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Thrombophilia testing in children and adolescents

Thrombophilia testing in children and adolescents
Literature review current through: Jan 2024.
This topic last updated: Aug 28, 2023.

INTRODUCTION — Thrombotic events (venous thromboembolism [VTE] and stroke) in children have become increasingly recognized in hospitalized pediatric patients, although they are rare in healthy children [1]. In most cases of pediatric VTE, there are underlying risk factors (table 1), the most common of which is the presence of an indwelling central venous catheter. Inherited thrombophilias (IT) also contribute to the risk of VTE; however, the prevalence of IT varies considerably depending upon the specific patient population. An underlying thrombophilia is far more likely in patients with unprovoked VTE compared with provoked (eg, catheter-related).

The approach to and rationale for thrombophilia testing in children who have had a thrombotic event and those who have a positive family history will be reviewed here. Diagnosis and management of VTE and stroke in children and the approach to IT testing in adults are discussed in separate topic reviews:

(See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis".)

(See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

(See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

(See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".)

(See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Screening for inherited thrombophilia in asymptomatic adults".)

TERMINOLOGY — The following terms are used throughout this topic:

Thrombophilia – Thrombophilia refers to the propensity to form blood clots and may be a result of inherited and/or acquired risk factors.

Inherited thrombophilia (IT) – IT refers to genetic risk factors that predispose individuals to developing venous thromboembolism (VTE). The ITs for which the pathogenic link is most clearly established include (table 2):

Factor V Leiden mutation (see "Factor V Leiden and activated protein C resistance")

Prothrombin G20210A mutation (see "Prothrombin G20210A")

Antithrombin deficiency (see "Antithrombin deficiency")

Protein C deficiency (see "Protein C deficiency")

Protein S deficiency (see "Protein S deficiency")

Among these, the risk of VTE is highest in individuals with antithrombin, protein C, or protein S deficiency and those with homozygous factor V Leiden or prothrombin G20210A mutations. Heterozygotes for factor V Leiden or the prothrombin G20210A mutation are at lower risk.

Although numerous other inherited defects have been described, none have gained widespread acceptance. In particular, polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene are generally not considered ITs because they are very common and are not, by themselves, associated with VTE [2]. (See "Overview of homocysteine" and "Overview of the causes of venous thrombosis", section on 'Other alleged inherited thrombophilias'.)

Acquired thrombophilia – Acquired thrombophilia refers to acquired laboratory abnormalities that may predispose individuals to developing VTE. Antiphospholipid antibody syndrome is an important acquired thrombophilia, and testing for this disorder should be included when performing thrombophilia testing in the setting of a prior history of VTE. (See 'Children with venous thromboembolism' below and "Diagnosis of antiphospholipid syndrome".)

Additional laboratory-based risk factors for VTE that may be included on a "thrombophilia panel" include homocysteine, factor VIII, lipoprotein(a) levels, and plasminogen activator inhibitor-1 (PAI-1) levels or PAI-1 4G/5G promotor polymorphism. However, as discussed below, we suggest not routinely performing these tests when evaluating for thrombophilia in children because guidance is lacking on how abnormal results should influence patient management. (See 'Tests to perform' below.)

ASSOCIATION BETWEEN INHERITED THROMBOPHILIA AND PEDIATRIC VTE — Most pediatric venous thromboembolism (VTE) episodes occur in hospitalized children with underlying medical conditions, such as prematurity, cancer, congenital heart disease, and infection (table 1). Often multiple VTE risk factors are present, the most common being the presence of a central venous catheter (CVC) [3-5]. Though the incidence of pediatric VTE is highest among hospitalized neonates and infants, there is a second "peak" in adolescence. VTE in adolescence often presents in the setting of oral contraceptive use, or it may be unprovoked. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Incidence'.)

In children with VTE, the prevalence of inherited thrombophilia (IT) varies greatly, ranging from approximately 10 to 60 percent, depending on the population studied and the tests used [5-14]. The prevalence is highest in children with unprovoked VTE and lowest in patients with CVC-associated VTE [13].

