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MP 2.04.82 Genetic Testing for Inherited Thrombophilia

Medical Policy    
Original Policy Date
 July 2012
Last Review Status/Date
Reviewed with literature search/7:2014
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Inherited thrombophilias are a group of disorders that predispose to thrombosis. Genetic testing is available for some of these disorders and could potentially assist in the diagnosis and/or management of patients with thrombosis.


Venous Thromboembolism

The overall U.S. incidence of venous thromboembolism (VTE) is approximately 1 per 1000 person-years, and the lifetime clinical prevalence is approximately 5%, accounting for 100,000 deaths annually.(1) Risk is strongly age-related, with the greatest risk in older populations. VTE also recurs frequently; estimated cumulative incidence of first VTE recurrence is 30% at 10 years.(1) These figures do not separate patients who had known predisposing conditions from those who did not.

Risk factors for thrombosis include a variety of clinical and demographic variables, and at least 1 risk factor can be identified in approximately 80% of patients who have a thrombosis. The following list includes the most important risk factors:

  • Malignancy
  • Immobility
  • Surgery
  • Obesity
  • Pregnancy
  • Hormonal therapy with estrogen/progesterones
  • Systemic lupus erythematosus, and/or other rheumatologic disorders
  • Myeloproliferative disorders
  • Liver dysfunction
  • Nephrotic syndrome
  • Hereditary factors

Treatment of thrombosis involves anticoagulation for a minimum of 3 to 6 months. After this initial treatment period, patients deemed to be at a continued high risk for recurrent thrombosis may be continued on anticoagulation for longer periods, sometimes indefinitely. Anticoagulation is effective for reducing subsequent risk of thrombosis but carries its own risk of bleeding.

Pregnancy often is considered a special circumstance because of its frequency and unique considerations of preventing and treating VTE in this setting. Pregnancy is associated with a 5- to 10-fold increase in VTE risk, and absolute VTE risk in pregnancy is estimated to be 1 to 2 per 1000 deliveries.(2) In women with a previous history of pregnancy-related VTE, risk of recurrent VTE with subsequent pregnancies is increased greatly at approximately 100-fold.(2)

Inherited Thrombophilia

Inherited thrombophilias are a group of clinical conditions characterized by genetic variant defects associated with a predisposition to thrombosis. However, not all patients with a genetic predisposition to thrombosis will develop VTE. The presence of inherited thrombophilia will presumably interact with other VTE risk factors to determine a patient’s VTE risk.

A number of conditions fall under the classification of inherited thrombophilias. Inherited thrombophilias include the following conditions, which are defined by defects in the coagulation cascade:

  • Activated protein C resistance (factor V Leiden mutations)
  • Prothrombin gene mutation (G20210A)
  • Protein C deficiency
  • Protein S deficiency
  • Prothrombin deficiency
  • Hyper-homocysteinemia (MTHFR mutations)

The most common type of inherited thrombophilia is factor V Leiden mutation, which accounts for up to 50% of inherited thrombophilia syndromes. In unselected patients with an idiopathic thrombosis, the rate of factor V Leiden positivity is 17% to 24%,(3) compared with a rate of 5% to 6% in normal controls. The prothrombin G20210A mutation is found less commonly, in approximately 5% to 8% of unselected patients who have thrombosis, compared with 2% to 2.5% of normal controls.(3)

Genetic testing for gene variants associated with thrombophilias is available for factor V Leiden, the prothrombin G20210A mutation, and MTHFR. Genetic testing for inherited thrombophilia can be considered in several clinical situations. Clinical situations that will be addressed in this policy include the following:

  • Assessment of thrombosis risk in asymptomatic patients (screening for inherited thrombophilia)
  • Evaluation of a patient with established thrombosis, for consideration of change in anticoagulant management based on results
  • Evaluation of close relatives of patients with documented inherited thrombophilia or with a clinical and family history that is consistent with an inherited thrombophilia
  • Evaluation of patients in other situations that are considered high risk for thrombosis, eg pregnancy, planned major surgery, or oral contraceptive use

FDA Status

Several genetic tests for thrombophilia have received U.S. Food and Drug Administration (FDA) marketing clearance for use as an aid in the diagnosis of patients with suspected thrombophilia. Several of these tests are listed in Table 1.

