Hereditary thrombophilia testing in adults without VTE

INTRODUCTION — 

Hereditary thrombophilia is a risk factor for venous thromboembolism (VTE); however, the absolute increase in risk is low, and management may not differ for many individuals.

This topic reviews an approach for deciding whether to test for hereditary thrombophilia and which thrombophilia to test for in adults who have not had VTE.

Separate topic reviews discuss testing for hereditary thrombophilia in selected populations:

●Adults with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

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

●Pregnant or considering pregnancy – (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

●Recurrent pregnancy loss – (See "Recurrent pregnancy loss: Evaluation".)

●Cryptogenic stroke – (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Advanced evaluation'.)

●Cerebral venous sinus thrombosis – (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Evaluation for thrombophilic state'.)

Management of specific hereditary thrombophilias is also discussed separately:

●Factor V Leiden (FVL) – (See "Factor V Leiden and activated protein C resistance".)

●Prothrombin G20210A (PGM) – (See "Prothrombin G20210A".)

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

●Protein S (PS) deficiency – (See "Protein S deficiency".)

●Protein C (PC) deficiency – (See "Protein C deficiency".)

TERMINOLOGY

List of hereditary thrombophilias — Thrombophilias include any condition that predisposes an individual to thrombosis.

Hereditary thrombophilia is generally used to refer to one of five established genetic conditions (or combinations of these conditions):

•Factor V Leiden (FVL) – (See "Factor V Leiden and activated protein C resistance".)

•Prothrombin G20210A, also called prothrombin gene mutation (PGM) – (See "Prothrombin G20210A".)

•Protein S (PS) deficiency – (See "Protein S deficiency".)

•Protein C (PC) deficiency – (See "Protein C deficiency".)

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

FVL and PGM are generally tested by genetic testing; PS, PC, and AT deficiency are generally diagnosed biochemically. Details of testing are discussed in the above topics.

Acquired risk factors include those listed in the table (table 1) and are discussed separately. (See "Overview of the causes of venous thrombosis in adults".)

Low risk versus high risk — Thrombophilias can be classified as low risk or high risk. This classification is based on the associated risk of a first VTE (table 2).

●Low-risk thrombophilias – These are the prevalent heterozygous FVL and PGM, which confer a two- to threefold increased risk of a first episode of VTE [1].

Most of these individuals will never have a VTE and are unaware that they carry one of these variants. (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A".)

●High-risk thrombophilias – These are deficiencies of PS, PC, or AT; and homozygous FVL or PGM. They confer a six- to sevenfold increased risk of a first episode of VTE for PS and PC deficiencies, approximately 12-fold increased risk with AT deficiency, and 12- to 80-fold increased risk for homozygous FVL [1].

Compound heterozygous FVL and PGM were generally considered high-risk thrombophilias, but a large individual patient data meta-analysis showed that the odds ratio (OR) for a first VTE is in the same range as for FVL heterozygosity.

Details are discussed separately:

•PS deficiency – (See "Protein S deficiency", section on 'Diagnosis'.)

•PC deficiency – (See "Protein C deficiency", section on 'Diagnostic evaluation'.)

•AT deficiency – (See "Antithrombin deficiency", section on 'Diagnostic evaluation'.)

•Homozygosity for FVL or PGM – (See "Factor V Leiden and activated protein C resistance", section on 'FVL homozygous carriers' and "Prothrombin G20210A".)

•Compound heterozygous FVL and PGM – (See "Factor V Leiden and activated protein C resistance", section on 'Other genetic variants'.)

Definition of a positive family history — A positive family history generally refers to one or more first-degree or second-degree relatives with VTE; a strongly positive family history generally refers to multiple relatives with VTE prior to age 50 [1,2].

DECIDING WHETHER TO TEST

General risks and benefits of testing — For most unselected individuals in the general population without a personal history of VTE, the risk-benefit analysis does not favor testing for hereditary thrombophilia. However, a personalized risk-benefit assessment can be made for any individual who wants to assess their risk of VTE, whether a finding of hereditary thrombophilia would alter their management, and whether the management of their relatives would be altered if the patient's test was positive.

●Reasons not to test

•Low prevalence – The prevalence of hereditary thrombophilia in the general population is low, with the exception of heterozygosity for factor V Leiden (FVL) or the prothrombin G20210A mutation (PGM). The table lists prevalence rates in White individuals (table 2). The prevalence in non-White individuals has been less well studied.