The most common ITs identified in pediatric VTE include factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, and proteins S and C deficiencies. In two studies including a total of 271 children with VTE, the relative frequencies of individual IT disorders was as follows [12,13]:

Factor V Leiden – Approximately 5 to 10 percent

Prothrombin G20210A mutation – Approximately 2 to 3 percent

Antithrombin deficiency – Approximately 1 percent

Protein S deficiency – Approximately 1 percent

Protein C deficiency – Approximately 1 percent

Combined defects – Approximately 2 to 3 percent

In one of the two studies, IT was most common in older children with unprovoked VTE (60 percent), whereas IT was relatively uncommon in children with VTEs secondary to an underlying medical condition (<10 percent) [13].

APPROACH TO THROMBOPHILIA TESTING — Our suggested approach to testing for thrombophilia is summarized in the figure and is discussed in detail in the following sections (algorithm 1).

Children with venous thromboembolism

General considerations — For children who have had a venous thromboembolism (VTE), the following questions should be considered prior to testing for inherited thrombophilias (IT) [15,16]:

How likely is it that the child has an IT? – As discussed above, most pediatric VTE episodes are associated with underlying medical conditions or provoking circumstances (eg, central venous catheter [CVC], cancer, congenital heart disease, estrogen, infection, trauma, immobilization); the likelihood of IT is highest among children with unprovoked VTE. (See 'Association between inherited thrombophilia and pediatric VTE' above.)

Will the test results affect the acute management of VTE? – Identification of a thrombophilic defect rarely influences the acute management of a patient with VTE, in whom the mainstay of therapy is therapeutic anticoagulation. The exception would be a neonate with severe (homozygous or compound heterozygous) deficiency of proteins C or S who presents with purpura fulminans, which can be life threatening and requires special interventions. (See "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)

With increasing use of direct oral anticoagulants (DOACS) in pediatric patients with VTE, one issue that may arise is the need to exclude antiphospholipid antibody syndrome (APS), an acquired thrombophilia, prior to treatment (since patients with APS who require long-term anticoagulation are generally treated with warfarin rather than DOACs) [17]. Therefore, in a patient who has a clinical history suggestive of APS (adolescent with unprovoked VTE, immune mediated cytopenias, or underlying rheumatologic condition) it is reasonable to test for antiphospholipid antibodies prior to using a DOAC. (See "Diagnosis of antiphospholipid syndrome" and "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation'.)

Will the test results affect the duration of anticoagulation? – The decision of how long to continue anticoagulation therapy for VTE in pediatric patients is based largely on the age of the child (shorter treatment courses may be used in neonates compared with older infants and children) and whether the VTE is provoked (ie, associated with a risk factor such as CVC, estrogen, infection, trauma, or immobilization) or unprovoked (unprovoked VTE is generally treated for a longer duration compared with provoked). (See "Neonatal thrombosis: Management and outcome" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE treatment'.)

Some patients with IT may benefit from a longer duration of anticoagulation for treatment of VTE. The decision should be assessed on an individual basis, weighing the risk of recurrence against the risk of bleeding. Factors that may influence the decision include the specific thrombophilic defect, age of the patient, whether the thrombus was unprovoked or provoked, and the child's risk of bleeding [4]. Published guidelines do not address whether the presence of an IT should influence the duration of therapy for a child with VTE [15]. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Inherited thrombophilia'.)

Are there other benefits of identifying an IT? – Identification of IT may help provide insight as to why the child developed thrombosis, particularly if the event was unprovoked. This information may help to inform decisions about thromboprophylaxis during future high-risk situations. In addition, patients and families often appreciate information about an underlying thrombophilia as an explanation for why a thrombosis occurred. Lastly, discovery of an inherited defect will allow other family members to be counseled on their potential risk, allowing them to make an informed decision on whether or not to be tested. Testing of other children in the family who are asymptomatic is discussed further below (see 'Asymptomatic children with a positive family history' below). Testing of asymptomatic adult family members is also discussed separately. (See "Screening for inherited thrombophilia in asymptomatic adults".)