Table 1. Genetic Tests for Thrombophilia Cleared by the Food and Drug Administration




Date Cleared

510(K) Number

IMPACT Dx™ Factor V Leiden and Factor II Genotyping Test

Agena Biosciencea

San Diego, CA



Invader® Factor II, V, and MTHFR tests

Hologic Inc.

Marlborough, MA


K100943, K100980, K100987, K100496

VeraCode® Genotyping Test for Factor V and Factor II

Illumina Inc.

San Diego, CA



eSensor® Thrombophilia Risk Test

GenMark Dxb

Carlsbad, CA



INFINITI™ System Assay for Factor II & Factor V

Autogenomics Inc.

Carlsbad, CA



Xpert® Factor II and Factor V Genotyping Assay


Sunnyvale, CA



Verigene® Factor F2, F5, and MTHFR Nucleic Acid Test

Nanosphere Inc.

Northbrook, IL



Factor V Leiden Kit

Roche Diagnostics

Indianapolis, IN



a FDA marketing clearance was granted to Sequenom Bioscience before it was acquired by Agena.

b FDA marketing clearance was granted to Osmetech Molecular Diagnostics.

Other commercial laboratories offer a variety of diagnostic procedures for F2 (prothrombin, coagulation factor II), F5 (coagulation factor V), and MTHFR (5, 10-methylenetetrahydrofolate reductase) genetic testing. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Commercial thrombophilia genetic tests are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA has chosen not to require any regulatory review of this test.


Genetic testing for inherited thrombophilia, including testing for factor V Leiden mutations, prothrombin gene mutations, and mutations in the MTHFR gene, is considered investigational.

Policy Guidelines

Specific CPT codes for this testing became available in 2012:

81240: F2 (prothrombin, coagulation factor II)(e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant

81241: F5 (coagulation Factor V)(e.g., hereditary hypercoagulability) gene analysis, Leiden variant

81291: MTHFR (5, 10-methylenetetrahydrofolate reductase)(e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)

Benefit Application
BlueCard/National Account Issues

No applicable information 


This policy was created in April 2012 with literature review covering the period from 1995 through February 2012. The most recent update includes a literature review through June 19, 2014.

MTHFR Mutation Testing

Mutations in the MTHFR gene are associated with hyperhomocysteinemia, which is in turn considered a weak risk factor for venous thromboembolism (VTE).(4) However, clinical utility of testing for homocysteine levels has not been established. There is a large body of literature on the association of homocysteine levels with coronary artery disease, and clinical trials have assessed the impact of lowering homocysteine levels. This body of evidence indicates that testing or treating for homocysteinemia is not associated with improved outcomes.

Evidence for the association of MTHFR with VTE is not definitive. Some studies have shown an association,(5-8) but others have not.(9-11) One larger study (N=9231), the 2007 MEGA study, showed no association between the MTHFR mutation with recurrent VTE.(9) A randomized controlled trial (RCT) reported no reduction in VTE associated with treatment of hyperhomocysteinemia.(12)

Section Summary

Published evidence on the utility of testing for MTHFR mutations in patients who have or are at risk for VTE is limited. Given the available evidence, and lack of clinical utility for serum homocysteine testing in general, it is unlikely that testing for MTHFR will improve outcomes.

Factor V Leiden and Prothrombin Mutation Testing

Analytic Validity

Analytic validity refers to the accuracy of detecting a specific mutation when it is present, and excluding it when absent.

