Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2024056
Category:	Laboratory
Initiated:	October 2024
Last Review:	October 2024

RTM_Venous and Arterial Thrombosis Risk Testing

Description:

A thrombosis, also known as a blood clot, occurs within blood vessels in the body. The two main types of thrombosis include venous thrombosis, which is when a vein is blocked due to a blood clot, and arterial thrombosis, which is when an artery is blocked due to a blood clot. Thrombophilias refer to hereditary and/or acquired abnormalities of hemostasis that predispose patients to thrombosis (Stevens et al., 2016). The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) and pulmonary embolism (PE) (Bartholomew, 2017).

Terms such as male and female are used when necessary to refer to sex assigned at birth.

Regulatory Status

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

This policy applies to health plans that utilize a routine laboratory management vendor, which include Arkansas Blue Cross and Blue Shield, Federal Employee Health Benefit Plan and Postal Service Health Benefit Plan, Health Advantage, and Octave Blue Cross and Blue Shield fully insured plans, including the Metallic and ARHOME plans and Complete/Complete Plus plans. Additionally, this policy will apply to the Farm Bureau and Level Funded plans.

Effective February 1, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency in individuals without recurrent venous thromboembolism (VTE) risk factors (e.g., surgery, prolonged immobilization, collagen vascular disease, malignancy, certain hematologic disorders) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any of the following situations:

Individuals less than 50 years of age who have experienced any deep venous thrombosis (DVT) or pulmonary embolism (PE);
Individuals who have experienced a DVT in unusual sites (e.g., hepatic mesenteric, or cerebral veins);
Individuals who have experienced a DVT and who have a strong family history of thrombotic disease;
Individuals who are pregnant or taking oral contraceptives and have experienced a DVT or recurrent pregnancy loss;
For first-degree (Includes parents, full siblings, and children of the individual), and second-degree relatives (Includes grandparents, aunts, uncles, nieces, nephews, grandchildren, and half siblings) of individuals who experienced a DVT before 50 years of age;
Women under the age of 50 who smoke and have suffered a myocardial infarction.
Before the administration of oral contraceptives, targeted testing of individuals with a personal or family history of DVT;
Pediatric individuals who have suffered from an arterial ischemic stroke.

Plasma testing for protein C deficiency and protein S deficiency (See Note 1) for individuals with warfarin-induced skin necrosis or infants who develop neonatal purpura fulminans meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Note 1: Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency should be performed at least six weeks after the acute thrombotic event and while the patient is not taking anticoagulants. Assays for clotting inhibitors amount and function should be performed prior to any molecular testing.

Note 2: In addition to plasma testing (protein C deficiency, protein S deficiency, antithrombin III deficiency), risk factor testing for individuals suspected of having a hereditary and/or acquired thrombophilia may benefit from genetic testing for Factor V Leiden and Prothrombin gene G20210A mutations.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency in individuals without recurrent venous thromboembolism (VTE) risk factors for any indication or circumstance not described above, including but not limited to the following, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes

For members with contracts without primary coverage criteria, plasma testing for protein C deficiency, protein S deficiency, and antithrombin III deficiency in individuals without recurrent venous thromboembolism (VTE) risk factors for any indication or circumstance not described above, including but not limited to the following, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities), does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, venous thrombosis risk testing for superficial venous thrombosis (including superficial thrombophlebitis and varicosities), is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Activated protein C (aPC) resistance assay for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, activated protein C (aPC) resistance assay for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

DVT risk testing as part of a pre-transplant evaluation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, DVT risk testing as part of a pre-transplant evaluation, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com

A thrombus is “an aggregate of coagulated blood within the vascular system or heart which contains platelets, fibrin, leukocytes, and red blood cells in varying amounts” (Herrmann, 2018). This aggregate of blood can be problematic as it may obstruct normal blood circulation throughout the body and even travel to peripheral areas. The primary manifestations of venous thromboembolisms (VTE) are deep vein thrombosis and pulmonary embolism. These conditions affect an estimated one million individuals in the United States annually (Bartholomew, 2017).

Thrombosis is widely theorized to develop due to Virchow’s Triad, which consists of abnormalities in blood flow, a vascular endothelial injury, and alterations in the blood constituents. Changes in any of these characteristics may cause the clot to form (Bauer, 2024). For example, sickle red blood cells may cause increased clumping or decreased adhesion to the vessel walls (Byrnes, 2017). There are two main types of thrombosis: venous thrombosis (when a vein is blocked due to a blood clot) and arterial thrombosis (when an artery is blocked due to a blood clot).