Our approach

Who should be tested — Based on the considerations outlined above, we suggest the following approach for thrombophilia testing in children with VTE (algorithm 1):

First episode of CVC-related VTE – We suggest not performing thrombophilia testing in this group of patients. The presence of CVC is the strongest risk factor, and treatment decisions do not depend upon test results. A systematic review and meta-analysis of 16 observational studies found that while the overall prevalence of IT was low and while IT was associated with increased likelihood of CVC-associated VTE, the association was largely accounted for by a relatively high prevalence of elevated factor VIII, which may represent an inherited disorder or may be acquired (since factor VIII is an acute phase reactant and is often transiently elevated after an acute thrombosis) [5]. The prevalence of most other IT traits in the meta-analysis was low and the association with CVC-related VTE was relatively weak. Based on the available evidence, we suggest not routinely performing IT testing to inform management decisions in children with CVC-related VTE. A possible exception is a child with a strong family history of VTE (VTE in first-degree relative <40 years of age) who develops CVC-related VTE, in whom IT testing may be considered. (See 'Asymptomatic children with a positive family history' below.)

Non-CVC-related VTE – We suggest performing thrombophilia testing in this group of patients, which includes all patients whose VTE is not felt to be related to a CVC, regardless of other risk factors. The prevalence of thrombophilia is higher in this group compared with those with CVC-related VTE, and identification of strong or combined thrombophilias may impact counseling or treatment duration [4].

Recurrent VTE – We suggest performing thrombophilia testing in this group of patients, including those with recurrent CVC-related VTE. Underlying thrombophilia is more likely in the setting of recurrent VTE compared with a first episode [4,14,18].

Tests to perform — The evaluation for thrombophilia in children with VTE includes testing for the five ITs that are most strongly associated with VTE and testing for antiphospholipid syndrome, as summarized in the table and discussed below (table 2). (See 'Tests to perform' below.)

Timing of testing — Thrombophilia testing is best performed after recovery from the acute VTE to avoid an incorrect diagnosis. However, as previously discusses, in patients suspected to have APS, testing for antiphospholipid antibodies may be considered prior to initiating a DOAC, because if positive, an alternative anticoagulant is warranted [17].

In the acute setting, results of thrombophilia testing are challenging to interpret because they can be influenced by the thrombosis itself and by the effects of anticoagulants and other comorbid conditions (eg, infection, cancer) (table 3). Therefore, any non-DNA-based test that is abnormal during the acute setting should be repeated later, ideally off anticoagulation. The diagnostic accuracy of molecular mutation testing is not affected by these factors, so these tests can be sent even during an acute episode. (See 'Confirmation of abnormal results' below.)

In a study of 52 children with thromboembolic events who underwent thrombophilia testing during the acute phase, 50 percent had a positive result initially; however, only 12 percent were eventually confirmed to have thrombophilia on follow-up testing [19].

Children with stroke — Testing for IT in children with ischemic stroke depends on the clinical circumstances as follows:

Perinatal/neonatal stroke – The role of thrombophilia in perinatal stroke appears to be minimal, and testing is generally not indicated in this population [20]. This is discussed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Coagulation testing'.)

Ischemic stroke in infants and children – We suggest IT testing for most children who have had an arterial ischemic stroke outside of the neonatal period (except for children with sickle cell disease [SCD], as discussed below). In a meta-analysis of observational studies in infants and children, the prevalence of thrombophilic defects was higher in patients with arterial ischemic stroke compared with controls [21]. However, as with VTE, how to best tailor management based upon IT results has not been determined. The evaluation for thrombophilia in the setting of pediatric acute ischemic stroke and considerations for reducing the risk of a recurrence (secondary prevention) are discussed in detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation' and "Ischemic stroke in children: Management and prognosis".)

