1. Introduction

Lipoprotein(a) (Lp(a)), a low-density lipoprotein (LDL)-like particle covalently bound to apolipoprotein(a) (apo(a)), has emerged as an independent risk factor for cardiovascular disease, irrespective of traditional lipid parameters. Elevated levels of Lp(a) are associated with an increased risk of coronary artery disease, myocardial infarction, and stroke, and contribute to the development and progression of atherosclerosis^[1]. Lp(a) concentration is 90% genetically determined by variants in the LPA gene^[2], and more than 20% of the population have concentrations in the atherogenic range (> 50 mg/dL)^[3]. The LPA gene is located on the long arm of chromosome 6 (6q26-27)^[4] and is one of the most polymorphic genes in humans, with multiple variants identified. The LPA gene is derived from a duplication of the plasminogen gene (PLG)^[2], and the apo(a) structure is homologous to that of plasminogen^[3]. Plasminogen contains five different coiled-coil regions, i.e., kringle domains (KI to KV), and an active protease domain. In contrast, apo(a) lacks the kringle KI, KII, and KIII domains, but contains KV and an inactive protease domain. It also contains ten different KIV subtypes (KIV1-10). The number of KIV2 repeats can range from one to over 40^[5]. Lp(a) probably plays an even greater role in the development of acute cardiovascular events than in the development and progression of atherosclerosis. Acute cardiovascular events most commonly result from both atherosclerotic plaque rupture and the subsequent thrombus formation^[6]. The concentration of Lp(a) significantly influences both the atherosclerotic plaque vulnerability and the thrombotic potential. Its structural properties contribute to atherosclerosis and plaque formation and instability via pro-inflammatory mechanisms. Simultaneously, Lp(a) affects thrombus formation by disrupting the balance between coagulation and fibrinolysis^[7]. The three defined roles of Lp(a) in the progression of atherosclerosis include its proatherogenic, prothrombotic and pro-inflammatory effects. The primary reason for Lp(a)’s proatherogenic role is its structural similarity to LDL particles, enabling cholesterol deposition in the vascular wall and accelerating atherosclerosis^[8]. The pro-inflammatory role of Lp(a) is a consequence of oxidised phospholipids (OxPL) being present on its surface, activating endothelial cells, monocytes, and macrophages. These cells then secrete inflammatory cytokines and adhesion molecules, which leads to chronic vascular inflammation and the progression of atherosclerosis^[9]. Increased inflammatory activity in the atherosclerotic plaque is also one of the main reasons for its tendency to rupture. The combined prothrombotic and antifibrinolytic effects of elevated Lp(a) levels increase the risk of arterial thrombosis, thereby predisposing to acute cardiovascular events. The prothrombotic role stems from the structural similarity of Lp(a) to plasminogen, which enables Lp(a) to competitively inhibit plasminogen binding to fibrin. Consequently, the production of plasmin, the main enzyme in fibrinolysis, is reduced, fibrin degradation is impaired, and the resulting thrombus is stabilised, thereby increasing the risk of thrombosis^[10].

It should be noted that the mechanisms linking elevated Lp(a) levels to alterations in the coagulation–fibrinolytic system are closely interconnected and, in many cases, cannot be clearly separated. This, together with the limited evidence on the effects of Lp(a) reduction on other atherosclerotic risk factors, and the even more limited data regarding its impact on cardiovascular events, largely explains why current recommendations for the management of elevated Lp(a) concentrations^[11] are based primarily on findings from large epidemiological studies^[12] rather than interventional outcome trials. This approach is reflected in the European Atherosclerosis Society consensus statement and earlier population-based analyses demonstrating the association between extreme Lp(a) levels and cardiovascular risk^[11,12]. In the future, we will likely need to consider not only the concentration of Lp(a), but also its pro-atherosclerotic properties, as reflected in the number of KIV2 repeats.

The aim of this review is to provide a detailed analysis of the mechanisms by which elevated Lp(a) levels contribute to arterial thrombosis. Specifically, we will assess its procoagulant role in thrombus formation and its antifibrinolytic role in impairing clot dissolution following plaque rupture (Figure 1). We will also examine how these mechanisms are related to each other, forming the total haemostatic potential, and how this contributes to the occurrence of arterial thrombosis and thus an acute cardiovascular event.

