsia; however, the onset of severe preeclampsia occurred significantly earlier in heterozygous women, suggesting that the allele may accelerate development of the disease [Gerhardt et al 2005].
  • 20210G>A heterozygosity had a stronger association with severe and early-onset preeclampsia than with mild forms of the disease in several studies [Mello et al 2005, Facchinetti et al 2009].
  • 20210G>A heterozygotes may have a higher risk for recurrent preeclampsia in a subsequent pregnancy. 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. The risk for recurrent severe preeclampsia was six- to sevenfold higher in women with thrombophilia [Facchinetti et al 2009].
  • Women with severe preeclampsia and an inherited thrombophilic disorder including a 20210G>A allele may have a higher risk for serious maternal complications and adverse perinatal outcomes than those without a thrombophilic disorder [Mello et al 2005, Facchinetti et al 2009].

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

  • Several studies found no association between 20210G>A and preeclampsia [Kupferminc et al 1999, Alfirevic et al 2001, D'Elia et al 2002, Morrison et al 2002, Kocher et al 2007].
  • 20210G>A heterozygosity did not increase the risk for preeclampsia in three prospective studies of unselected women screened during pregnancy [Karakantza et al 2008, Kahn et al 2009, Silver et al 2010].
  • A recent large prospective cohort study found a similar prevalence of 20210G>A heterozygosity in women who developed preeclampsia and a control group with uncomplicated pregnancies. Histopathologic features of placental insufficiency were found in 63% of preeclamptic women, but were not associated with 20210G>A heterozygosity [Kahn et al 2009].
  • Another large cohort study of unselected pregnant women found no association between 20210G>A and an increased risk for preeclampsia [Dudding et al 2008].
  • Two meta-analyses found no significant association between a 20210G>A allele and preeclampsia [Lin & August 2005, Rodger et al 2010]. The absolute risk for preeclampsia was similar in women with and without a 20210G>A allele (3.5% and 3%, respectively) [Rodger et al 2010]. One meta-analysis found a nonsignficant trend toward a twofold increased risk for severe preeclampsia in women with a 20210G>A allele but was underpowered to achieve statistical significance [Lin & August 2005].

Intrauterine growth restriction (IUGR). The data on the risk for IUGR associated with a 20210G>A allele are more limited and also conflicting.

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

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

  • A large case-control study found no significant association between maternal or fetal thrombophilia and IUGR. Women heterozygous for the 20210G>A allele had no increase in risk for a pregnancy complicated by IUGR compared with unaffected controls [Infante-Rivard et al 2002].
  • In several prospective studies of unselected pregnant women, a 20210G>A allele did not increase the risk for IUGR [Karakantza et al 2008, Said et al 2010, Silver et al 2010]. In one of these studies, 20210G>A heterozygosity was associated with an increased risk for a composite outcome of pregnancy complications which included IUGR, severe preeclampsia, placental abruption, or stillbirth [Said et al 2010].
  • A large cohort study found no association between a maternal or fetal 20210G>A allele (singly or in combination) and IUGR [Dudding et al 2008].
  • A meta-analysis found a nonsignificant trend toward a threefold increased risk for IUGR in 20210G>A heterozygous women [Robertson et al 2006].
  • A larger meta-analysis of 11 case-control studies found no significant association between a 20210G>A allele and IUGR [Facco et al 2009].

Placental abruption. The data on the risk for placental abruption in women with prothrombin-related thrombophilia are limited and conflicting. Because of the small number of individuals and conflicting results, no conclusions can be drawn from these studies.

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

  • 20210G>A heterozygosity was found in 18%-20% of women with placental abruption compared with 2%-3% of those with normal pregnancies, suggesting a six- to 12-fold increase in risk [Kupferminc et al 1999, Kupferminc et al 2000b, Facchinetti et al 2003].
  • A large prospective study of unselected pregnant women found that 20210G>A heterozygosity conferred a 12-fold increased risk for placental abruption [Said et al 2010].
  • In a meta-analysis, 20210G>A heterozygosity was associated with a nearly eightfold increased risk for placental abruption [Robertson et al 2006].

Studies showing no increased risk for placental abruption associated with a 20210G>A allele:

Preterm delivery. A 20210G>A allele was associated with a threefold increased risk for preterm delivery in one study [Kocher et al 2007]; however, there was no association with preterm delivery in a prospective study of unselected pregnant women [Silver et al 2010].

Factors that Predispose to Thrombosis

The clinical expression of prothrombin thrombophilia is influenced by four factors:

I. 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 have a higher risk, although the magnitude is not well defined. Although 20210G>A homozygotes tend to 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.

Several studies reported 20210G>A homozygosity in 1.8%-4.5% of individuals with a history of VTE and in no controls [Margaglione et al 1999, Barcellona et al 2003]. A pooled analysis of eight case-control studies found 20210G>A homozygosity in 0.2% of individuals with a history of VTE and in no controls [Emmerich et al 2001]. In other studies, however, no 20210G>A homozygotes were identified [Poort et al 1996].

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].

II. Coexisting Genetic Abnormalities

Eight percent to 14% of 20210G>A heterozygotes have other inherited thrombophilic disorders. The combination of 20210G>A heterozygosity and the presence of another thrombophilic disorder has a 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. 20210G>A heterozygosity is found in 6%-12% of individuals heterozygous for a factor V Leiden allele who have a history of VTE [Makris et al 1997, Emmerich et al 2001, Tirado et al 2001]. Conversely, heterozygosity for a factor V Leiden allele occurs in 20%-40% of symptomatic individuals who are 20210G>A heterozygotes [Poort et al 1996, Emmerich et al 2001]. Double heterozygosity for 20210G>A and factor V Leiden was found in 1%-5% of individuals with a history of VTE compared to 0%-1% of control individuals in multiple studies [Margaglione et al 1998, Salomon et al 1999, Simioni et al 2000]. Double heterozygosity for 20210G>A and factor V Leiden was found in 2.5% of children with a history of VTE compared to none of controls [Junker et al 1999, Schobess et al 1999].