Stroke in children with sickle cell disease – Stroke is a common complication of SCD that can affect children and adults. Approximately one-quarter of patients with SCD will have a stroke by age 45. Thrombophilia testing is not warranted in this setting because the mechanism is typically due to vascular occlusion caused by intimal proliferation rather than thromboembolic disease. This is discussed separately. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

Asymptomatic children with a positive family history

Advantages and disadvantages of testing — Testing children who have a family member with a known IT or VTE has become increasingly common. The decision regarding whether to test is likely to vary depending upon the clinical situation. The potential advantages and disadvantages of such testing are described below. In general, this discussion is relevant for children with a strong family history, such as a VTE in a first-degree relative younger than 40 years of age. Decision-making in adult patients is discussed separately. (See "Screening for inherited thrombophilia in asymptomatic adults".)

Advantages – There are some situations in which the presence of an inherited defect may influence medical decision-making. Note that these potential benefits are mostly relevant for older children and adolescents. Learning that the child has an IT may provide an opportunity to:

Provide informed contraceptive counseling for adolescent females considering oral contraceptive pills (OCPs) – Knowing whether a young woman has an IT can help inform contraceptive counseling. The baseline annual incidence of VTE is approximately 0.2 per 1000 for all women of reproductive age and increases to 0.8 to 1.6 per 1000 for those on OCPs, depending on the specific OCP used [22]. For women who are heterozygous for the factor V Leiden mutation and are taking an OCP, this risk is increased to approximately 2.4 to 8 per 1000 [22]. For women who are heterozygous for the prothrombin G20210A mutation and taking an OCP, the risk is approximately 2.5 per 1000 women [22]. Contraceptive counseling for women with IT is discussed in detail separately. (See "Contraception: Counseling for women with inherited thrombophilias".)

Provide targeted thromboprophylaxis in high-risk situations (eg, after a femur fracture in an obese teenager who also has an IT).

Educate about signs and symptoms of VTE, which could lead to earlier diagnosis.

Promote lifestyle modifications to avoid other prothrombotic risk factors (eg, sedentary lifestyle, overweight/obesity, and smoking).

Disadvantages – Disadvantages to IT testing during childhood include:

Low risk of thrombosis during childhood – The incidence of venous thrombosis in healthy children is extremely low (0.07/100,000 per year) [3].The risk of thrombosis in children with IT who are otherwise healthy also appears to be very low [23]. Thus, when an IT is discovered in an otherwise healthy child, there is little opportunity for the information to impact the child's health. In particular, long-term anticoagulation in asymptomatic children is generally unwarranted (see 'Clinical implications of a positive result' below). A prospective cohort study assessed the incidence of VTE (both spontaneous and risk-related) in 143 asymptomatic children aged 1 to 14 years who were family members of 63 probands with objectively diagnosed VTE and documented IT [23]. An IT disorder was identified in 57 percent of the children ("carriers"), whereas the remaining 43 percent tested negative for IT ("noncarriers"). During the study's follow-up, the "carriers" experienced 31 risk periods (eg, trauma, surgery, or prolonged immobilization) and the "noncarriers" experienced 20 risk periods. Neither spontaneous nor risk-related VTE occurred in either group during 395 and 296 observation years, respectively. However, circumstances where pediatric VTE most commonly occurs (eg, CVC, cancer, cardiovascular surgery) were not encountered in any subjects during the study period.

Ethical concerns – There are ethical issues of genetic testing in children who may lack the maturity and understanding to make an informed decision, especially without a clearly demonstrated benefit to IT testing during childhood. Guidelines of several organizations, including the World Health Organization, the American College of Medical Genetics, and the American Academy of Pediatrics, suggest that genetic testing in children and adolescents should be pursued only when there is a likely medical benefit, related to therapy or prevention [24,25].

