Clinical Utility and Costs of Inpatient Hereditary Thrombophilia Testing following Acute VTE: A 5-Year Retrospective Study

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Methods We conducted a retrospective, observational study of inpatient hereditary thrombophilia testing ordered during a hospital admission for acute VTE between 2019 and 2024. We aimed to characterize patterns of testing results, and costs, and to evaluate whether younger patients and those with unprovoked VTE were more likely to test positive for hereditary thrombophilia. Results A total of 835 hereditary thrombophilia tests – including those for factor V Leiden, prothrombin G20210A , deficiencies of protein S, protein C, and antithrombin, hyperhomocysteinemia, and plasminogen activator inhibitor-1 excess – were ordered in 220 patients. Overall, 19.6% of results were abnormal, and 45.0% of patients had at least one abnormal result. There was no difference in the rate of positive results among patients with provoked vs unprovoked VTE (30.7% vs 34.5%, p = .554) nor patients < 50 vs ≥ 50 years of age (33.1% vs 32.4%, p = .912). Only 4/99 (4.0%) patients with an abnormal result had their clinical management clearly changed due to the result. The tests totaled $ 385,161 USD in institutional charges and $ 26,029 USD in Medicare fees. Conclusion Inpatient hereditary thrombophilia testing during admission for acute VTE is low yield, with frequent abnormal results, many of which likely represented false positives, and minimal impact on clinical management with high costs. Hereditary thrombophilia Venous thromboembolism High-value care Costs Figures Figure 1 Figure 2 Key Points Thrombophilia testing following acute venous thromboembolism was commonly performed at an academic medical center with high associated costs, and nearly 20% of tests were abnormal Many results were below the limits of normal for the assay, but higher than expected in congenital deficiency, likely indicating false positives Young patients and those with unprovoked venous thromboembolism were not more likely to have positive test results Clinical management rarely changed in response to a positive result, indicating low value of testing in the inpatient setting Prospective studies with long-term outpatient follow-up would help determine the optimal timing of thrombophilia testing Introduction Hereditary thrombophilias are genetic disorders that increase the risk of venous thromboembolism (VTE) [1–4]. Laboratory testing for hereditary thrombophilia is thus a common approach in clinical practice to determine predisposing factors to VTE. However, studies indicate that this screening provides limited utility for predicting the risk of recurrent thrombosis in patients experiencing a first episode of VTE [5–8]. In patients being treated with anticoagulation, the presence of a thrombophilia does not predict a greater recurrence risk [9]. Further, antigen and activity assays for these conditions are susceptible to false positive results immediately following an acute VTE episode, due to factors such as anticoagulation therapy, protein consumption, acute phase reactant changes, and abnormal liver function [10–12]. Given the above, retrospective studies have found that management decisions are rarely influenced by testing [12–14] and positive tests are typically not repeated for confirmation [15]. Finally, tests for hereditary thrombophilias are expensive, with current estimates for a panel of tests costing more than $ 300 USD [15–17]. Given the limitations and costs, most guidelines have recommended against the use of routine thrombophilia testing, especially when results are unlikely to change a patient’s management [18–21]. The American Society of Hematology (ASH) previously recommended against thrombophilia testing after a VTE provoked by a major transient risk factor [20], while more recent ASH guidelines do conditionally recommend testing in select patients with VTE in whom results may dictate length of anticoagulation, including those with hormone-associated VTE or minor transient provoking risk factors and those with unusual site thrombosis being considered for time-limited anticoagulation [22]. However, they do not provide guidance on when testing should be ordered, and the risk of inappropriately recommending indefinite anticoagulation is increased when tests are ordered in settings in which false positive results are more likely. We sought to understand the pattern and cost of hereditary thrombophilia testing following an acute VTE and how positive results were managed, as our results may help inform future guidelines around thrombophilia testing and whether testing should be delayed after acute VTE. Methods Study Population and Selection Criteria We retrospectively analyzed all inpatient hereditary thrombophilia tests ordered at Thomas Jefferson University Hospitals (TJUH) – including its three primary flagship hospitals in Philadelphia, PA – an academic tertiary care center, between January 1, 2019 and December 31, 2023. Inclusion criteria comprised patients who underwent inpatient hereditary thrombophilia testing during an admission for acute VTE. Patients who had concurrent VTE and arterial thrombosis/ischemia were also eligible. Types of VTE included deep vein thrombosis (DVT) of the limbs, pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), as well as other rarer sites of VTE such as the inferior vena cava and gonadal veins. Patients who had thrombophilia workups performed for any non-VTE indications, or whose testing was done while inpatient but for a remote VTE, were excluded from the study. Tests for the following conditions were included in the study: Factor V Leiden (FVL; including activated protein C resistance and genetic testing), prothrombin G20210A variant (PT G20210A ), protein S deficiency (free, total, and functional protein S), protein C deficiency (antigen and function), antithrombin deficiency, hyperhomocysteinemia (homocysteine and MTHFR mutation testing), and plasminogen activator inhibitor-1 (PAI-1) excess. The study was approved by the Thomas Jefferson University Institutional Review Board. Data Collection We generated a list of all instances of inpatient orders of hereditary thrombophilia tests during the study period, then manually reviewed all charts in our institution’s electronic health record (Epic Systems©) for eligibility, demographics, rationale for testing, provoking risk factors, lab results, and documented management. The International Society on Thrombosis and Haemostasis’ (ISTH) guidance on provoking risk factors[23] was utilized to determine whether a VTE was provoked by a transient risk factor. Additionally, we considered longer-term risk factors such as active cancer or anatomic anomalies (May-Thurner syndrome or venous thoracic outlet syndrome) and transient risk factors not included by the ISTH, such as COVID-19 infection within the preceding 30 days and other conditions associated with splanchnic vein thrombosis (SVT) [24]. We reviewed all available documentation, including after the index hospital admission, to determine if any change in patients’ management was made citing a positive thrombophilia test result (including a decision to prescribe an anticoagulant or alter the dose or duration). We also reviewed occurrences of repeat outpatient orders after initial abnormal results on antigen or functional assays. Last, we queried both TJUH’s chargemaster to determine charges associated with each test and the Centers for Medicare & Medicaid Services’ (CMS) Clinical Laboratory Fee Schedule to obtain payment rates. For interpreting certain lab results with an upper limit of normal higher than is typically seen in hereditary deficiencies – including antithrombin activity, protein C antigen and function, and total protein S – values that fell below normal but > 60% were considered borderline positive and those < 60% were considered positive . Positive genetic assays were characterized as heterozygous, homozygous, or compound heterozygous. Statistical Analysis We de-identified and analyzed data using IBM SPSS version 29. Descriptive statistics were summarized according to tests and individual patients. Continuous variables were analyzed using independent sample t tests, and categorical variables Pearson χ 2 and Fisher’s Exact Test. Results Patient Characteristics The study included 220 patients, among which 61.8% were female and the median age was 48 years (interquartile range 33-62). 195 (88.6%) patients had only VTE (whether single or multiple sites) and 25 (11.9%) had concurrent VTE and arterial thrombotic or ischemic events. Among patients with single-site VTE, the most common events were PE (27.3%), CVST (21.4%), DVT (15.0%), and SVT (8.2%). 