On the Way to a Next-Generation Lp(a) Reference Measurement System Based on Quantitative Protein Mass Spectrometry and Molar Units

Metrological traceability of medical test results is essential to guarantee their comparability in time and space across the globe. This comparability (also called standardization) enhances the validity of diagnoses and supports correct treatment as well as the development of new therapies. In this chapter, the authors describe the state-of-the-science around the current Lp(a) measurement procedures. The principles of metrological traceability are not yet correctly implemented, and this has masked the clinical utility of Lp(a) in the past. The unique structural characteristics of polymorphic apolipoprotein(a) in Lp(a) lead to a high variability in Lp(a) mass. In addition, the calibrator isoform composition also affects Lp(a) recovery in clinical specimens, small isoform carriers being underestimated and large apo(a) isoforms carriers being overestimated. Tests expressing Lp(a) in mass units further use incorrect assumptions regarding the protein: lipid ratio of Lp(a). A new reference measurement system that considers the unique apolipoprotein(a) features and produces test results traceable to the International System of Units (SI) is proposed by the IFCC working group on apolipoproteins by mass spectrometry (WG-APO MS). The rationale for the development of this higher-order reference measurement system and for transitioning from the former WHO-IFCC immunoassay-based reference measurement system for Lp(a) into a more robust immunoassay-independent mass spectrometry-based reference measurement system and molar units is pointed out in this chapter. The final goal is to guarantee that all commercial Lp(a) tests are fit for clinical purpose and produce accurate and comparable results within allowable limits of uncertainty.