Screening for inherited thrombophilia in asymptomatic adults

INTRODUCTION — Inherited thrombophilia denotes several genetic risk factors that predispose individuals to developing venous thromboembolism. Factor V Leiden is the most common. Prothrombin G20210A, deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases, while rare causes include certain dysfibrinogenemias. The total prevalence of an inherited thrombophilia in patients with venous thromboembolism (VTE) varies based upon patient selection and ethnicity; in White populations, it can be as high as 40 percent overall, compared with about 8 to 10 percent in those without VTE. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

This review will discuss the usefulness of screening for these conditions in asymptomatic adults [1,2].

Separate topic reviews discuss screening for inherited thrombophilia in children and the diagnostic approach to a patient presenting with venous thromboembolism (VTE):

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

●Diagnostic approach in a patient with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Management implications of specific inherited thrombophilias are also discussed separately:

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

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

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

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

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

GENERAL SCREENING ISSUES — Screening techniques are used clinically to identify individuals at risk for a preventable disease or complication. Reliable assays are now available to test for the presence of the various causes of inherited thrombophilia (table 1).

However, unselected population-based screening for inherited thrombophilia is not recommended because of three salient factors:

●The low frequency of the symptomatic condition in the general population (table 2)

●The low penetrance of the symptomatic condition among carriers of the most common thrombophilic conditions (eg, factor V Leiden and prothrombin G20210A), AND

●The lack of a safe, cost-effective, long-term method of prophylaxis if an abnormality is found

Patients with a family history of thrombosis are at increased risk for a pathogenic variant in one of the inherited thrombophilia genes (a mutation or other genetic change associated with thrombosis). However, a simple positive history is not a reliable criterion to select patients for screening. This was illustrated in a report of 101 patients who had their first and single thromboembolic event while using oral contraceptives [3]. A family history of thrombosis in a first-degree relative had a positive predictive value of only 14 percent for factor V Leiden.

The usefulness of screening for hereditary thrombophilia has been considered in family members of patients with a history of venous thromboembolism (VTE) and a thrombophilic defect, especially antithrombin (AT), protein S, or protein C deficiencies. As examples:

●A meta-analysis of case-control and cohort studies showed that compared with controls, AT-deficient individuals had an odds ratio (OR) of VTE of 16.3 (95% CI 9.9-26.7); this was substantially higher than the VTE risk attributed to protein S or protein C deficiency (ORs 5.4 and 7.5, respectively) [4].

●In a report of 150 pedigrees with factor V Leiden or AT, protein C, or protein S deficiency, the lifetime probability of developing thrombosis compared with those with no defect was 8.5 times higher for carriers of protein S deficiency, 8.1 for AT deficiency, 7.3 for protein C deficiency, and 2.2 for carriers of factor V Leiden [5].

●A retrospective cohort study of 2479 relatives of individuals with thrombosis and a thrombophilic defect found that relatives who shared an inherited defect in protein S, protein C, or AT had an annual risk of VTE of 1.5 to 1.9 percent and a cumulative VTE incidence of 55 percent at 10 years; individuals who shared other thrombophilic defects with the index case had lower cumulative risks (eg, 7 percent for factor V Leiden and 11 percent for prothrombin mutations) [6].

●A prospective observational study of 206 pediatric patients who presented with VTE found that 27 percent of first and second degree relatives had an inherited thrombophilia, the most common of which was heterozygosity for factor V Leiden (57 percent) [7]. Of these relatives with inherited thrombophilia, 23 percent (33 of 146) had VTE. In contrast, only 3.6 percent of relatives without an inherited defect had VTE. The risk of clinically important thrombotic events was greatest in individuals with protein S, protein C, and AT deficiencies and least with factor V Leiden.

Since the genetic pattern for the inherited thrombophilias is autosomal dominant, one-half of the relatives of each patient with thrombosis and hereditary thrombophilia will carry the same gene variant. However, the value of screening for the presence of a gene variant or deficiency state remains controversial. The following sections provide arguments for and against such screening.

Arguments against screening — Identification via screening of an inherited thrombophilia would theoretically permit the institution of prophylactic anticoagulation, either permanently or during high-risk situations. However, there are no data that justify the risks of long-term or permanent prophylactic anticoagulation in the asymptomatic individual (ie, an individual who has not had a thromboembolic event).