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Figure 1. Lipoprotein(a) [Lp(a)] promotes a prothrombotic and proatherogenic state. Lp(a) increases TF secretion, resulting in enhanced activation of the extrinsic coagulation pathway and increased fibrin clot formation. Concurrently, Lp(a) elevates PAI-1 levels, leading to impaired fibrinolytic capacity and reduced fibrin degradation. Furthermore, Lp(a) promotes foam cell formation within atherosclerotic plaques, thereby increasing plaque vulnerability and susceptibility to rupture. Created in BioRender. Zupan, J. (2026) https://app.biorender.com/citation/69f1a98d6ce5cfa3808c3ddd. TF: tissue factor; PAI-1: plasminogen activator inhibitor-1; LDL: low-density lipoprotein.

2. Coagulation

2.1 Overview of coagulation and tissue factor (TF)

The coagulation system is a vital defence mechanism that prevents excessive bleeding when the vascular wall is damaged. Haemostasis begins with vasoconstriction and the formation of a primary platelet plug, which is facilitated by platelet adhesion, activation, and aggregation. This is stabilised during secondary haemostasis, where a cascade of plasma coagulation factors is activated. This occurs via both the extrinsic and intrinsic pathways, which converge in the common factor X activation pathway. Consequently, thrombin is produced from prothrombin. Thrombin then converts fibrinogen into fibrin, stabilising the platelet plug by forming a solid fibrin clot^[13].

TF, also known as coagulation factor III, triggers the extrinsic pathway of coagulation, which is therefore central to the rapid haemostatic response to vascular injury. Under physiological conditions, TF is primarily localised within subendothelial tissues, isolated from the bloodstream. Following vascular injury, however, it becomes exposed to circulating blood, enabling it to bind to circulating factor VII. This forms the TF–VIIa complex after the proteolytic activation of factor VII, which initiates the coagulation cascade by activating factors IX and X. Activated factor X then leads to the formation of thrombin, which is essential for forming a stable fibrin clot. Excessive or uncontrolled TF expression, as occurs in conditions such as atherosclerosis, cancer, or sepsis, increases the thrombogenic potential and the risk of acute thrombotic events. Thus, TF represents a key interface between haemostasis, inflammation, and pathological thrombosis^[14].

2.2 TF expression: From normal vasculature to atherosclerotic plaque

The TF expression varies greatly across the vascular system, influencing its role in site-specific thrombotic occlusions. In healthy vessels, TF messenger RNA (mRNA) and protein are absent from endothelial cells in both veins and arteries. Expression is low in the venous media and minimal in the arterial media. The highest constitutive expression is found in the adventitia of vessels such as the saphenous vein and the internal mammary artery^[15,16]. This pattern shifts dramatically in atherosclerosis, where TF expression increases significantly. Within the atherosclerotic plaques, TF mRNA and protein levels are markedly higher in the fibrous cap, shoulder regions, and the base. The most intense expression localises to the necrotic core and to macrophage-rich foam cells. Notably, TF expression is strongly evident in the extracellular matrix of the necrotic core. In contrast, the media underlying the plaque remains devoid of TF expression.

Within the necrotic core, which consists largely of inflammatory cells such as monocytes and macrophages, TF gene expression is accelerated via the transcription factors activator protein 1 and nuclear factor-κB (NF-κB)^[17]. Although peripheral blood monocyte counts may not directly reflect their plaque concentration, evidence suggests that individuals with more vulnerable plaques have a higher proportion of circulating pro-inflammatory monocytes^[18].

2.3 The Lp(a)-monocyte-TF axis in thrombosis

Monocytes are a highly heterogeneous population that play distinct roles in atherosclerosis. They can be divided into three types: CD14++CD16- (classical monocytes), CD14++CD16+ (intermediate monocytes (IM)), and CD14+CD16++ (non-classical monocytes)^[19]. Although the IM subpopulation is the smallest of the monocyte subsets, its concentration has been shown to be an independent predictor of future coronary events in patients undergoing elective coronary angiography^[20]. The distribution of individual monocyte subsets is closely related to lipid risk factors. Notably, in patients with stable coronary artery disease, proatherogenic monocyte subsets have been shown to be more strongly associated with the concentration of small dense LDL cholesterol particles than with LDL cholesterol alone^[21]. A similar pattern has been observed for high-density lipoprotein (HDL) cholesterol^[22], where monocyte subpopulations were more closely associated with the concentration of small dense HDL cholesterol particles than with HDL cholesterol concentration alone. This suggests that proatherogenic and antiatherogenic lipoprotein subfractions may be more physiologically relevant than total concentrations in modulating monocyte phenotype.