Interpretation of screening tests can be challenging and may result in misdiagnosis, as discussed below. (See 'Confirmation of abnormal results' below.)

For family members who have not had IT testing, negative results for IT testing in the child may provide a false sense of security.

Our approach — For healthy children who have a family history of thrombosis or IT, the decision to perform IT testing should be made on an individual basis only after counseling the family regarding the potential benefits and drawbacks [26]. During the counseling, the clinician should explain how the results of IT testing might affect the medical management of the child. Our general approach is as follows (algorithm 1):

Whom to test – For individuals who have a strong family history of VTE or IT (eg, VTE in a first-degree relative <40 years old), we suggest IT testing if there are additional risk factors or underlying medical problems that place them at risk for thrombosis (cancer, CVC, trauma, or major surgery). In this setting, knowing that the child has an IT is helpful because it may alter therapy (eg, avoidance of CVC, targeted thromboprophylaxis). In addition, it is reasonable to perform thrombophilia testing in adolescent girls with a strong family history of IT or VTE, particularly if they are on or considering an estrogen-containing contraceptive.

Tests to perform – We suggest testing only for the well-established genetic thrombophilias, which are summarized in the table and are discussed further below (table 2) (see 'Tests to perform' below). Abnormal results of tests that are not DNA-based should be confirmed with repeat testing. (See 'Confirmation of abnormal results' below.)

Clinical implications of a positive result — For patients who test positive for an IT, clinical decisions about anticoagulation depend on the strength of the thrombophilia and the strength of the family history. In general, patients with laboratory-only evidence of high-risk IT are not given long-term prophylactic anticoagulation. However, they require special management for the following special situations, which are discussed in greater detail separately:

Selection of contraceptive method (see "Contraception: Counseling for women with inherited thrombophilias")

Pregnancy (see "Inherited thrombophilias in pregnancy")

Surgery, trauma, and other high-risk situations (see "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis')

Confirmation of abnormal results — The age of the child and the presence of other acquired conditions (table 3) can influence results of tests that are not DNA-based (including proteins C and S, and antithrombin levels). Thus, any abnormal non-DNA-based test result should be confirmed with repeat testing. When repeat testing is not possible, the hereditary nature of IT may be confirmed by testing the parents. DNA-based tests for factor V Leiden mutation and prothrombin G20210A mutation are not affected by age or acquired conditions, and they need not be repeated.

Results of non-DNA-based tests can be influenced by:

Age (ie, developmental hemostasis) – This is especially important for infants <6 months old. While the basic pathways for coagulation, anticoagulation, and fibrinolysis are maintained, the concentrations of many of the factors vary widely during fetal and postnatal development [27]. Protein C levels in particular typically remain "low" throughout early childhood and do not reach adult levels until adolescence. This is important when evaluating children due to a family history of protein C deficiency in whom repeat testing during adolescence is necessary to confirm low values [28].

When interpreting levels of protein C, protein S, and antithrombin, particularly in infants in whom physiologic values are changing rapidly over time, there are rarely "absolute cutoffs" that are useful. Often the normal range overlaps with values found in adults with heterozygous defects, and retesting is required as the child matures [29]. Pediatric reference ranges are often not available for tests that are performed in most laboratories. While published, age-related normal values exist, it is important to be aware that direct comparison of test results from different laboratories is often not appropriate because of the use of different reagents and measuring instruments.

Other conditions – There are numerous nongenetic factors that may influence the results of thrombophilia testing, including acute thrombosis, infection, inflammation, and nephrotic syndrome. Additional factors are summarized in the table (table 3).

TESTS TO PERFORM — When thrombophilia testing is undertaken in children, the testing performed varies slightly depending upon whether the child has had a venous thromboembolism (VTE) (algorithm 1).