As examples, two studies of the incidence of thromboembolic disease in family members of patients with factor V Leiden suggest that neither of these strategies would be of value [8,9]. In a retrospective, blinded analysis, the incidence of VTE was assessed in 437 first-degree relatives of 112 symptomatic heterozygotes and 30 relatives of six homozygotes [8]. The annual incidence of thromboembolism in relatives of heterozygous patients was 0.45 percent in those with the mutation and 0.1 percent in those without the mutation; 20 percent of the episodes were related to surgery and 30 percent to pregnancy or the use of oral contraceptives.

The 0.35 percent difference between the two groups suggests that approximately 300 women would have to be treated (and suffer the risks and burdens of anticoagulation) in an attempt to prevent one episode of VTE per year. This absolute benefit does not appear to justify life-long anticoagulation. It was also estimated that, if all identified pregnant carriers were treated with anticoagulant prophylaxis, treatment would be given unnecessarily in 98 percent of pregnant carriers who would be exposed to the risks of bleeding, bone loss, and thrombocytopenia. Similarly, if all potential users of oral contraceptives were screened and then discouraged from use of the drugs if they tested positive, 333 women would be identified for every episode of VTE prevented.

Similar arguments against screening for the prothrombin G20210A mutation have been presented, in which the annual incidence of thromboembolism in relatives of heterozygous patients was 0.37 percent in those with the mutation and 0.12 percent in those without the mutation [10].

Arguments in favor of screening — Although prophylactic anticoagulation in the asymptomatic individual (ie, an individual who has not had a thromboembolic event) cannot be universally justified, there are high-risk situations (eg, major surgery, trauma, immobilization for >7 days, pregnancy and puerperium) that may prompt consideration of prophylactic treatment in relatives who are screened and found to carry a thrombophilic defect [11-13].

In addition, individuals can be educated about precautions and early symptoms. As an example, women can be made aware of the risk/benefit ratio associated with oral contraceptives and hormone replacement therapy and make more informed decisions [14]. This applies particularly to individuals who are heterozygous for protein C, protein S, or AT deficiency, conditions that appear to have a higher thrombosis risk than heterozygous factor V Leiden [5,12]. (See "Menopausal hormone therapy and cardiovascular risk".)

SCREENING FOR SPECIFIC INHERITED THROMBOPHILIAS — For all of the inherited thrombophilias, we believe that the benefits of screening are likely to be significant in the asymptomatic family member with thrombophilia only if there is a strong family history of VTE (ie, multiple first-degree relatives with thrombotic events prior to age 50) [6]. Following an informed discussion with such patients with VTE and thrombophilia, we recommend screening first-degree family members for the identified defect. How this should be performed is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Hypercoagulable tests'.)

We do not recommend screening for high homocysteine levels, presence of MTHFR variants, or 4G/5G variants in plasminogen activator inhibitor-1 (PAI-1) in any setting.

In patients with thrombophilia who have had a VTE but have no family history, the benefit of screening first-degree family members is not established. An individualized approach should be taken to testing such individuals after discussing the potential benefits and risks and taking personal preference into account.

Factor V Leiden — Factor V Leiden is the most common inherited thrombophilia. This topic is discussed separately. (See "Factor V Leiden and activated protein C resistance".)

Protein C deficiency — Patients with protein C deficiency are at potential risk of warfarin-induced skin necrosis and should be aware of this diagnosis, if present. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Antithrombin deficiency — Pregnant women with hereditary antithrombin (previously called antithrombin III) deficiency have an unusually high risk for thromboembolism. One study, for example, evaluated 78 women with inherited deficiency in antithrombin, protein S, or protein C [15]. Deep vein thrombosis occurred in 18 percent of patients with type I antithrombin deficiency during pregnancy and in 33 percent in the postpartum period. By comparison, thrombosis during pregnancy occurred in only 7 percent of patients with protein C deficiency and in none of the patients with protein S deficiency. Thrombosis in the postpartum period occurred in 19 percent of protein C and 17 percent of protein S deficient patients. (See "Antithrombin deficiency".)