•Low penetrance/low VTE risk – For individuals who are heterozygous for FVL or PGM, the penetrance of thrombosis is low; most individuals who carry these pathogenic variants will never have a VTE. (See 'Risk of a first VTE' below.)

•Low likelihood of altered management – For most individuals, identifying one of the hereditary thrombophilias does not alter clinical management. This includes most individuals without VTE, for whom prophylaxis is generally not altered, as well as many individuals with VTE, who are usually managed based on the circumstances of their VTE event. (See "Venous thromboembolism: Anticoagulation after initial management".)

●Reasons testing may be helpful despite absence of VTE

•Possible altered management – For some individuals, management may differ if they have hereditary thrombophilia. This includes individuals with a sufficiently large increase in thrombotic risk over baseline that would result in a change in management. (See 'Settings in which testing may be appropriate' below.)

Examples are discussed in the 2023 American Society of Hematology (ASH) guidelines on thrombophilia testing [1]. These are summarized in the linked sections directly below and may include:

-Family history of VTE and known high-risk hereditary thrombophilia in relatives – In an individual with a positive family history of VTE due to a high-risk thrombophilia, management may be altered when they have a minor provoking risk factor, if they are deciding whether to take an oral contraceptive or other estrogen-containing medication, or if they become pregnant. (See 'Minor provoking risk factor and positive family history' below and 'Estrogens (COCs, MHT) and positive family history' below and 'Pregnancy and positive family history for VTE' below.)

-Cancer and positive family history of VTE – If an individual with cancer who has a positive family history for VTE tests positive for a high-risk thrombophilia, they may choose more aggressive thromboprophylaxis in some situations. (See 'Certain individuals with cancer' below.)

Virtually all recommendations in the ASH guidelines are weak, as they are based on modeling risks and benefits of thrombophilia testing and a subsequent management consequence in a virtual, 1000 individual population, without taking into account pitfalls of thrombophilia testing [1]. Modeling used the median prevalence of the thrombophilias, whereas geographic variation is large. Randomized trials of testing have not been performed. Hence, there is room for discussion, and patient preferences should be taken into account.

•Possible implications for first-degree relatives – In kindreds with a strong history of VTE, identifying the familial variant may facilitate testing of relatives and may in turn affect the relatives' management. Once the familial variant is identified, other individuals in the kindred can be selectively tested for that variant.

If at all possible, the individual(s) with VTE should be tested first. If no known hereditary thrombophilia is identified in the symptomatic individual, negative thrombophilia testing in an asymptomatic relative is generally not informative. However, circumstances may arise in which it is not possible to test any of the individuals with VTE. If there is a strong family history of VTE and no relatives with VTE can be tested, it may be reasonable to test an unaffected relative for hereditary thrombophilia in the aforementioned scenarios in which the ASH guidelines suggest testing.

Regardless of whether testing is done, all individuals with provoking factors that increase the risk of VTE such as immobility, cancer, surgery, certain medications, or pregnancy should be offered educational information; this includes appropriate preventive interventions and information about signs and symptoms of VTE. These are discussed in separate topic reviews:

●Hospitalization – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

●Pregnancy – (See "Venous thromboembolism in pregnancy: Prevention".)

●Surgery – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Gynecologic surgery: Overview of preoperative evaluation and preparation".)

●Cancer – (See "Risk and prevention of venous thromboembolism in adults with cancer".)

●Travel – (See "Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers".)

Risk of a first VTE — The risk of VTE depends on the specific thrombophilia (table 2).

●High risk (protein S [PS], protein C [PC], or antithrombin [AT] deficiency, homozygous FVL or PGM) –High-risk thrombophilias (PS, PC, or AT deficiency, homozygous FVL or PGM) confer a six- to sevenfold increased risk of a first episode of VTE for PS and PC deficiencies, approximately 12-fold increased risk with AT deficiency, and 12- to 80-fold increased risk for homozygous FVL [1].

●Low risk (FVL or PGM heterozygosity, compound heterozygous FVL and PGM) – Low-risk thrombophilias (FVL, PGM, or compound heterozygous FVL and PGM) confer an approximately threefold increased risk of a first VTE [1].

