Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)–like particle and an established independent risk factor for cardiovascular disease. Its plasma concentration and antifibrinolytic properties are largely genetically determined, primarily by variation in the LPA gene, and in particular, by the number of kringle IV type 2 repeats. Lp(a) contributes to atherogenesis partly through its structural similarity to LDL, promoting cholesterol deposition within the vascular wall. Beyond its proatherogenic effects, Lp(a) plays a key role in acute cardiovascular events through pro-inflammatory and prothrombotic mechanisms. Elevated Lp(a) levels promote a prothrombotic state by increasing tissue factor expression andaccelerating activation of the coagulation cascade. Simultaneously, Lp(a) enhances plaque inflammation and vulnerability by stimulating monocyte activation and through the presence of oxidized phospholipids on its surface. Its structural homology with plasminogen further confers antifibrinolytic properties, allowing Lp(a) to competitively inhibit plasminogen binding to fibrin and impair fibrinolysis. This effect is compounded by increased levels of plasminogen activator inhibitor-1 (PAI-1) and a dysregulation of plasminogen activators (tPA, uPA), plasmin, and other fibrinolytic modulators. The resulting thrombotic risk reflects the dynamic balance between coagulation and fibrinolysis, which can be evaluated using global assays such as overall hemostatic potential. Although novel Lp(a)-lowering therapies achieve substantial reductions in circulating Lp(a) concentrations, their effects on hemostatic balance and clinical outcomes remain to be fully elucidated. This review summarizes current evidence on the role of Lp(a) in coagulation and fibrinolysis, with particular emphasis on the complex interplay between its concentration, structure, genetic deteminants, and contribution to cardiovascular risk.

Lipoprotein(a) [Lp(a)] is a genetically determined cardiovascular risk factor that has traditionally been considered stable throughout life, leading major scientific societies to recommend a single lifetime measurement in most individuals. However, emerging evidence challenges this long-standing assumption, suggesting the presence of clinically relevant intra-individual variability. While many individuals remain within the same risk category over time, a non-negligible proportion, particularly those with intermediate or borderline levels, may experience changes sufficient to alter cardiovascular risk classification or potential eligibility for emerging Lp(a)-lowering therapies. Variability appears more pronounced at lower baseline concentrations and may be influenced by demographic, metabolic, and inflammatory factors. Importantly, although long-term studies confirm that a single Lp(a) measurement is predictive of cardiovascular risk, the growing recognition of biological variability raises questions regarding risk stratification in selected patients. Standardization of variability definitions and further longitudinal research are needed to clarify the clinical implications of repeat testing. These considerations are particularly relevant in the era of targeted Lp(a)-lowering therapies, where accurate classification may influence treatment decisions. In this review, we summarize current data on Lp(a) variability across diverse populations and clinical contexts.

This review summarizes our current knowledge and understanding of the biosynthesis and assembly of lipoprotein(a) [Lp(a)] with a focus on diagnostic and therapeutic implications. Lp(a) is composed of a low-density lipoprotein (LDL)-like particle and the covalently bound apolipoprotein(a) [apo(a)]. Our understanding of the physiology and pathophysiology of the atherogenic Lp(a) has considerably increased over the past decades. The precise mechanisms regulating the biosynthesis, secretion, and assembly of Lp(a) have been extensively investigated but are, nevertheless, still incompletely understood or, at least, controversially discussed. Lp(a) plasma concentrations are mainly determined by synthesis and, to a minor extent, also by catabolism. Assembly of Lp(a) occurs in a complex 2-step procedure, starting with an intracellular non-covalent association between lysine-binding sites on apo(a) and lysine residues on apoB-100, the two major protein components of Lp(a). The final assembly of Lp(a) occurs extracellularly and/or transiently associated with the cell membrane by covalent disulfide bonding from newly synthesized apolipoprotein(a) and circulating LDL. Lp(a)-lowering therapies have been developed that specifically inhibit apo(a) biosynthesis and Lp(a) particle assembly. The inhibition of Lp(a) assembly raises interesting questions regarding the quantification of Lp(a) since it leads to the release of substantial amounts of LDL-unbound apo(a), which is co-measured by routine laboratory assays. The complex biosynthesis and assembly pathway of Lp(a) has been intensively investigated since its discovery more than 60 years ago. It is not only of basic-scientific interest but also concerns actual issues of diagnosis and therapy of elevated plasma concentrations of this enigmatic lipoprotein.

Aims: Atherosclerosis, affecting the aorta, cervical, or intracranial arteries, is a common cause of stroke. Previous studies have shown a strong link between high Lp(a) levels and atherosclerotic stroke due to intracranial atherosclerotic disease, implicating Lp(a) in disease development and progression. The precise role of Lp(a) in stroke subtypes remains unclear, although smaller isoform sizes and oxidized phospholipids on Lp(a) are associated with the disease presence. To clarify Lp(a)’s connection with ischemic stroke subtypes, we evaluated various plasma biomarkers previously linked to Lp(a) and disease.