In the same group of patients, it was shown that those with Lp(a) concentrations above 500 mg/L had a significantly higher proportion of proatherogenic IM monocytes than those with Lp(a) concentrations below 500 mg/L^[23]. As monocytes and macrophages are a significant source of TF, these risk factors, specific monocyte subsets, atherogenic lipoprotein subfractions, and high Lp(a), may contribute to a prothrombotic state by enhancing TF expression.

In a cohort of 64 patients with stable atherosclerotic cardiovascular disease (ASCVD), categorised by high (≥ 150 nmol/L) or low (< 75 nmol/L) Lp(a) levels, those with high Lp(a) exhibited elevated circulating markers of inflammation (e.g., CCL28 and IL-17D) and TF, indicating vascular dysfunction. While total monocyte counts and high-sensitivity C-reactive protein levels were comparable between the two groups, CD14+ monocytes from patients with high Lp(a) were more activated and expressed higher levels of TF. This resulted in a significantly greater concentration and activity of TF.

Lp(a) activates monocytes via the toll-like receptor 2 (TLR2) and NF-κB signalling pathways, thereby upregulating TF expression and activity^[24]. Transcriptomic profiling confirmed enhanced pro-inflammatory and prothrombotic gene activation, particularly following TLR stimulation. Additionally, purified Lp(a) was shown to induce TF expression on monocytes through TLR2 and NF-κB signalling. These findings reveal a causal link between elevated Lp(a), monocyte-driven inflammation, and thrombosis, which helps to explain the increased atherogenic risk in ASCVD patients with high Lp(a).

2.4 Therapeutic targeting of TF: Mechanisms and clinical implications

Proprotein convertase subtilisin/kexin 9 (PCSK9) is one of the main enzymes that determines LDL cholesterol levels^[25], and is also an independent predictor of future cardiovascular events^[26]. Scalise et al.^[27] demonstrated that PCSK9 increases TF procoagulant activity, TF mRNA, and TF protein levels in a dose-dependent manner in both peripheral blood mononuclear cells and a human monocytic cell line derived from monocytes of a patient with acute monocytic leukaemia (THP-1). This effect was prevented by inhibitors of the TLR4 or NF-κB pathways, or by an anti-PCSK9 antibody. In contrast, statins downregulate TF expression and activity via multiple pathways. Several statins (simvastatin, fluvastatin, cerivastatin, atorvastatin, pravastatin, lovastatin) have been shown to reduce TF mRNA in macrophages, endothelial and smooth muscle cells in vitro, largely via the inhibition of NF-κB transcription^[28,29]. In vivo, statin therapy reduces TF activity and expression in hypercholesterolaemic patients^[30]. Notably, a clinical trial involving patients undergoing endarterectomy found that pretreatment with atorvastatin was associated with a 29% reduction in TF antigen levels and a 56% reduction in TF activity compared to placebo^[31]. A similar statin-induced reduction in TF expression has been reported in atherosclerotic plaques removed from coronary arteries^[32]. The ability of statins to downregulate TF independently of cholesterol-lowering effects has also been demonstrated in animal models^[33,34]. One specific mechanism involves statin-mediated inhibition of thrombin-induced TF expression in endothelial cells via relocation and suppression of ERK1/2 phosphorylation by protease-activated receptor-1, most likely due to decreased cell-membrane cholesterol^[35].

Although TF levels correlate with acute thrombotic events, they have limited prognostic value. Even though they are elevated in unstable angina compared to stable angina or controls^[36], and higher in apparently healthy individuals who subsequently suffered a myocardial infarction, TF has not been proven to be an independent predictive factor of future cardiovascular events^[37].

