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

Programme(s): H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
Topic(s): MSCA-IF-2018 - Individual Fellowships
Call for proposal: H2020-MSCA-IF-2018
Funding Scheme: MSCA-IF-EF-RI - RI – Reintegration panel

Grant agreement ID: 843615

Project description
A novel thrombosis test
Antithrombin (AT) is a liver-secreted protein that regulates the coagulation system by inactivating specific enzymes in the pathway of blood clotting. Diagnostic tests of AT deficiency rely on its activity, disregarding the existence of many different proteoforms and their clinical meaning. The EU-funded HarmonizATforms project is working to harmonise AT tests and develop an assay that generates clinically meaningful results. Researchers are investigating all clinically relevant ATs and will develop a test based on mass spectrometry rather than on immunoassay, which is the current gold standard. The test is expected to bring diagnostic superiority in the fields of thrombosis and haemostasis.

Objective
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 fellow's 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. The candidate is a passionate scientist with a strong background in the development of MS-based tests for proteins. He plans to perform the project in collaboration with his 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 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 his own independent research group.