The relative risk (risk increase over baseline) of a first VTE has been comprehensively synthesized for the ASH guideline [1]. For counseling purposes, absolute risks for a first episode of VTE are also important. Absolute risks from selected studies include:

●A 2009 retrospective cohort study of 2479 relatives of individuals with hereditary thrombophilia and VTE found that relatives who also had hereditary PS, PC, or AT deficiency had an annual VTE risk of 1.5 to 1.9 percent and a cumulative VTE incidence of 55 percent at 10 years [2]. The cumulative VTE risk at 10 years was lower for relatives of individuals who coinherited FVL (7 percent) or PGM (11 percent). A smaller prospective study from 2010 found similar results (annual VTE incidence in those who coinherited PS, PC, or AT deficiency, 1.53 percent; 95% CI, 1.00-2.34, versus 0.29 percent in those who did not coinherit the familial variant) [3].

●In a 1998 report of 150 pedigrees with FVL or AT, PS, or PC deficiency, the lifetime probability (risk ratio) of developing thrombosis compared with those with no hereditary thrombophilia was 8.5 for PS deficiency, 8.1 for AT deficiency, 7.3 for PC deficiency, and 2.2 for FVL [4].

●In a 1998 report of 118 pedigrees with FVL (112 heterozygous and six homozygous), the annual incidence of VTE in relatives who coinherited the FVL variant was 0.45 percent (95% CI 0.28-0.61 percent) [5]. As with general population risk, the annual incidence was higher in individuals >60 years (1.1 percent) and with pregnancy, oral contraceptives, or surgery. Half of the VTE episodes occurred spontaneously. A subsequent report of FVL carriers found similar results [6]. A similar study with carriers of PGM found an annual VTE rate of 0.37 percent in individuals who coinherited the variant (95% CI 0.01-1.08), versus 0.12 percent (95% CI 0.00-0.69), resulting in a hazard ratio (HR) of 3.1 (95% CI 0.3-29.6) [7].

Likelihood of identifying hereditary thrombophilia with positive family history — Patients with a family history of thrombosis are at increased risk for having hereditary thrombophilia. (See 'Definition of a positive family history' above.)

However, a positive family history alone is not a reliable criterion to select patients for screening. This was illustrated in a large retrospective study involving 1605 patients with a first episode of VTE, of whom 505 (31.5 percent) reported having one or more first-degree relatives with a history of VTE [8]. VTE risk was twofold higher in those with a single relative with VTE (odds ratio [OR] 2.2, 95% CI 1.9-2.6) and up to fourfold higher when more than one relative had VTE (OR 3.9, 95% CI 2.7-5.7). However, family history corresponded poorly with known genetic risk factors; the prevalence of hereditary thrombophilia ranged from 30 percent with any relative with VTE to 36 percent if more than one relative was affected. The prevalence of hereditary thrombophilia was 22 percent in patients with a first VTE who had a negative family history.

The five isolated hereditary thrombophilias are autosomal dominant. (See 'List of hereditary thrombophilias' above.)

If an individual is heterozygous for a single hereditary thrombophilia, their children have a 50 percent chance of inheriting the variant. If an individual is homozygous for a thrombophilia variant, their children have a 100 percent chance of being heterozygous for the variant, provided the other parent does not carry the variant. If an individual is homozygous for a thrombophilia variant, their siblings have a 25 percent chance of being homozygous, 50 percent chance of being heterozygous, and 25 percent chance of not having the variant.

Settings in which testing may be appropriate — For all the hereditary thrombophilias, the benefits of testing are likely to be greatest in an asymptomatic individual who has a strong family history of VTE, rather than one who has a negative, unknown, or relatively weak family history. (See 'Definition of a positive family history' above.)

Knowledge that a relative with a history of VTE carries hereditary thrombophilia increases the utility of testing; otherwise, a negative test in a relative may be less informative. (See 'Likelihood of identifying hereditary thrombophilia with positive family history' above.)

Among individuals with a positive family history, the benefit of testing is likely to be greatest in the presence of an acquired VTE risk factor such as surgery or pregnancy, for which routine thromboprophylaxis is not routinely indicated, but that might warrant thromboprophylaxis if the individual was aware that they carried a thrombophilia. (See 'Estrogens (COCs, MHT) and positive family history' below and 'Pregnancy and positive family history for VTE' below.)

Appropriateness of testing in individuals who have a personal history of VTE is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Patient selection for additional testing'.)

