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.