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 markedly. In one analysis, factor V Leiden heterozygosity alone and 20210G>A heterozygosity alone were associated with a fivefold and fourfold increased risk, respectively. However, the risk was increased 20-fold in individuals heterozygous for both mutations, suggesting a mulitiplicative effect on overall thrombotic risk [Ehrenforth et al 1999, Emmerich et al 2001]. A 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 develop thrombotic complications at a significantly younger age and are more likely to develop thrombosis in unusual locations (e.g., hepatic, mesenteric, or cerebral veins) than those with a single or no thrombophilic allele.

Protein S 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. An F8 normal variant in combination with 20210G>A heterozygosity was associated with a 12-fold increased risk for myocardial infarction (MI) [Butt et al 2003]. Preliminary evidence suggests that the F8 Val34Leu variant has a weakly protective effect against VTE [Van Hylckama Vlieg et al 2002, 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 4 or 5 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]. The risk is higher when multiple members are affected and thrombosis occurs at a young age.

III. Acquired Thrombophilic Disorders

Hyperhomocysteinemia increases the thrombotic risk associated with 20210G>A heterozygosity. In one study, high plasma concentrations of homocysteine (>12 µmol/L) and 20210G>A heterozygosity conferred a 3.8- and 2.5-fold increased risk for VTE, respectively. However, the combination of the two risk factors was associated with an estimated 50-fold increase in risk, indicating a multiplicative effect on overall thrombotic risk [De Stefano et al 2001].

Antiphospholipid antibodies (APLA). 20210G>A heterozygosity did not increase the risk for thrombosis in individuals with antiphospholipid antibodies in several studies that evaluated this combination of risk factors [Galli et al 2000, Chopra et al 2002]. A more recent 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 2010a].

Malignancy. Persons with cancer have a markedly increased risk for VTE, especially during the first few months after diagnosis and in those with distant metastases [Blom et al 2005]. 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 mutation may increase the risk for malignancy-related VTE:

  • 20210G>A heterozygosity was associated with a two- to threefold increased risk for VTE in persons with gastrointestinal adenocarcinoma, a trend that did not reach statistical significance due to the small number of people in the study [Pihusch et al 2002].
  • 20210G>A heterozygosity was associated with a nearly sevenfold increased risk for VTE in persons with non-hematologic malignancies [Kennedy et al 2005].
  • 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 2005].
  • 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 2005].
  • The results of a meta-analysis suggest that a 20210G>A allele may contribute to central venous catheter thrombosis in persons with cancer [Dentali et al 2008b].

IV. 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 2003].

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

20210G>A heterozygosity is identified in 6%-26% of unselected women with a history of VTE during pregnancy or the puerperium:

  • 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 not well defined. Estimates from the following studies suggest that the absolute risk for VTE is low in the absence of other predisposing factors and that most events occur 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].
  • 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 another large family study, the absolute incidence of pregnancy-related VTE was 2.8% in women with a 20210G>A allele, which did not differ significantly from the incidence in family members without the allele [Bank et al 2004].
  • A population study estimated that VTE occurs in approximately one in 111 20210G>A heterozygotes during pregnancy [Jacobsen et al 2010].
  • In two recent 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 the highest 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].
  • In a study of families with thrombophilia, VTE complicated 4% of pregnancies in women doubly heterozygous for 20210G>A and factor V Leiden, compared with 0.5% of those in unaffected relatives [Martinelli et al 2001a].
  • 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].
  • 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].
  • Assuming a baseline incidence of one VTE event/1000 pregnancies, the estimated absolute risk in 20210G>A homozygotes is approximately 1/40 pregnancies [Robertson et al 2006]; however, because of the lack of data, the risk for pregnancy-related VTE cannot be accurately determined.

Oral contraceptive use. The use of oral contraceptives substantially increases the risk for VTE in women heterozygous for the F2 20210G>A allele:

  • 20210G>A heterozygosity is found in 9%-13% of women with a history of VTE during oral contraceptive use [Legnani et al 2002, Laczkovics et al 2007, DeSancho et al 2010b].
  • In a study of families with prothrombin-related thrombophilia, VTE occurred in 49% of 20210G>A heterozygous oral contraceptive users compared to 25% of 20210G>A heterozygous non-users. Sixty percent of VTE episodes in 20210G>A heterozygotes were associated with oral contraceptive use [Santamaria et al 2001].
  • 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 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].
  • In a meta-analysis, the combination of a 20210G>A allele and oral contraceptive use was associated with a 16-fold increased risk for VTE, also suggesting a supra-additive effect on overall thrombotic risk [Wu et al 2005].
  • Women with a 20210G>A allele who use oral contraceptives have an 80- to 150-fold higher risk for cerebral vein thrombosis than non-users without the allele [Martinelli et al 1998, Martinelli et al 2003a]. Other evidence suggests 20210G>A heterozygotes who use oral contraceptives have a nine- to 14-fold increased risk for unprovoked upper-extremity DVT [Martinelli et al 2004, Blom 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].
  • No studies have estimated the thrombotic risk associated with oral contraceptives in 20210G>A homozygotes due to the relative rarity of the disorder. Because of the higher baseline thrombotic risk in homozygous women, the risk associated with oral contraceptives is likely to be substantially higher than the risk in heterozygous women.
  • 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. For example, in a 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]. In another prospective family study, 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].
  • Women with inherited thrombophilic disorders such as prothrombin-related thrombophilia who use oral contraceptives tend to develop thrombotic complications sooner than oral contraceptive users without thrombophilia. The risk for thrombosis is much higher during the first year of oral contraceptive use than during subsequent years of use [Bloemenkamp et al 2000].
  • Oral contraceptives containing the third-generation progestagen desogestrel are associated with a twofold higher risk for VTE than second-generation preparations. No studies have estimated the thrombotic risk of third-generation preparations in women heterozygous for 20210G>A.
  • Unopposed progestin contraception is associated with a much lower risk for thrombosis than estrogen-containing contraception, although the risk in women with a thrombophilia is not well defined. 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.
  • 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.
  • No studies have evaluated the thrombotic risk of oral contraceptives in women with thrombophilia being treated for VTE with anticoagulation [Culwell & Curtis 2009].