Minor provoking risk factor and positive family history — Individuals with a positive family history of VTE and a known deficiency of AT, PS, or PC in one or more relatives may choose to test for the thrombophilia, as they could use prophylactic anticoagulation for a minor provoking risk factor such as immobility, illness, or infection. This approach also makes sense for individuals with possible homozygosity for FVL or PGM or compound heterozygosity for FVL and PGM.

Since it takes time for a thrombophilia test to get the result, it makes more sense to consider this scenario when counseling individuals about the potential benefit of testing and not to wait for the minor provoking risk factor to occur.

In the ASH thrombophilia guideline, this testing is not suggested for individuals with a positive family history of heterozygosity for FVL or PGM, as the benefits were considered trivial by the guideline panel. However, an individualized approach may justify testing as the guidelines used population approach and the recommendation was conditional. (See 'Low risk versus high risk' above.)

For individuals with a minor provoking risk factor (immobility, minor injury, illness, or infection), we suggest the following, consistent with the conditional recommendations in the 2023 ASH guidelines and 2023 British Society for Haematology (BSH) guideline [1,9]:

●Positive family history of PS, PC, or AT deficiency – Test for the familial thrombophilia. The value of testing is greatest when the family history is positive for VTE and the hereditary thrombophilia is present in a first-degree (rather than a second-degree) relative. If the family history is negative for VTE and the thrombophilia is only present in a second-degree relative, decisions about testing can be individualized.

●Positive family history of homozygous or compound heterozygous FVL or PGM – Test for the familial variant(s) taking the autosomal inheritance pattern and chance of having high-risk thrombophilia into consideration. As examples:

•An individual whose parent is homozygous for FVL does not require testing, as the chances of being heterozygous are 100 percent, and the chance of being homozygous is only approximately 2.5 percent, based on the general population frequency and likelihood of FVL in the other parent.

•An individual with one parent who is homozygous for FVL and the other parent who is heterozygous for FVL may be tested, as there is a 100 percent chance that they will inherit FVL from the homozygous parent and a 50 percent chance they will inherit FVL from the heterozygous parent and themself be homozygous for FVL.

●Positive family history of heterozygous FVL or PGM – Do not test for the familial variant. An individualized approach may justify testing, as the guidelines used population approach, and the recommendation was conditional.

●Very strongly positive family history of VTE with no hereditary thrombophilia variant identified in a relative with VTE – Consider testing for all five hereditary thrombophilias. This would apply to individuals with multiple relatives diagnosed with VTE, especially <50 years old. (See 'Definition of a positive family history' above and 'List of hereditary thrombophilias' above.)

●Positive family history of VTE but no hereditary thrombophilia variant identified in a relative with VTE – Do not test for hereditary thrombophilia.

●Negative family history for VTE or thrombophilia – Do not test for hereditary thrombophilia.

The rationale for this approach is that in the setting of a minor provoking risk factor, we would provide thromboprophylaxis to an individual who tested positive for PS, PC, or AT deficiency, homozygosity for FVL or PGM, or compound heterozygosity for FVL and PGM, but not for the others. An individualized approach may justify testing in these other individuals if they highly value VTE risk reduction, as the guidelines used a population-based approach, and the recommendation was conditional.

Recommendations for VTE prophylaxis in hospitalized medical and surgical patients are presented separately:

●Medical illness – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

●Hip surgery or knee replacement – (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

●Other orthopedic surgery – (See "Prevention of venous thromboembolism (VTE) in adults with non-major extremity orthopedic injury with or without surgical repair".)

●Non-orthopedic surgery – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Estrogens (COCs, MHT) and positive family history — Individuals with a positive family history of AT, PS, or PC deficiency may choose to test if they are considering using a medication that contains estrogen (combined oral contraceptive [COC], menopausal hormone therapy [MHT]) or a selective estrogen response modifier (such as tamoxifen or raloxifene), as they may be able to avoid prothrombotic medication and use an alternative.

This approach also applies to individuals with possible compound heterozygosity for FVL and PGM or homozygosity for FVL.

Advice to avoid estrogen-containing medicines does not apply to individuals with a positive family history of heterozygosity for FVL or PGM. (See 'Low risk versus high risk' above.)

If the medication is absolutely required, they may use a less thrombogenic preparation (eg, transdermal rather than oral MHT, or raloxifene rather than tamoxifen) or use a brief period of anticoagulation (eg, prophylactic anticoagulation in case of ovarian hyperstimulation in the context of vitro fertilization).