31 (14.1%) patients had VTE at multiple sites, including 25 (11.4%) with concurrent DVT and PE. VTE was considered provoked in 101 (45.9%) patients; 11 (5.0%) patients had at least 2 provoking risk factors. Among patients with provoked VTE, the most common provoking factors were pregnancy/combined oral contraceptive (COC) pills (35.6%), antecedent hospitalization (15.8%), major surgery (13.9%), trauma or prolonged immobility (8.9%), and liver or gastrointestinal disease (7.9%) in the case of SVT. Details on the types of thrombosis and risk factors are shown in Table 1. Test results A total of 835 tests were ordered. The counts and percentages of each test in context of their lab outcomes are detailed in table 2. The most commonly ordered tests were for FVL (25.1%), PT G20210A (19.4%), and deficiencies of protein S (18.0%), protein C (14.5%), and antithrombin (12.8%). Regarding results, 19.6% of tests were abnormal, including 50.5% of antithrombin activities, 24.8% of protein C assays, 20.0% of protein S assays, and 6.7% of assays for FVL. Regarding the most common genetic tests, 9.1% of FVL and 6.2% of PT G20210A tests were positive (all heterozygous, with two patients double heterozygous for FVL and PT G20210A ). The four tests with a lower limit of normal higher than 60% were frequently borderline positive (i.e., > 60% but below the normal limit), including 33.6% of antithrombin activity, 14.3% of total Protein S, 13.9% of protein C function and 7.7% of protein C antigen assays. The total institutional charges for these tests were $385,161, while Medicare fees totaled $26,029.55, based on CMS fee schedules for the first quarter of 2025. Table 3 displays our institution’s chargemaster rates and the CMS fee schedule for all thrombophilia tests. Patient-level Results We found that in the patient cohort, 99/220 (45.0%) had at least one abnormal result. Of these, 72 (32.7%) patients had a positive result on an activity assay or any gene variant, while 27 (12.3%) had only borderline positive findings. 43 (19.5%) patients had multiple abnormal results. There was no significant difference in the rate of positive test results among patients whose thromboses were provoked vs unprovoked (69.3% vs 65.5%, p=.554). We also observed no association between age and likelihood of a positive result. 33.1% of patients age < 50 years had a positive result vs 32.4% of patients ≥ 50 years (p=.912), and the mean age of patients with positive results was similar (47.6 vs 48.3 years, p=.794). When evaluating test results based on the type of presentation, the rate of positive tests was similar among patients with VTE only vs combined VTE and arterial thrombosis (31.8% vs 40.0%, p=.410). Regarding management, at a median time to last documentation of 215 days, only 4 out of 99 (4.0%) patients with any abnormal result had a clearly defined, documented change in management that was implemented after the abnormal result became available – either adding an anticoagulant, changing it, or prolonging the duration. An additional 6 (6.1%) patients had results which may have influenced management, but for whom documentation was inconclusive in demonstrating a link between clinical management and abnormal results. The characteristics of the four patients with a clear change in management in response to an abnormal test are summarized in Table 3. They included patients with a provoked DVT with heterozygosity for both FVL and PT G20210A , an unprovoked CVST heterozygous for PT G20210A , a hormone-associated PE with low free protein S, and an unprovoked CVST heterozygous for both FVL and PT G20210A . In 3 of the 4 cases, the indication for testing fit the 2023 ASH recommendations. We observed no difference in the number of patients whose management clearly changed according to whether the VTE was provoked vs unprovoked (4.1% vs 4.0%). And including patients with an inconclusive management change, there was also no significant difference between those with provoked vs unprovoked VTE (8.2% vs 12.0%, p=.716). Among the 84 patients whose abnormal result(s) included only non-genetic assays, only 8 (9.5%) had the abnormal test(s) repeated. Finally, 6 (2.7%) patients died during the index hospitalization. Discussion In this 5-year retrospective study of inpatient hereditary thrombophilia testing after acute VTE, we found that abnormal results were very common and rarely changed clinical management. These findings highlight a disconnect between current practice and most evidence-based recommendations. Testing was frequently performed immediately following a VTE event, when results are more likely to be misleading, and was associated with significant costs. First, our study found a high rate of test utilization in groups for whom hereditary thrombophilia testing has not been recommended. British Society for Haematology guidelines advise against routine thrombophilia testing when results are unlikely to affect clinical management decisions [21]. These further note that the presence of hereditary thrombophilias rarely alters intensity, choice, or monitoring of anticoagulant therapy, and instead emphasize using clinical history and assays such as D-dimer in selected patients to guide management [21]. Similarly, ASH Choosing Wisely® recommendations include not ordering thrombophilia tests after VTE by a major risk factor [20]. However, multiple studies have reported high rates of thrombophilia testing after a provoked VTE [13–15, 25–28]. Our study similarly found testing following provoked VTE was very common, comprising 45.9% of our patients and 47.3% of total tests. Even excluding VTE provoked by pregnancy or estrogen – a group for whom recent ASH guidelines support testing [22] – 29.5% of patients had a provoked VTE. Furthermore, while some advocate for selective thrombophilia testing in young patients and those without a strong provoking risk factor [29], we found that the rate of positive tests was not significantly greater in patients with unprovoked as compared to provoked VTE, nor in patients younger than 50 years of age. The utility of thrombophilia testing is further limited by the potential for false positives when ordered in the acute setting. Testing following acute VTE is more likely to yield false positive results due to anticoagulation therapy that affects certain functional assays, protein consumption by acute thrombus or mechanical circulatory support systems, or acute phase reactant changes related to inflammation and/or the predisposing condition to VTE [10, 11, 25, 30]. We found 21.9% of antigen and functional assays with a lower limit of normal of 70% or higher yielded results below normal but above typical values in autosomal dominant deficiency, indicating a high likelihood of being a false positive. This has the potential to yield mismanagement of patients when results are misinterpreted or not repeated. Furthermore, we found that fewer than 10% of patients with an abnormal antigen or activity assay had repeat testing for confirmation after the hospitalization. Others have found that while abnormal tests may be repeated, it is often during the index admission, when false positive results are still likely [15]. Given the high rate of likely false abnormal results and low rate of test repetition for confirmation, our data suggests that guidelines such as those from ASH should directly address timing of testing in order to reduce confounding variables and the risk of clinical mismanagement of patients. The management of patients in our study reflects that clinicians likely viewed the test results with skepticism. Only 4% of patients with any abnormal result had a documented change in clinical management in response to an abnormal result. This is consistent with other studies which found that inpatient thrombophilia testing was not clinically useful or reliable and rarely changed management [13, 14, 26, 27]. Additionally, many of these studies included acquired thrombophilias such as antiphospholipid syndrome, which often requires a change in anticoagulant – specifically to warfarin – and thus may be a higher yield test to order, especially in patients for a whom a high clinical suspicion exists. One single-center study, for example, found that 87% of patients were tested inappropriately and in no cases was the duration of treatment impacted by the result. However, among the 7 patients who experienced any clinical change in management, all had antiphospholipid syndrome, which was not included in our study [14]. Together with our study, this reinforces the concept that these tests rarely provide valuable data that impacts treatment decisions. Finally, thrombophilia testing is expensive. When these tests are used inappropriately, they offer minimum clinical benefit but also contribute to significant spending, which may be costly to health care systems when ordered in the inpatient setting [13, 15, 25, 28]. Although cost-analysis of thrombophilia testing in acute VTE is sparce, estimates for the panel of tests included in our study range from approximately $ 187 to $ 974 USD per patient [14, 15, 25, 27, 31]. To provide a broad estimate of costs, we calculated charges using both our institution’s chargemaster and the most recent publicly available CMS fee schedule. In our study, the total institutional charges by chargemaster were greater than $ 385,000 USD and by CMS fee schedule greater than $ 26,000 USD over the 5-year study period. The corresponding per-patient charges were $ 1,750 and $ 118 USD, respectively. Our study has certain limitations. The retrospective, observational design from a single academic hospital system may limit the applicability of our findings to other institutions or patient populations. Additionally, the reliance on reviewing documentation to understand clinical outcomes and indications for therapy represents a weakness. Incomplete documentation, particularly from outside our EHR system, restricted our ability to fully understand and assess outcomes and potential changes in management. Many patients had no documented encounters after hospital discharge, which limited our ability to assess long-term clinical management, but also highlights the low yield of thrombophilia testing when ordered inpatient. To mitigate