For a 2009 evidence review prepared for the Agency for Healthcare Research and Quality (AHRQ), researchers performed a comprehensive review of analytic validity studies.(13) Forty-one studies compared genetic testing for factor V Leiden (FVL) with a reference standard. Concordance between the tests was high, ranging from 93% to 100%, and was 100% in most studies. This evidence report also reviewed 23 studies on the concordance of prothrombin gene mutations with a reference standard and found that nearly all studies reported a 100% concordance. Twelve studies reported multiplex methods to test simultaneously for both FVL and the prothrombin G20210A mutation, all of which reported 100% concordance with reference standards.

Bradley et al (2012) reviewed the analytic validity of FVL and prothrombin mutation testing in pregnancy as reported in individual studies and meta-analyses.(14) For studies performed in the U.S., combined analytic sensitivity and specificity for FVL testing exceeded 99%. For the prothrombin G20210A mutation, analytic sensitivity was 98.4%, and analytic specificity was 99.7%.

Section Summary

Analytic validity of genetic testing for inherited thrombophilia is high. Analytic sensitivity and specificity for FVL testing exceeds 99%, and analytic sensitivity and specificity for the prothrombin G20210A mutation exceeds 98%.

Clinical Validity

Clinical validity and clinical utility will be discussed for 4 distinct patient populations. These are:

  • Individuals without a personal history of VTE
  • Individuals with a personal history of VTE
  • Family members of individuals with thrombophilia
  • Pregnant women

Clinical validity of testing for inherited thrombophilias is best determined by the predictive ability of the test for future thromboembolic events, both in patients with and without prior VTE. Highest quality evidence for this question comprises prospective cohort studies in which patients with and without the mutation are followed for the development of VTE. A few studies are prospective studies nested within RCTs, in which patients with and without mutations are compared.

Individuals without a personal history of VTE

Individuals with both FVL and prothrombin mutations have an elevated risk of thrombosis compared with the general population. For individuals with the FVL mutation, the risk may be 2- to 5-fold higher than the general population. In 1 study of asymptomatic individuals, those with an FVL mutation had an annual incidence of VTE of 0.45%, compared with an annual incidence of 0.1% in those without the mutation.(15)

For the prothrombin G20210A mutation, risk also has been estimated to be 2 to 5 times greater than the general population.(16) In a meta-analysis of 79 studies, combined risk ratio was 3.0.(17) Heterozygosity for the prothrombin G20210A mutation also is associated with an increased risk of upper extremity thrombosis, estimated to be 5 times that of the general population.(16)

Individuals with a personal history of VTE

Factor V Leiden. The 2009 AHRQ report reviewed the evidence on recurrence risk for patients with a history of VTE who have the FVL mutation. For individuals with a heterozygous FVL mutation, 13 studies compared recurrence risk with a mutation with recurrence risk without a mutation. Pooled analysis of these 13 studies yielded an odds ratio (OR) of 1.56 (95% confidence interval [CI], 1.14 to 2.12) for recurrent VTE in patients with the FVL mutation. For patients with a homozygous mutation, 7 studies evaluated recurrence risk. Pooled OR for recurrent VTE in these studies was 2.65 (95% CI, 1.18 to 5.97).

Not all studies report an increased risk of recurrent VTE in patients with inherited thrombophilia. For example, the Leiden thrombophilia study (LETS)(18) followed 474 patients who had completed a course of anticoagulation for a mean of 7.3 years. All patients were tested for thrombophilia at baseline, with 20% found to have an FVL mutation and 6%, a prothrombin mutation. Recurrence was not increased either for patients with a FVL mutation or for patients with a prothrombin mutation. For FVL, there was a mild increase in recurrence risk that did not reach statistical significance on multivariate analysis (hazard ratio [HR], 1.3; 95% CI, 0.8 to 2.1). For the prothrombin G20210A mutation, there was no increased risk of recurrence (HR=0.7; 95% CI, 0.3 to 2.0). Factors that predicted recurrence were mainly clinical variables, such as provoked versus unprovoked VTE, patient sex, and oral contraceptive use.