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 [Hulley et al 1998, 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]. Most studies show a similar risk with unopposed estrogen and combined estrogen and progestin therapy [Canonico et al 2010, Renoux et al 2010].

Based on the known interaction with estrogen, the use of HRT is expected to increase the risk for VTE in women heterozygous or homozygous for the 20210G>A allele. Limited data suggest that heterozygous women 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].
  • Although 20210G>A heterozygosity did not significantly increase the thrombotic risk associated with combined estrogen and progestin in a case-control study of participants in the Women's Health Initiative trial [Cushman et al 2004], only a small number of women heterozygous for the 20210G>A allele on HRT were included.
  • 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].
  • Preliminary data suggest that the combination of HRT and 20210G>A heterozygosity may increase the risk for myocardial infarction (MI) nearly 11-fold in hypertensive postmenopausal women [Psaty et al 2001, Hindorff et al 2006].
  • One case-control study suggested that the risk for VTE may differ with the type of hormonal content. The use of conjugated equine estrogen (CEE) was associated with a ninefold increased risk for VTE in women with a 20210G>A allele or a factor V Leiden allele, compared to non-users with neither mutation. In contrast, the use of esterified estrogen (EE) was associated with a nonsignificant twofold increased risk among women with a 20210G>A allele or the factor V Leiden allele. The risk for VTE was fivefold higher with CEE use than with EE use among women with a 20210G>A allele or factor V Leiden allele [Smith et al 2006].

Transdermal hormone replacement therapy

  • There is increasing evidence that transdermal estrogen is associated with a lower thrombotic risk than oral estrogen in women with and without inherited thrombophilic disorders such as prothrombin-related thrombophilia [Canonico et al 2007, Canonico et al 2010].
  • In several case-control studies and a meta-analysis, 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].
  • Preliminary data suggest the use of transdermal estrogen confers no additional thrombotic risk in women with inherited thrombophilic disorders. 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 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. 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. Larger studies are required to determine the effect of 20210G>A heterozygosity on the risk for SERM-associated VTE.

Obesity. Obesity (BMI>30kg/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 <30kg/m2) with the allele have a fivefold increased thrombotic risk [Pomp et al 2007].

Organ transplantation

  • Renal. The prevalence of 20210G>A heterozygosity in individuals undergoing renal transplantation is similar to that in the general population, suggesting that 20210G>A heterozygosity is not a risk factor for developing end-stage renal disease (ESRD) [Fischereder et al 2001, Pherwani et al 2003]. However, some evidence suggests that 20210G>A heterozygosity may contribute to thrombotic and other complications after renal transplantation [Pherwani et al 2003, Kujovich 2004c]. A 20210G>A allele or a factor V Leiden allele was found in 42% of renal allograft recipients with avascular necrosis of the femoral head compared to 7% of control recipients, suggesting that heterozygosity for one of these alleles may increase the risk for this rare complication [Ekmekci et al 2006]. 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].

    The conflicting results of the following studies suggest that 20210G>A heterozygosity has at most a weak effect on renal allograft survival and the risk for rejection:
    • Studies showing an association of a 20210G>A allele and an increased risk for graft failure and/or acute rejection:
      • 20210G>A heterozygotes had a significantly reduced median graft survival time and a nearly threefold increased risk for graft failure, compared to renal transplant recipients without the 20210G>A allele [Fischereder et al 2001].
      • A prospective study found that 20210G>A heterozygosity was associated with a 12-fold increased risk for acute rejection and a tenfold increased risk for graft loss within the first year after transplantation. Renal transplant recipients heterozygous for the 20210G>A allele had elevated levels of the prothrombin activation fragment F1+2, a marker of coagulation activation prior to transplantation [Heidenreich et al 2003]. In both studies, graft failure resulted from arterial or venous thrombosis in the majority of individuals.
    • Studies showing no association with graft survival or rejection:
      • A 20210G>A allele in renal transplant donors or recipients had no significant effect on 30-day or one-year graft survival [Pherwani et al 2003].
      • 20210G>A was not associated with decreased one-year graft survival or an increased risk for acute rejection in cadaveric renal transplant recipients [Alakulppi et al 2008].
      • 20210G>A had no significant effect on renal allograft survival at one and three years after adjustment for other SNPs (single nucleotide polymorphisms) [Meyer et al 2007].
  • Hepatic. The contribution of 20210G>A heterozygosity to thrombotic complications after other types of organ transplantation is uncertain. Hepatic artery thrombosis was reported in individuals who acquired prothrombin-related thrombophilia after liver transplantation. 20210G>A heterozygosity was identified in 14% of allografts complicated by hepatic artery thrombosis, but not in recipient peripheral blood leukocytes [Mas et al 2003]. However, it is unknown whether 20210G>A heterozygosity predisposes to this particular transplantation complication.

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 2005]. 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].
  • A meta-analysis found that a 20210G>A allele is associated with a fivefold increased risk for central venous catheter-related thrombosis in persons with cancer [Dentali et al 2008b].
  • A central venous catheter is one of the most common circumstantial risk factors provoking thrombosis in children [Young et al 2008].
  • 20210G>A may also increase the risk for arteriovenous fistula thrombosis [Ataç et al 2002].

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 of surgery:

  • Surgery and the postoperative state were associated with a significantly increased risk for VTE in persons with a 20210G>A allele or a factor V Leiden allele [DeSancho et al 2010a].
  • 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 2005].
  • 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].
  • 20210 G>A was found in 23% of persons with VTE after total hip arthroplasy compared to only 2% of a control group, suggesting that the allele may increase postoperative venous thrombotic risk [Salvati et al 2005].
  • 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. 20210G>A heterozygosity was identified in 12% of individuals with VTE within 30 days after air travel [McQuillan et al 2003]. Another 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 these 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 suggests 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 to be small; however, the 20210G>A allele may interact with other genetic and environmental risk factors to promote arterial thrombosis.

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 [Redondo et al 1999, Ridker et al 1999, Smiles et al 2002, Linnemann et al 2008b]. The allele did not confer an increased risk for MI or stroke in an analysis of the Physicians’ Health Study [Ridker et al 1999]. Another large population study also found no association with an increased risk for MI or stroke in elderly individuals (age >65 years) [Smiles et al 2002].

