Prothrombin Thrombophilia

Clinical characteristics.

Prothrombin 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 thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A F2 variant 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 variant is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. Heterozygosity for 20210G>A has at most a modest effect on recurrence risk after a first episode. Although prothrombin 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 thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after air travel.

Diagnosis/testing.

The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in F2, the gene encoding prothrombin.

Management.

Treatment of manifestations: Management depends on the clinical circumstances. The first acute thrombosis is treated according to standard guidelines. The duration of anticoagulation therapy is determined by assessment of the risks for VTE recurrence and anticoagulant-related bleeding. 20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors.

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

Agents/circumstances to avoid: Women heterozygous for 20210G>A with a history of VTE and women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT).

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

Genetic counseling.

Prothrombin thrombophilia is inherited in an autosomal dominant manner: heterozygosity for the 20210G>A variant results in an increased risk for thrombosis; homozygosity for this variant confers a higher risk for thrombosis than heterozygosity. Occasionally (because of the relatively high frequency of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant. The genetic status of both parents and/or the reproductive partner of an affected individual needs to be evaluated before information regarding potential risks to sibs or offspring can be provided. If one parent of a heterozygous proband is heterozygous for the 20210G>A variant, the sibs of the proband are at 50% risk of being heterozygous; if one parent is homozygous, the sibs of the proband will be heterozygous. Once the 20210G>A variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

No clinical features are specific for prothrombin thrombophilia. The diagnosis should be suspected in individuals with at least one of the following more specific findings:

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

Prothrombin thrombophilia testing may be considered in individuals who have less specific findings, including the following:

• A history of unprovoked VTE considering discontinuation of anticoagulation
• A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
• Age greater than 50 years with a first unprovoked VTE
• Neonates and children with non-catheter related idiopathic VTE or stroke

Molecular genetic testing for the F2 20210G>A variant is not recommended for the following:

• General population screening
• Routine initial testing prior to the use of estrogen-containing contraceptives, HRT, or selective estrogen receptor modulators
• Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma)
• Routine initial testing in adults with arterial thrombosis
• Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
• Routine initial testing during pregnancy
• Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia
• Prenatal or newborn testing
• Neonates and children with asymptomatic central venous catheter-related thrombosis
• Routine testing in asymptomatic children
• Routine testing of unselected children with a first episode of VTE

Establishing the Diagnosis

The diagnosis of prothrombin thrombophilia is established in a proband with a heterozygous or homozygous pathogenic variant(s) 20210G>A in F2 identified by molecular genetic testing (see Table 1).

Note: The range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range. Therefore, plasma prothrombin concentration is not reliable for diagnosis.

Molecular genetic testing approaches can include targeted analysis for the F2 20210G>A variant (see Table 1) or a multigene panel that includes the analysis of the F2 variant and other genes of interest (see Differential Diagnosis). Note: The genes included and sensitivity of multigene panels vary by laboratory and are likely to change over time. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: The diagnosis of prothrombin thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis.

Table 1.

Molecular Genetic Testing Used in Prothrombin Thrombophilia

Clinical Description

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

Additional Factors that Predispose to Thrombosis

In addition to the number of variants, the clinical expression of prothrombin thrombophilia is influenced by: family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors.

Circumstantial Risk Factors for VTE

The 20210G>A variant interacts with multiple environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with the 20210G>A variant are provoked by additional risk factors, with pregnancy being the most common [Gerhardt et al 2000, Campello et al 2019].

Table 2.

Circumstantial Risk Factors: Increased Risk for Thrombophilia in Persons with the 20210G>A Variant

Pregnancy. Women with thrombophilia are at higher risk for VTE during pregnancy. In several studies 20210G>A heterozygotes had a three- to 15-fold higher risk for pregnancy-associated VTE than pregnant women without inherited thrombophilia [Gerhardt et al 2000, Martinelli et al 2002, Robertson et al 2006]. Heterozygous women without a family history of VTE have a lower thrombotic risk than women with prothrombin thrombophilia and a family history of VTE. Although 20210G>A heterozygosity increases the relative risk for pregnancy-associated VTE, the absolute risk in asymptomatic heterozygotes is low in the absence of other predisposing factors with an estimated probability in the range of 1:200 to 1:300 pregnancies [Gerhardt et al 2000, Gerhardt et al 2003]. The highest risk occurs during the first six weeks post partum but the risk does not return to pre-pregnancy baseline until three months post partum.