A larger RCT included in the AHRQ review was the 2008 ELATE trial, which randomized 738 patients from 16 clinical centers who were randomized to low-intensity versus conventional-intensity anticoagulation.(19) All patients were tested for inherited thrombophilias, and recurrence risk was calculated in patients with and without inherited thrombophilia. For patients with an FVL mutation, there was no increased risk of recurrence over a mean follow-up of 2.3 years (HR=0.7; 95% CI, 0.2 to 2.6).

ProthrombinG20210Amutation. The 2009 AHRQ evidence report identified 18 studies that evaluated recurrence risk in patients heterozygous for the prothrombin G20210A mutation. Some of these studies included only heterozygotes, and others combined both heterozygotes and homozygotes. For 9 studies that included only heterozygotes, pooled OR for recurrent VTE was 1.45 (95% CI, 0.96 to 2.2). For 7 studies that did not specify whether patients were homozygous or heterozygous, the combined OR was 0.73 (95% CI, 0.37 to 1.44).

The prothrombin G20210A mutation is less common, and therefore, the number of patients evaluated in clinical trials and cohort studies is less than for FVL. In the 2008 ELATE trial, risk of recurrent VTE in those with the prothrombin G20210A mutation could not be calculated because there were no recurrences among 60 patients with the mutation.(19) In the 2005 LETS study, 29 patients had a prothrombin mutation.(18) For patients with a prothrombin mutation, there was no increased risk of recurrence (HR=0.7; 95% CI, 0.3 to 2.0). Factors that predicted recurrence were mainly clinical variables, such as provoked versus unprovoked VTE, patient sex, and oral contraceptive use.

Family members of individuals with thrombophilia

Factor V Leiden. The 2009 AHRQ report identified 9 studies that evaluated VTE risk in family members of a proband with a heterozygous mutation. Pooled OR for future VTE was 3.49 (95% CI, 2.46 to 4.96). Six studies evaluated a total of 48 probands with homozygous FVL mutations. Pooled OR for family members of homozygous individuals was 18 (95% CI, 7.8 to 40).

In a larger, more recent study of VTE risk in family members, Lijfering et al (2009) pooled results from 5 retrospective family studies of thrombophilia.(20) A total of 2479 relatives of patients with thrombophilia who were themselves also tested for thrombophilia were included. For relatives with FVL mutations, annual incidence of thrombosis was 0.49% (95% CI, 0.39 to 0.60). In relatives without thrombophilia, incidence of VTE was approximately 0.05% per year, and adjusted relative risk for VTE in relatives with an FVL mutation was 7.5 (95% CI, 4.4 to 12.6). In patients treated with anticoagulation, annual risk of major bleeding was 0.29% (95% CI, 0.03 to 1.04).

Prothrombin mutations. Evidence on VTE risk for family members of individuals with a prothrombin mutation is less than for FVL, with 5 studies identified by AHRQ evaluating heterozygotes and only 1 study evaluating homozygotes. For heterozygote probands, family members had an OR for future VTE of 1.89 (95% CI, 0.35 to 10.2).

In the 2009 Lijfering family study, relatives with prothrombin mutations had an annual VTE incidence of 0.34% (95% CI, 0.22 to 0.49).(20) In relatives without thrombophilia, incidence of VTE was approximately 0.05% per year, and adjusted relative risk for VTE in relatives with a prothrombin mutation was 5.2 (95% CI, 2.8 to 9.7).

Pregnancy and other high-risk situations

Pregnancy. Evidence on the risk of recurrent pregnancy loss in women with FVL or a prothrombin gene mutation comprises primarily retrospective case-control studies and cohort studies. Several case-control studies reported a higher prevalence of FVL in women with recurrent, unexplained pregnancy loss compared with controls (OR=2–5).(21) Retrospective cohort studies have found a 2- to 3-fold increased risk of pregnancy loss in FVL heterozygous carriers; homozygotes have a 2-fold higher risk than heterozygous carriers. Risk of pregnancy loss for heterozygous carriers is highest during the second and third trimesters.