Several other studies 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 one 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 results of several meta-analyses suggest at most a weak association with arterial thrombosis. In one of these studies, a 20210G>A allele did not increase the risk for MI, ischemic stroke, or peripheral vascular disease. However, a modest increase in risk was observed when these three forms of arterial disease were analyzed collectively. The association was stronger in individuals younger than age 55 years and in women [Kim & Becker 2003]. Another meta-analysis found a similar modest but statistically significant association between a 20210G>A allele and ischemic stroke (pooled OR = 1.44) [Casas et al 2004].

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). A pooled analysis found no association of 20210G>A heterozygosity with MI [Boekholdt et al 2001]. A larger meta-analysis of 40 studies found that a 20210G>A allele conferred a mildly increased risk for coronary heart disease and myocardial infarction (per allele relative risk = 1.31) [Ye et al 2006].

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 in individuals with major cardiovascular risk factors in several studies [Rosendaal et al 1997, Doggen et al 1998, Franco et al 1999]. 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].
  • Hypertensive postmenopausal women with a 20210G>A allele who used HRT had an 11-fold higher risk for MI than women without the allele who were not on HRT [Psaty et al 2001]. In another study, the allele was associated with a twofold increased risk for MI in postmenopausal women. The risk was increased nearly sixfold in 20210G>A heterozygotes who used HRT [Hindorff et al 2006].
  • Other evidence suggests that 20210G>A heterozygosity increases the risk for MI primarily in individuals without major cardiovascular risk factors or significant coronary artery disease [Van de Water et al 2000, Burzotta et al 2002].
  • In a large cohort study, family members with a 20210G>A allele had a nearly fivefold borderline significant increased risk for a first MI compared to relatives without the allele. The first arterial thrombotic event occurred before age 50 years in 43% of persons [Bank et al 2004]. 20210G>A heterozygosity was associated with a nearly sixfold increased risk for early-onset MI before age 50 years in a Newfoundland population [Butt et al 2003]. In contrast, another study of persons younger than age 45 years found no association between a 20210G>A allele and the risk for MI [Atherosclerosis Thrombosis and Vascular Biology Italian Study Group 2003].

Stroke in adults. Most studies of unselected adult populations found no significant association between 20210G>A and ischemic stroke [Ridker et al 1999, Smiles et al 2002, Linnemann et al 2008b]. In a prospective cohort study, the annual incidence of ischemic stroke or TIA was similar in family members with and without the allele (0.33% and 0.23%, respectively) [Coppens et al 2006].

Although 20210G>A is not a general risk factor for stroke, it may contribute to the risk for stroke in selected populations:

  • A 20210G>A allele was associated with a sixfold increased risk for stroke before age 60 years in men, but was not an independent risk factor among women [Lalouschek et al 2005].
  • 20210G>A heterozygosity was a risk factor for severe carotid disease, primarily in men (OR = 2.9) and individuals with no traditional risk factors for atherosclerosis (OR = 6.0) [Marcucci et al 2005].
  • 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]. The risk was exceedingly high in homozygotes (estimated OR > 200), based on a small number of individuals [De Stefano et al 1998].
  • In contrast, two other large studies found no significant association between a 20210G>A allele and stroke at a young age. However, both studies noted a nonsignficant twofold increased risk for cryptogenic and premature stroke, respectively [Austin et al 2002, Pezzini et al 2005].
  • Arterial thromboembolism may also occur “paradoxically” through a patent foramen ovale (PFO) in the heart of individuals with venous thrombosis. One study found a high prevalence of the 20210G>A or factor V Leiden allele in individuals with cryptogentic stroke and a patent foramen ovale, suggesting possible paradoxical thromboembolism [Karttunen et al 2003]. 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].
  • 20210G>A heterozygosity increased the risk for systemic embolism in individuals with atrial fibrillation in one study [Pengo et al 2002], but not in another [Poli et al 2003].

Peripheral vascular disease. The few studies evaluating the association of 20210G>A heterozygosity and peripheral vascular disease reported conflicting results. One study found a significantly increased risk for peripheral vascular disease, particularly in smokers [Reny et al 2004]. Another study found no association [Renner et al 2000]. In a large family cohort study, the annual incidence of a first peripheral arterial thrombotic event was not increased in relatives with a 20210G>A allele (0.03%) compared to relatives without the allele (0.02%) [Bank et al 2004].

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 case series and case-control studies, many of which lacked statistical power due to small sample size. 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. Stroke accounted for 67% of arterial thrombotic events [Young et al 2003]. An International Pediatric Stroke Study (IPSS) is prospectively evaluating the association between inherited thrombophilia and acute ischemic stroke in neonates and children (see International Paediatric Stroke Study).

Studies supporting the association of an F2 20210G>A allele with stroke in children;

  • 20210G>A heterozygosity was found in 6%-9% of children with ischemic stroke compared to 1% of controls, suggesting a nearly fivefold increase in risk [Nowak-Gottl et al 1999, Barreirinho et al 2003].
  • In a longitudinal study of children with a first acute ischemic stroke, 20210G>A was associated with a sevenfold increased recurrence risk in previously healthy children with no predisposing underlying disorder [Ganesan et al 2006].
  • 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].

Studies that do not support the association of an F2 20210G>A allele with stroke in children;

  • Several other small studies found a low prevalence of 20210G>A heterozygosity in children with ischemic stroke, similar to that found in normal controls or the general population [Zenz et al 1998, Kenet et al 2000, Bonduel et al 2003].
  • In a prospective study of children with a first acute ischemic stroke, a 20210G>A allele was not associated with an increased recurrence risk [Sträter et al 2002].
  • A smaller meta-analysis found no significant association between 20210G>A heterozygostiy and first ischemic stroke in children (pooled OR = 1.10) [Haywood et al 2005].

