Diagnostic Performance of Commercial Antithrombin Activity Assays: Do We Get What We Expect?

Area of Science:

• Clinical Chemistry
• Hematology
• Medical Diagnostics

Background:

• Hereditary antithrombin (AT) deficiency is a rare, autosomal dominant disorder linked to recurrent venous thromboembolism (VTE).
• Accurate diagnosis relies on measuring plasma AT activity, but commercial assays vary in sensitivity to different AT mutations.

Purpose of the Study:

• To compare the diagnostic performance of commonly used AT activity assays for inherited antithrombin deficiency.
• To specifically evaluate assay sensitivity for type II AT deficiencies, including heparin-binding site (HBS) variants.

Main Methods:

• Evaluated five commercial AT activity assays across three different analyzers.
• Utilized plasma samples from 76 genetically confirmed AT-deficient subjects and 152 patients undergoing diagnostic AT activity testing.
• Assessed specificity and diagnostic sensitivity of each reagent/analyzer combination.

Main Results:

• Assay specificities ranged from 87% to 100%, with one assay showing 56.5% specificity.
• Diagnostic sensitivity varied significantly (36.8% to 100%) across assays.
• All assays detected type I AT deficiencies, but only one identified the type II HBS variant p.Arg79Cys; sensitivity for type II HBS variants differed based on the analyzer used.

Conclusions:

• Current commercial AT activity assays exhibit substantial variability in detecting inherited antithrombin deficiency, particularly type II variants.
• The choice of coagulation analyzer can significantly impact assay sensitivity for specific AT mutations.
• Inherited antithrombin deficiency may be underdiagnosed, necessitating the development of improved diagnostic strategies.