Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot ... Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot dislodges and travels to the lung. Other manifestations include thromboses of the cerebral or visceral veins and recurrent pregnancy loss (summary by Seligsohn and Lubetsky, 2001 and Varga and Kujovich, 2012). - Genetic Heterogeneity of Thrombophilia THPH2 (188055) is caused by mutation in the F5 gene (612309) on chromosome 1q23; THPH3 (176860) and THPH4 (612304) are both caused by mutation in the PROC gene (612283) on 2q; THPH5 (612336) and THPH6 (614514) are caused by mutation in the PROS1 gene (176880) on 3q11; THPH7 (613118) is caused by mutation in the AT3 gene (107300) on 1q23-q25; THPH8 (300807) is caused by mutation in the F9 gene (300746) on Xq27; THPH9 (612348) is associated with decreased release of tissue plasminogen activator (PLAT; 173370); THPH10 (612356) is caused by mutation in the HCF2 gene (142360) on 22q11; THPH11 (613116) is caused by mutation in the HRG gene (142640) on 3q27; and THPH12 (614486) is associated with variation in the THBD gene (188040) on 20p11. Susceptibility to thrombosis has also been associated with variation in additional genes, including MTHFR (607093.0003); F13B (134580.0003); plasminogen activator inhibitor (SERPINE1; 173360); SERPINA10 (605271); and several genes encoding fibrinogen (FGA, 134820; FGB, 134830; FGG, 134850). Variation in the KNG1 (612358) and HABP2 (603924) genes has also been reported. Protection against venous thrombosis is associated with variation in the F13A1 gene (134570) on 6p25.
Miyawaki et al. (2012) reported a Japanese family, originating from Yukuhashi in the northern part of the Kyushu islands, with recurrent thrombophilia. The family had originally been reported by Sakai et al. (2001). There were at least 9 ... Miyawaki et al. (2012) reported a Japanese family, originating from Yukuhashi in the northern part of the Kyushu islands, with recurrent thrombophilia. The family had originally been reported by Sakai et al. (2001). There were at least 9 affected individuals spanning 3 generations. The proband had onset of recurrent deep vein thrombosis at age 11 years, and many affected family members had onset of deep vein thrombosis or pulmonary embolism before age 50 years.
Poort et al. (1996) found that a common 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (176930.0009) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. The SNP was found ... Poort et al. (1996) found that a common 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (176930.0009) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who were also heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. In affected members of a Japanese family with recurrent thrombophilia, Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene (R596L; 176930.0015). The family had originally been reported by Sakai et al. (2001). In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; 107300) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. Miyawaki et al. (2012) concluded that although the procoagulant activity of the R596L mutant prothrombin was somewhat impaired, the antithrombin:thrombin complex was considerably impaired, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.'
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). ...
Diagnosis
Clinical DiagnosisNo 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]. See . A first unprovoked VTE before age 50 yearsA 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: No randomized controlled trials have confirmed that early identification of thrombophilia affects the risk for recurrent VTE. A case-control study found that testing individuals with a first VTE for thrombophilia did not reduce the incidence of recurrence [Coppens et al 2007]. There is no evidence that early diagnosis improves outcomes for family members who undergo screening [Segal et al 2009]. Recent consensus recommendations differ on the indications for testing women for thrombophilia who have had adverse pregnancy outcomes [Duhl et al 2007, Bates et al 2008, American College of Obstetricians and Gynecologists 2010, Baglin et al 2010]. See . Note: Routine testing in women who have experienced fetal loss or other adverse outcomes is not recommended [American College of Obstetricians and Gynecologists 2010].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 thrombosisRoutine testing in asymptomatic childrenTestingProthrombin 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 TestingGene. 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 testingTargeted mutation analysis. Targeted mutation analysis for the 20210G>A (c.*97G>A) allele is performed by a variety of comparable methods [Spector et al 2005; see (registration or institutional access required)]. Table 1. Summary of Molecular Genetic Testing Used in Prothrombin-Related ThrombophiliaView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityF2Targeted mutation analysis
20210G>A (c.*97G>A) 2100% Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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. Genetically Related (Allelic) DisordersProthrombin deficiency, including hypoprothrombinemia and dysprothrombinemia, results from F2 missense, nonsense, and splicing mutations and deletions that inactivate or decrease prothrombin levels.
