Genetics
Global Lp(a) standardization nears reality with a mass-spectrometry reference method, review (Clin Chem Lab Med 2026)
Original title: On the cusp of global lipoprotein(a) standardization
Review of the decades-long effort toward global lipoprotein(a) standardization, addressing why Lp(a) has been called the most misunderstood metric in laboratory medicine. The heterogeneous kringle IV domain of apolipoprotein(a), built from 3 to about 40 KIV2 repeats forming 12 to 50 kringles, causes KIV2-dependent antibodies to over-recover larger and under-recover smaller apo(a) particles relative to the calibrator, undermining the analyte-calibrator identity that immunoassays require. Following the 1990s IFCC ELISA-based reference measurement procedure and the WHO-IFCC SRM2B reference material, a second-generation, ISO 15193-compliant, IFCC-endorsed multiplex mass-spectrometry reference measurement procedure has now been developed, with traceability to SRM2B maintained through a network of three calibration laboratories running ISO 15194-compliant serum reference materials. The authors conclude the field is now equipped for global Lp(a) standardization, enabling effective guideline implementation and refined cardiovascular precision diagnostics.
Original abstract
Lipoprotein(a) (Lp(a)) has the reputation of being the most misunderstood metric in laboratory medicine. The unique apolipoprotein(a) (apo(a)) in Lp(a) is very heterogenous, the kringle IV domain of apo(a) being formed by 12-50 kringles due to 3 to ∼40 KIV2 repeats. The variable number of repeated identical KIV2 domains causes KIV2-dependent antibodies to form different amounts of immunocomplexes with apo(a), leading to higher recovery for larger and lower recovery for smaller apo(a) particles than the calibrator. Consequently, the required identity between the analyte in samples and in assay calibrator(s), which is at the basis of any immunoassay, cannot be accomplished in the case of Lp(a). Global Lp(a) standardization was first attempted in the nineties by an IFCC Working Group on Lp(a) Standardization using an ELISA-based reference measurement procedure (RMP) with monoclonal anti-apo(a) antibodies against unique epitopes. WHO-IFCC reference material (RM), named SRM2B, was established with apo(a) expressed in molar units. Currently, a 2nd generation, ISO 15193 compliant, IFCC-endorsed multiplex RMP based on quantitative Mass Spectrometry (MS) has been developed. Traceability to SRM2B is maintained using a value transfer protocol that assigned values to commutable serum-based secondary RMs. ISO 15194 compliant serum-based RMs are currently available. A network of three calibration laboratories runs the harmonized apo(a) RMP. Equipped with a state-of-the-art calibration hierarchy for Lp(a) and using a 2-step approach, it is prime time for global Lp(a) standardization to ensure effective implementation of Lp(a) clinical guidelines and refined cardiovascular precision diagnostics.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.