A deep vein thrombosis (DVT) refers to a thrombus in a “deep” vein whereas a pulmonary embolism (PE) refers to an obstruction of the pulmonary artery (or one of its branches) by foreign material (Bauer, 2024a; Thompson, 2023). DVT of the lower extremities may cause symptoms, such as swelling or edema in the lower extremities, pain, and warmth in the affected area (Bauer, 2024a). This thrombus may travel to the lungs (becoming an embolus) and cause a PE. A PE has similar symptoms to DVT but may include pulmonary issues, such as shortness of breath. The risk factors for VTE, PE, and DVT are similar (Thompson, 2023). The two primary categories of risk factors for VTE are hereditary and acquired, and the genetic tendency toward VTE is referred to as inherited thrombophilia. Hereditary risk factors include genetic mutations such as Factor V Leiden (FVL) mutations. The five most common genetic risk factors for VTE are FVL mutations, prothrombin mutations, protein S defect, protein C defect, and antithrombin defect (Bauer, 2024). Approximately 50–60% of the variance in VTE incidence are attributed to genetic effects (Crous-Bou, 2016).

A modified activated partial thromboplastin time (aPTT) assay detects the anticoagulant activity of activated protein C (aPC). FVL mutations cause coagulation factor V to be unresponsive to aPC and initially, these changes were termed “aPC resistance” due to the reduced activity of aPC on a modified aPTT assay. A single nucleotide change (G1691A) results in a point mutation of glutamine to arginine at position 506. Approximately 99% of carriers of this mutation are heterozygous, and only 5% of these heterozygotes will experience a VTE in their lifetime. These mutations are often suspected in patients experiencing a VTE at a young age (under 50), a VTE in unusual areas such as a portal vein, or recurrent VTEs (Bauer, 2023a). Protein C may also be genetically deficient, but this mutation is only seen in 2-5% of individuals with a VTE (Bauer, 2022). Protein S, a cofactor for the aPC control mechanism, and deficiencies in this protein may also confer additional risk for VTE (Bauer, 2024b).

The second most common inherited thrombophilia is the G20210A mutation of prothrombin. This mutation is a gain of function mutation where clotting activity is increased by creating more thrombin and fibrin. The overall prevalence of this mutation is about 2% (Bauer, 2023c). Genetic defects of antithrombin (an inhibitor of thrombin) may also occur, but the estimated prevalence of antithrombin defects is only a maximum of 0.2% (Bauer, 2023b).

Acquired risk factors or predisposing conditions for thrombosis include a prior thrombotic event, recent major surgery, presence of a central venous catheter, trauma, immobilization, malignancy, pregnancy, the use of oral contraceptives or heparin, myeloproliferative disorders, antiphospholipid syndrome (APS), and a number of other major medical illnesses (Bauer, 2024). Patients with acquired hypercoagulability have an increased risk of venous thrombosis, arterial thrombosis, or both; however, there is a low risk of recurrence, regardless of thrombophilia status (Connors, 2017). A rare complication of warfarin treatment, warfarin-induced skin necrosis is commonly due to protein C deficiency, with rare cases of protein S deficiency or PVL having been reported (Bauer, 2023).

Risk factors for arterial thrombosis are lesser known. The relationship between FVL and arterial thrombosis is controversial with studies reporting varying results; overall, FVL is not currently considered a major risk factor for arterial thrombosis (Carroll, 2018; Kujovich, 2011). Kujovich (2018) states that FVL testing should not be performed on persons with any type of arterial thrombosis including myocardial infarction and stroke in children or adults. It has also been reported that while inherited antithrombin, protein S and protein C deficiencies are important risk factors for venous thrombosis, “they have little or no effect on arterial thrombosis” (Previtali, 2011). Further, prothrombin gene mutation is not consistently shown to increase the risk of an arterial thromboembolism, and “There is no association of antithrombin deficiency with arterial thrombosis” (Carroll, 2018).

It has been proposed that venous thrombosis risk testing may be beneficial as a pre-transplant evaluation test. However, no studies have been identified suggesting this. The North American Thrombosis Forum (NAFT) states that even though certain genetic conditions predispose a small proportion of the population to the development of blood clots, “few people with thrombophilias develop symptoms”; further, there is no cost-effective, safe or long-term method to prevent a blood clot from forming even if a genetic predisposition is identified (NATF, 2019).