A 2012 systematic review by Bradley et al analyzed evidence on the association of FVL and prothrombin mutations with pregnancy loss.(14) These authors identified the highest quality studies, which were cohort studies that: (1) excluded patients with other causes of VTE, (2) tested eligible women for thrombophilia at baseline, (3) reported on subsequent pregnancy outcomes, and (4) compared rates of pregnancy loss between carriers and noncarriers. Four cohort studies met all these criteria; these studies primarily included patients with FVL mutations. Two of the 4 studies reported a significantly increased rate of recurrence for carriers, and 2 studies did not. Pooled analysis of these 4 studies yielded a significantly increased OR for recurrent pregnancy loss in carriers (OR=1.93; 95% CI, 1.21 to 3.09).

A number of meta-analyses have concluded that risk of pregnancy loss for patients who are heterozygous for the prothrombin G20210A mutation also is increased, with increases in the 2- to 3-fold range.(16)

Oral contraceptives. Oral contraceptive use alone is associated with an approximately 4-fold increase in risk of thrombosis; in combination with FVL, risk multiplies 34-fold in heterozygotes and more than 100-fold in homozygotes. However, the absolute incidence estimated by 1 published study was 28 thrombotic events per 10,000 per year, 2% of which were estimated to be fatal.(22)

Hormone replacement therapy. Women using hormone replacement therapy have a 2- to 4-fold increased risk of thrombosis.(21) Absolute risk is low and may be restricted to the first year of use. Limited data suggest that women using selective estrogen receptor modulators (eg, tamoxifen) may have a similarly increased risk.(21)

Section Summary

Clinical validity of genetic testing for thrombophilia has been evaluated by assessing the association between thrombophilia status and VTE in a variety of clinical populations. For populations discussed here, clinical validity has been reported in numerous case-control and cohort studies. The presence of an FVL or a prothrombin gene mutation is associated with an increased risk for subsequent VTE across a variety of populations studied. However, magnitude of the association is relatively modest, with ORs most commonly between 1 and 2, except for the case of family members of individuals with inherited thrombophilia, in which ORs are somewhat higher.

Clinical Utility

Clinical utility of genetic testing depends on the ability of testing results to change management that results in improved outcomes. Clinical utility of genetic testing for thrombophilia is considered in the context of overall VTE risk and risk/benefit ratio of treatment, primarily with anticoagulants. The following factors are part of the decision-making process on whether to test:

  • Overall low incidence of thromboembolism in the general population
  • Modest increased risk associated with most forms of inherited thrombophilia, meaning that the absolute risk of thrombosis in patients with inherited thrombophilia is still relatively low.
  • Potential risk of prophylactic treatment, especially bleeding risk with anticoagulation. This risk may outweigh benefit in patients with a relatively low absolute risk of thrombosis.

Individuals without a personal history of VTE

No published studies were identified that directly evaluated the clinical utility of screening asymptomatic individuals for inherited thrombophilia. However, it is unlikely that screening asymptomatic individuals will result in a net health benefit, as prophylactic anticoagulation is likely to have more harms than benefits. Risk of major bleeding with full anticoagulation is approximately 1% per year; therefore the number of major bleeding episodes may far exceed the number of VTEs prevented. Knowledge of thrombophilia status may lead to behaviors that reduce VTE risk, such as avoidance of prolonged immobility, but this is unproven.

Individuals with a personal history of VTE

The 2008 MEGA study was a large, population-based, case-control study that evaluated whether testing for thrombophilia in patients with a first episode of VTE was associated with a decrease in recurrence rate.(23) The MEGA database comprised 5051 patients between the ages of 18 and70 years with a first episode of VTE. Researchers identified 197 patients with a recurrence of VTE and matched these patients on age, sex, year of VTE, and geographic region with 324 patients who were free of recurrent VTE. Recurrence rate for VTE was similar in patients who were tested for thrombophilia compared with patients who were not tested (OR=1.2; 95% CI, 0.9 to 1.8). The presence of FVL or the prothrombin G20210A mutation was not associated with an increased recurrence rate, with an OR of 0.8 (95% CI, 0.3 to 2.6).