A significant knowledge gap exists regarding the interaction between Lp(a), TF, and modern therapies. Although reducing Lp(a) is expected to lower TF concentration and activity, there is no clinical data to confirm this. Furthermore, while PCSK9 inhibitors lower both LDL cholesterol and Lp(a), it remains unclear to what extent their observed modulation of TF is due to the reduction in Lp(a) versus the reduction in LDL cholesterol. The absence of clinically useful drugs specifically designed to lower Lp(a) means we cannot answer the question of how reducing Lp(a) by over 90% affects both the atherothrombotic process itself and the incidence of cardiovascular events.

3. Fibrinolysis

3.1 Impaired fibrinolysis in atherosclerosis: From PAI-1 to Lp(a)

Impaired fibrinolysis is a key mechanism through which thrombi formed on or within atherosclerotic plaques persist, contributing to plaque progression and clinical events. At a molecular level, this phenomenon is primarily driven by elevated local and systemic levels of PAI-1 alongside alterations in the balance and localisation of plasminogen activators (tPA and uPA), plasmin, and other modulators. Elevated PAI-1 rapidly inhibits tissue-type and urokinase-type plasminogen activators, reducing the conversion of plasminogen to plasmin and thus attenuating fibrin degradation, the biochemical hallmark of impaired fibrinolysis^[38]. Within atherosclerotic lesions, impaired fibrinolysis has both local and systemic contributors. Endothelial dysfunction and an inflammatory plaque microenvironment increase the expression and release of PAI-1 from endothelial cells, vascular smooth muscle cells, and infiltrating inflammatory cells. Simultaneously, the expression and activity of tPA and uPA show an altered distribution (often cell-associated rather than freely soluble) in advanced lesions. The net effect is reduced local plasmin generation and defective clearance of fibrin deposits in the intima. These local fibrin deposits are commonly observed in human plaques and are associated with areas of intimal thickening and previous micro-haemorrhage^[39]. Blood PAI-1 antigen levels and activity are strongly correlated, and both parameters have been shown to be important factors in the fibrinolytic process and to predict future coronary events independently, in both patients with^[40] and without previously known coronary disease^[41]. However, both PAI-1 activity and concentration are associated with numerous atherosclerotic risk factors and preclinical atherosclerotic changes. Consequently, PAI-1 concentration and activity have been found to be associated with obesity and type 2 diabetes^[42,43].

In patients with familial hypercholesterolemia, both the concentration and activity of PAI-1 are strongly associated with features of the metabolic syndrome, including insulin levels, insulin resistance, body mass index, and triglyceride concentrations, and are inversely related to HDL cholesterol^[42]. In contrast, we found no association between LDL cholesterol or Lp(a) concentrations and prior myocardial infarction. Notably, PAI-1 remained an independent predictor of myocardial infarction irrespective of LDL cholesterol and Lp(a) levels, a finding that is somewhat unexpected given the well-established role of Lp(a) in modulating fibrinolysis.

Adipose tissue, particularly subcutaneous abdominal fat, constitutes a major source of PAI-1 and reflects key components of the metabolic syndrome. Consistent with this notion, Mavri et al.^[43] reported increased PAI-1 mRNA expression in individuals with increased BMI, with a strong correlation between adipose tissue expression and circulating PAI-1 levels. Although we found no evidence that Lp(a) directly modulates PAI-1 secretion by adipose tissue, circulating PAI-1 originates from multiple cellular sources, including endothelial cells, which also serve as a major source of t-PA.

Lp(a) promotes a prothrombotic state primarily through antifibrinolytic mechanisms driven by the structural homology between apolipoprotein(a) and plasminogen. This similarity allows Lp(a) to competitively inhibit plasminogen binding to fibrin and cellular surfaces, thereby impairing plasmin generation and fibrin degradation^[44,45]. Additionally, Lp(a) can bind directly to fibrin, further restricting plasminogen access to fibrin matrices^[10]. Elevated Lp(a) levels have also been shown to stimulate endothelial cells, leading to increased expression and activity of PAI-1 without affecting t-PA levels^[46]. Together, these effects result in a reduction of overall fibrinolytic capacity, thereby increasing susceptibility to thrombus formation following plaque rupture and TF release. Overall, both the circulating concentration and the functional properties of Lp(a) appear to be critical determinants of its pathogenic potential.