challenges due to incomplete documentation, charts were reviewed independently by both members of our study team, and the median time from testing to the last VTE-related documentation was 215 days, indicating extensive follow-up for many patients. Another limitation is that our study did not specifically measure the percentage of patients who were receiving anticoagulation – and which agent was being used – at the time of thrombophilia testing, which would have provided insight into reasons for false positive results. It is noted, however, that most patients had been started on anticoagulation before testing was ordered. Important strengths of this study include its use of real-world data and long study period and follow-up time, which can add valuable insights into current hereditary thrombophilia ordering patterns and we feel may inform future guidelines, especially those addressing the timing of testing. Conclusion Our retrospective study of inpatient hereditary thrombophilia testing at an academic hospital system revealed a high rate of testing in patients with acute VTE, despite many clinical guidelines discouraging to do so. We found that in the presence of abnormal thrombophilia test results, clinical management rarely changed, likely due in part to high rates of presumed false positive results and utilizing the tests inappropriately, such that no result would alter management. We also found high costs associated with these tests. This study sheds light on the disconnect between clinical practice and evidence-based recommendations regarding hereditary thrombophilia testing. We feel it provides further evidence supporting a more selective approach to ordering thrombophilia tests in clinical practice and a shift away from the acute, inpatient setting when testing is utilized. 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Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA, et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost. 2016;14(7):1480–3. doi: 10.1111/jth.13336. Di Nisio M, Valeriani E, Riva N, Schulman S, Beyer-Westendorf J, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J Thromb Haemost. 2020;18(7):1562–8. doi: 10.1111/jth.14836. Virparia R, Brunetti L, Vigdor S, Adams CD. Appropriateness of thrombophilia testing in patients in the acute care setting and an evaluation of the associated costs. J Thromb Thrombolysis. 2020;49(1):108–12. doi: 10.1007/s11239-019-01930-w. Meyer MR, Witt DM, Delate T, Johnson SG, Fang M, Go A, et al. Thrombophilia testing patterns amongst patients with acute venous thromboembolism. Thromb Res. 2015;136(6):1160–4. doi: 10.1016/j.thromres.2015.10.019. Gaddh M, Cheng E, Elsebaie MAT, Bodo I. Clinical Utilization and Cost of Thrombophilia Testing in Patients with Venous Thromboembolism. TH Open. 2020;4(3):e153–e62. doi: 10.1055/s-0040-1714334. Lim MY, Greenberg CS. Inpatient thrombophilia testing: Impact of healthcare system technology and targeted clinician education on changing practice patterns. Vasc Med. 2018;23(1):78–9. doi: 10.1177/1358863X17742509. Connors JM. Thrombophilia Testing and Venous Thrombosis. N Engl J Med. 2017;377(23):2298. doi: 10.1056/NEJMc1713797. Petrilli CM, Heidemann L, Mack M, Durance P, Chopra V. Inpatient inherited thrombophilia testing. J Hosp Med. 2016;11(11):801–4. doi: 10.1002/jhm.2616. Berse B, Lynch JA, Bowen S, Grosse SD. In Reference to: "Cost and Utility of Thrombophilia Testing". J Hosp Med. 2017;12(9):783. doi: 10.12788/jhm.2818. Tables Table 1 Clinical Presentation and Risk Factors Presentation N (%) Isolated VTE 164 (74.5%) PE 60 (27.3%) CVST 47 (21.4%) DVT 33 (15.0%) Lower limb 26 (11.8%) Upper limb 7 (3.2%) Splanchnic vein thrombosis 18 (8.2%) Other VTE† 6 (2.7%) VTE at Multiple Sites 31 (14.1%) DVT + PE 25 (11.4%) PE + renal vein thrombosis 2 (0.9%) DVT + CVST 1 (0.5%) Multiple other VTE† 3 (1.4%) Combined Venous + Arterial Thrombosis 25 (11.4%) CVA + DVT/PE 18 (8.2%) Myocardial infarction + PE 2 (0.9%) CVA + Other VTE 1 (0.5%) Other arterial‡ + VTE 4 (1.8%) VTE Provoking Risk Factors Provoked* 101 (45.9%) Pregnancy/combined oral contraceptives 36 (16.4%) Antecedent hospitalization 16 (7.3%) Major surgery 14 (6.4%) Active cancer 10 (4.5%) Major trauma/prolonged immobilization 9 (4.1%) Liver/gastrointestinal disease (for SVT) 8 (3.6%) COVID-19 5 (2.3%) Indwelling venous catheter 4 (1.8%) Venous anomaly (May-Thurner or thoracic outlet syndrome) 4 (1.8%) Other risk factors 7 (3.2%) Unprovoked 119 (54.1%) CVA, cerebrovascular accident (including stroke, retinal artery occlusion, and transient ischemic attack); CVST, cerebral venous sinus thrombosis; DVT, deep vein thrombosis; PE, pulmonary embolism †Includes renal, ovarian, inferior vena cava, and cephalic vein thromboses. ‡Includes radial artery, superficial femoral artery, left ventricular, and arteriovenous graft thromboses *11 patients had multiple risk factors Table 2 Results of Hereditary Thrombophilia Testing Lab Results Test Condition No. Test (% of total) Ref Range Negative (% within test) Borderline positive / Heterozygous (%) Positive / Homozygous (%) All Tests 835 (100.0) 671 (80.4) 80 (9.6) 84 (10.1) Factor V Leiden (FVL) 210 (25.1) 196 (93.3) 8 (3.8) 6 (2.9) Activated Protein C Resistance 122 (14.6) >2.2 116 (95.1) 0 (0.0) 6 (4.9) FVL mutation 88 (10.5) 80 (90.9) 8 (9.1) 0 (0.0) Prothrombin G20210A 162 (19.4) 152 (93.8) 10 (6.2) 0 (0.0) Protein S Deficiency 150 (18.0) 120 (80.0) 4 (2.7) 26 (17.3) Protein S, free 115 (13.8) 53–141% 93 (80.9) 0 (0.0) 22 (19.1) Protein S, total 28 (3.4) 70–140% 23 (82.1) 4 (14.3) 1 (3.6) Protein S, activity 7 (0.8) 60–140% 4 (57.1) 0 (0.0) 3 (42.9) Protein C Deficiency 121 (14.5) 91 (75.2) 16 (13.2) 14 (11.6) Protein C, function 108 (12.9) 78–160% 81 (75.0) 15 (13.9) 12 (11.1) Protein C, antigen 13 (1.6) 70–140% 10 (76.9) 1 (7.7) 2 (15.4) Antithrombin activity 107 (12.8) 86–122% 53 (49.5) 36 (33.6) 18 (16.8) Hyperhomocysteinemia 84 (10.1) 59 (70.2) 6 (7.1) 19 (22.6) Homocysteine 75 (9.0) 5–15 µmol/L 57 (76.0) 0 (0.0) 18 (24.0) MTHFR Mutation 9 (1.1) 2 (22.2) 6 (66.7) 1 (11.1) PAI-1 activity 1 (0.1) 4.43 ng/mL 0 (0.0) 0 (0.0) 1 (100.0) MTHFR, methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1 Table 3 Thrombophilia Tests with Associated Institutional Chargemaster and CMS Fees Thrombophilia Tests TJUH Chargemaster ($) CMS Fee Schedule ($) Factor V Leiden (FVL) - - Activated Protein C Resistance $334 $15.32 FVL mutation $373 $73.37 Prothrombin G20210A $410 $65.69 Protein S Deficiency - - Protein S, free $765 $15.32 Protein S, total $765 $11.61 Protein S, activity $268 $15.32 Protein C Deficiency - - Protein C, function $480 $13.84 Protein C, antigen $480 $12.01 Antithrombin activity $480 $11.85 Hyperhomocysteinemia - - Homocysteine $235 $17.92 MTHFR mutation $737 $65.34 PAI-1 activity $200 $17.19 MTHFR, methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1 Table 4 Characteristics of patients with documented management change following positive result Clinical Scenario Provoking Risk Factor(s) Abnormal Test Result(s) Documented Clinical Decision Change Compatible with 2023 ASH Guidelines 33-year-old male with distal (gastrocnemius and peroneal veins) DVT Yes: traumatic spinal cord injury and surgery within 14 days Heterozygous for both FVL and PT G20210A Prescribed long-term apixaban at dose of 2.5mg BID due to thrombophilia and permanent immobility No 56-year-old male with CVST None Heterozygous for PT G20210A Discharged on warfarin, switched to apixaban 2.5mg BID as long-term therapy Yes 20-year-old female with massive PE requiring thrombolysis Yes: Combined oral contraceptive Low free protein S (26%), normal total protein S (70%) Prescribed long-term rivaroxaban 10mg due in part to free protein S result Yes 22-year-old male with CVST None Heterozygous for both FVL and PT G20210A Maintained on rivaroxaban 20mg as long-term therapy Yes Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Oct, 2025 Read the published version in Journal of Thrombosis and Thrombolysis → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7024163","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":488827554,"identity":"ca09456a-a201-4aca-9707-ee7e1c8d2083","order_by":0,"name":"Eliakim Munda","email":"","orcid":"","institution":"Thomas Jefferson University","correspondingAuthor":false,"prefix":"","firstName":"Eliakim","middleName":"","lastName":"Munda","suffix":""},{"id":488827555,"identity":"57669773-21e7-4d55-9e35-56618aacc659","order_by":1,"name":"Ruben Rhoades","email":"data:image/png;base64,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","orcid":"","institution":"Thomas Jefferson University","correspondingAuthor":true,"prefix":"","firstName":"Ruben","middleName":"","lastName":"Rhoades","suffix":""}],"badges":[],"createdAt":"2025-07-02 01:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7024163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7024163/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11239-025-03183-2","type":"published","date":"2025-10-05T15:58:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87345765,"identity":"2ba458fd-d1c0-40e8-81c8-2d8a994a26e4","added_by":"auto","created_at":"2025-07-23 02:20:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12118,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage of positive lab results in patients with provoked versus unprovoked VTE\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7024163/v1/d8cb80099c478c4b34d6b313.png"},{"id":87345383,"identity":"e94e1c11-f9ca-4bd4-a9d0-ced5e8955221","added_by":"auto","created_at":"2025-07-23 02:12:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11386,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage of positive lab results in patients \u0026lt; 50 vs ≥ 50 years of age\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7024163/v1/57c3d8833ee98a304bdc9575.png"},{"id":92883921,"identity":"b69e1160-6727-4baa-aafe-675f2bbd75da","added_by":"auto","created_at":"2025-10-06 16:10:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":972100,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7024163/v1/34157184-7d7e-412e-8756-822c18566145.