For individuals considering use of combined estrogen-progestin COCs for any reason (birth control, acne, dysmenorrhea), or for those considering MHT, we suggest the following, consistent with the 2023 ASH guidelines and 2023 BSH guideline [1,9]:

●Positive family history of PS, PC, or AT deficiency – Test for the familial thrombophilia. The value of testing is greatest when the family history is positive for VTE and the condition is present in a first-degree (rather than a second-degree) relative. If the family history is negative for VTE and the condition is only present in a second-degree relative, decisions about testing can be individualized.

●Positive family history of heterozygous FVL or PGM – Do not test for the familial variant. An individualized approach may justify testing in individuals who have a high level of concern regarding potential thrombotic risk of a combined oral contraceptive, as the guidelines used a population-based approach, and the recommendation was conditional.

●Positive family history of homozygous or compound heterozygous FVL or PGM – Test for the familial variant(s), taking the autosomal inheritance pattern and chance of having high-risk thrombophilia into consideration. As examples:

•An individual with a parent who is homozygous for FVL does not require testing, as the chances of being heterozygous are 100 percent, and the chance of being homozygous is only approximately 2.5 percent (based on the general population frequency and likelihood of FVL in the other parent). This situation is not addressed in the ASH guidelines.

•An individual with one parent who is homozygous for FVL and the other parent who is heterozygous for FVL may be tested, as there is a 100 percent chance that they will inherit FVL from the homozygous parent and a 50 percent chance they will inherit FVL from the heterozygous parent and themself be homozygous for FVL.

●Positive family history of VTE but hereditary thrombophilia not identified in a relative with VTE – Do not test for hereditary thrombophilia.

●Very strongly positive family history of VTE with no hereditary thrombophilia variant identified in a relative with VTE – Consider testing for all five hereditary thrombophilias. This would apply to individuals with multiple relatives diagnosed with VTE, especially at a young age (eg, <50 years). (See 'List of hereditary thrombophilias' above.)

●Negative family history of thrombophilia/general population – Do not test for hereditary thrombophilia.

The rationale is that we would avoid COCs and oral MHT in individuals who tested positive for PS, PC, or AT deficiency, homozygosity for FVL, or compound heterozygosity for FVL and PGM, but not for the others. If the indication for these medications is strong and there is not a good alternative such as transdermal MHT, we would use a medication with the lowest possible estrogen dose (eg, lowest-estrogen COC).

Alternative medications, details of administration, and supporting evidence for the increased risk of VTE are presented separately in UpToDate and by the Centers for Disease Control and Prevention (CDC):

●COCs

•UpToDate – (See "Contraception: Counseling regarding inherited thrombophilias", section on 'Individualized risk-based counseling'.)

•CDC – Information for laypersons and Clinical information.

●MHT – (See "Treatment of menopausal symptoms with hormone therapy", section on 'Estrogens'.)

●Tamoxifen and raloxifene – (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Hormonal therapies'.)

Pregnancy and positive family history for VTE — Individuals with a known positive family history of AT, PS, or PC deficiency may choose to test if they are pregnant, postpartum, or planning to become pregnant, as thromboprophylaxis is suggested either postpartum, antepartum, or both depending on the type of thrombophilia and VTE history in relatives. (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

Certain individuals with cancer — Ambulatory cancer patients receiving systemic therapy may be treated with thromboprophylaxis if their VTE risk is increased, according to the ASH cancer guideline [10].

●Possible use of thrombophilia testing – Individuals with cancer who have a known family history of VTE or known thrombophilia in a relative, and for whom there would not otherwise be an indication for prophylactic anticoagulation, may choose to test for hereditary thrombophilia if the results might sway them to use prophylactic anticoagulation [1].

This conditional recommendation from the ASH 2023 thrombophilia testing guidelines is based on a calculated reduction of VTE of 6 to 9 per 1000 patients with cancer and a positive family history of VTE or known thrombophilia, in whom those who tested positive for thrombophilia would use thromboprophylaxis for six months. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Primary prevention'.)

●Increased risk of VTE in patients with cancer – VTE risk is increased in individuals with cancer, especially around the time of diagnosis, and by some cancer treatments (surgery, some chemotherapy and biologic therapies), as discussed separately. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)

In most ambulatory individuals, this risk is not sufficient to justify prophylactic anticoagulation, unless they have a high Khorana score. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'VTE risk assessment/Khorana score'.)

