Defining the antithrombin measurand: role of proteoforms in harmonisation of diagnostic tests in thrombosis

ended

Current medical tests for antithrombin deficiency generally measure the overall activity, being blind for the actual proteoforms of AT that contribute to the test. To ensure accurate test results, a traceability chain needs to be in place, which requires the accurate definition of the exact analyte to be measured. I hypothesize that an in-depth understanding of the pathological molecular proteoforms of antithrombin (AT) will allow for the identification of clinically relevant proteoforms and enable test harmonization, resulting in a test with a well-defined clinical outcome that are actionable by clinicians. Mass spectrometry (MS) is an emerging technique in the field of clinical chemistry, which is well suited for the detection of proteoform characteristics and outperforms testing methods based on immunoassays. Therefore my aims are 1. To develop a mass spectrometry based test for the quantification of individual characteristics of molecular proteoforms of AT. 2. Analytically validate the developed method according to clinical chemistry procedures, and 3. Assess the role of MS based test for the standardization of AT tests. I am a passionate scientist with a strong background in the development of MS-based tests for proteins. I plan to perform the project in collaboration with my supervisor, who has large experience in medical test development and the ECAT foundation, who is specialized in proficiency testing of AT and test harmonization. This project will allow me to obtain skills and experience to oversee and develop a clinical test from biomarker discover to test evaluation and implementation, specifically in the niche of thrombosis and haemostasis, as well as the transferable skills required to eventually establish my own independent research group.