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Utility and Costs of Inpatient Hereditary Thrombophilia Testing following Acute VTE: A 5-Year Retrospective Study","fulltext":[{"header":"Key Points","content":"\u003cul\u003e\n \u003cli\u003eThrombophilia testing following acute venous thromboembolism was commonly performed at an academic medical center with high associated costs, and nearly 20% of tests were abnormal\u003c/li\u003e\n \u003cli\u003eMany results were below the limits of normal for the assay, but higher than expected in congenital deficiency, likely indicating false positives\u003c/li\u003e\n \u003cli\u003eYoung patients and those with unprovoked venous thromboembolism were not more likely to have positive test results\u003c/li\u003e\n \u003cli\u003eClinical management rarely changed in response to a positive result, indicating low value of testing in the inpatient setting\u003c/li\u003e\n \u003cli\u003eProspective studies with long-term outpatient follow-up would help determine the optimal timing of thrombophilia testing\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eHereditary thrombophilias are genetic disorders that increase the risk of venous thromboembolism (VTE) [1\u0026ndash;4]. Laboratory testing for hereditary thrombophilia is thus a common approach in clinical practice to determine predisposing factors to VTE. However, studies indicate that this screening provides limited utility for predicting the risk of recurrent thrombosis in patients experiencing a first episode of VTE [5\u0026ndash;8]. In patients being treated with anticoagulation, the presence of a thrombophilia does not predict a greater recurrence risk [9]. Further, antigen and activity assays for these conditions are susceptible to false positive results immediately following an acute VTE episode, due to factors such as anticoagulation therapy, protein consumption, acute phase reactant changes, and abnormal liver function [10\u0026ndash;12]. Given the above, retrospective studies have found that management decisions are rarely influenced by testing [12\u0026ndash;14] and positive tests are typically not repeated for confirmation [15]. Finally, tests for hereditary thrombophilias are expensive, with current estimates for a panel of tests costing more than \u003cspan\u003e$\u003c/span\u003e300 USD [15\u0026ndash;17].\u003c/p\u003e\u003cp\u003e Given the limitations and costs, most guidelines have recommended against the use of routine thrombophilia testing, especially when results are unlikely to change a patient\u0026rsquo;s management [18\u0026ndash;21]. The American Society of Hematology (ASH) previously recommended against thrombophilia testing after a VTE provoked by a major transient risk factor [20], while more recent ASH guidelines do conditionally recommend testing in select patients with VTE in whom results may dictate length of anticoagulation, including those with hormone-associated VTE or minor transient provoking risk factors and those with unusual site thrombosis being considered for time-limited anticoagulation [22]. However, they do not provide guidance on when testing should be ordered, and the risk of inappropriately recommending indefinite anticoagulation is increased when tests are ordered in settings in which false positive results are more likely.\u003c/p\u003e\u003cp\u003e We sought to understand the pattern and cost of hereditary thrombophilia testing following an acute VTE and how positive results were managed, as our results may help inform future guidelines around thrombophilia testing and whether testing should be delayed after acute VTE.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eStudy Population and Selection Criteria\u003c/span\u003e\u003c/p\u003e\u003cp\u003e We retrospectively analyzed all inpatient hereditary thrombophilia tests ordered at Thomas Jefferson University Hospitals (TJUH) \u0026ndash; including its three primary flagship hospitals in Philadelphia, PA \u0026ndash; an academic tertiary care center, between January 1, 2019 and December 31, 2023. Inclusion criteria comprised patients who underwent inpatient hereditary thrombophilia testing during an admission for acute VTE. Patients who had concurrent VTE and arterial thrombosis/ischemia were also eligible. Types of VTE included deep vein thrombosis (DVT) of the limbs, pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), as well as other rarer sites of VTE such as the inferior vena cava and gonadal veins. Patients who had thrombophilia workups performed for any non-VTE indications, or whose testing was done while inpatient but for a remote VTE, were excluded from the study. Tests for the following conditions were included in the study: Factor V Leiden (FVL; including activated protein C resistance and genetic testing), prothrombin G20210A variant (PT\u003csub\u003eG20210A\u003c/sub\u003e), protein S deficiency (free, total, and functional protein S), protein C deficiency (antigen and function), antithrombin deficiency, hyperhomocysteinemia (homocysteine and \u003cem\u003eMTHFR\u003c/em\u003e mutation testing), and plasminogen activator inhibitor-1 (PAI-1) excess. The study was approved by the Thomas Jefferson University Institutional Review Board.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eData Collection\u003c/span\u003e\u003c/p\u003e\u003cp\u003e We generated a list of all instances of inpatient orders of hereditary thrombophilia tests during the study period, then manually reviewed all charts in our institution\u0026rsquo;s electronic health record (Epic Systems\u0026copy;) for eligibility, demographics, rationale for testing, provoking risk factors, lab results, and documented management. The International Society on Thrombosis and Haemostasis\u0026rsquo; (ISTH) guidance on provoking risk factors[23] was utilized to determine whether a VTE was provoked by a transient risk factor. Additionally, we considered longer-term risk factors such as active cancer or anatomic anomalies (May-Thurner syndrome or venous thoracic outlet syndrome) and transient risk factors not included by the ISTH, such as COVID-19 infection within the preceding 30 days and other conditions associated with splanchnic vein thrombosis (SVT) [24]. We reviewed all available documentation, including after the index hospital admission, to determine if any change in patients\u0026rsquo; management was made citing a positive thrombophilia test result (including a decision to prescribe an anticoagulant or alter the dose or duration). We also reviewed occurrences of repeat outpatient orders after initial abnormal results on antigen or functional assays. Last, we queried both TJUH\u0026rsquo;s chargemaster to determine charges associated with each test and the Centers for Medicare \u0026amp; Medicaid Services\u0026rsquo; (CMS) Clinical Laboratory Fee Schedule to obtain payment rates.\u003c/p\u003e\u003cp\u003eFor interpreting certain lab results with an upper limit of normal higher than is typically seen in hereditary deficiencies \u0026ndash; including antithrombin activity, protein C antigen and function, and total protein S \u0026ndash; values that fell below normal but \u0026gt;\u0026thinsp;60% were considered \u003cem\u003eborderline positive\u003c/em\u003e and those\u0026thinsp;\u0026lt;\u0026thinsp;60% were considered \u003cem\u003epositive\u003c/em\u003e. Positive genetic assays were characterized as heterozygous, homozygous, or compound heterozygous.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eWe de-identified and analyzed data using IBM SPSS version 29. Descriptive statistics were summarized according to tests and individual patients. Continuous variables were analyzed using independent sample t tests, and categorical variables Pearson χ\u003csup\u003e2\u003c/sup\u003e and Fisher\u0026rsquo;s Exact Test.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study included 220 patients, among which 61.8% were female and the median age was 48 years (interquartile range 33-62). 195 (88.6%) patients had only VTE (whether single or multiple sites) and 25 (11.9%) had concurrent VTE and arterial thrombotic or ischemic events. Among patients with single-site VTE, the most common events were PE (27.3%), CVST (21.4%), DVT (15.0%), and SVT (8.2%). 