Mahajerin et al (2014) conducted a single-center, retrospective cohort study of pediatric patients (mostly adolescents) who presented with VTE (88% DVT) “to help clarify the role of thrombophilia testing in pediatric VTE.”(24) Of 392 inpatients and outpatients, thrombophilia tests (FVL; prothrombin gene mutation; MTHFR; protein C, protein S, and antithrombin activity; antiphospholipid antibodies; plasminogen activator inhibitor-1 levels and mutation testing) were ordered in 310 (79%); of these, positive results returned in 37 (12%). Given that most patients had at least 1 risk factor for VTE and, as noted by the authors, “presence or absence of thrombophilia rarely influences VTE management,” this evidence does not support thrombophilia genetic testing in pediatric patients who present with VTE.

A 2009 study surveyed 112 primary care physicians about the impact of FVL testing in patients with VTE.(25) Most physicians indicated that they would use results in clinical practice, with 82% reporting that they would use results to counsel patients on risk of recurrence and 67% reporting that they would use results to make treatment changes. However, physician confidence in their decisions was not high, including decisions to order FVL testing.

Family members of individuals with thrombophilia

There are no comparative trials of testing versus no testing in relatives of individuals with thrombophilia. Clinical utility of testing depends on the balance between the benefit of altering management as a result of knowledge of mutation status versus the risk of bleeding with intensification of anticoagulation. This risk-benefit is unknown, as previously discussed. Absolute risk of VTE remains low even in patients with inherited thrombophilia, and potential risks of prophylactic treatment with anticoagulants may outweigh potential benefits.

Pregnancy and other high-risk conditions

No studies directly evaluated clinical utility of thrombophilia testing in pregnant women. Clinical utility of testing depends on the efficacy of potential treatments in decreasing fetal loss versus the risks of treatment. Potential treatments in pregnancy include aspirin, low-dose unfractionated or low molecular weight heparin, and full-dose heparin. Benefits of these treatments in reducing pregnancy loss are questionable. At least 2 RCTs have reported that there is no significant reduction in risk with aspirin or heparin therapy.(26,27) Additionally, several meta-analyses reported that evidence is insufficient to conclude that these interventions reduce recurrent pregnancy loss in patients with FVL or prothrombin mutations.(14) In contrast, real risks of anticoagulation include bleeding, thrombocytopenia, and allergic reactions. There also are costs and inconvenience associated with these treatments.

Bradley et al reviewed the evidence on clinical utility of testing for heritable thrombophilias in pregnancy and concluded that evidence is adequate to conclude that there are no safe and effective treatments to reduce recurrent pregnancy loss in women with inherited thrombophilia.(14) Certainty of the evidence that treatment resulted in net harm was moderate.

Section Summary

Clinical utility of testing for FVL or prothrombin mutations has not been demonstrated. Although the presence of inherited thrombophilia increases risk for subsequent VTE events, the increase is modest and the absolute risk of thrombosis remains low. Available prophylactic treatments, such as anticoagulation, have defined risks of major bleeding and other adverse events that may outweigh the reduction in VTE and therefore result in a net harm. The currently available evidence has not defined a role for thrombophilia testing for decisions on the length of anticoagulation treatment.

Clinical Input Received Through Specialty Medical Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. In response to requests, input was received from 4 physician specialty societies (6 reviewers) and 6 academic medical centers, for a total of 12 reviewers, while this policy was under review for July 2012. Overall, input was mixed, and there was not uniform consensus that genetic testing for thrombophilia was medically necessary for any of the specific clinical situations included. Several reviewers noted that testing could be useful in isolated instances, but were unable to define specific criteria that could be used for testing.