Women homozygous for 20210G>A or compound heterozygous for 20210G>A and factor V Leiden have a higher relative risk for pregnancy-associated VTE, but the absolute risk is less well defined [Robertson et al 2006, van Vlijmen et al 2011]. The probability of VTE during pregnancy and the puerperium is lower in compound heterozygous women younger than age 35 years (5.5%) than in older women (8.2%) [Gerhardt et al 2016].

Combined oral contraceptive (COC) use substantially increases the relative risk for VTE in women heterozygous for 20210G>A [Bistervels et al 2019]. The additive effect of both a 20210G>A variant and COC use was confirmed in multiple studies in which the odds ratios for VTE in women with both risk factors ranged from 16 to 59 [Martinelli et al 1999b, Wu et al 2005]. For women who are compound heterozygous for a 20210G>A variant and factor V Leiden, the odds ratios for VTE ranged from 17 to 110 [Mohllajee et al 2006, van Vlijmen et al 2016]. Despite the marked increase in relative risk, the absolute incidence of VTE is low because of the low baseline risk in young healthy women [van Vlijmen et al 2011]. The incidence of VTE in COC users with either factor V Leiden or a 20210G>A variant ranged from 0.49 to 2.0 VTE/100 pill-years compared to 0.19 to 0 VTE/100 pill-years in COC users without these variants. The absolute VTE risk is substantially higher in women who are compound heterozygous for 20210G>A and factor V Leiden variants or homozygous for either variant (0.86 vs 0.19 VTE/100 pill-years) [van Vlijmen et al 2016].

Other newer forms of combined hormonal, transdermal, and vaginal ring contraception have not been studied in 20210G>A heterozygotes but the risk is likely at least as great as the risk associated with COC use.

Oral hormone replacement therapy (HRT) is associated with a two- to fourfold increased relative risk for VTE in healthy postmenopausal users of HRT compared to non-users [Renoux et al 2010, Eisenberger & Westhoff 2014]. The risk of VTE in HRT users is threefold greater in postmenopausal women with a factor V Leiden or prothrombin 20210G>A variant than in HRT users without a thrombophilic variant [Roach et al 2013].

Transdermal HRT. Multiple observational studies consistently found that transdermal HRT did not increase the risk of VTE [Canonico et al 2010, Sweetland et al 2012, ACOG 2013a, Rovinski et al 2018]. There is also evidence that transdermal estrogen is associated with a lower thrombotic risk than oral estrogen in women with a thrombophilic variant including 20210G>A [Canonico et al 2010]. Women with a 20210G>A variant using transdermal estrogen had a risk of VTE similar to that of non-users with the variant [Straczek et al 2005]. However no prospective randomized trials have confirmed the safety of transdermal HRT in women with inherited thrombophilia.

Selective estrogen receptor modulators (SERMs). Limited data suggest that SERMs (e.g., tamoxifen, raloxifene) are associated with a twofold increased risk for VTE, similar to the risk associated with HRT [Barrett-Connor et al 2006]. The risk for VTE in 20210G>A heterozygotes who use SERMs is uncertain but likely higher than that associated with SERM use alone.

Arterial Thrombosis: NOT Convincingly Associated with Prothrombin Thrombophilia

The available evidence indicates that the 20210G>A variant is not a major risk factor for arterial thrombosis of any sort including myocardial infarction and stroke in fetuses, children, and adults.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified for other F2 variants.

Nomenclature

Prothrombin thrombophilia may also be referred to as F2-related thrombophilia, factor II-related thrombophilia, or prothrombin 20210G>A thrombophilia.

Prevalence

F2 20210G>A heterozygosity is the second most common inherited thrombophilia, after factor V Leiden. The prevalence varies by population. Heterozygosity for 20210G>A occurs in 1.7%-3% of the general US and European populations. The highest heterozygosity rate is found in Europe; the variant is extremely rare in Asian, African, and Native American populations. Within Europe, prevalence varies from 3% in southern Europe to 1.7% in northern countries [Rosendaal et al 1998]. In the US, the 20210G>A variant is present in 2%-5% of Americans of European origin, 2.2% of Hispanic Americans, and 0%-0.6% of African Americans [Dowling et al 2003, Chang et al 2009].