31 (14.1%) patients had VTE at multiple sites, including 25 (11.4%) with concurrent DVT and PE. VTE was considered provoked in 101 (45.9%) patients; 11 (5.0%) patients had at least 2 provoking risk factors. Among patients with provoked VTE, the most common provoking factors were pregnancy/combined oral contraceptive (COC) pills (35.6%), antecedent hospitalization (15.8%), major surgery (13.9%), trauma or prolonged immobility (8.9%), and liver or gastrointestinal disease (7.9%) in the case of SVT. Details on the types of thrombosis and risk factors are shown in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTest results\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 835 tests were ordered. The counts and percentages of each test in context of their lab outcomes are detailed in table 2. The most commonly ordered tests were for FVL (25.1%), PT\u003csub\u003eG20210A\u003c/sub\u003e (19.4%), and deficiencies of protein S (18.0%), protein C (14.5%), and antithrombin (12.8%). Regarding results, 19.6% of tests were abnormal, including 50.5% of antithrombin activities, 24.8% of protein C assays, 20.0% of protein S assays, and 6.7% of assays for FVL. Regarding the most common genetic tests, 9.1% of FVL and 6.2% of PT\u003csub\u003eG20210A\u003c/sub\u003e tests were positive (all heterozygous, with two patients double heterozygous for FVL and PT\u003csub\u003eG20210A\u003c/sub\u003e). The four tests with a lower limit of normal higher than 60% were frequently borderline positive (i.e., \u0026gt; 60% but below the normal limit), including 33.6% of antithrombin activity, 14.3% of total Protein S, 13.9% of protein C function and 7.7% of protein C antigen assays. The total institutional charges for these tests were $385,161, while Medicare fees totaled $26,029.55, based on CMS fee schedules for the first quarter of 2025. Table 3 displays our institution\u0026rsquo;s chargemaster rates and the CMS fee schedule for all thrombophilia tests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePatient-level Results\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe found that in the patient cohort, 99/220 (45.0%) had at least one abnormal result. Of these, 72 (32.7%) patients had a positive result on an activity assay or any gene variant, while 27 (12.3%) had only borderline positive findings. 43 (19.5%) patients had multiple abnormal results. There was no significant difference in the rate of positive test results among patients whose thromboses were provoked vs unprovoked (69.3% vs 65.5%, p=.554). We also observed no association between age and likelihood of a positive result. 33.1% of patients age \u0026lt; 50 years had a positive result vs 32.4% of patients \u0026ge; 50 years (p=.912), and the mean age of patients with positive results was similar (47.6 vs 48.3 years, p=.794). When evaluating test results based on the type of presentation, the rate of positive tests was similar among patients with VTE only vs combined VTE and arterial thrombosis (31.8% vs 40.0%, p=.410).\u003c/p\u003e\n\u003cp\u003eRegarding management, at a median time to last documentation of 215 days, only 4 out of 99 (4.0%) patients with any abnormal result had a clearly defined, documented change in management that was implemented after the abnormal result became available \u0026ndash; either adding an anticoagulant, changing it, or prolonging the duration. An additional 6 (6.1%) patients had results which may have influenced management, but for whom documentation was inconclusive in demonstrating a link between clinical management and abnormal results. The characteristics of the four patients with a clear change in management in response to an abnormal test are summarized in Table 3. They included patients with a provoked DVT with heterozygosity for both FVL and PT\u003csub\u003eG20210A\u003c/sub\u003e, an unprovoked CVST heterozygous for PT\u003csub\u003eG20210A\u003c/sub\u003e, a hormone-associated PE with low free protein S, and an unprovoked CVST heterozygous for both FVL and PT\u003csub\u003eG20210A\u003c/sub\u003e. In 3 of the 4 cases, the indication for testing fit the 2023 ASH recommendations. We observed no difference in the number of patients whose management clearly changed according to whether the VTE was provoked vs unprovoked (4.1% vs 4.0%). And including patients with an inconclusive management change, there was also no significant difference between those with provoked vs unprovoked VTE (8.2% vs 12.0%, p=.716). Among the 84 patients whose abnormal result(s) included only non-genetic assays, only 8 (9.5%) had the abnormal test(s) repeated. Finally, 6 (2.7%) patients died during the index hospitalization.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this 5-year retrospective study of inpatient hereditary thrombophilia testing after acute VTE, we found that abnormal results were very common and rarely changed clinical management. These findings highlight a disconnect between current practice and most evidence-based recommendations. Testing was frequently performed immediately following a VTE event, when results are more likely to be misleading, and was associated with significant costs.\u003c/p\u003e\u003cp\u003eFirst, our study found a high rate of test utilization in groups for whom hereditary thrombophilia testing has not been recommended. British Society for Haematology guidelines advise against routine thrombophilia testing when results are unlikely to affect clinical management decisions [21]. These further note that the presence of hereditary thrombophilias rarely alters intensity, choice, or monitoring of anticoagulant therapy, and instead emphasize using clinical history and assays such as D-dimer in selected patients to guide management [21]. Similarly, ASH Choosing Wisely\u0026reg; recommendations include not ordering thrombophilia tests after VTE by a major risk factor [20]. However, multiple studies have reported high rates of thrombophilia testing after a provoked VTE [13\u0026ndash;15, 25\u0026ndash;28]. Our study similarly found testing following provoked VTE was very common, comprising 45.9% of our patients and 47.3% of total tests. Even excluding VTE provoked by pregnancy or estrogen \u0026ndash; a group for whom recent ASH guidelines support testing [22] \u0026ndash; 29.5% of patients had a provoked VTE. Furthermore, while some advocate for selective thrombophilia testing in young patients and those without a strong provoking risk factor [29], we found that the rate of positive tests was not significantly greater in patients with unprovoked as compared to provoked VTE, nor in patients younger than 50 years of age.\u003c/p\u003e\u003cp\u003eThe utility of thrombophilia testing is further limited by the potential for false positives when ordered in the acute setting. Testing following acute VTE is more likely to yield false positive results due to anticoagulation therapy that affects certain functional assays, protein consumption by acute thrombus or mechanical circulatory support systems, or acute phase reactant changes related to inflammation and/or the predisposing condition to VTE [10, 11, 25, 30]. We found 21.9% of antigen and functional assays with a lower limit of normal of 70% or higher yielded results below normal but above typical values in autosomal dominant deficiency, indicating a high likelihood of being a false positive. This has the potential to yield mismanagement of patients when results are misinterpreted or not repeated. Furthermore, we found that fewer than 10% of patients with an abnormal antigen or activity assay had repeat testing for confirmation after the hospitalization. Others have found that while abnormal tests may be repeated, it is often during the index admission, when false positive results are still likely [15]. Given the high rate of likely false abnormal results and low rate of test repetition for confirmation, our data suggests that guidelines such as those from ASH should directly address timing of testing in order to reduce confounding variables and the risk of clinical mismanagement of patients.\u003c/p\u003e\u003cp\u003eThe management of patients in our study reflects that clinicians likely viewed the test results with skepticism. Only 4% of patients with any abnormal result had a documented change in clinical management in response to an abnormal result. This is consistent with other studies which found that inpatient thrombophilia testing was not clinically useful or reliable and rarely changed management [13, 14, 26, 27]. Additionally, many of these studies included acquired thrombophilias such as antiphospholipid syndrome, which often requires a change in anticoagulant \u0026ndash; specifically to warfarin \u0026ndash; and thus may be a higher yield test to order, especially in patients for a whom a high clinical suspicion exists. One single-center study, for example, found that 87% of patients were tested inappropriately and in no cases was the duration of treatment impacted by the result. However, among the 7 patients who experienced any clinical change in management, all had antiphospholipid syndrome, which was not included in our study [14]. Together with our study, this reinforces the concept that these tests rarely provide valuable data that impacts treatment decisions.\u003c/p\u003e\u003cp\u003eFinally, thrombophilia testing is expensive. When these tests are used inappropriately, they offer minimum clinical benefit but also contribute to significant spending, which may be costly to health care systems when ordered in the inpatient setting [13, 15, 25, 28]. Although cost-analysis of thrombophilia testing in acute VTE is sparce, estimates for the panel of tests included in our study range from approximately \u003cspan\u003e$\u003c/span\u003e187 to \u003cspan\u003e$\u003c/span\u003e974 USD per patient [14, 15, 25, 27, 31]. To provide a broad estimate of costs, we calculated charges using both our institution\u0026rsquo;s chargemaster and the most recent publicly available CMS fee schedule. In our study, the total institutional charges by chargemaster were greater than \u003cspan\u003e$\u003c/span\u003e385,000 USD and by CMS fee schedule greater than \u003cspan\u003e$\u003c/span\u003e26,000 USD over the 5-year study period. The corresponding per-patient charges were \u003cspan\u003e$\u003c/span\u003e1,750 and \u003cspan\u003e$\u003c/span\u003e118 USD, respectively.