Genetic testing is available for a number of types of inherited thrombophilia, including mutations in the MTHFR gene, the factor V Leiden (FVL) gene, and the prothrombin gene. For MTHFR testing, clinical validity and clinical utility of genetic testing is uncertain. Because clinical utility of testing for elevated serum homocysteine itself has not been established, utility of genetic testing also has not been established.

For FVL and prothrombin gene testing, clinical validity has been established in a variety of clinical situations, by the association of genetic status with subsequent risk of venous thromboembolism (VTE). Increased risk of VTE has been demonstrated for asymptomatic patients, patients with a personal history of VTE, family members of a patient with established inherited thrombophilia, and pregnant women. However, in most reports, the magnitude of this association is modest, resulting in a relatively low absolute rate of VTE even in patients with a genetic mutation.

Clinical utility of genetic testing for thrombophilia is less certain. Surveys of physicians indicate that a substantial number order thrombophilia testing with the intent of influencing management, but specific management changes and the impact of those management changes on outcomes is uncertain. According to existing evidence and recent guidelines, the presence of inherited thrombophilia is not an important factor in determining the optimum length of anticoagulation in patients with VTE. For other clinical situations, given the low absolute risk of VTE, and the defined risks of anticoagulation, it is not possible to define a clinical situation in which the benefit of testing clearly outweighs the risk. Clinical vetting performed in 2012 did not identify consensus for testing in any of the clinical scenarios that were outlined. Because of the lack of documented clinical utility, and the lack of consensus on clinical vetting as to which populations benefit from testing, genetic testing for inherited thrombophilia is considered investigational.

Practice Guidelines and Position Statements

Many guidelines and position statements on testing for thrombophilia have been published over the last 2 decades. These guidelines have evolved with time, often do not agree with each other, and do not typically give specific parameters for when to perform genetic testing. The following are examples of U.S. guidelines developed by major specialty societies and published in the last 5 years.

Evaluation of Genomic Applications in Practice and Prevention Working Group

In 2011, EGAPP published recommendations for genetic testing for Factor V Leiden mutations and prothrombin mutations.(28) Recommendations on the clinical utility of genetic testing were:

  • There is no evidence that knowledge of FVL/PT mutation status in patients with VTE affects anticoagulation treatment to avoid recurrence.
  • There is convincing evidence that anticoagulation beyond 3 months reduces recurrence of VTE, regardless of mutation status.
  • There is no evidence that knowledge of FVL/PT mutation status among asymptomatic family members of patients with VTE leads to anticoagulation aimed at avoiding initial episodes of VTE.

American College of Chest Physicians

In 2012, the American College of Chest Physicians (ACCP) published the ninth edition of their evidence-based guidelines on antithrombotic therapy and the prevention of thrombosis.(29) For pregnant women with no prior history of VTE who are known to be homozygous for FVL or the prothrombin G20210A mutation, ACCP made the following recommendations:

  • Positive family history for VTE: ACCP suggests antepartum prophylaxis with prophylactic- or intermediate-dose low molecular weight heparin (LMWH) and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or warfarin (international normalized ratio [INR] target, 2.0-3.0) rather than no prophylaxis (Grade 2B [weak] recommendation, based on moderate-quality evidence)
  • No family history for VTE: ACCP suggests antepartum clinical vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or warfarin (INR target, 2.0-3.0) rather than routine care (Grade 2B recommendation)

In 2008, ACCP published evidence-based guidelines for the treatment of thromboembolic disease in 2008.(30) These guidelines stated the following concerning genetic testing for thrombophilia:

  • The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence.

American College of Obstetricians and Gynecologists

The American College of Obstetricians and Gynecologists published clinical management guidelines for inherited thrombophilias in pregnancy in 2013.(4) These guidelines stated that a definitive causal link between inherited thrombophilias and adverse pregnancy outcomes cannot be made. Screening for inherited thrombophilias is controversial, but may be considered for pregnant women in the following situations:

  • A personal history of venous thromboembolism that was associated with a nonrecurrent risk factor (eg, fracture, surgery, or prolonged immobilization).
  • A first-degree relative (eg, parent, sibling) with a history of high-risk thrombophilia.