3.2 The dual pathogenic role of Lp(a): Fibrinolysis inhibition and OxPL transport

Lp(a) plays a central role in the transport and biological activity of OxPLs, which are now widely recognized as key mediators of vascular inflammation and cardiovascular disease. OxPLs are generated through the oxidative modification of phospholipids containing polyunsaturated fatty acids. This process predominantly occurs at sites of increased oxidative stress, such as atherosclerotic plaques. These bioactive lipids trigger pro-inflammatory signalling cascades that promote endothelial dysfunction, lipid accumulation within the arterial wall, and the progression of atherosclerosis^[44].

A defining feature of OxPL biology is their exceptionally high affinity for Lp(a). Multiple studies have demonstrated that, under steady-state conditions, over 85% of circulating OxPLs are bound to Lp(a), establishing it as the primary plasma carrier of OxPLs^[45]. This preferential association suggests that Lp(a) functions not merely as a passive transporter but as an active vector that concentrates pro-inflammatory and proatherogenic OxPLs within the circulation.

The dynamic redistribution of OxPLs among lipoproteins is particularly evident following percutaneous coronary intervention (PCI), a clinical situation characterised by acute vascular injury and heightened oxidative stress. Following PCI, the concentrations of both Lp(a) and OxPLs in plasma increase rapidly and substantially. Immediately after the procedure, only around 50% of OxPLs are found in Lp(a), with the rest distributed among other apolipoprotein B–containing lipoproteins, such as LDL. However, within six hours post-PCI, nearly all circulating OxPLs become localised to Lp(a), a pattern that persists thereafter^[47]. This temporal shift strongly supports the concept of the active transfer of OxPLs from LDL and other apoB-containing lipoproteins to Lp(a), thereby reinforcing the role of Lp(a) as the primary carrier of OxPLs in both stable and acute cardiovascular conditions.

The CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study investigated whether elevated Lp(a) and associated OxPLs are linked to progression from the asymptomatic or pre–heart failure (HF) stages (HF stages A or B) to symptomatic HF^[48]. This prospective cohort study followed 714 individuals with HF stage A or B who underwent coronary angiography for a median of 3.7 years. Lp(a) concentrations were measured using an isoform-independent immunoassay, with elevated Lp(a) defined as ≥ 150 nmol/L. OxPLs bound to apolipoprotein B-100 and apolipoprotein(a) were also quantified. The primary outcomes were progression to symptomatic HF (stages C or D), and a composite endpoint of HF or cardiovascular death. During follow-up, 14.7% of participants progressed to symptomatic HF, and 8.0% experienced cardiovascular death. After adjusting for multiple HF risk factors, including age, sex, coronary artery disease severity, aortic stenosis, inflammatory markers, and a history of myocardial infarction, elevated Lp(a) was found to be an independent predictor of incident symptomatic HF (hazard ratio [HR] ≈ 1.9), and of the composite endpoint of HF or cardiovascular death (HR ≈ 1.7). Similar associations were observed for OxPL concentrations, with the highest risks seen in individuals with elevated levels of both Lp(a) and OxPL, suggesting additive or synergistic effects. Importantly, these associations persisted despite widespread statin use and well-controlled LDL cholesterol levels, highlighting the mechanisms beyond traditional lipid-mediated atherosclerosis. These reinforce the growing body of evidence that Lp(a) and OxPLs may directly contribute to myocardial injury, inflammation, and fibrosis, in addition to their well-established roles in coronary and valvular disease.