\u003c/p\u003e\u003cp\u003eOur study has certain limitations. The retrospective, observational design from a single academic hospital system may limit the applicability of our findings to other institutions or patient populations. Additionally, the reliance on reviewing documentation to understand clinical outcomes and indications for therapy represents a weakness. Incomplete documentation, particularly from outside our EHR system, restricted our ability to fully understand and assess outcomes and potential changes in management. Many patients had no documented encounters after hospital discharge, which limited our ability to assess long-term clinical management, but also highlights the low yield of thrombophilia testing when ordered inpatient. To mitigate challenges due to incomplete documentation, charts were reviewed independently by both members of our study team, and the median time from testing to the last VTE-related documentation was 215 days, indicating extensive follow-up for many patients. Another limitation is that our study did not specifically measure the percentage of patients who were receiving anticoagulation \u0026ndash; and which agent was being used \u0026ndash; at the time of thrombophilia testing, which would have provided insight into reasons for false positive results. It is noted, however, that most patients had been started on anticoagulation before testing was ordered. Important strengths of this study include its use of real-world data and long study period and follow-up time, which can add valuable insights into current hereditary thrombophilia ordering patterns and we feel may inform future guidelines, especially those addressing the timing of testing.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e Our retrospective study of inpatient hereditary thrombophilia testing at an academic hospital system revealed a high rate of testing in patients with acute VTE, despite many clinical guidelines discouraging to do so. We found that in the presence of abnormal thrombophilia test results, clinical management rarely changed, likely due in part to high rates of presumed false positive results and utilizing the tests inappropriately, such that no result would alter management. We also found high costs associated with these tests. This study sheds light on the disconnect between clinical practice and evidence-based recommendations regarding hereditary thrombophilia testing. We feel it provides further evidence supporting a more selective approach to ordering thrombophilia tests in clinical practice and a shift away from the acute, inpatient setting when testing is utilized.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eE.M. and R.R. independently collected all data via chart review; E.M. and R.R. jointly performed statistical analysis and wrote and edited the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVossen CY, Conard J, Fontcuberta J, Makris M, Van Der Meer FJ, Pabinger I, et al. Familial thrombophilia and lifetime risk of venous thrombosis. J Thromb Haemost. 2004;2(9):1526\u0026ndash;32. doi: 10.1111/j.1538-7836.2004.00852.x.\u003c/li\u003e\n\u003cli\u003eSegal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301(23):2472\u0026ndash;85. doi: 10.1001/jama.2009.853.\u003c/li\u003e\n\u003cli\u003eLijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, 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\u0026ndash;22. doi: 10.1182/blood-2008-10-184879.\u003c/li\u003e\n\u003cli\u003eRyu J, Ramo JT, Jurgens SJ, Niiranen T, Sanna-Cherchi S, Bauer KA, et al. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank. Blood. 2024;143(23):2425\u0026ndash;32. doi: 10.1182/blood.2023023326.\u003c/li\u003e\n\u003cli\u003eBaglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003;362(9383):523\u0026ndash;6. doi: 10.1016/S0140-6736(03)14111-6.\u003c/li\u003e\n\u003cli\u003eChristiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293(19):2352\u0026ndash;61. doi: 10.1001/jama.293.19.2352.\u003c/li\u003e\n\u003cli\u003eHo WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166(7):729\u0026ndash;36. doi: 10.1001/archinte.166.7.729.\u003c/li\u003e\n\u003cli\u003eCoppens M, Reijnders JH, Middeldorp S, Doggen CJ, Rosendaal FR. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost. 2008;6(9):1474\u0026ndash;7. doi: 10.1111/j.1538-7836.2008.03055.x.\u003c/li\u003e\n\u003cli\u003eKearon C, Julian JA, Kovacs MJ, Anderson DR, Wells P, Mackinnon B, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112(12):4432\u0026ndash;6. doi: 10.1182/blood-2008-06-163279.\u003c/li\u003e\n\u003cli\u003eMarciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin-III. Lancet. 1977;2(8038):581\u0026ndash;4. doi: 10.1016/s0140-6736(77)91429-5.\u003c/li\u003e\n\u003cli\u003eVigano D\u0026apos;Angelo S, Comp PC, Esmon CT, D\u0026apos;Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest. 1986;77(2):416\u0026ndash;25. doi: 10.1172/JCI112319.\u003c/li\u003e\n\u003cli\u003eMajmundar S, Thapa S, Miller ES, Bell R, Dharia R, Tzeng D, et al. Low value of inherited thrombophilia testing among patients with stroke or transient ischemic attack: A three-year retrospective study. J Stroke Cerebrovasc Dis. 2023;32(10):107308. doi: 10.1016/j.jstrokecerebrovasdis.2023.107308.\u003c/li\u003e\n\u003cli\u003eCox N, Johnson SA, Vazquez S, Fleming RP, Rondina MT, Kaplan D, et al. Patterns and Appropriateness of Thrombophilia Testing in an Academic Medical Center. J Hosp Med. 2017;12(9):705\u0026ndash;9. doi: 10.12788/jhm.2804.\u003c/li\u003e\n\u003cli\u003eSiu CT, Wolfe Z, DelaTorre M, Rehim E, Decker R, Zaffiri K, et al. Evaluation of thrombophilia testing in the inpatient setting: A single institution retrospective review. PLoS One. 2021;16(9):e0257687. doi: 10.1371/journal.pone.0257687.\u003c/li\u003e\n\u003cli\u003eShen YM, Tsai J, Taiwo E, Gavva C, Yates SG, Patel V, et al. Analysis of Thrombophilia Test Ordering Practices at an Academic Center: A Proposal for Appropriate Testing to Reduce Harm and Cost. PLoS One. 2016;11(5):e0155326. doi: 10.1371/journal.pone.0155326.\u003c/li\u003e\n\u003cli\u003eGupta A, Sarode R, Nagalla S. Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Intern Med. 2017;177(8):1195\u0026ndash;6. doi: 10.1001/jamainternmed.2017.1815.\u003c/li\u003e\n\u003cli\u003eLynch JA, Berse B, Dotson WD, Khoury MJ, Coomer N, Kautter J. Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data. Genet Med. 2017;19(8):890\u0026ndash;9. doi: 10.1038/gim.2016.209.\u003c/li\u003e\n\u003cli\u003eBaglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209\u0026ndash;20. doi: 10.1111/j.1365-2141.2009.08022.x.\u003c/li\u003e\n\u003cli\u003eEvaluation of Genomic Applications in P, Prevention Working G. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G\u0026gt;A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med. 2011;13(1):67\u0026ndash;76. doi: 10.1097/GIM.0b013e3181fbe46f.\u003c/li\u003e\n\u003cli\u003eHicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A, et al. The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question. Blood. 2013;122(24):3879\u0026ndash;83. doi: 10.1182/blood-2013-07-518423.\u003c/li\u003e\n\u003cli\u003eArachchillage DJ, Mackillop L, Chandratheva A, Motawani J, MacCallum P, Laffan M. Thrombophilia testing: A British Society for Haematology guideline. Br J Haematol. 2022;198(3):443\u0026ndash;58. doi: 10.1111/bjh.18239.\u003c/li\u003e\n\u003cli\u003eMiddeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton D, James AH, et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv. 2023;7(22):7101\u0026ndash;38. doi: 10.1182/bloodadvances.2023010177.\u003c/li\u003e\n\u003cli\u003eKearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA, et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost. 2016;14(7):1480\u0026ndash;3. doi: 10.1111/jth.13336.\u003c/li\u003e\n\u003cli\u003eDi Nisio M, Valeriani E, Riva N, Schulman S, Beyer-Westendorf J, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J Thromb Haemost. 2020;18(7):1562\u0026ndash;8. doi: 10.1111/jth.14836.\u003c/li\u003e\n\u003cli\u003eVirparia R, Brunetti L, Vigdor S, Adams CD. Appropriateness of thrombophilia testing in patients in the acute care setting and an evaluation of the associated costs. J Thromb Thrombolysis. 2020;49(1):108\u0026ndash;12. doi: 10.1007/s11239-019-01930-w.\u003c/li\u003e\n\u003cli\u003eMeyer MR, Witt DM, Delate T, Johnson SG, Fang M, Go A, et al. Thrombophilia testing patterns amongst patients with acute venous thromboembolism. Thromb Res. 2015;136(6):1160\u0026ndash;4. doi: 10.1016/j.thromres.2015.10.019.\u003c/li\u003e\n\u003cli\u003eGaddh M, Cheng E, Elsebaie MAT, Bodo I. Clinical Utilization and Cost of Thrombophilia Testing in Patients with Venous Thromboembolism. TH Open. 2020;4(3):e153\u0026ndash;e62. doi: 10.1055/s-0040-1714334.\u003c/li\u003e\n\u003cli\u003eLim MY, Greenberg CS. Inpatient thrombophilia testing: Impact of healthcare system technology and targeted clinician education on changing practice patterns. Vasc Med. 2018;23(1):78\u0026ndash;9. doi: 10.1177/1358863X17742509.\u003c/li\u003e\n\u003cli\u003eConnors JM. Thrombophilia Testing and Venous Thrombosis. N Engl J Med. 2017;377(23):2298. doi: 10.1056/NEJMc1713797.