Benefits of the Randox Lp(a) Assay

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Clinical Significance

Lp(a) is a highly prevalent and largely genetically determined cardiovascular risk factor, with approximately 1 in 5 individuals worldwide having elevated levels. Unlike many traditional lipid markers, Lp(a) concentrations are minimally influenced by lifestyle or environmental factors.

Despite high prevalence and clear genetic basis, Lp(a) is not routinely included in cardiovascular risk calculators such as QRISK3, meaning inherited risk may go undetected during standard risk assessment. This is clinically significant, as approximately 30% of CVD-related mortality occurs in individuals without elevated conventional risk factors.

A recent Frontiers in Cardiovascular Medicine paper led by Randox researchers reported that in a large UK clinical cohort, a significant proportion of individuals classified as 'increased cardiovascular risk' on the basis of Lp(a) would not be identified using standard QRISK3 scores alone — underscoring the limitations of current risk models in capturing inherited risk conferred by Lp(a).

Challenges

A major analytical challenge in measuring lipoprotein(a) [Lp(a)] is the heterogeneity of apo(a) isoforms. This variability arises from differences in the number of kringle IV type 2 (KIV-2) repeats, which directly affects immunoassay performance.

In immunoassays, each KIV-2 repeat functions as an epitope. If calibrators do not adequately reflect the full range of apo(a) isoforms present in patient samples, Lp(a) concentrations may be inaccurately reported. Larger isoforms tend to be overestimated, while smaller isoforms — which are more strongly associated with elevated Lp(a) levels and increased cardiovascular risk — may be underestimated. As a result, poor assay standardisation can lead to under-recognition of Lp(a)-associated cardiovascular disease (CVD) risk.

Importance of Standardisation and Reporting Units

To minimise isoform-related bias, robust standardisation is essential. Assays calibrated in nmol/L and traceable to the WHO/IFCC reference material (SRM 2B) demonstrate improved comparability and reduced size-related bias.

The European Atherosclerosis Society (EAS) recommends reporting Lp(a) in nmol/L rather than mg/dL, as nmol/L more accurately reflects particle concentration and mitigates distortion caused by apo(a) size variability. This approach also supports harmonisation between laboratories and facilitates transition from legacy mass-based reporting systems.

Commercial assays based on the Denka Seiken methodology have demonstrated acceptable bias when compared with the NLMDRL reference method, supported by:

• Use of multiple serum pools spanning a wide range of Lp(a) concentrations
• Calibrators that reflect the inverse relationship between apo(a) isoform size and Lp(a) concentration
• Traceability to WHO/IFCC reference material and calibration in nmol/L

Frequency of Testing

Lp(a) levels are predominantly genetically determined and remain stable throughout life. As a result, a single lifetime measurement is generally sufficient for cardiovascular risk assessment in most individuals.

Repeat testing may be appropriate:

• When results are close to clinical decision thresholds
• If a secondary cause is suspected
• When Lp(a)-lowering therapies are initiated

This approach aligns with recent European guidelines, which aim to identify individuals at very high inherited risk (e.g. >430 nmol/L). In contrast, HEART UK recommends targeted testing in higher-risk populations and recognises clinically relevant risk at lower thresholds (e.g. >90 nmol/L).

Given its high prevalence, strong genetic basis, and absence from tools such as QRISK3, Lp(a) represents a substantial and under-recognised contributor to cardiovascular risk.

WHO/IFCC

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), through its Working Group on Lp(a) and together with research institutions and several diagnostic companies recommends that laboratories use assays which do not suffer from apo(a) size-related bias. The IFCC SRM 2B was accepted by the WHO Expert Committee on Biological Standardisation as the First WHO/IFCC International Reference Reagent for Lp(a) to ensure conformity by diagnostic companies to the European Union's Directive on In vitro Diagnostic Medical Devices for the metrological traceability of calibrator materials ⁴.

HEART UK

Download the Health UK Consensus statement on Lipoprotein(a): A call to action Download