3.3 Pharmacological Lp(a) lowering and its effect on fibrinolysis

In recent years, several Lp(a)-specific therapies have been developed and are currently being evaluated in clinical trials; however, none are yet available for routine clinical use^[49,50]. Among these, the most advanced drugs are olpasiran and pelacersen, which are currently being investigated in large phase 4 outcome trials. Olpasiran is being evaluated in the OCEAN(a) trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction, NCT05581303), while pelacersen is under investigation in the Lp(a)HORIZON trial (Assessing the Impact of Lipoprotein(a) Lowering with Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD, NCT04023552). Results from both studies are anticipated within the next two years. Olpasiran is a small interfering RNA molecule that disrupts hepatic expression of LPA by promoting degradation of apolipoprotein(a) mRNA, thereby preventing assembly of the Lp(a) particle in hepatocytes. Phase 2 clinical trial data demonstrated that olpasiran substantially reduced plasma Lp(a) levels in a dose-dependent manner and was generally well tolerated. At higher doses, olpasiran therapy achieved reductions in Lp(a) concentrations exceeding 95% compared to placebo^[51]. Pelacersen is an antisense oligonucleotide (ASO) that suppresses the hepatic production of apolipoprotein(a), the primary source of circulating Lp(a). In a phase 2 clinical study, pelacersen also produced a dose-dependent reductions in Lp(a) levels without significant safety concerns^[52]. A key limitation of both phase 2 studies, however, is their relatively short duration, which precludes definitive conclusions regarding long-term efficacy and safety. In addition to these two leading candidates, other si RNA-based therapies targeting LPA are under development, including zarlasiran and lepodisiran, both of which are currently in phase 2 clinical trials. In a phase 1 study, zarlasiran reduced Lp(a) levels by 46%, 86%, 96% and 98% following a single s.c. dose of 30 mg, 100 mg, 300 mg and 600 mg, respectively. Notably, at the highest dose, an approximate 80% reduction in Lp(a) levels persisted for up to 150 days^[53]. Lepodisiran similarly demonstrated potent and sustained Lp(a) lowering. Between days 60 and 180, Lp(a) concentrations were reduced by 41% in the 16-mg group and by 75% in the 96-mg group. In the pooled 400-mg group, which included participants receiving one or two doses of lepodisiran, Lp(a) levels were reduced by up to 94%^[54]. Based on the clinical and laboratory characteristics of the patients included in the study, in relation to the results of randomized, double-blind, placebo-controlled clinical trials, we aim to more reliably define patient groups that are at the highest risk or are most likely to benefit from treatment. Given that these trials (NCT05581303 and NCT04023552) each include more than 10,000 patients, whose only common characteristic is a prior cardiovascular event, while other features vary considerably, their results will likely enable such stratification. It will be particularly interesting to examine the differences in patients who are already receiving PCSK9 inhibitors and therefore have very low LDL cholesterol levels.

A decrease of Lp(a) values has not been reflected in an improvement in the fibrinolytic properties of the blood^[55]. The latter study investigated whether Lp(a) has a clinically significant antifibrinolytic effect in humans by examining the impact of potent Lp(a)-lowering treatment on fibrinolysis. Patients with very high Lp(a) levels were treated with the ASO pelacarsen, which achieved a ~70% reduction in Lp(a). These patients were then compared with placebo-treated controls. Ex vivo clot lysis times and key coagulation and fibrinolysis biomarkers were measured at baseline, at the peak of the drug’s effect, and following cessation of treatment. Despite the significant reduction in Lp(a), there were no notable changes in clot lysis times or fibrinolytic markers. Additionally, exogenously added purified Lp(a) did not impair fibrinolysis; however, recombinant apolipoprotein(a) exhibited strong antifibrinolytic effects. This suggests that free apo(a), rather than intact Lp(a), drives antifibrinolytic activity in vitro. These findings indicate that even extreme reductions in circulating Lp(a) do not affect ex vivo fibrinolysis in humans. These findings naturally raise several important questions. To date, evidence is available for only one Lp(a)-lowering agent with respect to its potential effects on fibrinolysis, and there is currently no proof that the specific mechanism by which Lp(a) is reduced directly accounts for differences in fibrinolytic activity. It is well-established that free apo(a) and Lp(a) exert distinct effects on the fibrinolytic system. This suggests that the association of apo(a) with the remaining Lp(a) might alter the fibrinolytic properties of both components. However, the confirmation of these hypotheses will require further investigation, including additional clinical and, at least initially, mechanistic preclinical research. It should be recognized that ongoing clinical trials are currently enrolling patients at the highest cardiovascular risk, specifically, those with a prior cardiovascular event and markedly elevated Lp(a) levels exceeding the threshold considered clinically significant in current guidelines^[11]. This is an important limitation, as it remains unclear whether the relationship between Lp(a) concentration and its effect on the coagulation-fibrinolytic system is linear or whether a threshold exists beyond which further increases in Lp(a) no longer exert an additional effect. Addressing this uncertainty will require both clinical and preclinical studies spanning a wide range of elevated Lp(a) concentrations. Such investigations would allow for a more precise identification of patient populations most likely to derive benefit from this type of therapy. Of course, at least in the initial preclinical studies, and probably later in clinical studies as well, we will have to take into account qualitative properties of Lp(a) in addition to its concentration, as these largely determine its atherothrombotic potential. In particular, we refer to the number of KIV2 repeats, which primarily determine the properties of apo(a) and, consequently, its prothrombogenic potential, as well as the properties of OxPL, whose pro-inflammatory effects contribute to all stages of the atherosclerotic process, from endothelial dysfunction to rupture of the atherosclerotic plaque and the resulting acute thrombotic event^[7].