●Approach to testing based on magnitude of increased risk – Our approach is based on the risk of VTE and whether identification of a hereditary thrombophilia would impact management.

•Low to intermediate VTE risk (based on a Khorana or other VTE prediction score for ambulatory cancer patients) and positive family of VTE – Testing for hereditary thrombophilia in these individuals may be reasonable to identify individuals for whom the diagnosis of hereditary thrombophilia would lead to a change in management, such as use of prophylactic anticoagulation [1,10].

•Low to moderate VTE risk and negative family history of VTE – We do not test for hereditary thrombophilia in these individuals, as their risk of VTE is low, and hereditary thrombophilia is unlikely to alter management.

•High VTE risk – We do not test for hereditary thrombophilia in individuals with cancer who have a high risk of VTE who are treated with prophylactic anticoagulation. In these individuals, information about hereditary thrombophilia would not alter management.

Settings in which thrombophilia testing is not appropriate — As a general rule, we do not test for hereditary thrombophilia if the information would be unlikely to affect management of the patient and/or their relatives. Typically this applies when the risk of finding hereditary thrombophilia is very low or the disease penetrance (likelihood of VTE) is very low.

●General population – We suggest not screening for hereditary thrombophilia in the general population [1,9].

●Prior to starting oral contraceptives – We suggest not screening for hereditary thrombophilia prior to starting estrogen-containing medications or other medications that increase VTE risk outside the specific settings discussed above. (See 'Settings in which testing may be appropriate' above.)

●Positive family history for heterozygous FVL or PGM – We do not test for FVL or PGM in individuals who have a family history for heterozygosity for one of these variants, especially if the family history is negative for VTE. An exception may be an individual with a strongly positive family history of VTE, but no relatives are available for testing. (See 'Low risk versus high risk' above and 'Risk of a first VTE' above.)

●Pregnancy loss – Although hereditary thrombophilias have been linked to obstetric complications, we do not test for thrombophilia variants in these individuals, based on findings in a 2016 meta-analysis as well as the randomized ALIFE2 trial, both of which found that low molecular weight heparin anticoagulation of individuals with hereditary thrombophilia and recurrent pregnancy loss did not increase the chance of a live birth [11,12]. Additional recommendations are presented separately. (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

WHICH THROMBOPHILIAS TO TEST — 

If a decision has been made to test (see 'Deciding whether to test' above), the details of testing depend on whether a familial variant is known.

●If a familial variant is known, testing can be restricted to the known variant.

●If there is a positive family history of VTE and a familial thrombophilia variant has not been identified, test an affected individual (an individual with VTE) first to identify the familial variant(s). If this is not possible, test for all five hereditary thrombophilias.

High-risk thrombophilias that may alter management — Testing may be reasonable in selected scenarios mentioned above if there is a family history of VTE and a high-risk thrombophilia. (See 'Settings in which testing may be appropriate' above and 'Low risk versus high risk' above.)

Supporting evidence is presented above. (See 'Risk of a first VTE' above.)

Heterozygous FVL or PGM (testing generally not indicated in individuals without VTE) — Factor V Leiden (FVL) is the most common hereditary thrombophilia (prevalence 0.5 percent to >10 percent, depending on the population). Prothrombin G20210A (PGM) has a prevalence of 1 to 6 percent (table 2). (See "Factor V Leiden and activated protein C resistance", section on 'Epidemiology' and "Prothrombin G20210A", section on 'Epidemiology'.)

We generally do not test for FVL or PGM in people without a VTE, even if the family history is positive. If the family history is strongly positive for VTE, testing of affected relatives may be appropriate to identify the cause(s); details are discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Testing generally not indicated outside of research — We do not test for the following outside of a research study or unusual familial VTE risk syndrome due to lack of well-defined VTE risk and lack of impact on VTE risk reduction.

●Homocysteine levels

●Variants in the MTHFR gene, which encodes methylenetetrahydrofolate reductase, such as 677C—>T or 1298 A—>C

●Variants in the PAI1 gene, which encodes plasminogen activator inhibitor-1, such as the 4G/5G promoter variant

●Factor VIII activity levels

If the patient has an abnormal result on one of these tests, we counsel that high-quality evidence for any effect on VTE risk is lacking, and there are no implications for VTE risk reduction in the individual or their relatives.