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. ...
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 alleleThe relative risk for VTE is increased 2- to 5-fold 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 3-fold 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 3- to 6-fold 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 5-fold 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 3-fold 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 adultsThe risk for cerebral vein thrombosis is increased 10-fold in individuals with prothrombin-related thrombophilia [Martinelli et al 1998, Martinelli et al 2003a]. The prevalence of a heterozygous 20210G>A allele was 2-fold 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 9-fold 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 8-fold increased risk for extrahepatic portal vein thrombosis [Primignani et al 2005].A meta-analysis concluded that 20210G>A heterozygosity was associated with a 4-fold increased risk for both idiopathic and liver disease-associated portal vein thrombosis [Dentali et al 2008a]Thrombosis in other unusual locations in adultsRetinal vein thrombosis and other ocular thrombotic events are reported in 20210G>A heterozygotes [Ben-Ami et al 2002, Glueck & Wang 2009, Incorvaia et al 1999]. Superficial venous thrombosis was increased nearly 4-fold in 20210G>A heterozygotes in one study [Martinelli et al 1999a]. 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 3- to 4-fold 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 8-fold 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 2- to 3-fold increased risk for a first VTE in children. The risk was increased more than 9-fold 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 4-fold 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 2-fold increased risk for cerebral vein thrombosis in children (pooled OR = 1.95); however, 20210G>A was associated with a significant 2-fold 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 heterozygotesSummary. 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 2- to 5-fold 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 2-fold 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 3- to 9-fold higher recurrence risk than those with neither allele, and a 3-fold 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 5-fold 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 2- to 3-fold 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 5-fold increase in relative risk [Kenet et al 2007].In a meta-analysis of 12 observational studies, 20210G>A was associated with a 2-fold increased risk for recurrent VTE. The risk was increased 4- to 5-fold 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 3- to 4-fold 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 2-fold 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 2- to 3-fold 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 6- to 7-fold 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 2- to 3-fold 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 2- to 3-fold 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 2- to 3-fold increased risk for pregnancy loss during all three trimesters. 20210G>A heterozygosity was associated with a nearly 3-fold increased risk fof recurrent first trimester loss and a nearly 9-fold 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 2- to 3-fold 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 3-fold higher risk for fetal loss in the second trimester compared to the first trimester. The allele was also associated with a 2- to 3-fold 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 complicationsAlthough 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 2- to 7-fold 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 3-fold 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 2- to 3-fold 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 3-fold higher risk for recurrent preeclampsia which occurred in 50% of heterozygous women. The risk for recurrent severe preeclampsia was 6- to 7-fold 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 2-fold 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:20210G>A heterozygosity was found in 7%-15% of women with pregnancies complicated by IUGR, compared with 2%-4% of controls, with odds ratios ranging from four to nine [Kupferminc et al 1999, Kupferminc et al 2000b, Martinelli et al 2001b, Kupferminc et al 2002]. A large cohort study found a 2-fold increased risk for IUGR in women with a 20210G>A allele of borderline statistical significance [Kocher et al 2007].Two meta-analyses found that a 20210G>A allele was associated with a 2- to 3-fold increased risk for IUGR [Howley et al 2005, Kist et al 2008]. The association was stronger in white women and when IUGR was combined with other adverse pregnancy outcomes [Kist et al 2008].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 3-fold 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 6- 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 8-fold increased risk for placental abruption [Robertson et al 2006].Studies showing no increased risk for placental abruption associated with a 20210G>A allele:Several studies found no association between a 20210G>A allele and placental abruption [Alfirevic et al 2001, Camilleri et al 2004, Procházka et al 2007, Nath et al 2008]. Placental abruption was associated with neonatal low birth weight, but the association was similar in women with and without thrombophilic disorders [Nath et al 2008]. In two prospective studies of unselected pregnant women, a 20210G>A allele did not increase the risk for placental abruption [Karakantaza et al 2008, Silver et al 2010].A meta-analysis of prospective cohort studies found no association between a 20210G>A allele and placental abruption or a composite outcome that included this complication [Rodger et al 2010].Preterm delivery. A 20210G>A allele was associated with a 3-fold 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].
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. ...
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.
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.)...