Thrombotic events such as thrombophilia and stroke have become increasingly documented in hospitalized pediatric patients with underlying medical conditions such as prematurity, cancer, and congenital heart disease, but they are rarely identified in healthy children. Furthermore, in most cases of pediatric venous thromboembolism, there exist other underlying risk factors such as indwelling central venous catheter and inherited thrombophilia that are worthy of further investigation. The incidence of venous thromboembolisms is highest in neonates and infants, but there is a second peak recorded in adolescence, coinciding with the use of oral contraceptives. However, as in the case with adults, little to no evidence suggests that the use of venous thrombosis risk testing in children will affect the acute management of venous thromboembolisms. In a study including a total of 271 children with VTE, it was found that the relative frequencies of individually inherited thrombophilias were low—for example, the highest recorded frequency of IT disorders was of Factor V Leiden, occurring in only 5 to 10 percent of the samples. Moreover, a study of 52 children with thromboembolic events during the acute phase did not urge any changes to acute management, regardless of the result of the test (Raffini, 2023).

Venous thrombosis risk testing has also been entertained as a manner of combatting pediatric stroke, which can be characterized in a variety of ways, such as by age and by presentation. Arterial ischemic infarctions are the most common, comprising approximately 80% of all perinatal strokes, and this form of stroke can occur in up to 1 in 3500 of newborns. However, though it would seem reasonable for venous thrombosis risk testing to be employed here, recent prospective case-control studies suggest that routine thrombophilia testing is not warranted. The study showed that conditions associated with thrombophilia rarely coincided with arterial ischemic strokes, and these conditions included, but were not limited to, decreased levels of protein C, protein S, or prothrombin, and genotyping of factor V Leiden (FVL) and factor II (FII, prothrombin) G20210A. Of the 14 parameters examined, 12 showed no difference, including all common thrombophilias examined, with specific mention that FVL and FII were comparable to population norms (Curtis, 2017; Ferriero, 2019). Subsequent evaluation deemed thrombophilia evaluation in neonates as having limited clinical utility because “levels of protein C, protein S, antithrombin, and factor XI are normally decreased to 30% of adults levels, and these levels only approach adult levels at various time points during childhood”. Therefore, the use of thrombophilia testing for these proteins may be misleading in the neonatal period, and MRIs instead should be used to diagnose the thrombosis (Ferriero et al., 2019). Moreover, studies focusing on the roles of thrombophilia, arteriopathy, and cardiac abnormalities in perinatal ischemic stroke find that these risk factors were at best unclear, weakening what predictive power they were believed to contain for even recurrent events after perinatal stroke and leading researchers to conclude that thrombophilia evaluation should rarely be considered in cases of perinatal stroke (Lehman, 2017).

While the initial aPTT assays used unaltered plasma (first-generation assays), some versions were neither sensitive nor specific for FVL. Modifications to this test resulted in second generation functional aPC resistance assays that correlate well with the presence of FVL. However, in rare cases, functional assays for aPC resistance can give misleading results (e.g., the presence of a lupis anticoagulant can cause falsely abnormal results in some assays; therapy with a direct thrombin inhibitor or oral factor Za inhibitor can cause falsely normal results). In addition, while FVL can be detected by genetic testing or a second-generation functional coagulation test for aPC resistance, individuals with a positive aPC resistance assay would still need to receive genetic testing to confirm a diagnosis (Bauer, 2023a). Due to difficulty with interpretation, a need for confirmatory genetic testing, and the overall declining cost of genetic testing, aPC resistance assays are performed infrequently. When performed, they are simply reported as positive, borderline, or negative (Middledrop, 2023).

The term FVL paradox describes the different risk of DVT and PE in FVL carriers; there is data to suggest that FLV carriers are less likely to experience isolated PE (without DVT) than the general population (Bauer, 2023a). de Moerloose and others studied the prevalence of FVL in people suspected of DVT and/or PE. The 99 participants with PE were categorized based on “those with PE but without DVT (n = 57) and those with PE and DVT (n = 42).” The odds ratio for the prevalence of FVL was higher (19.1%) in patients with DVT and PE than the odds ratio for the prevalence of FVL in patients with only PE (10.5%), suggesting that “patients with primary PE are less often affected by the factor V Leiden mutation” (de Moerloose et al., 2000). In another study, the relative risk of DVT in FVL carriers compared to non-carriers was 7.0, while the relative risk of PE in FVL carriers compared to non-carriers was 2.8 (Mäkelburg, 2010).

Analytical Validity

A study by Murphy and Sabath compared the accuracy and reliability of two tests: a genotypic assay which identifies FVL mutations, and a phenotypic aPC resistance assay. Data from 1596 patients was analyzed; each patient had received both types of testing. The authors state that the phenotypic testing exhibited both high sensitivity and specificity compared to genotypic testing. “Phenotypic assays had close to total concordance with genotypic assays over 16 years of testing. Changing ordering practices could result in up to an 80% reduction in testing costs” (Murphy, 2019).

