Lp(a)
Lipoprotein(a)
What it is
Lipoprotein(a) [Lp(a)] is a lipoprotein particle structurally resembling LDL — it contains an apolipoprotein B-100 (ApoB) core bound to cholesterol and other lipids — with one critical addition: an extra glycoprotein called apolipoprotein(a) [apo(a)], attached via a disulfide bond. Apo(a) has structural homology to plasminogen, the precursor of the fibrinolytic enzyme plasmin. This structural resemblance gives Lp(a) its unique and dangerous dual mechanism: it is simultaneously atherogenic (like LDL, it deposits in arterial walls and contributes to plaque formation) and antifibrinolytic (apo(a) competes with plasminogen for binding sites on fibrin clots and endothelium, impairing the natural dissolution of clots that have already formed). Lp(a) concentration in the blood is approximately 80–90% genetically determined by the LPA gene, specifically by the number of kringle IV type 2 repeats in the apo(a) protein — individuals with fewer repeats produce more apo(a) and have higher Lp(a) levels. Lp(a) varies more than 1,000-fold across the population, is set largely at birth, and remains essentially stable throughout adult life. It is not meaningfully altered by diet, exercise, statins, ezetimibe, or most conventional lipid-lowering therapies — a defining characteristic that distinguishes it from every other cardiovascular risk marker in the Blueprint protocol.
Why we measure it
Lp(a) is the most common inherited cause of premature cardiovascular disease. Approximately 20% of the global population has Lp(a) above 50 mg/dL (105 nmol/L) — the level most commonly associated with clinically meaningful elevated cardiovascular risk — and the vast majority of these individuals do not know their Lp(a) level, because it is not included in a standard lipid panel. A large Mendelian randomisation analysis by Clarke and colleagues, published in the New England Journal of Medicine, used genetic variants in the LPA locus as proxies for lifelong high Lp(a) and demonstrated a causal relationship between elevated Lp(a) and coronary heart disease — independent of LDL cholesterol and other traditional risk factors. The European Atherosclerosis Society consensus statement, updated in 2022, characterises high Lp(a) as an independent, causal cardiovascular risk factor with sufficient evidence to justify universal once-in-a-lifetime screening for all adults. Lp(a) is also the principal driver of calcific aortic valve stenosis in genetically susceptible individuals — a separate and serious condition. Knowing Lp(a) changes clinical management in multiple ways. In risk stratification: an individual who appears low-risk by traditional metrics (normal LDL, no hypertension, non-smoker) but has Lp(a) above 150 nmol/L has substantially elevated actual risk and warrants a different monitoring intensity and earlier lipid-lowering treatment target. In LDL management: because Lp(a) carries its own ApoB-containing particle, total ApoB is a more accurate measure of atherogenic particle burden in high-Lp(a) individuals than LDL alone. And in the near future: pelacarsen (AKCEA-APO(a)-LRx) and olpasiran, RNA-based therapies targeting Lp(a) synthesis, have demonstrated greater than 90% Lp(a) reduction in Phase II and III trials, with outcome trials ongoing — establishing Lp(a) as a therapeutically targetable risk factor for the first time.
Why once at enrollment
Lp(a) is genetically determined and does not change meaningfully over a lifetime. A single measurement at enrollment establishes the individual's lifelong Lp(a) status. The European Atherosclerosis Society and American Heart Association both support once-in-a-lifetime measurement as sufficient for most individuals.
What movement means
Lp(a) is reported in either mg/dL or nmol/L. The nmol/L unit is preferred by most specialists because it directly measures the number of particles (analogous to ApoB for LDL) rather than the mass, and is less affected by variability in apo(a) isoform size between individuals. Conversion between units is not straightforward due to apo(a) size heterogeneity — results should be interpreted in the unit reported by the laboratory. Risk thresholds below reflect mg/dL values with approximate nmol/L equivalents where established.
Normal
< 30 mg/dL (< 75 nmol/L)
Not associated with meaningfully elevated cardiovascular risk from Lp(a) specifically. Standard protocol management of modifiable risk factors (ApoB, hsCRP, blood pressure, metabolic health) applies. No additional Lp(a)-specific clinical action is required.
Nordestgaard BG et al., European Heart Journal, 2010 — doi:10.1093/eurheartj/ehq386
Borderline
30 – 50 mg/dL (75 – 105 nmol/L)
Modestly elevated. Warrants consideration as an additional factor in overall cardiovascular risk assessment. In individuals with other risk factors (elevated ApoB, family history, ε4 APOE genotype), the combination shifts the risk calculus toward more proactive management of modifiable factors.
Nordestgaard BG et al., European Heart Journal, 2010 — doi:10.1093/eurheartj/ehq386
High
> 50 mg/dL (> 105 nmol/L)
The threshold most commonly cited in clinical guidelines for elevated Lp(a)-associated cardiovascular risk, present in approximately 20% of the population. Associated with approximately 1.5–2-fold increased coronary artery disease risk above background. Justifies more aggressive management of all modifiable cardiovascular risk factors — particularly ApoB, blood pressure, and inflammation — and warrants explicit consideration in shared decision-making about lipid-lowering intensity.
Kronenberg F et al., European Heart Journal, 2022 — doi:10.1093/eurheartj/ehac179
Very High
> 180 mg/dL (> 430 nmol/L)
Associated with cardiovascular risk equivalent in magnitude to heterozygous familial hypercholesterolaemia — one of the highest-risk inherited lipid conditions. Strong indication for specialist lipidology or preventive cardiology input. Warrants consideration as a priority candidate for emerging Lp(a)-lowering pharmacotherapy (pelacarsen, olpasiran) when these reach clinical approval.
Kronenberg F et al., European Heart Journal, 2022 — doi:10.1093/eurheartj/ehac179
In the protocol
References
- 1.
Kronenberg F, Mora S, Stroes ESG, et al.. “Lipoprotein(a) in Atherosclerotic Cardiovascular Disease and Aortic Stenosis: A European Atherosclerosis Society Consensus Statement.” European Heart Journal. 2022.
- 2.
Nordestgaard BG, Chapman MJ, Ray K, et al.. “Lipoprotein(a) as a Cardiovascular Risk Factor: Current Status.” European Heart Journal. 2010.
- 3.
Clarke R, Peden JF, Hopewell JC, et al.. “Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease.” New England Journal of Medicine. 2009.
- 4.
Tsimikas S. “A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies.” Journal of the American College of Cardiology. 2017.