No Thrombotic Risk From Higher Lp(a) Levels

For the study, Lp(a) levels, as well as an Lp(a) genetic risk score, were assessed in almost 500,000 participants in a prospective cohort study who were followed for both major coronary and venous thromboembolic events.

The results, presented at the European Atherosclerosis Society 2022 congress on May 24, showed that there was a strong association between the incidence of major coronary events, including fatal or nonfatal myocardial infarction (MI) or coronary revascularization, and both increased Lp(a) levels and higher Lp(a) genetic risk scores.

However, no such association was found between determinants of Lp(a) concentrations and outcomes, such as venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism.

And although Lp(a) was highly associated with major coronary events, the risk associated with Lp(a) did not appear to be diminished among those with genetic scores that mimicked the effects of antiplatelet or antithrombin therapies.

Study presenter Elena Olmastroni, PhD, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, said the "take-home messages from this study are quite simple but extremely important from a clinical point of view."

Essentially, the findings show that Lp(a) does not have a clinically significant venous or arterial prothrombotic effect, and that the increased risk for major coronary events, "is unlikely to be reduced by an antiplatelet or antithrombin therapy," Olmastroni said.

She added that there is therefore an "urgent need for drugs specifically aimed at lowering Lp(a)," noting that drugs targeting apolipoprotein(a) production are in clinical development.

An "Enigmatic" Lipoprotein

In her presentation, Olmastroni called Lp(a) an "enigmatic" lipoprotein that is thought to contribute to atherosclerosis by binding low-density-lipoprotein cholesterol, calcium, and other components.


Moreover, recent Mendelian randomization analyses and genome-wide association studies "have clearly demonstrated that Lp(a) is an independent and causal contributor to cardiovascular disease events," she said.


Although Lp(a) is known to be proatherogenic, Olmastroni noted, researchers have suggested that it might also have a prothrombotic effect after a meta-analysis indicated that increased levels of the lipoprotein were associated with an increased risk for VTE.


In contrast, a genetic study showed the opposite, with the rs3798220 and rs10455872 single-nucleotide polymorphisms (SNPs) associated with Lp(a) concentrations showing no increase in the odds ratio of VTE per variant allele.


To investigate further, the researchers examined data from the UK Biobank, which contains genetic, physical, and health-related data on approximately 500,000 individuals 40 to 70 years of age.


This includes Lp(a) measurements at the time of enrolment in the databank and the determination of an Lp(a) genetic risk score based on the two SNPs previously studied.


The team calculated the association between Lp(a) concentrations and subsequent major coronary events and VTE, stratified not only by Lp(a) genetic score, but also by the GUCY1A3 score and Factor II and V polygenic risk score to replicate the effect of antiplatelet and antithrombin therapies.


They assessed 445,774 participants from the UK Biobank who had an average age of 57.3 years, and of whom 54.3% were women. During follow-up, there were 23,302 major coronary events (MCE), 15,974 VTEs, 11,097 DVTs, and 6602 pulmonary embolisms.


The results showed that, among individuals with Lp(a) levels of at least 100 nmol/L, the hazard ratio for MCE was 1.35 (95% CI, 1.32 - 1.38).


Looking at the Lp(a) genetic score, they found that, compared with individuals with a score of 0, those with a score of 1 had a hazard ratio for major cardiovascular events of 1.47 (95% CI, 1.43 - 1.52), rising to 1.89 (95% CI, 1.70 - 2.10) in individuals with a score of 2.


In contrast, there was no associated between Lp(a) concentrations of at least 100 nmol/L and the risk for VTE, DVT, or pulmonary embolism, even when stratifying by Lp(a) genetic score.


Although GUCY1A3 and Factor II and V scores were significantly associated with the risk for both MCE and VTE, that effect disappeared when the researchers focused on individuals with Lp(a) levels of at least 100 nmol/L.

She told | Medscape Cardiology that the main implication of their findings is that, whether in primary or secondary prevention, antiplatelet or anticoagulant therapy "is not effective in reducing the risk" for major cardiac events in patients with high Lp(a) levels.

Florian Kronenberg, MD, who was not involved in the study, called the findings "very important" because previous small studies "gave the impression" that giving aspirin might lower the risk for cardiac outcomes in patients with high Lp(a) levels.

However, the current analysis is the "best evidence that we can have at the moment," he told | Medscape Cardiology, as the genetic data that were used are "not confounded” and not subject to reverse causality.

The results therefore show "very clearly" that "if someone has an Lp(a) variant associated with a lifelong increase in Lp(a) concentrations, there is absolutely no association" with thromboembolic events, said Kronenberg, from the Medical University of Innsbruck, Austria.


In contrast, such people have a "markedly increased risk for cardiovascular events," which is a "very important point."