Testing in asymptomatic children – In an asymptomatic child (ie, without current or prior VTE) who is undergoing evaluation because of a strong family history of VTE, we suggest performing only the following tests (table 2):

Factor V Leiden mutation testing (or functional assay for activated protein C resistance) (see "Factor V Leiden and activated protein C resistance", section on 'Diagnostic tests')

Prothrombin G20210A mutation testing (see "Prothrombin G20210A", section on 'Genetic testing')

Antithrombin activity (see "Antithrombin deficiency", section on 'Choice of assay')

Protein C activity (see "Protein C deficiency", section on 'Assays')

Protein S testing, which can be with a total or free protein S level (free is preferred) (see "Protein S deficiency", section on 'Choice and interpretation of protein S assay')

We limit inherited thrombophilia (IT) testing to these tests since the pathogenic link to VTE is most clearly established for these five defects. Numerous other inherited defects have been described; however, none have gained widespread acceptance. In particular, testing for polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene is not helpful because they are very common and they are not, by themselves, associated with VTE [2,30]. (See "Overview of homocysteine" and "Overview of the causes of venous thrombosis", section on 'Other alleged inherited thrombophilias'.)

Testing in children with prior VTE – In a child with a history of VTE, we test for antiphospholipid antibody syndrome (APS) in addition to the five IT tests listed above. The approach to APS testing is described separately. (See "Diagnosis of antiphospholipid syndrome".)

Tests that we suggest NOT performing – Additional laboratory-based risk factors for VTE that may be included on a "thrombophilia panel" include homocysteine, factor VIII, and lipoprotein(a) levels. We suggest not routinely performing these tests when evaluating for thrombophilia in children because guidance is lacking on how abnormal results should influence patient management.

We suggest not testing for hyperhomocysteinemia (including homocysteine levels and/or testing for MTHFR polymorphisms) because, though there may be an association with VTE, a causal role has not been established and lowering homocysteine levels does not appear to reduce the rate of VTE. Hyperhomocysteinemia can occur from different mechanisms, including vitamin deficiency (eg, vitamin B6, B12, folate), genetic factors (MTHFR variants), or medication side effect (see "Overview of homocysteine"). Hyperhomocysteinemia occurring through these mechanisms is distinct from that of homocystinuria (MIM # 236200), which is a rare autosomal recessive disorder characterized by markedly elevated homocysteine levels and increased risk of thrombosis. Homocystinuria is generally detected on the newborn screen. (See "Overview of newborn screening".)

We suggest not routinely including factor VIII levels in the evaluation for thrombophilia. Though elevated factor VIII levels appear to be a marker of increased thrombotic risk, this testing is generally not useful since the assays are not standardized for this purpose, and the factor VIII level above which there is an increased risk of VTE may differ substantially between populations. Mildly elevated factor VIII levels are unlikely to indicate increased thrombotic risk. In reports of families with IT due to elevated factor VIII, levels were typically >300 IU/dL [31]. (See "Overview of the causes of venous thrombosis", section on 'Factor VIII' and "Screening for inherited thrombophilia in asymptomatic adults".)

We suggest not including plasminogen activator inhibitor-1 (PAI-1) levels or testing for PAI-1 polymorphisms in the evaluation for thrombophilia. PAI-1 is a central component of the fibrinolytic system. A polymorphism (4G/5G) in the promoter region of the PAI-1 gene has been reported to be associated with increased levels of PAI-1 in the plasma; however, whether this correlates with increased thrombotic risk remains uncertain [32]. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1'.)

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: Thrombotic diseases in infants and children".)

SUMMARY AND RECOMMENDATIONS

Inherited thrombophilia (IT) – IT refers to genetic risk factors that predispose individuals to developing venous thromboembolism (VTE). The ITs for which the pathogenic link is most clearly established include (table 2):

Factor V Leiden mutation (see "Factor V Leiden and activated protein C resistance")

Prothrombin G20210A mutation (see "Prothrombin G20210A")

Antithrombin deficiency (see "Antithrombin deficiency")

Protein C deficiency (see "Protein C deficiency")

Protein S deficiency (see "Protein S deficiency")

ITs contribute to the risk of VTE in children; however, the prevalence of IT varies considerably in different populations. An underlying IT is far more likely in patients with unprovoked VTE compared with provoked (eg, catheter-related). (See 'Introduction' above.)