As a result, women with antithrombin deficiency should receive anticoagulant prophylaxis with low molecular weight (LMW) heparin during pregnancy and for six weeks postpartum. Administration of antithrombin concentrate immediately prior to delivery is often appropriate given the need to discontinue anticoagulation temporarily during the delivery process. (See "Inherited thrombophilias in pregnancy" and "Use of anticoagulants during pregnancy and postpartum".)

Homozygosity and multiple defects — Rarely, an asymptomatic high risk homozygote with the factor V Leiden or prothrombin G20210A mutation can be diagnosed by family screening. Infrequently, a second hereditary defect, particularly factor V Leiden, is identified in a patient with one of the other inherited thrombophilic defects. (See "Overview of the causes of venous thrombosis".)

Carriers of two defects seem to be at a higher risk for thrombosis than their relatives with a single defect. In one review of four studies, approximately 75 percent of the family members who were carriers of two defects had experienced thrombosis compared with 10 to 30 percent of the carriers of a single defect [16]. However, these data may reflect an artificially elevated risk based on reporting bias.

The lack of utility of screening asymptomatic relatives of homozygous probands with a negative family history of venous thromboembolism (VTE) is supported by a study that retrospectively evaluated the risk of VTE in family members of individuals with inherited defects [17]. This study found that VTE was less likely in homozygotes for factor V Leiden or prothrombin G20210A with a negative family history of VTE than in individuals who were heterozygous for an inherited defect with a positive family history of VTE (adjusted hazard ratio [HR] 1.3; 95% CI 1.3-5.4 and HR 4.1; 95% CI 1.2-14.7, respectively).

SCREENING IN HIGH RISK SITUATIONS

Oral contraceptives — We typically do not screen asymptomatic women taking oral contraceptives (OCs) for inherited thrombophilia. In reproductive-aged women, both the incidence of venous thromboembolism (VTE) with estrogen-progestin use (30 to 40 events per 100,000 person-years) and the estimated mortality rate from VTE (3 per 1 million for estrogen-progestin users and 14 per 1 million in estrogen-progestin users with the factor V Leiden mutation) are so low that the number of women who would need to be screened for inherited thrombophilias to prevent one death is very large (more than 92,000 FVL carriers in one American study) and the cost of screening to prevent one death would be extremely high (more than USD $300 million) [18-21].

Screening for inherited thrombophilia prior to initiating estrogen-progestin contraception may be appropriate in women with no personal history of VTE if a first-degree relative has a history of VTE associated with inherited thrombophilia; or if multiple first-degree relatives have a history of VTE, particularly at a younger age (eg, <50 years). The detection of single or multiple genetic defects in the patient provides information that is helpful for her in balancing the risks and benefits of using estrogen-progestin contraceptives and making a contraceptive choice [22-25]. This is especially true for individuals with antithrombin deficiency, protein S deficiency, or protein C deficiency, and less clear for those with the factor V Leiden mutation or the prothrombin G20210A mutation. Estrogen-progestin contraception is not strongly contraindicated in women heterozygous for these mutations, given the smaller increase in VTE risk related to these thrombophilias compared with other thrombophilias. We individualize decisions about screening based on the specific details of the family history (eg, age of occurrence, provoked versus unprovoked, number of VTE events) and patient values and preferences. If the appropriateness of screening a specific patient is unclear, referral to a hematologist can be useful.

We do not screen for inherited thrombophilia in women with a personal history of VTE when the purpose of screening is to inform counseling about estrogen-progestin contraceptives as a contraception option. Screening results would not affect this decision, as we and most other clinicians would advise against starting or continuing estrogen-progestin contraceptives after a previous thrombotic episode because of the risk of recurrent VTE. More information can be found in the Centers for Disease Control and Prevention United States Medical Eligibility Criteria for Contraceptive Use.

Contraceptive counseling for women known to have an inherited thrombophilia is presented separately. (See "Contraception: Counseling for women with inherited thrombophilias".)

Pregnancy — The overall maternal death rate due to pulmonary embolism in the United States is estimated at 1.2 per 100,000 [26]. In a study of over 72,000 deliveries, the incidence of deep vein thrombosis alone was much higher at 71 per 100,000 deliveries; factor V Leiden accounted for 8 percent of the patients with thrombosis [27]. If one-half of the fatal pulmonary emboli were to occur in the 10 percent of women with factor V Leiden, the risk would be approximately 1 in 13,000. This is lower than the risk of fatal bleeding or intracranial bleeding that leads to lifelong handicap [24]; the latter risk has been estimated at about 0.5 patients per 100 treatment years or 1 in 2000 mothers anticoagulated for at least six weeks [28]. (See "Inherited thrombophilias in pregnancy".)