A systematic review and meta-analysis by Chiasakul and colleagues researched the relationship between inherited thrombophilia and the risk of arterial ischemic stroke in adults. Inherited thrombophilias included FVL, protein C and S deficiency, antithrombin deficiency and prothrombin G20210A mutation. For this study, 11,916 stroke patients and 96,057 controls were identified. The authors concluded that “Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08-1.44; I2=0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22-1.80; I2=0%), protein C deficiency (OR, 2.13; 95% CI, 1.16-3.90; I2=0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34-3.80; I2=8.8%)” (Chiasakul, 2019). Antithrombin deficiency did not reach statistical significance in this study. Hence, in this review, inherited thrombophilias were found to be associated with an increased risk of arterial ischemic stroke in adults.

In a systematic review, Ortega studied the predictive value of D-dimer testing for venous thrombosis diagnosis in unusual locations. 3378 patients from 23 articles with thrombosis in unusual sites, such as upper extremity deep vein thrombosis (DVT), cerebral vein thrombosis (CVT) and splanchnic vein thrombosis (SVT), were studied. 12 articles on CVT concluded that timing of D-dimer testing is important and patients with short duration of symptoms displayed higher D-dimer levels. Sensitivity and specificity in these patients ranged from 58% to 97% and from 77% to 97.5%, respectively. The authors conclude that "D-dimer testing should not be currently recommended for the diagnosis of thrombosis in unusual sites as a first line diagnostic tool. The development of algorithms combining biomarkers such as D-dimer and clinical decision tools could improve the diagnosis" (Ordieres-Ortega, 2020).

Clinical Utility and Validity

A D-dimer assay is a blood test that is used in clinical practice to assist in identifying if a patient has a DVT or PE; this test may also help patients experiencing unprovoked VTE to determine if anticoagulation treatment should continue or halt after initial treatment is complete (Linkins, 2017). A D-dimer assay may vary greatly based on the type of antibody used, the method of capture, calibration, and instrumentation. Currently, 30 different assays as available which use 20 different monoclonal antibodies; various studies have reported a broad sensitivity and specificity range for D-dimer assays from 69-97% and 43-99% respectively (Linkins, 2017). Hence, all D-dimer assays differ and need to be validated within the population of interest. Because of this, comparing study results is challenging.

Factor VIII is a blood clotting protein encoded by the F8 gene. A case report by Algahtani and Stuckey (2019) suggests that high factor VIII levels may also assist in risk factor determination for thrombosis or ischemic heart disease. “We conclude that high factor VIII levels are a risk factor for thrombosis, with a greater impact on venous than on arterial thrombosis. However, due to a lack of international consensus on methods for the laboratory testing of factor VIII levels in plasma, we would not currently recommend the measurement of factor VIII levels as part of routine thrombophilia screening" (Algahtani, 2019). This relationship has been shown previously as elevated levels of coagulation factor VIII:C were identified in a retrospective study of 584 first-degree relatives of 177 patients with high coagulation factor VIII:C levels; the researchers found that 40% of first degree relatives also had high VIII:C levels and were at an increased risk for VTE and arterial thrombosis when compared to other first-degree relatives with normal VIII:C levels (Bank, 2005).

Lee and colleagues performed whole exome sequencing on 64 patients with VTE to assess the types of mutations of inherited thrombophilias. Of these 64 patients, 39 of them were found to have a pathogenic variant or variant of unknown significance (VUS). Further, eight were found to have a Factor V mutation (six with FVL and two with less common mutations), two were found to have a prothrombin G20210A mutation, six were found to have a protein S mutation, two were found to have a protein C mutation, and three were found to have an antithrombin mutation (Lee, 2017).

Segal and others reviewed the utility of FVL and prothrombin G20210A testing. The authors reviewed 124 articles and concluded that although genetic testing for these two risk factors is very accurate (valid), the clinical utility is lacking due to lack of evidence demonstrating improvement in clinical outcomes (Segal et al., 2009).

Onda studied the clinical utility of a new diagnostic algorithm based on serum D-dimer levels for VTE after hepatectomy. A total of 742 patients who underwent hepatectomy were enrolled in the study and measured for serum D-dimer levels post-op. CT scan was performed for patients who had a D-dimer level of greater than 20 μg/mL. Based on D-dimer and CT scan, VTE was diagnosed in 26 patients and pulmonary embolism (PE) was diagnosed in 18 patients. Multivariate analysis also showed that a resected liver weight of more than 120 grams is a significant predictor of VTE. Overall, “patients who undergo hepatectomy are at high risk for VTE, especially when the resected liver weight is high. The proposed diagnostic algorithm based on serum D-dimer levels for VTE after hepatectomy can be useful for early diagnosis" (Onda, 2021).