Perinatal acute ischemic stroke. Perinatal acute ischemic stroke is defined as cerebral infarction occurring between 28 weeks’ gestation and 28 days after birth. It is a unique thrombotic complication with a complex etiology that may differ from stroke in older children [Kenet et al 2010]. Arterial thrombosis may occur in the fetus as a result of placental venous thrombi entering the fetal circulation, crossing the foramen ovale, and entering the cerebral arterial vasculature.

A 20210G>A allele is reported in 5%-10% of infants with perinatal arterial stroke compared to 2%-3% of a control or general population [Miller et al 2006, Curry et al 2007, Simchen et al 2009]. In one study, the prevalence of the allele was increased in infants with perinatal arterial ischemic stroke (10%), but lower in mothers of affected infants (4%) [Curry et al 2007].

  • Two other studies found a twofold increase in risk which did not reach statistical significance due to small sample size [Miller et al 2006, Simchen et al 2009].
  • In a meta-analysis, a 20210G>A allele was associated with a twofold increased risk for perinatal arterial ischemic stroke [Kenet et al 2010].

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.

Penetrance

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].

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. In several studies, the annual incidence of VTE was higher among members of families with thrombophilia and a strong history of VTE at a young age, underscoring the importance of family history when assessing risk [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.

  • 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. The annual incidence of a first arterial thrombotic event was also similar in relatives with and without a 20210G>A allele [Coppens et al 2006].
  • 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].
  • The presence of additional inherited or acquired thrombophilic disorders in 202010G>A heterozygotes substantially increases the absolute risk for VTE. The annual incidence of a first VTE was 0.19%/year in relatives with 20210G>A heterozygosity alone, compared to 0.05%/year in relatives without the allele. Relatives with 20210G>A heterozygosity in combination with other inherited thrombophilic disorders had a much higher risk of 0.45%-0.59%/year [Lijfering et al 2009]. The incidence of VTE was 0.4%/year to 0.5%/year in family members doubly heterozygous for the 20210G>A and factor V Leiden alleles [Faioni et al 1999, Martinelli et al 2000a, Lijfering et al 2009].
  • The probability of remaining free of thrombosis at age 50 years was 95% for 20210G>A heterozygotes, compared to 97% for family members without the allele [Martinelli et al 2000a]. At least 50% of thrombotic events were associated with other risk factors, especially pregnancy.
  • Another family study found that 38% of first VTE episodes in heterozygous or homozygous family members were spontaneous, in contrast to VTE events in relatives without the allele, which were all related to transient risk factors [Bank et al 2004].

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 [Rosendaal et al 1998].
  • Within Europe the prevalence of 20210G>A heterozygosity 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 and 0%-0.3% in African Americans, reflecting the world distribution of the allele [Dilley et al 1998, Dowling et al 2003].
  • 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].
  • A recent US population survey conducted by the CDC found 20210G>A heterozygosity in 2.2%, 2.2%, and 0.6% of non-Hispanic whites, Hispanic whites, and African American populations, respectively [Chang et al 2009].
  • 20210G>A heterozygosity was not detected in a population of black individuals with VTE in the United Kingdom [Patel et al 2003].
  • 20210G>A heterozygosity was found in 1.6% of a healthy Kurdish population in Iran [Rahimi et al 2008].

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 2001a].

The prevalence of 20210G>A homozygosity is approximately one in 10,000. Double heterozygosity for the 20210G>A and factor V Leiden alleles occurs in approximately one in 1000 individuals in the general population and 2%-4.5% of persons with VTE [Margaglione et al 1999, Emmerich et al 2001, Barcellona et al 2003].

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 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, 15%-20% of individuals with a first VTE, and up to 50% of individuals with recurrent VTE or an estrogen-related thrombosis. Coinheritance of both a factor V Leiden allele and an F2 20210G>A allele occurs in 2%-4.5% of individuals with venous thromboembolism [De Stefano et al 1999, Simioni et al 2000, Emmerich et al 2001]. 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 point mutation (677C>T) in MTHFR, encoding methylenetetrahydrofolate reductase, results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Homozygosity for the mutation 677C>T (also known as C677T) predisposes to mild hyperhomocysteinemia, usually in the setting of suboptimal folate stores. Homozygosity for 677C>T occurs in 10%-20% of the general population. The MTHFR variant is not associated with an increased risk for VTE independent of plasma homocysteine concentrations [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.

Acquired

High plasma concentration of homocysteine occurs in 10% of individuals with a first VTE and is associated with a two- to threefold increase in relative risk. The plasma concentration of homocysteine reflects genetic as well as environmental factors and is more directly associated with thrombotic risk than MTHFR variants.

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 IgG anticardiolipin antibodies, anti-beta2 gycoprotein 1 antibodies, and lupus inhibitors are most strongly associated with arterial and venous thromboembolism [Galli et al 2003]. Recent evidence suggests that the combination of a lupus inhibitor and anti-beta2 glycoprotein 1 antibodies may confer the highest thrombotic risk.

An elevated factor VIII level greater than 150% of normal is a common independent risk factor for VTE, conferring a four- to fivefold increase in risk in several studies [Koster et al 1995, Bank et al 2005]. A high factor VIII level also significantly increases the risk for recurrent thrombosis [Kyrle et al 2000]. There are reports of a familial form of high factor VIII levels, although a genetic basis has not been identified.

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 heterozygosity and also increases the thrombotic risk of oral contraceptives [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, several single-nucleotide polymorphisms (SNPs) in coagulation proteins, and variants in the tissue factor pathway inhibitor gene [Smith et al 2007, Bezemer et al 2008].

Homozygosity for the factor XIII p.Val34Leu polymorphism is associated with a 30% reduced risk for VTE [van Hylckama Vlieg et al 2002, Rosendaal & Reitsma 2009].

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

To evaluate the risk for thrombosis in an individual diagnosed with prothrombin-related thrombophilia, the following evaluations are recommended:

Individuals heterozygous for the F2 20210G>A allele should be tested for other inherited and acquired thrombophilic disorders. 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 since no data support the use of vitamin supplementation or a change in duration of anticoagulation in individuals with hyperhomocysteinemia and a history of VTE. In a randomized placebo-controlled trial, supplementation with folic acid, vitamin B12, and pyridoxine did not reduce the incidence of recurrent VTE [den Heijer et al 2007]. (2) There is no clinical rationale for DNA testing for MTHFR variants. (3) Routine measurement of factor VIII and other clotting factor levels is not recommended; however, such testing may be useful in certain instances [Chandler et al 2002, Bauer 2010].