Other VTE risk factors – The most common risk factor for VTE is the presence of an indwelling central venous catheter (CVC). Other risk factors include prematurity, cardiac disease, inflammation, infection, nephrotic syndrome, cancer, surgery, trauma, use of oral contraceptives, immobilization, and structural venous abnormalities (table 1). Risk factors for VTE in childhood are discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk factors'.)

Who should be tested for thrombophilia – The utility of thrombophilia testing depends on the clinical circumstances as follows (algorithm 1) (see 'Who should be tested' above):

Venous thromboembolism (see 'Who should be tested' above):

-CVC-related VTE – In patients presenting with a first episode of VTE that is CVC-related, we suggest not performing thrombophilia testing. This is because the prevalence of thrombophilia is relatively low in this group, and identification of a thrombophilic defect does not influence the acute management or duration of anticoagulation therapy in such patients.

-Non-CVC-related VTE – In patients presenting with a first episode of VTE that is not CVC-related, we suggest performing thrombophilia testing. This is because the prevalence of thrombophilia is higher in this group as compared with those with CVC-related VTE, and identification of high-risk or combined thrombophilias may impact counseling or treatment duration.

-Recurrent VTE – In patients with recurrent VTE (including recurrent CVC-related VTE), we suggest performing thrombophilia testing.

Arterial ischemic stroke (see 'Children with stroke' above):

-Perinatal/neonatal stroke – The role of thrombophilia in perinatal stroke appears to be minimal and testing is generally not indicated. This is discussed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Coagulation testing'.)

-Ischemic stroke in infants and children – We suggest thrombophilia testing for most children who have had an arterial ischemic stroke outside of the neonatal period (except for children with sickle cell disease). The evaluation for thrombophilia in the setting of pediatric acute ischemic stroke is discussed in detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Hypercoagulable evaluation'.)

Asymptomatic children with a family history of IT – For individuals who have a strong family history of VTE or IT (eg, VTE in a first-degree relative <40 years old), we suggest IT testing if there are additional risk factors or underlying medical problems that place them at risk for thrombosis (cancer, CVC, trauma, major surgery). In this setting, knowing that the child has an IT is helpful because it may alter therapy (eg, avoidance of CVC, targeted thromboprophylaxis). In addition, it is reasonable to perform thrombophilia testing in adolescent girls with a strong family history of IT or VTE, particularly if they are on or considering an estrogen-containing contraceptive. (See 'Asymptomatic children with a positive family history' above.)

Tests to perform – When thrombophilia testing is undertaken, we suggest the following tests to evaluate for IT (table 2) (see 'Tests to perform' above):

Factor V Leiden mutation testing (see "Factor V Leiden and activated protein C resistance", section on 'Diagnostic tests')

Prothrombin G20210A mutation testing (see "Prothrombin G20210A", section on 'Genetic testing')

Antithrombin activity (see "Antithrombin deficiency", section on 'Choice of assay')

Protein C activity (see "Protein C deficiency", section on 'Assays')

Protein S testing, which can be with a total or free protein S level (free is preferred) (see "Protein S deficiency", section on 'Choice and interpretation of protein S assay')

In addition, for patients who have had a VTE event or ischemic stroke, the evaluation includes antiphospholipid antibody testing. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)

Confirmation of abnormal results – The age of the child and the presence of other acquired conditions (table 3) can influence results of tests that are not DNA-based (including proteins C and S, and antithrombin). Thus, any abnormal non-DNA-based test result should be confirmed with repeat testing. (See 'Confirmation of abnormal results' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lisa A Michaels, MD, who contributed to an earlier version of this topic review.

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Topic 5920 Version 35.0

References

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