Additional information about these variants and possible other indications for testing other than VTE risk reduction are presented separately. (See "Overview of homocysteine", section on 'Decision to test' and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1 deficiency'.)

Elevated levels of several procoagulant coagulation factors may increase risk for a first episode of VTE; elevated factor VIII level is the strongest of these risk factors. (See "Overview of the causes of venous thrombosis in adults", section on 'Abnormal levels of clotting factors and chemokines'.)

Increased factor VIII activity is seen with non-O ABO blood group alleles, which act by increasing von Willebrand factor [9]. (See "Pathophysiology of von Willebrand disease", section on 'VWF functions'.)

However, the relative contributions of genetic and acquired factors to VTE risk with elevated factor VIII have not been determined. Furthermore, factor VIII activity assays are not standardized for this purpose, and the factor VIII activity level above which there is an increased risk may differ substantially between populations. Thus, it is not useful to measure the levels of these factors in asymptomatic individuals. If an individual is found to have increased factor activity, we do not test their relatives.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation in pregnancy" and "Society guideline links: Contraception".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Factor V Leiden (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Hereditary thrombophilia is a genetic tendency to venous thromboembolism (VTE). Hereditary thrombophilias include (see 'List of hereditary thrombophilias' above):

•Factor V Leiden (FVL)

•Prothrombin G20210A, also called prothrombin gene mutation (PGM)

•Protein S (PS) deficiency

•Protein C (PC) deficiency

•Antithrombin (AT) deficiency

High-risk thrombophilias include PS, PC, or AT deficiency, homozygosity for FVL or PGM, or compound heterozygosity for FVL and PGM. Heterozygosity for FVL or PGM are low risk. Positive family history refers to one or more first-degree or second-degree relatives with VTE; strongly positive family history generally refers to more than one relative with VTE prior to age 50. (See 'Low risk versus high risk' above and 'Definition of a positive family history' above.)

●Whether to test – For adults without VTE, we stratify testing decisions based on risk factors, such as positive family history of VTE with a thrombophilic variant in the affected individuals. We suggest testing only if the test result would alter management. (See 'Deciding whether to test' above and 'Risk of a first VTE' above.)

•General population – We do not screen for hereditary thrombophilia in the general adult population. (See 'General risks and benefits of testing' above.)

•Positive family history of VTE and high-risk thrombophilia – Individuals who have a positive family history of VTE with a high-risk thrombophilia in one or more relatives and who would receive thromboprophylaxis in situations of increased VTE risk only if they tested positive for the thrombophilia may choose to test. (See 'Settings in which testing may be appropriate' above.)

Examples of situations with increased VTE risk include:

-Transient illness

-Minor injury

-Infection

-Cancer

-Considering using a combined oral contraceptive or oral menopausal hormone therapy with estrogen

Autosomal dominant inheritance should be considered.

•Positive family history of VTE and low risk thrombophilia – For individuals who have a positive family history of VTE with heterozygosity for FVL or PGM in one or more relatives, we do not test for the thrombophilia, even if they have a transient risk factor (illness, minor injury, infection) or are considering using a medication with estrogen. (See 'Settings in which thrombophilia testing is not appropriate' above.)

•Positive family history of VTE with no familial thrombophilia variant identified – For individuals with a positive family history in whom the affected relative(s) were tested and did not have a known thrombophilia variant, we do not test the asymptomatic individual. An exception may be if there are no relatives available, willing, or able to undergo testing. (See 'Settings in which thrombophilia testing is not appropriate' above.)

●How to test – For adults in whom the decision has been made to test, approach to testing depends on whether the familial thrombophilia variant is known. (See 'Which thrombophilias to test' above.)

•Known familial variant – Test for that variant alone. (See 'Which thrombophilias to test' above.)

•Familial variant not known – Test for all five hereditary thrombophilias. We do not test homocysteine, factor VIII activity, or variants in MTHFR or PAI1 genes to assess VTE risk outside of a research study. (See 'Testing generally not indicated outside of research' above.)

●Testing in other populations

•Adults with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

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

•Pregnant or considering pregnancy – (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for testing'.)

•Recurrent pregnancy loss – (See "Recurrent pregnancy loss: Evaluation".)

•Cryptogenic stroke – (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Advanced evaluation'.)

•Cerebral venous sinus thrombosis – (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Evaluation for thrombophilic state'.)