Developing an SI-traceable Lp(a) reference measurement system: a pilgrimage to selective and accurate apo(a)...

Area of Science:

• Clinical Chemistry
• Cardiovascular Disease Biomarkers
• Mass Spectrometry

Background:

• Lipoprotein(a) (Lp(a)) is a recognized independent risk factor for cardiovascular disease (CVD).
• Recent consensus statements highlight the causal association between Lp(a) levels and cardiovascular outcomes across diverse ethnic groups.
• The development of novel Lp(a)-lowering therapies necessitates accurate Lp(a) measurement for patient risk stratification and treatment monitoring.

Purpose of the Study:

• To describe the development of a next-generation, apo(a)/Lp(a) reference measurement system (RMS).
• To establish a standardized and accurate method for quantifying Lp(a) concentrations.
• To enable reliable performance evaluation and certification of clinical Lp(a) field tests.

Main Methods:

• Development of an apo(a) RMS utilizing quantitative protein mass spectrometry (MS).
• Measurement of selected proteotypic fragments of apolipoprotein(a) (apo(a)) after proteolytic digestion.
• Demonstration of complete proteolysis and equimolar conversion of apo(a) to peptide measurands for accurate Lp(a) quantification.

Main Results:

• A candidate apo(a) reference measurement procedure (RMP) based on MS has been developed and endorsed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC).
• The MS-based approach is inherently apo(a) isoform insensitive, ensuring accurate measurements regardless of apo(a) size.
• Commutability studies have provided recommendations for suitable secondary reference materials.

Conclusions:

• The proposed MS-based apo(a) RMS represents a significant advancement over existing methods.
• Ongoing efforts focus on peptide-based calibration and establishing a harmonized network of calibration laboratories for global standardization.
• This next-generation RMS will be crucial for certifying the accuracy of Lp(a) field methods, supporting clinical decision-making and therapeutic advancements.