Treatment of Manifestations

Thrombosis. The management of 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, fondaparinux (a pentasaccharide) or intravenous unfractionated heparin [Kearon et al 2008b]. Oral administration of warfarin is started concurrently with low molecular-weight heparin 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. Low molecular-weight heparin (or fondaparinux) and warfarin therapy should be overlapped for at least five days, and until the INR has been within the therapeutic range on two consecutive measurements over two days. Note: Low molecular-weight heparin and warfarin are both safe in women who are breast-feeding.

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 an incident VTE experience recurrent thrombosis within the subsequent five years [Prandoni et al 2007]. Because individuals remain at risk for recurrence even after ten years, VTE is now considered a chronic disease.

The risk for VTE recurrence is higher in persons with proximal deep vein thrombois (DVT) than distal DVT (relative risk = 0.5) and in those with one or more prior episodes of VTE. Other risk factors for recurrent VTE include male sex (relative risk = 1.6) and an elevated D-dimer level one month after stopping anticoagulation [McRae et al 2006, Palareti et al 2006, Eichinger & Kyrle 2009]. Residual vein thrombosis after a course of anticoagulation is also a risk factor for recurrence [Siragusa et al 2008, Prandoni et al 2009].

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 major factor determining the duration of anticoagulation in the 2008 American College of Chest Physicians Guidelines on Antithrombotic Therapy based on evidence that inherited thrombophilic disorders are not major determinants of recurrence risk [Kearon et al 2008b]. Other clinical guidelines and expert opinion also recommend that identification of 20210G>A heterozygosity not affect clinical decision making [Baglin et al 2010 (full text; registration or institutional access required), Bauer 2010, Kyrle et al 2010].

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 2008b]

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 2008b]. 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 individuals homozygous for the 20210G>A allele or with multiple inherited or acquired thrombophilic disorders [Kearon et al 2008b]. In these individuals at high risk for recurrence, the potential benefits of long-term warfarin may outweigh the bleeding risks.

Unfractionated and low molecular-weight heparin, fondaparinux, and warfarin are the primary antithrombotic agents used for the acute and long-term treatment of VTE. Low molecular-weight heparins and fondaparinux have largely replaced unfractionated heparin because of their many advantages [Hirsh et al 2008].

Several direct thrombin inhibitors (lepirudin, argatroban, and dabigatran) are approved for use in specific circumstances.

A new oral direct factor Xa inhibitor (rivaroxaban) and an oral direct thrombin inhibitor (dabigatran) were effective for prophylaxis and treatment of VTE in multiple randomized trials [Gross & Weitz 2008, Laux et al 2009].

The US Food and Drug Administration approved dabigatran for the prevention of stroke and thrombosis in patients with atrial fibrillation in October 2010. Its role in the long-term prevention and treatment of VTE in individuals with inherited thrombophilic disorders is still unclear [Sattari & Lowenthal 2011].

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

Treatment of thrombosis in children. There is no evidence that a 20210G>A allele should influence decisions about the duration of anticoagulation in children. Treatment recommendations for children with VTE are largely adapted from studies in adults. Randomized controlled trials are required for the development of evidence-based guidelines for treatment in children.

The American College of Chest Physicians 2008 guidelines for antithrombotic therapy in children recommend the following* [Monagle et al 2008 (full text)]:

  • At least three months of anticoagulation after a provoked VTE
  • A minimum of six months of anticoagulation after the first idiopathic (unprovoked) VTE
  • Indefinite anticoagulation for those with recurrent idiopathic VTE

*Note: The presence of inherited thrombophilic disorders was not included as a major factor influencing recommendations regarding duration of anticoagulation [Monagle et al 2008].

Expert opinion emphasizes the importance of a careful risk/benefit assessment in each individual [Manco-Johnson 2006, Raffini & Thornburg 2009].

Consensus guidelines are also available for management of stroke in infants and children [Roach et al 2008; full text (registration or institutional access required)].

There are no evidence-based guidelines for thromboprophylaxis in children with inherited thrombophilia.

Prevention of Primary Manifestations

In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic 20210G>A heterozygotes, since the 1%-3% yearly risk for major bleeding from warfarin is greater than the estimated less than 1% yearly risk for thrombosis [Faioni et al 1999, Martinelli et al 2000a, Middeldorp & van Hylckama Vlieg 2008, EGAPP Working Group 2011].

Prophylactic anticoagulation should 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.

Decisions regarding prophylactic anticoagulation should be based on a risk/benefit assessment in each individual. 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 2008 ACCP consensus guidelines [Geerts et al 2008 (full text)].

Pregnancy. There is no consensus on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are similar to those for individuals who are not pregnant [Kujovich 2004a, Duhl et al 2007, Bates et al 2008, Royal College of Obstetricians and Gynaecologists 2009, Baglin et al 2010 (full text; registration or institutional access required)]. Low molecular-weight heparin is the preferred antithrombotic agent for prophylaxis during pregnancy. Until more specific recommendations are defined by prospective trials, decisions about anticoagulation should be individualized based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis [American College of Obstetricians and Gynecologists 2010].

Prophylactic anticoagulation during pregnancy:

Prevention of Secondary Complications

Prevention of pregnancy loss. The results of observational studies and several randomized trials suggest that prophylactic antithrombotic therapy may improve pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss:

  • In one study, 50 women with inherited or acquired thrombophilic disorders and recurrent pregnancy loss received enoxaparin throughout 61 subsequent pregnancies. The live birth rate was 75% with enoxaparin prophylaxis, compared to 20% in prior untreated pregnancies [Brenner et al 2000].
  • Another study reported a similar live birth rate of 77% in women with inherited thrombophilia who received enoxaparin prophylaxis compared to 44% in untreated historical control women [Carp et al 2003].
  • 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, suggesting a 15-fold higher likelihood of a successful outcome. In the subgroup of women heterozygous for the 20210G>A allele, the live birth rate was 80% with enoxaparin prophylaxis, compared to 33% with aspirin, suggesting an eightfold higher likelihood of a successful pregnancy outcome [Gris et al 2004].
  • A prospective randomized trial compared two different prophylactic doses of enoxaparin in women with thrombophilia and a history of recurrent pregnancy loss (including 19 20210G>A heterozygotes). Both prophylactic doses (40 mg/day and 80 mg/day) achieved similar high live birth rates of 84% and 78%, respectively. These rates were substantially higher than the 23% live birth rate in prior untreated pregnancies [Brenner et al 2005].