CPT/HCPCS:

References:

ACOG(2013) ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol, 122(3), 706-717. https://doi.org/10.1097/01.AOG.0000433981.36184.4e

ACOG(2018) ACOG Practice Bulletin No. 197 Summary: Inherited Thrombophilias in Pregnancy. Obstet Gynecol, 132(1), 249-251. https://doi.org/10.1097/aog.0000000000002705

Algahtani FH, Stuckey R.(2019) High factor VIII levels and arterial thrombosis: illustrative case and literature review. Ther Adv Hematol, 10, 2040620719886685. https://doi.org/10.1177/2040620719886685

ASCLS(2021) American Society for Clinical Laboratory Science. https://www.choosingwisely.org/clinician-lists/ascls7-do-not-order-a-homocysteine-assay-as-part-of-the-thrombophilia-work-up/

ASCP(2017) American Society for Clinical Pathology. http://www.choosingwisely.org/clinician-lists/ascp-testing-for-protein-c-protein-s-or-antithrombin-during-active-clotting-event/.

ASCP(2019) American Society of Clinical Pathology. American Society of Clinical Pathology. https://www.choosingwisely.org/clinician-lists/ascp-hypercoagulable-workup/.

ASH(2013) Testing for thromboembolism - Choosing Wisely. http://www.choosingwisely.org/clinician-lists/american-society-hematology-testing-for-thrombophilia-in-adults/

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Barnes G.(2017) Thrombophilia Testing for Provoked VTE. American College of Cardiology. Retrieved 02/13/2019 https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2017/06/05/12/46/thrombophilia-testing-in-provoked-venous-thromboembolism.

Barnes GD.(2017) Thrombophilia Testing and Venous Thrombosis. American College of Cardiology. https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2017/10/20/11/18/thrombophilia-testing-and-venous-thrombosis.

Bartholomew JR.(2017) Update on the management of venous thromboembolism. Cleve Clin J Med, 84(12 Suppl 3), 39-46. https://doi.org/10.3949/ccjm.84.s3.04.

Bashford MT, Hickey SE, Curry CJ, et al.(2020) Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine, 22(12), 2125-2125. https://doi.org/10.1038/s41436-020-0843-0.

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Bauer K, Lip G.(2024) Overview of the causes of venous thrombosis. https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis.

Bauer K.(2023) Factor V Leiden and activated protein C resistance. https://www.uptodate.com/contents/factor-v-leiden-and-activated-protein-c-resistance.

Bauer K.(2023) Protein C deficiency. https://www.uptodate.com/contents/protein-c-deficiency.

Bauer K.(2023) Prothrombin G20210A mutation. https://www.uptodate.com/contents/prothrombin-g20210a-mutation.

Bauer K.(2024) Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity. https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-deep-vein-thrombosis-of-the-lower-extremity.

Bauer K.(2024) Protein S deficiency. https://www.uptodate.com/contents/protein-s-deficiency.

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Carroll BJ, Piazza G.(2018) Hypercoagulable states in arterial and venous thrombosis: When, how, and who to test? Vasc Med, 23(4), 388-399. https://doi.org/10.1177/1358863x18755927.

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EGAPP(2011) 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, 13(1), 67-76. https://doi.org/10.1097/GIM.0b013e3181fbe46f.

Ferriero DM, Fullerton HJ, Bernard TJ, et al.(2019) Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke, 50(3). https://doi.org/10.1161/str.0000000000000183.

Gupta A, Sarode R, Nagalla, S.(2017) Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Internal Medicine, 177(8), 1195-1196. https://doi.org/10.1001/jamainternmed.2017.1815.

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Kujovich JL.(2018) Factor V Leiden Thrombophilia. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews((R)). University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK1368/.

Lee EJ, Dykas DJ, Leavitt AD, et al.(2017) Whole-exome sequencing in evaluation of patients with venous thromboembolism. Blood Adv, 1(16), 1224-1237. https://doi.org/10.1182/bloodadvances.2017005249.

Lehman LL, Beaute J, Kapur K, et al.(2017) Workup for Perinatal Stroke Does Not Predict Recurrence. Stroke, 48(8), 2078-2083. https://doi.org/10.1161/STROKEAHA.117.017356.

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Lim W, LeGal G, Bates SM, et al.(2018) American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood Adv, 2(22), 3226. https://doi.org/10.1182/bloodadvances.2018024828.

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