Thus, screening all pregnant women for an inherited thrombophilia is not recommended [24,29].

Obstetric complications — In addition to an association with venous thrombosis, inherited thrombophilia has also been linked to obstetric complications such as second and third trimester fetal loss, which are associated with intervillous or spiral artery thrombosis and inadequate placental perfusion. The value of screening women with one of these complications is uncertain. (See "Inherited thrombophilias in pregnancy".)

VARIANTS FOR WHICH SCREENING IS NOT HELPFUL — There are some gene variants for which screening is not indicated in asymptomatic individuals. We also do not alter management if screening for these defects has been conducted and abnormalities are found, based on lack of evidence that risk is significantly increased or that anticoagulation reduces risk.

Homocysteine, MTHFR variants, and PAI-1 4G/5G promoter variants — There is no clinical rationale for measurement of fasting plasma homocysteine levels or for assaying for presence of the methylenetetrahydrofolate reductase (MTHFR) 677C—>T, MTHFR 1298 A—>C, or plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter variants in asymptomatic individuals, and we never order these tests when evaluating patients with venous or arterial thrombosis. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1 deficiency' and "Overview of homocysteine", section on 'Decision to test'.)

If the patient has had this biochemical or genetic testing and findings are abnormal, we counsel that the result is of no clinical significance, and relatives should not be tested.

Elevated coagulation factor levels — Elevated levels of several procoagulant coagulation factors may increase risk for a first episode of venous thromboembolism; elevated factor VIII level is the strongest of these risk factors. It has not been determined whether there is a genetic basis for these elevations. Furthermore, factor VIII assays are not standardized for this purpose, and the factor VIII 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. We recommend against screening relatives for such abnormalities, even if a first degree relative has been found to have an abnormally high level of a coagulation factor.

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".)

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

●Definitions – Inherited thrombophilia is a genetic tendency to venous thromboembolism (VTE). Common causes include factor V Leiden (the most common condition), prothrombin G20210A, and deficiencies in protein S, protein C, and antithrombin (AT). (See 'Introduction' above.)

●Arguments against general population screening – Unselected population-based screening for inherited thrombophilic states is not recommended because of their low frequency, low penetrance, and lack of a safe, cost-effective, long-term method of prophylaxis if an abnormality is found. Specifically, there are no data that justify the risks of prophylactic anticoagulation in the asymptomatic patient with inherited thrombophilia. (See 'Arguments against screening' above.)

●Settings in which screening may be reasonable – The benefits of screening are likely to be significant in the asymptomatic family member with thrombophilia only if there is a strong family history of VTE (ie, multiple first-degree relatives with thrombotic events prior to age 50); such histories are more common in patients with deficiencies of AT, protein C, or protein S. (See 'Arguments in favor of screening' above.)

In certain high thrombotic risk situations (eg, major surgery, trauma, immobilization for >7 days, pregnancy and puerperium), screening for inherited thrombophilia, if present, may prompt consideration of prophylactic treatment or alteration in the type/duration of antithrombotic prophylaxis. These scenarios include (see 'Screening for specific inherited thrombophilias' above and 'Screening in high risk situations' above):

•Homozygosity for factor V Leiden, prothrombin G20210A, or more than one thrombophilic variant.

•Initiation of a vitamin K antagonist in an individual with protein C deficiency given potential for the rare complication of warfarin-induced skin necrosis.

•Consideration of AT concentrate administration in AT deficiency in the peri-partum period or in conjunction with surgical procedures when anticoagulants cannot be safely administered (eg, during delivery or immediately following neurosurgery or spinal surgery)

●Contraceptive counseling or hormone replacement – We typically do not screen for inherited thrombophilia before prescribing an estrogen-containing contraceptive or hormone replacement therapy unless a first-degree relative has inherited thrombophilia and clinical thromboembolic disease. (See "Contraception: Counseling for women with inherited thrombophilias".)

●Management – Management of inherited thrombophilia is discussed separately. (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A" and "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency".)