Patterns and Appropriateness of Thrombophilia Testing in an Academic Medical Center

Data Analysis

Patient and laboratory characteristics were summarized using descriptive statistics, including mean and standard deviation (SD) for continuous variables and proportions for categorical variables. Data analysis was performed using Excel (Version 2013, Microsoft Corporation. Redmond, Washington).

During the 6-month study period, 163 patients received at least 1 thrombophilia test during an ED visit or inpatient admission. Patient characteristics are summarized in Table 1. Tested patients were most commonly inpatients (96%) and female (71%). A total of 1451 thrombophilia tests were performed with a mean (± SD) of 8.9 ± 6.0 tests per patient. Testing characteristics are summarized in Table 2. Of the 39 different test types performed, the most commonly ordered were cardiolipin IgG and IgM antibodies (9% each), lupus anticoagulant (9%), and β₂-glycoprotein 1 IgG and IgM antibodies (8% each). When combined with testing for phosphatidyl antibodies, antiphospholipid tests accounted for 70% of all tests. Overall, 134 (9%) test results were positive. The mean time for results to become available was 2.2 ± 2.5 days. The frequency of test types with corresponding positivity rates and mean time for results to become available are summarized in Supplementary Table 4.

The indications for thrombophilia testing are summarized in Table 3. Ischemic stroke was the most common indication for testing (50% of tests; 35% of patients), followed by VTE (21% of tests; 21% of patients), and pregnancy-related conditions (eg, preeclampsia, intrauterine fetal demise; 15% of tests; 25% of patients). Overall, 911 tests (63%) occurred in situations associated with minimal clinical utility, with 126 patients (77%) receiving at least one of these tests (Table 4).

In this retrospective analysis, 1451 thrombophilia tests were performed in 163 patients over 6 months. Tested patients were relatively young, which is likely explained by the number of patients tested for pregnancy-related conditions and the fact that a stroke or VTE in younger patients more frequently prompted providers to suspect thrombophilia. Nearly three-fourths of patients were female, which is likely due to testing for pregnancy-related conditions and possibly diagnostic suspicion bias given the comparative predilection of antiphospholipid syndrome for women. The patient characteristics in our study are consistent with other studies evaluating thrombophilia testing.^21,22

Thrombophilia testing was most frequently prompted by stroke, VTE, and pregnancy-related conditions. Only 26% of patients had acute thrombosis identified during the admission, primarily because of the high proportion of tests for cryptogenic strokes and pregnancy-related conditions. Thrombophilia testing is recommended in patients who have had a stroke when the stroke is considered to be cryptogenic after a standard stroke evaluation.²³ Thrombophilia testing in pregnancy-related conditions is controversial but is often considered in situations such as stillbirths with severe placental pathology and/or significant growth restriction, or in mothers with a personal or family history of thrombosis.²⁴ The proportion of testing for pregnancy-related conditions may be greater than at other institutions because UUHC Maternal Fetal Medicine is a referral center for women with conditions associated with hypercoagulability. Anticoagulant therapy was initiated in 21% of patients, but specifically in response to thrombophilia testing in only 2 instances; in most cases, anticoagulant therapy was initiated regardless of thrombophilia test results.

The results of this study confirm our hypothesis because the majority of thrombophilia tests occurred in situations associated with minimal clinical utility. Testing in these situations was not isolated to specific patients or medical services because 77% of tested patients received at least 1 test associated with minimal clinical utility. Our study took a conservative approach in defining scenarios associated with minimal clinical utility because other situations can also affect testing accuracy (eg, hepatic disease, nephrotic syndrome) but were not included in our analysis of this outcome.

The results of this study highlight opportunities to improve thrombophilia testing practices at our institution and may be generalizable to institutions with similar testing patterns. Because multiple medical services order thrombophilia tests, strategies to improve testing practices are still being determined. The results of this study can serve as a baseline for comparison after strategies are implemented. The most common situation associated with minimal clinical utility was the use of test types not generally recommended by guidelines or UUHC Thrombosis Service physicians for thrombophilia testing (eg, β₂-glycoprotein 1 IgA antibodies, phosphatidyl antibodies). We intend to require a hematology or thrombosis specialty consult prior to ordering these tests. This intervention alone could potentially decrease unnecessary testing by a third. Another consideration is to require a specialty consult prior to any inpatient thrombophilia testing. This strategy has been found to decrease inappropriate testing at other institutions.²¹ We also intend to streamline available thrombophilia testing panels because a poorly designed panel could lead to ordering of multiple tests associated with minimal clinical utility. At least 12 different thrombophilia panels are currently available in our computerized physician order entry system (see Supplementary Table 5). We hypothesize that current panel designs contribute to providers inadvertently ordering unintended or duplicate tests and that reducing the number of available panels and clearly delineating what tests are contained in each panel is likely to reduce unnecessary testing. Other strategies being considered include using electronic clinical decision support tools, implementing strict ordering criteria for all inpatient testing, and establishing a thrombosis stewardship program.

Our study was unique in at least 2 ways. First, previous studies describing thrombophilia testing have described testing patterns for patients with specific indications (eg, VTE), whereas our study described all thrombophilia tests regardless of indication. This allows for testing pattern comparisons across indications and medical services, increasing the generalizability of our results. Second, this study quantifies tests occurring in situations associated with a practical definition of minimal clinical utility.

Our study has several limitations: (1) Many variables were reliant on provider notes and other documentation, which allows for potential misclassification of variables. (2) It was not always possible to determine the ultimate utility of each test in clinical management decisions, and our study did not investigate the impact of thrombophilia testing on duration of anticoagulant therapy. Additionally, select situations could benefit from testing regardless if anticoagulant therapy is altered (eg, informing contraceptive choices). (3) Testing performed following a provoked acute thrombosis was defined as testing within 3 months following administratively defined major surgery. This definition could have included some minor procedures that do not substantially increase VTE risk, resulting in underestimated clinical utility. (4) The UUHC University Hospital serves as a referral hospital for a large geographical area, and investigators did not have access to outpatient records for a large proportion of discharged patients. As a result, frequency of repeat testing could not be assessed, possibly resulting in overestimated clinical utility. (5) In categorizing indications for testing, testing for CVST was subcategorized under testing for ischemic stroke based on presenting symptoms rather than on underlying pathophysiology. The rationale for this categorization is that patients with CVST were often tested based on presenting symptoms. Additionally, tests for CVST were ordered by the neurology service, which also ordered tests for all other ischemic stroke indications. (6) The purpose of our study was to investigate the subset of the hospital’s patient population that received thrombophilia testing, and patients were identified by tests received and not by diagnosis codes. As a result, we are unable to provide the proportion of total patients treated at the hospital for specific conditions who were tested (eg, the proportion of stroke patients that received thrombophilia testing). (7) Current practice guidelines do not recommend testing for phosphatidyl antibodies, even when traditional antiphospholipid testing is negative.^25-27 Although expert panels continue to explore associations between phosphatidyl antibodies and pregnancy morbidity and thrombotic events, the low level of evidence is insufficient to guide clinical management.²⁸ Therefore, we categorized all phosphatidyl testing as associated with minimal clinical utility.