\u003c/li\u003e\n\u003cli\u003ePetrilli CM, Heidemann L, Mack M, Durance P, Chopra V. Inpatient inherited thrombophilia testing. J Hosp Med. 2016;11(11):801\u0026ndash;4. doi: 10.1002/jhm.2616.\u003c/li\u003e\n\u003cli\u003eBerse B, Lynch JA, Bowen S, Grosse SD. In Reference to: \u0026quot;Cost and Utility of Thrombophilia Testing\u0026quot;. J Hosp Med. 2017;12(9):783. doi: 10.12788/jhm.2818.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"498\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 498px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eClinical Presentation and Risk Factors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresentation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIsolated VTE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e164 (74.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e60 (27.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eCVST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e47 (21.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eDVT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e33 (15.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lower limb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e26 (11.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Upper limb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eSplanchnic vein thrombosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e18 (8.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eOther VTE\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6 (2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVTE at Multiple Sites\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e31 (14.1%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eDVT + PE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e25 (11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003ePE + renal vein thrombosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eDVT + CVST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eMultiple other VTE\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e3 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCombined Venous + Arterial Thrombosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25 (11.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eCVA + DVT/PE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e18 (8.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eMyocardial infarction + PE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eCVA + Other VTE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eOther arterial\u0026Dagger;\u0026nbsp;+ VTE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e4 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVTE Provoking Risk Factors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProvoked*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e101 (45.9%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003ePregnancy/combined oral contraceptives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e36 (16.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eAntecedent hospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e16 (7.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eMajor surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e14 (6.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eActive cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e10 (4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eMajor trauma/prolonged immobilization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e9 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eLiver/gastrointestinal disease (for SVT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e8 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eCOVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e5 (2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eIndwelling venous catheter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e4 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eVenous anomaly (May-Thurner or thoracic outlet syndrome)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e4 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003eOther risk factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 399px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnprovoked\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e119 (54.1%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCVA, cerebrovascular accident (including stroke, retinal artery occlusion, and transient ischemic attack); CVST, cerebral venous sinus thrombosis; DVT, deep vein thrombosis; PE, pulmonary embolism\u003c/p\u003e\n\u003cp\u003e\u0026dagger;Includes renal, ovarian, inferior vena cava, and cephalic vein thromboses.\u003c/p\u003e\n\u003cp\u003e\u0026Dagger;Includes radial artery, superficial femoral artery, left ventricular, and arteriovenous graft thromboses\u003c/p\u003e\n\u003cp\u003e*11 patients had multiple risk factors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eResults of Hereditary Thrombophilia Testing\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"731\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 359px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLab Results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest Condition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eNo. Test\u003cbr\u003e\u0026nbsp;(% of total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eRef Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003eNegative\u003cbr\u003e\u0026nbsp;(% within test)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003eBorderline positive /\u0026nbsp;\u003cbr\u003e\u0026nbsp;Heterozygous (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ePositive / Homozygous (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Tests\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e835 (100.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e671 (80.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e80 (9.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e84 (10.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFactor V Leiden (FVL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e210 (25.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e196 (93.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8 (3.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 (2.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eActivated Protein C Resistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e122 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026gt;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e116 (95.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e6 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eFVL mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e88 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e80 (90.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e8 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProthrombin G20210A\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e162 (19.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e152 (93.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 (6.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein S Deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e150 (18.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e120 (80.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (2.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26 (17.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eProtein S, free\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e115 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e53\u0026ndash;141%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e93 (80.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e22 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eProtein S, total\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e28 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e70\u0026ndash;140%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e23 (82.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eProtein S, activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e7 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e60\u0026ndash;140%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e4 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e3 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein C Deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e121 (14.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e91 (75.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (13.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14 (11.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eProtein C, function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e108 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e78\u0026ndash;160%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e81 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e15 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e12 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eProtein C, antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e13 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e70\u0026ndash;140%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e10 (76.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e2 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntithrombin activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e107 (12.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e86\u0026ndash;122%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e53 (49.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e36 (33.