In contrast, other studies found no benefit of low molecular-weight heparin on pregnancy outcome in women with inherited thrombophilia:

  • A retrospective cohort study evaluated a group of women with inherited thrombophilia, 58% of whom had a prior history of adverse pregnancy outcomes. The use of heparin or low molecular-weight heparin during pregnancies following a diagnosis of thrombophilia did not result in a higher live birth rate than in untreated pregnancies (86% vs 82%, respectively [Warren et al 2009].
  • A small prospective randomized trial compared prophylactic-dose dalteparin and low-dose aspirin with aspirin alone in 88 women with antiphospholipid antibodies or inherited thrombophilia and a history of unexplained recurrent pregnancy loss. In the group of women with inherited thrombophilia, dalteparin did not improve the live birth rate, which was high in both groups (83% and 87%, respectively) [Laskin et al 2009].

There are no prospective randomized trials including an untreated control group confirming the benefit of LMWH in preventing pregnancy loss in women with inherited thrombophilia. These trials are required to confirm efficacy in this population of women.

ACCP 2008, recent obstetric consensus guidelines (ACOG), and expert opinion do not routinely recommend antithrombotic therapy for women with a 20210G>A allele and pregnancy loss because of the lack of sufficient evidence confirming benefit [Duhl et al 2007, Bates et al 2008, Rodger et al 2008, Dao & Rodger 2009, American College of Obstetricians and Gynecologists 2010]. The results of several ongoing randomized trials are required to confirm or refute the benefit of antithrombotic therapy in women with inherited thrombophilia and pregnancy loss [Bates 2010].

Antithrombotic prophylaxis may be considered in selected women with 20210G>A heterozygosity and unexplained recurrent or late pregnancy loss after an informed discussion of the risks of antithrombotic therapy and the lack of definitive data confirming benefit [Kujovich 2005, Walker et al 2005, Bates 2010]. Assessment of the maternal thrombotic risk during pregnancy should also be incorporated into the decision regarding prophylaxis.

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.

In the Live-Enox study, the incidence of preeclampsia, placental abruption, and intrauterine growth restriction was substantially lower with enoxaparin prophylaxis than in prior untreated pregnancies [Brenner et al 2005].

A study of women with thrombophilia and a prior fetal loss who received either enoxaparin or aspirin during a subsequent pregnancy found that those who received enoxaparin had more newborns with significantly higher birth weights and fewer classified as small for gestational age [Gris et al 2004]. However, neither study was designed to evaluate these complications as primary outcomes.

A randomized trial comparing prophylaxis with low molecular-weight heparin and aspirin to aspirin alone in women with recurrent pregnancy loss included preeclampsia as a secondary outcome. This trial included only a small number of women with thrombophilia. Prophylaxis with low molecular-weight heparin with or without aspirin did not reduce the risk for preeclampsia or other obstetric complications [Kaandorp et al 2010].

There is currently no evidence that prophylaxis with low molecular-weight heparin reduces the risk for preeclampsia in women with thrombophilia including 20210G>A heterozygosity. ACCP 2008 Guidelines on Antithrombotic Therapy (full text) recommend low-dose aspirin throughout pregnancy for women at high risk for preeclampsia. Low molecular-weight or unfractionated heparin is not routinely recommended for women with inherited thormbophilia and a history of preeclampsia or other adverse pregnancy outcomes [Duhl et al 2007, Bates et al 2008].

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 be encouraged to 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, the indications for family testing are unresolved. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several novel inhibitors of the initiation of coagulation and fibrin formation are in various stages of clinical development. None of these new antithrombotic agents is specific for the 20210G>A allele or thrombophilia in general.

Two new oral direct factor Xa inhibitors (rivaroxaban and apixaban) and an oral direct thrombin inhibitor (dabigatran) were effective for prophylaxis and treatment of VTE in multiple randomized trials. Dabigatran and rivaroxaban are currently approved for VTE prevention after orthopedic surgery in Europe. Dabigatran was approved by the US FDA in October 2010 for the prevention of stroke and thrombosis in patients with atrial fibrillation.

Long-acting pentasaccharides administered on a weekly basis are also in advanced clinical trials [Gross & Weitz 2008, Weitz et al 2008, Laux et al 2009].

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: the presence of one mutant allele results in the phenotype; the presence of two mutant alleles results in more severe manifestations of the phenotype and/or an increased risk for the phenotype.

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 20210G>A allele.
  • Prothrombin-related thrombophilia as the result of a 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, 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 of a proband. 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 prothrombin 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 pathogenic allelic variant, possible non-medical explanations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Informed consent. Specific informed consent is not generally required for molecular genetic testing for the 20210G>A allele, although it may be required in some states. However, prior to testing, individuals should be made aware that genetic test results have implications for risk to other family members and thus, for issues of confidentiality [Grody 2001].

Note: The Genetic Information Nondiscrimination Act (GINA) passed in 2008 protects individuals from discrimination by health insurers or employers on the basis of genetic information.

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.

The indications for testing at-risk family members are unresolved. Since 20210G>A heterozygosity confers an only mildly increased risk for thrombosis, routine testing of at-risk family members is not recommended.