The 20210G>A variant is present in:

• 8.2% of Americans of European origin with VTE;
• 1.1% of African Americans with VTE;
• 6%-14% of adults with a first VTE;
• 18%-21% of adults with VTE and a personal or family history of recurrent VTE [Poort et al 1996, Tosetto et al 1999];
• 3.7% of children with a first spontaneous VTE [Nowak-Göttl et al 2001].

The frequency of homozygosity for the 20210G>A variant is 1:10,000. 20210G>A homozygosity is found in 1.8%-4.5% of individuals with VTE [Margaglione et al 1999, Barcellona et al 2003].

Evaluations Following Initial Diagnosis

To assess the risk for venous thromboembolism (VTE) in an individual found to have the F2 20210G>A variant, the following are recommended:

• An activated protein C resistance or DNA assay for factor V Leiden
• Serologic assays for anticardiolipin antibodies and anti-beta₂ glycoprotein 1 antibodies
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor

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

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

Note: Measurement of the following is NOT recommended:

• Plasma concentration of homocysteine, since no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
• MTHFR variants, as no clinical rationale for this testing exists
• Factor VIII and other clotting factor levels [Moll 2015]

Treatment of Manifestations

Prevention of Primary Manifestations

In the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes because the 1%-3%/year risk for major bleeding from anticoagulation is greater than the estimated less than 1%/year risk for thrombosis [Berg et al 2011].

Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the American College of Chest Physicians and American Society of Hematology consensus guidelines [Guyatt et al 2012] (full text) [Anderson et al 2019, Schünemann et al 2018].

Surveillance

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

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

Women with a history of VTE who are heterozygous for 20210G>A should avoid estrogen-containing contraception and hormone replacement therapy (HRT).

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

Asymptomatic women heterozygous for 20210G>A:

• Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
• Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
• Electing short-term hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations [Renoux et al 2010].

Evaluation of Relatives at Risk

The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the 20210G>A variant.

Note: The indications for family testing are unresolved.

• In the absence of evidence that early identification of the 20210G>A variant reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
• Clarification of 20210G>A variant status may be useful in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age if the results are likely to affect management.

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

Pregnancy Management

No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals [Bates et al 2012, ACOG 2013b, Bates et al 2018]; see Published Guidelines / Consensus Statements. All women with inherited thrombophilia should undergo individualized risk assessment. Decisions about anticoagulation should be based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis.

LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. The oral direct thrombin inhibitor, dabigatran, and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are contraindicated during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animial studies that showed reproductive toxicity [Ageno et al 2012, Bates et al 2018].

Prophylactic anticoagulation during pregnancy is recommended for all women:

• With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [ACOG 2013b, Bates et al 2018].
• Heterozygous for 20210G>A with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [ACOG 2013b, Bates et al 2018].

Prophylactic anticoagulation during pregnancy may be considered for asymptomatic women who:

• Are homozygous for 20210G>A and have a family history of thrombosis [ACOG 2013b, Bates et al 2018].
• Are compound heterozygotes for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [ACOG 2013b, Bates et al 2018].

Prophylactic anticoagulation during pregnancy is not routinely recommended in asymptomatic women heterozygous for 20210G>A with no history of thrombosis. All women heterozygous for 20210G>A should be warned about potential thrombotic complications and counseled regarding the risks and benefits of anticoagulation during pregnancy [ACOG 2013b, Bates et al 2018].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Prothrombin thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• All individuals reported to date with prothrombin thrombophilia have had a parent who is heterozygous or homozygous for the F2 20210G>A variant.
• Prothrombin thrombophilia as the result of a de novo pathogenic variant has not been reported.
• Occasionally (because of the relatively high prevalence of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant.
• The family history of some individuals diagnosed with prothrombin thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize prothrombin thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing for the 20210G>A variant has been performed on the parents of the proband.

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 is heterozygous for the 20210G>A variant, each sib of the proband is at a 50% risk of being heterozygous for the 20210G>A variant.
• If one parent is homozygous for the 20210G>A variant, each sib of the proband has a 100% chance of being heterozygous for the 20210G>A variant.
• If both parents are heterozygous for the 20210G>A variant, each sib of the proband has a 25% chance of being homozygous for the 20210G>A variant, a 50% chance of being heterozygous for the 20210G>A variant, and a 25% chance of inheriting both normal F2 alleles.