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18 (16.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperhomocysteinemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e84 (10.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59 (70.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 (7.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e19 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003eHomocysteine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e75 (9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e5\u0026ndash;15 \u0026micro;mol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e57 (76.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e18 (24.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cem\u003eMTHFR\u003c/em\u003e Mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e6 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAI-1 activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 (0.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4.43 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 (100.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMTHFR, methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003eThrombophilia Tests with Associated Institutional Chargemaster and CMS Fees\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"549\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThrombophilia Tests\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTJUH Chargemaster ($)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCMS Fee Schedule ($)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFactor V Leiden (FVL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eActivated Protein C Resistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$334\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$15.32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eFVL mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$373\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$73.37\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProthrombin G20210A\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$410\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$65.69\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein S Deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eProtein S, free\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$765\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$15.32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eProtein S, total\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$765\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$11.61\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eProtein S, activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$268\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$15.32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein C Deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eProtein C, function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$480\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$13.84\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eProtein C, antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$480\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$12.01\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntithrombin activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$480\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$11.85\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperhomocysteinemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eHomocysteine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$235\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$17.92\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eMTHFR\u003c/em\u003e mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;$737\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;$65.34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAI-1 activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$200\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;$17.19\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMTHFR, methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"636\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 636px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e Characteristics of patients with documented management change following positive result\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Scenario\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProvoking Risk Factor(s)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal Test Result(s)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDocumented Clinical Decision Change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCompatible with 2023 ASH Guidelines\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e33-year-old male with distal (gastrocnemius and peroneal veins) DVT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eYes: traumatic spinal cord injury and surgery within 14 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eHeterozygous for both FVL and PT\u003csub\u003eG20210A\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePrescribed long-term apixaban at dose of 2.5mg BID due to thrombophilia and permanent immobility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e56-year-old male with CVST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eHeterozygous for PT\u003csub\u003eG20210A\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDischarged on warfarin, switched to apixaban 2.5mg BID as long-term therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e20-year-old female with massive PE requiring thrombolysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eYes: Combined oral contraceptive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eLow free protein S (26%), normal total protein S (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePrescribed long-term rivaroxaban 10mg due in part to free protein S result\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e22-year-old male with CVST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eHeterozygous for both FVL and PT\u003csub\u003eG20210A\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMaintained on rivaroxaban 20mg as long-term therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hereditary thrombophilia, Venous thromboembolism, High-value care, Costs","lastPublishedDoi":"10.21203/rs.3.rs-7024163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7024163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003e Hereditary thrombophilia testing is frequently ordered after venous thromboembolism (VTE), despite little evidence of clinical utility and most guidelines cautioning against testing.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective, observational study of inpatient hereditary thrombophilia testing ordered during a hospital admission for acute VTE between 2019 and 2024. We aimed to characterize patterns of testing results, and costs, and to evaluate whether younger patients and those with unprovoked VTE were more likely to test positive for hereditary thrombophilia.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 835 hereditary thrombophilia tests \u0026ndash; including those for factor V Leiden, prothrombin\u003csub\u003eG20210A\u003c/sub\u003e, deficiencies of protein S, protein C, and antithrombin, hyperhomocysteinemia, and plasminogen activator inhibitor-1 excess \u0026ndash; were ordered in 220 patients. Overall, 19.6% of results were abnormal, and 45.0% of patients had at least one abnormal result. There was no difference in the rate of positive results among patients with provoked vs unprovoked VTE (30.7% vs 34.5%, p\u0026thinsp;=\u0026thinsp;.554) nor patients\u0026thinsp;\u0026lt;\u0026thinsp;50 vs\u0026thinsp;\u0026ge;\u0026thinsp;50 years of age (33.1% vs 32.4%, p\u0026thinsp;=\u0026thinsp;.912). Only 4/99 (4.0%) patients with an abnormal result had their clinical management clearly changed due to the result. The tests totaled \u003cspan\u003e$\u003c/span\u003e385,161 USD in institutional charges and \u003cspan\u003e$\u003c/span\u003e26,029 USD in Medicare fees.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eInpatient hereditary thrombophilia testing during admission for acute VTE is low yield, with frequent abnormal results, many of which likely represented false positives, and minimal impact on clinical management with high costs.\u003c/p\u003e","manuscriptTitle":"Clinical Utility and Costs of Inpatient Hereditary Thrombophilia Testing following Acute VTE: A 5-Year Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 02:12:19","doi":"10.21203/rs.3.rs-7024163/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a3e2b12-58c6-4f17-b6c8-0742912269f9","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:05:03+00:00","versionOfRecord":{"articleIdentity":"rs-7024163","link":"https://doi.org/10.1007/s11239-025-03183-2","journal":{"identity":"journal-of-thrombosis-and-thrombolysis","isVorOnly":false,"title":"Journal of Thrombosis and Thrombolysis"},"publishedOn":"2025-10-05 15:58:14","publishedOnDateReadable":"October 5th, 2025"},"versionCreatedAt":"2025-07-23 02:12:19","video":"","vorDoi":"10.1007/s11239-025-03183-2","vorDoiUrl":"https://doi.org/10.1007/s11239-025-03183-2","workflowStages":[]},"version":"v1","identity":"rs-7024163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7024163","identity":"rs-7024163","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}