On the diversity of antithrombin proteoforms: the role of a diagnostic mass spectrometry-based test for antithrombin deficiency

Antithrombin is one of the most important regulators of the clotting cascade and a deficiency therein leads to high risk of venous thromboembolism. Antithrombin deficiency exists in two forms; a quantitative deficiency leading to overall lower levels of antithrombin, known as type I antithrombin deficiency; and a qualitative deficiency leading to antithrombin proteoforms with altered functionality, known as type II antithrombin deficiency. The current diagnostic tests for diagnosing patients with antithrombin deficiency lack sensitivity, especially for type II antithrombin deficiency. Furthermore, they do not provide enough level of detail to enable p5 medicine. To this end a new diagnostic test was developed and analytically validated based on mass spectrometry. This test measures the diversity of antithrombin proteoforms present in a sample. The test provides a detailed diagnosis encompassing: 1) the concentration of antithrombin in µmol/L, 2) the presence of mutations, and 3) the glycosylation status of the protein. This enables a more sensitive and detailed approach to identify antithrombin deficiency, by providing the necessary information to enable p5 medicine in the future, potentially leading to improved patient diagnosis, stratification, and future therapies.<br>