The low absolute thrombotic risk in asymptomatic 20210G>A heterozygotes argues against a general policy of testing at-risk family members. In the absence of evidence that early diagnosis reduces morbidity or mortality, the decision to test at-risk family members should be made on an individual basis. Clarification of 20210G>A allele status may be useful in women considering use of estrogen contraception or pregnancy, or in families with a strong history of recurrent thrombosis at a young age. At-risk family members often request testing prior to exposure to recognized risk factors or simply from a desire to know their status. Individuals requesting testing for the 20210G>A allele and those identified as heterozygotes should be counseled regarding the implications of the diagnosis, including the potential need for prophylactic anticoagulation in high-risk settings and the signs and symptoms of thrombosis that require immediate medical attention. They should be informed that whereas the presence of a 20210G>A allele is an established risk factor, it does not predict thrombosis with certainty and that the clinical course is variable even within the same family.

Molecular genetic testing of asymptomatic individuals younger than age 18 years Currently no consensus exists on the indications for testing individuals younger than age 18 years for prothrombin thrombophlia. Early diagnosis of prothrombin-related thrombophilia has not been shown to improve clinical outcome in adults or children.

Asymptomatic at-risk individuals younger than age 18 years are not usually tested because thrombosis rarely occurs before young adulthood, even in homozygous individuals. Earlier testing may be considered in families with other known thrombophilic disorders or a strong history of thrombosis at a young age.

The decision to test for the 20210G>A allele should be made on an individual basis only after counseling the family about potential benefits and limitations. The test results should be interpreted by a physician experienced in the management of children with thrombophilia and thrombosis [Raffini 2008, Raffini & Thornburg 2009].

In 2002 the subcommittee for perinatal and pediatric hemostasis of the International Society for Thrombosis and Haemostasis published guidelines for laboratory testing for thrombophilia in children. Complete thrombophilia testing was recommended for children with thrombosis. However, the committee acknowledged the requirement for further studies to validate this recommendation [Manco-Johnson et al 2002]. Based on more recent data, expert opinion now recommends that decisions be made on an individual basis after careful consideration of the limitations and potential benefits [Manco-Johnson 2006, Raffini & Thornburg 2009]. 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 diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for the 20210G>A allele are very rare 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 pathogenic variant has been identified.

Although technically possible, 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

Normal allelic variants. Two F2 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.

Pathogenic allelic variants. The 20210G>A pathogenic variant is located in the 3' untranslated region of the gene 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 the mutation arose 21,000-24,000 years ago in whites towards the end of the last glaciation [Zivelin et al 2006].

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, although 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].
  • One case-control study found a lower prevalence of a 20210G>A allele in individuals with spontaneous intracranial hemorrhage (1.5%) compared to controls (3%), although the difference was not statistically significant because of the small number of individuals with prothrombin-related thrombophlia who were included [Corral et al 2001].

Table 2. Selected F2 Pathogenic Variants

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. The asterisk 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 (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 result in increased thrombin generation and a prothrombotic state [Kyrle et al 1998, Butenas et al 1999].

Thrombin generation (measured as endogenous thrombin potential) was significantly increased in 20210G>A heterozygotes with a history of VTE compared to asymptomatic heterozygotes and controls without the allele. The increased thrombin generation in symptomatic heterozygotes was only partly due to higher plasma prothrombin levels, suggesting that other mechanisms may influence thrombin generation and thrombotic risk [Lavigne-Lissalde et al 2010]. Possible mechanisms include the following:

  • High prothrombin levels may inhibit activated protein C-mediated inactivation of activated factor Va, further enhancing thrombin generation [Smirnov et al 1999]. 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].
  • Impaired fibrinolysis resulting from enhanced activation of thrombin-activatable fibrinolysis inhibitor (TAFI) may be an additional mechanism contributing to the increased thrombotic risk [Colucci et al 2004].

References

Published Guidelines/Consensus Statements

  1. American College of Obstetricians and Gynecologists; Practice Bulletin Number 113. Inherited thrombophilias in pregnancy. Obstet Gynecol. 2010;116:212–22. [PubMed: 20567195]
  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. Br J Haematol. 2010; 149:209-20. Available online (registration or institutional access required). Accessed 3-3-14. [PubMed: 20128794]
  3. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J; American College of Chest Physicians. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8 ed. Chest. 2008; 133:844S-86S. Available online. Accessed 3-3-14. [PubMed: 18574280]
  4. 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 prothormbin (20210G>A) mutations in adults with a history of idiopathic VTE and their adult family members. Genet Med. 2011; 13:67-76. Available online. Accessed 3-3-14. [PubMed: 21150787]
  5. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133:381S-453S. Available online. Accessed 3-3-14. [PubMed: 18574271]
  6. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8 ed. Chest. 2008; 133:454S-545S. Available online. Accessed 3-3-14. [PubMed: 18574272]
  7. Monagle P, Chalmers E, Chan A, DeVeber G, Kirkham F, Massicotte P, Michelson AD; American College of Chest Physicians. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133:887S-968S. Available online. Accessed 3-3-14. [PubMed: 18574281]
  8. Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G, Ferriero D, Jones BV, Kirkham FJ, Scott RM, Smith ER; American Heart Association Stroke Council; Council on Cardiovascular Disease in the Young. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008; 39:2644-91. Available online (registration or institutional access required). Accessed 3-3-14. [PubMed: 18635845]
  9. 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. Genet Med. 2005; 7:444-53. Available online. Accessed 3-3-14. [PubMed: 16024978]

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Suggested Reading

  1. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S. Women's Health Initiative Steering Committee; Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701–12. [PubMed: 15082697]
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  3. Canonico M, Oger E, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost. 2006;4:1259–65. [PubMed: 16706969]
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  5. Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M, Whyte S, Greer IA. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115:4162–7. [PubMed: 20237316]
  6. Curb JD, Prentice RL, Bray PF, Langer RD, Van Horn L, Barnabei VM, Bloch MJ, Cyr MG, Gass M, Lepine L, Rodabough RJ, Sidney S, Uwaifo GI, Rosendaal FR. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006;166:772–80. [PubMed: 16606815]
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  14. Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, Morin F, Demers C, Kahn SR, Magee LA, Rodger M. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost. 2009;7:58–64. [PubMed: 19036070]
  15. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med. 1995;332:1661–5. [PubMed: 7760866]
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Chapter Notes

Revision History

  • 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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