BACKGROUND: Inherited thrombophilia testing following venous thromboembolism (VTE) is of limited utility and, performed in the setting of an acute thrombotic episode, is especially unreliable. Studies suggest that inpatient thrombophilia workups, often performed in the context of acute VTE or stroke, lead to high rates of false positives and can result in inappropriate long-term management decisions. Therefore, various professional societies advise against such testing, especially in acute care settings. These include Choosing Wisely recommendations from the American Society of Hematology, who recommend against routine testing following first episode of provoked VTE, and the American Society for Clinical Pathology, who advise against ordering these tests during an active clotting event. However, these studies continue to be ordered regularly, increasing the overall cost of health care with limited clinical benefit.

METHODS: We carried out a retrospective chart review of all inpatient inherited thrombophilia tests ordered between January 1st, 2019 and December 31st, 2021 at Thomas Jefferson University Hospitals, including its 3 primary hospitals in Philadelphia, PA. The goal was to determine indications for testing, rate of positivity, and whether positive results changed patients’ clinical management. Tests included in the study were for the following conditions: Factor V Leiden (FVL); prothrombin G20210A variant (PTG20210A); Protein C, S, and antithrombin deficiency; hyperhomocysteinemia; and plasminogen activator inhibitor-1 (PAI-1) elevation. The study included 152 patients, among whom 574 unique tests were ordered. Tests sent for non-thrombotic indications or in patients with a known factor deficiency were excluded.

RESULTS: Patient demographics, clinical presentations, and VTE risk factors are summarized in Table 1. Median age of the patients was 49 years (IQR 34-62) and 53.9% were under age 50. 93 patients (61.2%) were female. VTE was associated with a major transient risk factor or cancer in 44.7% of patients. Conditions for which testing was ordered included FVL (24.7%), PTG20210A (20.4%) Protein S deficiency (16.5%), Protein C deficiency (14.8%), antithrombin deficiency (13.0%), hyperhomocysteinemia (10.3%), and PAI-1 elevation (0.2%).

Overall, 81.9% of tests were normal. Among unique tests, MTHFR analysis was most frequently abnormal (71.4% of ordered tests), followed by antithrombin (44.0%), Protein C antigen (27.3%), total Protein S (26.7%), Protein C function (25.7%), and free protein S (20.0%). Certain tests, including antithrombin activity, Protein C antigen and function, and total Protein S, have reference ranges in our lab that start well above 50%, so results that fell below normal but >60% were termed "borderline positive” and considered to be likely false positives.

Among individual patients, 62/152 (40.8%) had at least one abnormal result and 47/152 (30.9%) had at least one positive result not considered borderline. There was no significant difference in rate of having at least one non-borderline positive result between patients with unprovoked VTE (27/84, 32.1%) and those with a major transient risk factor, estrogen use/pregnancy, or cancer (20/68, 29.4%; χ2, P=.717). There was also no difference in positive test rate between patients age < 50 years (24/82, 29.3%) and those ≥ 50 years (23/70, 32.9%; P=.633) (Figure 1).

All charts were reviewed for inpatient and outpatient documentation to determine short- and long-term clinical decision-making. In 2/152 (1.3%) patients, documentation supported a definitive change in management because of a positive thrombophilia test result. These included a 20-year-old woman with large PE while on a combined oral contraceptive and a 33-year-old man with provoked DVT following severe spinal cord injury (resulting in tetraplegia) who were continued on long-term anticoagulation for Protein S deficiency and double heterozygosity for FVL and PTG20210A, respectively. Based on query of the hospital chargemaster, all tests during the study period totaled $264,913 in charges.

CONCLUSION: Our single-institution study found that following acute VTE, inpatient testing for inherited thrombophilias was frequently done in patients with provoked events and resulted in many abnormal tests likely comprising false positives, rarely changed clinical management, and was associated with high costs.

No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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