The guidelines also state that:

  • Testing for inherited thrombophilias should include FVL, prothrombin G20210A mutation, and tests for deficiencies in antithrombin, protein S and protein C (Level C recommendation, based primarily on consensus and expert opinion).
  • Testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear whether anticoagulation therapy reduces recurrence (Level B recommendation, based on limited or inconsistent scientific evidence).
  • Because an association between either heterozygosity or homozygosity for the MTHFR C677T polymorphism and any negative pregnancy outcomes, including any increased risk for VTE, has not been shown, screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended (Level B recommendation).

U.S. Preventive Services Task Force

U.S. Preventive Services Task Force recommendations for genetic testing for thrombophilia were not identified.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


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  15. Middeldorp S, Henkens CM, Koopman MM et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998; 128(1):15-20.
  16. Kujovich JL. Prothrombin-Related Thrombophilia. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews . Seattle (WA) 2011.
  17. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102(2):360-70.
  18. Christiansen SC, Cannegieter SC, Koster T et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293(19):2352-61.
  19. Kearon C, Julian JA, Kovacs MJ et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008; 112(12):4432-6.
  20. Lijfering WM, Brouwer JL, Veeger NJ et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113(21):5314-22.
  21. Press RD, Bauer KA, Kujovich JL et al. Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med 2002; 126(11):1304-18.
  22. Vandenbroucke JP, Koster T, Briet E et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344(8935):1453-7.
  23. Coppens M, Reijnders JH, Middeldorp S et al. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 6(9):1474-7.
  24. Mahajerin A, Obasaju P, Eckert G et al. Thrombophilia testing in children: a 7 year experience. Pediatr Blood Cancer 2014; 61(3):523-7.
  25. Hindorff LA, Burke W, Laberge AM et al. Motivating factors for physician ordering of factor V Leiden genetic tests. Arch Intern Med 2009; 169(1):68-74.
  26. Clark P, Walker ID, Langhorne P et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 2010; 115(21):4162-7.
  27. Kaandorp SP, Goddijn M, van der Post JA et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362(17):1586-96.
  28. 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 venous thromboembolism and their adult family members. Genet Med 2011; 13(1):67-76.
  29. Guyatt GH, Akl EA, Crowther M et al. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(2_suppl):7S-47S.
  30. Hirsh J, Guyatt G, Albers GW et al. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl):110S-12S.




CPT  81240 F2 (prothrombin, coagulation factor II)(e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant
  81241 F5 (coagulation Factor V)(e.g., hereditary hypercoagulability) gene analysis, Leiden variant
  81291 MTHFR (5, 10-methylenetetrahydrofolate reductase)(e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)
ICD-9-CM Diagnosis    Investigational for all relevent diagnoses
ICD-10-CM (effective 10/1/15)   Investigational for all relevent diagnoses
  D68.51 Activated protein C resistance (includes Factor V Leiden mutation)
  D68.52 Prothrobin gene mutation
  D68.59 Other primary thrombophilia
  D68.61-D68.69 Other thrombophilia (includes other hypercoagulable states)
ICD-10-PCS (effectve 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


F2 Prothrombin Coagulation Factor II, Genetic Testing
Factor V Leiden, Genetic Testing
Hypercoagulability, Genetic Testing
MTHFR, Genetic Testing

Policy History

Date Action Reason
07/12/12 Add to Medicine -Pathology/Laboratory section New policy developed including results of clinical vetting. Policy statement investigational for all indications.
7/11/13 Replace policy Policy updated with literature review, no new references added. No change to policy statement
7/10/14 Replace policy Policy updated with literature review through June 19, 2014; references 5-8, 10-11, 24, and 29 added; references 4 and 12 updated. No change to policy statement.


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