Offspring of a heterozygous proband

• Each child has a 50% chance of inheriting the 20210G>A variant.
• If the proband's reproductive partner is also heterozygous for the 20210G>A variant, each of their children has a 25% chance of inheriting two 20210G>A variants, a 50% chance of inheriting one 20210G>A variant, and a 25% chance of inheriting neither 20210G>A variant.

Offspring of a homozygous proband

• A proband homozygous for the 20210G>A variant will transmit the 20210G>A variant to all offspring.
• If the proband's reproductive partner is heterozygous for the 20210G>A variant, each of their children has a 50% chance of inheriting two 20210G>A variants and a 50% chance of inheriting one 20210G>A variant.

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the F2 20210G>A variant has been identified in a family member, prenatal testing for a pregnancy at increased risk for prothrombin thrombophilia and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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

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

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

Mechanism of disease causation. Gain of function

Table 3.

Notable F2 Variants

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

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

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

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

• c.1621C>T, a novel missense variant in exon 12 resulting in increased thrombin potential and resistance to heparin was identified in a Dutch family with unexplained thrombosis [Mulder et al 2020].
• c.1787G>T, a novel missense variant in exon 14 (prothrombin Yukuhashi) results in resistance to antithrombin and a prothrombotic state. Prothrombin Yukuhashi (p.Arg596Leu) was identified in a Japanese family in which five members developed thrombosis at a very young age [Miyawaki et al 2012]. Several other missense variants involving Arg596 and resulting in resistance to antithrombin were identified in thrombophilic individuals (e.g., prothrombin Belgrade and prothrombin Amrita p.Arg596Gln, prothrombin Padua 2 p.Arg596Trp) [Djordjevic et al 2013, Sivasundar et al 2013, Bulato et al 2016].
• 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 as to whether this variant is an independent risk factor for thrombosis are conflicting [Itakura et al 2005, Danckwardt et al 2006, Hooper et al 2006, Warshawsky et al 2009].

Revision History

• 4 February 2021 (sw) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 29 March 2011 (me) Comprehensive update posted live
• 25 July 2006 (me) Review posted live
• 25 April 2005 (jk) Original submission

Published Guidelines / Consensus Statements

• American College of Obstetricians and Gynecologists Women's Health Care Physicians. Practice Bulletin No.138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122:706–17. [PubMed: 23963422]

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• Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Available online. 2010. Accessed 1-25-22. [PubMed: 20128794]

• Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO; American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy. In: Antithrombotic Therapy and Prevention of Thrombosis. 9 ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 1-25-22. [PMC free article: PMC3278054] [PubMed: 22315276]

• Bates SM, Middeldorp S, Rodger M, James AH, Greer I. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. Available online. 2016. Accessed 1-25-22. [PMC free article: PMC4715853] [PubMed: 26780741]

• Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James AH, Vazquez SR, Greer IA, Riva JJ, Bhatt M, Schwab N, Barrett D, LaHaye A, Rochwerg B. Amertican Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Available online. 2018. Accessed 1-25-22. [PMC free article: PMC6258928] [PubMed: 30482767]

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 1-25-22.

• Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic VTE and their adult family members. Available online. 2011. Accessed 1-25-22. [PubMed: 21150787]

• Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 2-25-22. [PMC free article: PMC3278060] [PubMed: 22315257]

• Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis. 9 ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Available online. 2012. Accessed 2-25-22. [PMC free article: PMC3278049] [PubMed: 22315268]

• Monagle P, Chan AK, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, Vesely SK; American College of Chest Physicians. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Available online. 2012. Accessed 2-25-22. [PMC free article: PMC3278066] [PubMed: 22315277]

• Monagle P, Cuello CA, Augustine C, Bonduel M, Brandão LR, Capman T, Chan AKC, Hanson S, Male C, Meerpohl J, Newall F, O'Brien SH, Raffini L, van Ommen H, Wiernikowski J, Williams S, Bhatt M, Riva JJ, Roldan Y, Schwab N, Mustafa RA, Vesely SK. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Available online. 2018. Accessed 1-25-22. [PMC free article: PMC6258911] [PubMed: 30482766]

• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 1-25-22.

• Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA, Jaff MR, Manja V, Schulman S, Thurston C, Vedantham S, Verhamme P, Witt DM, D Florez I, Izcovich A, Nieuwlaat R, Ross S, J Schünemann H, Wiercioch W, Zhang Y, Zhang Y. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Available online. 2020. Accessed 1-25-22.

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