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.)InheritedFactor 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 10-fold 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. AcquiredHigh plasma concentration of homocysteine occurs in 10% of individuals with a first VTE and is associated with a 2- to 3-fold 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 4- to 5-fold 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 2-fold 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 8-fold 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 2-fold 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]. OtherAlthough 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).HeterozygotesHomozygotes
To evaluate the risk for thrombosis in an individual diagnosed with prothrombin-related thrombophilia, the following evaluations are recommended: ...
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 ManifestationsThrombosis. 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 [Kyrle et al 2010, Bauer 2010, Baglin et al 2010]. See .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 2010].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; see ]: 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; see (registration or institutional access required)]. There are no evidence-based guidelines for thromboprophylaxis in children with inherited thrombophilia. Prevention of Primary ManifestationsIn 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; see ].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; see ]. 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: Is not routinely recommended in asymptomatic heterozygous women with no history of thrombosis. These women should be warned about potential thrombotic complications, counseled about the risks and benefits of anticoagulation during pregnancy, and offered a short course of anticoagulation after delivery, as the greatest thrombotic risk is in the initial postpartum period [American College of Obstetricians and Gynecologists 2010].Two large prospective studies evaluated risk-stratified prophylaxis strategies for pregnant women at increased risk for VTE. In both studies, low-risk asymptomatic women with thrombophilia (including 20210G>A heterozygosity) did not receive low molecular-weight heparin during pregnancy in the absence of additional risk factors. All women received a two- to eight-week course of postpartum anticoagulation. The low incidence of antepartum VTE in both studies (0% and 0.34%, respectively) suggests that anticoagulation may be safely withheld during pregnancy in low-risk 20210G>A heterozygotes who do not have other risk factors [Bauersachs et al 2007, Dargaud et al 2009].Is recommended for women heterozygous for 20210G>A with a history of unprovoked VTE. Low molecular-weight heparin (or unfractionated heparin) should be given during pregnancy followed by four to six weeks of postpartum anticoagulation [Duhl et al 2007, Bates et al 2008, Royal College of Obstetricians and Gynaecologists 2009, American College of Obstetricians and Gynecologists 2010, Baglin et al 2010].Should be considered in women heterozygous for the 20210G>A allele with a prior estrogen-related thrombosis (associated with oral contraceptives or pregnancy), who are also at an increased risk for recurrence [Pabinger et al 2005, De Stefano et al 2006, Bates et al 2008, Royal College of Obstetricians and Gynaecologists 2009, American College of Obstetricians and Gynecologists 2010, Baglin et al 2010].Should be considered for asymptomatic homozygotes or women doubly heterozygous for 20210G>A and factor V Leiden or with other inherited thrombophilic disorders, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [Duhl et al 2007, Bates et al 2008, Royal College of Obstetricians and Gynaecologists 2009, American College of Obstetricians and Gynecologists 2010].Prevention of Secondary ComplicationsPrevention 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 8-fold 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 (see ) 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]. SurveillanceIndividuals 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 AvoidF2 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 RiskThe 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 InvestigationSeveral 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDF211p11.2
ProthrombinF2 homepage - Mendelian genesF2Data 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) View in own window 176930COAGULATION FACTOR II; F2 188050THROMBOPHILIA DUE TO THROMBIN DEFECT; THPH1Normal 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.19911A>G in intron 1 is a mild independent risk factor for VTE. The data are conflicting on the extent to which this variant increases the thrombotic risk in individuals with a 20210G>A allele [Pérez-Ceballos et al 2002, Chinthammitr et al 2006, Martinelli et al 2006, Gohil et al 2009].20209C>T in the 3’ untranslated region of the gene is a rare variant of unclear significance reported primarily in individuals of African descent with a history of thrombosis or obstetric complications. Data are conflicting on whether this variant is an independent risk factor for thrombosis [Warshawsky et al 2002, Arya 2005, Itakura et al 2005, Danckwardt et al 2006, Hooper et al 2006, Warshawsky et al 2009].Pathologic allelic variants. The 20210G>A pathologic allelic 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 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference SequencesAlias 1Standard Nomenclature20210G>A or G20210Ac.*97G>A 2NoneNM_000506.3 NP_000497.11. Variant designation that does not conform to current naming conventions2. See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). The asterisk indicates that the variant is in the 3’ untranslated region of F2 and 97 indicates the variant is the 97th nucleotide 3’ of the translation stop codon, which are numbered as *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 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].