3.4 Genetic modulation of fibrinolytic capacity: LPA and SERPINE1 variants

Since Lp(a) values are largely genetically determined^[56], it is natural to ask whether its effects on coagulation and fibrinolysis parameters are related only to Lp(a) concentration, or also to genetic polymorphisms that determine its concentration.

The number of KIV-2 repeats determines both Lp(a) plasma concentration and apo(a) structure, thereby modulating its proatherosclerotic, pro-inflammatory, and antifibrinolytic properties^[57]. Our research group^[58] investigated whether two common LPA gene variants (rs10455872 and rs3798220) and the number of KIV-2 repeats are associated with disturbances in coagulation and fibrinolysis in patients who experienced myocardial infarction at a young age and had markedly elevated Lp(a) levels. Among carriers of the AC haplotype, levels of the antifibrinolytic marker PAI-1 were significantly higher than among non-carriers, suggesting a more prothrombotic profile. Although Lp(a) concentration itself was not directly associated with haemostatic markers, the number of KIV-2 repeats was inversely correlated with overall fibrinolytic potential (OFP). These findings indicate that genetic variation within the LPA locus influences not only Lp(a) levels, but also its pro-inflammatory and antifibrinolytic effects. This could potentially contribute to residual cardiovascular risk, even when receiving optimal medical therapy. Genetic polymorphisms in the gene encoding PAI-1 (SERPINE) are clinically relevant. Patients with concomitantly elevated Lp(a) levels and the 4G/4G genotype exhibit more extensive coronary artery disease, a higher incidence of intracoronary thrombus, and more frequent abnormalities in thrombolysis in myocardial infarction flow. Moreover, the 4G/4G genotype is more prevalent among patients with ST-elevation acute coronary syndrome (ACS) compared to those with non-ST elevation ACS^[59]. In particular, the higher incidence of ST-elevation ACS, which is most often caused by a thrombus at the site of a ruptured atherosclerotic plaque that did not previously cause haemodynamically significant stenosis^[60], may lead us to conclude that an increased Lp(a) value, together with a mutated PAI-1 genotype increases the likelihood of intra-arterial thrombosis. Of course, it would also be interesting to determine whether polymorphisms in the LPA gene (e.g. the number of kringle type repeats) or even a combination of these polymorphisms increase the tendency towards intra-arterial thrombosis.

4. Balance between Coagulation and Fibrinolysis

The development of intra-arterial thrombosis following atherosclerotic plaque rupture, and the subsequent acute cardiovascular events, does not depend on individual factors of the coagulation-fibrinolytic system. Rather, it reflects the complex interplay among multiple procoagulant and fibrinolytic factors. The overall haemostatic potential (OHP) is a global plasma assay that captures this balance by simultaneously assessing fibrin formation and fibrinolysis. Unlike conventional coagulation tests, OHP provides an integrated evaluation of haemostatic function by encompassing both procoagulant and fibrinolytic processes. Clinically, OHP is particularly valuable for detecting hypercoagulability states, including in patients with otherwise normal routine coagulation parameters. Elevated OHP values indicate increased fibrin generation and/or impaired fibrinolysis and have been reported in cardiovascular disease, venous thromboembolism, malignancy, and metabolic disorders^[61]. As such, OHP may aid in identifying patients with residual thrombotic risk despite optimal therapy. Furthermore, OHP allows assessment of fibrinolytic capacity through derived parameters such as overall coagulation potential (OCP) and OFP. Reduced OFP reflects impaired fibrinolysis and has been associated with atherosclerosis, obesity, insulin resistance, and elevated Lp(a) levels, thereby contributing to a prothrombotic phenotype.