Methods: We used stored plasma samples and data from 244 participants enrolled in an acute ischemic stroke registry at Columbia University Medical Center in New York. Plasma Lp(a) concentrations, apolipoprotein B100 (APOB), and oxidized phospholipids were measured via enzyme-linked immunosorbent assay. APO(a) isoform size was measured via gel electrophoresis. Stroke subtypes were classified based on etiologies using clinical and imaging data. Adjusted multivariate logistic regression models were built to assess associations between Lp(a)-related biomarkers and stroke subtype.

Results: In participants with acute ischemic stroke, high Lp(a) concentrations, percentage of APOB in Lp(a), and OxPL-APO(a) concentrations were significantly associated with the presence of atherosclerotic stroke compared to those with non-atherosclerotic strokes [OR = 1.30 (p = 5.7e - 3), 1.29 (p = 6.9e - 3), 1.27 (p = 1.7e - 2), respectively]. In participants with atherosclerotic stroke, these changes were significantly associated with extracranial atherosclerotic stroke (ECAD), with an OR = 0.69, p = 4e - 2.

Conclusion: In addition to Lp(a) concentrations, the percentage of APOB in Lp(a), and OxPL-APO(a) concentrations are positively associated with acute atherosclerotic ischemic stroke, specifically ECAD.

Lipoprotein(a) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), with strong evidence of causality from genetic and epidemiological studies. This recognition has led to the development of multiple potent lipoprotein(a)-lowering therapies, four of which are currently in phase 3 cardiovascular outcomes trials. Despite this progress, several critical knowledge gaps remain. Notably, the potential role of high lipoprotein(a) in non-coronary vascular diseases, specifically peripheral arterial disease, major adverse limb events, and abdominal aortic aneurysms, has not been adequately investigated, despite the considerable morbidity and mortality associated with these conditions. Furthermore, recent findings suggest that systemic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), may modify the ASCVD risk attributable to high lipoprotein(a). This raises the possibility that future lipoprotein(a)-lowering therapies may only benefit individuals with concomitantly elevated hsCRP. This review summarizes the current knowledge of lipoprotein(a) as a risk factor for cardiovascular disease and aortic valve stenosis, outlines the emerging evidence linking lipoprotein(a) with peripheral arterial disease, major adverse limb events, and abdominal aortic aneurysms, and examines whether high lipoprotein(a) independently predicts the risk of ASCVD and aortic valve stenosis regardless of the presence or absence of systemic low-grade inflammation. By placing recent studies within a broader scientific landscape, we will thus attempt to clarify the vascular relevance of high lipoprotein(a) beyond coronary disease and inform precision targeting of future lipoprotein(a)-lowering therapies.

Current Lp(a)-related scientific literature is mainly related to cardiovascular diseases, while less attention has been paid to the role of Lp(a) in both the severity of infections and the vascular disease events that follow them. In this perspective article, we highlight findings related to lipoprotein(a) [Lp(a)] in infectious diseases, including those caused by the severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, hepatitis C virus (HCV), Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus, or the Plasmodium and trypanosomal parasites. Based on the data from the above-mentioned infections and Lp(a), the role of Lp(a) in these common infectious diseases will be discussed. Of particular interest is that Lp(a) can inhibit HCV infection and is also important for protection against parasitic infections such as malaria and trypanosomiasis. New drugs, like muvalaplin, significantly lower Lp(a) levels, and it is therefore important to learn about the significance of low Lp(a) levels in terms of the potential course of an infection. It remains to be seen whether Lp(a) drugs with different mechanisms of action are relevant for infections.

Aims: Elevated lipoprotein(a) [Lp(a)] is an overlooked and underdiagnosed risk factor for peripheral artery disease (PAD). Negligible testing rates of Lp(a) in patients with PAD are suspected to be largely caused by implementation barriers and poor awareness. Here, we report pilot results of the newly initiated Lp(a)-PAD inpatient care pathway that employs the LILAC-for-Lp(a) framework.

Methods: A review of the process of implementation of the inpatient Lp(a)-PAD pathway was undertaken using quality improvement methods. The prevalence of elevated Lp(a), and its association with the severity of chronic limb ischaemia were investigated.

Results: At 3 months after integrating detection of Lp(a) in the care of patients admitted to hospital for PAD-related limb ischaemia issues, 22.6% of the 106 patients were detected to have elevated Lp(a) levels ≥ 120 nmol/L, and 34.9% with mildly raised Lp(a) ≥ 70 nmol/L. There was a higher proportion of patients with levels ≥ 120 nmol/L compared with Lp(a) < 120 nmol/L who had category 6 classification of chronic limb ischaemia by Rutherford classification (95.8% vs 70.7%, p-value = 0.011). Lp(a) ≥ 120 nmol/L and Lp(a) as a continuous variable were associated with the highest severity of limb ischaemia, p = 0.032 and p = 0.045, respectively. The low-density lipoprotein (LDL) attainment goal in our patients with PAD was suboptimal; LDL-C < 1.4 mmol/L goal attainment was achieved in 30.2% of all patients and 25.0% of the group of elevated Lp(a), respectively.

Conclusion: This pilot study suggests that the LILAC-for-Lp(a) framework, via multidisciplinary collaboration and quality improvement methods, is helpful to integrate Lp(a) testing into PAD management.