In addition, OHP can be used to monitor therapeutic effects, including those of anticoagulant and lipid-lowering therapies, by detecting global changes in hemostatic balance that may not be captured by standard laboratory assays. From an integrative perspective, OHP reflects the dynamic interplay between coagulation, endogenous anticoagulant pathways, and fibrinolysis. It is influenced by a range of cardiometabolic and inflammatory factors, thereby linking metabolic dysfunction with thrombotic risk. Furthermore, OHP captures the hemostatic impact of emerging risk factors such as elevated Lp(a) and endothelial dysfunction^[62].

In our research group, we studied the influence of both Lp(a) concentration and genetic polymorphisms in the LPA gene on all three parameters (OCP, OFP, and OHP) in patients after myocardial infarction who were treated with statins and had highly elevated Lp(a)^[58]. In these patients, who had average Lp(a) values of around 1500mg/L, we were unable to demonstrate any influence of Lp(a) concentration on the parameters examined. However, we found that OFP was strongly correlated with the number of KIV2 repeats. This suggests that, in addition to the Lp(a) concentration, atherogenic potential is also important and increases with a lower number of KIV2 repeats. Of course, our research is limited by the fact that we did not have a control group and only included patients with significantly elevated Lp(a) values. In the same group of patients, we also studied the effect of PCSK9 inhibitors on OCP, OFP and OHP. These drugs have a primary effect of reducing LDL cholesterol concentrations and have also been shown to significantly reduce Lp(a) concentrations and cardiovascular mortality^[63]. Despite the fact that lowering Lp(a) with PCSK9 inhibitors is an independent predictive factor for reducing cardiovascular events, particularly in patients with high Lp(a) levels at baseline^[64,65], we found no associations between decreased Lp(a) and changes in OCP, OFP and OHP^[65]. It should be noted that all of our patients had Lp(a) levels high in the atherogenic range according to current recommendations^[66], even after treatment with PCSK9 inhibitors. Therefore, our findings may not be generalizable to patients with lower, yet still elevated, Lp(a) levels. Further studies encompassing a broader range of Lp(a) values are warranted. Following treatment with a drug specifically designed to lower Lp(a)^[55], there were no significant changes in factors participating in or indicating the functioning of the fibrinolytic process. However, we lack data on the overall functioning of the coagulation or fibrinolytic processes.

Based on previously published studies, if studies examining the impact of drugs specifically designed to lower Lp(a) on the incidence of cardiovascular events^[67-69] show that the incidence of primarily ST elevation ACS is reduced, it would be concluded that the coagulation/fibrinolysis ratio changes in favour of the latter. We know that the most common cause of ST elevation ACS is intracoronary thrombosis following the rupture of an unstable lesion that was previously considered haemodynamically insignificant^[69]. Of course, an even better answer could be provided by a study that examines not only the impact on the incidence of cardiovascular events, but also the impact on OCP, OFP, and OHP.

5. Conclusions

Elevated Lp(a) levels increase cardiovascular risk through multiple independent mechanisms. Lp(a) exhibits the full atherogenic potential of low-density lipoprotein cholesterol but is more susceptible to oxidation and has greater transendothelial penetration. This accelerates foam cell formation. Furthermore, OxPLs associated with Lp(a) induce pro-inflammatory macrophage differentiation and the release of cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumour necrosis factor-α. This contributes to the formation of more unstable atherosclerotic lesions. The prothrombotic effects of Lp(a) derive from its structural similarity to plasminogen, which is encoded by the PLG gene. This gene shares up to 70% sequence homology with the LPA gene, resulting in the competitive inhibition of plasminogen binding, impaired fibrinolysis, and the promotion of intravascular thrombosis. While there is ample evidence for Lp(a)’s involvement in all phases of the atherosclerotic process^[70], the absence of clinically useful drugs specifically designed to lower Lp(a) means we cannot answer the question of how reducing Lp(a) by over 90% affects both the atherothrombotic process itself and the incidence of cardiovascular events.

Authors contribution

Šebeštjen M: Conceptualization, writing-original draft, writing-review & editing, visualization, supervision.

Ugovšek S, Zupan J: Conceptualization, writing-original draft, writing-review & editing, visualization.

Meglič H, Lunar P: Writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

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Consent for publication

Not applicable.

Availability of data and materials

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Funding

None.

Copyright

© The Author(s) 2026.