Lipoprotein(a) and Venous Thromboembolism: Association, Causality, and Medications

Abstract

Lipoprotein(a) [Lp(a)] is a circulating plasma lipoprotein with structural similarities to low-density lipoprotein (LDL), distinguished by the addition of apolipoprotein(a) to the LDL structure. Lp(a) levels are approximately 80% genetically determined, and distinct components of this complex particle are thought to confer atherogenic, inflammatory, and antifibrinolytic properties contributing to cardiovascular risk. A growing body of evidence has shown a causal association between elevated Lp(a) levels and both atherosclerotic cardiovascular disease (ASCVD) and valvular aortic stenosis. However, the link with venous thromboembolism (VTE) (encompassing deep vein thrombosis [DVT] and pulmonary embolism [PE]) has been less clear. Although in vitro studies suggest antifibrinolytic and prothrombotic properties for Lp(a), clinical and genetic studies have yielded inconsistent results related to thrombogenicity, with some studies suggesting an association with VTE only with very high Lp(a) levels. The effect of Lp(a) levels on outcomes in patients with incident VTE has not been comprehensively investigated. Although there are currently no approved therapies specifically targeting Lp(a) reduction, at least five agents are in development, with preliminary data demonstrating reductions in Lp(a) levels of up to 98%. The impact of these therapies on VTE events remains unknown. In turn, other lipid-modifying agents, which have no effect on reducing Lp(a), such as statins, were shown to reduce incident VTE. This review summarizes the current evidence regarding the association between Lp(a) and VTE, focusing on its pathophysiology and critically analyzing the existing evidence from experimental, epidemiological, and genetic studies.

 

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Keywords

lipoprotein(a) - apolipoprotein(a) - venous thromboembolism - deep vein thrombosis - pulmonary embolism - thrombosis

Introduction

Lipoprotein(a) [Lp(a)] is a circulating plasma lipoprotein, primarily synthesized in the liver, with plasma concentration largely determined genetically.[1] [2] As a result, Lp(a) levels tend to remain stable throughout life, with an intraindividual variability of approximately 13%.[3] [4] Lp(a) consists of a low-density lipoprotein (LDL)-like particle containing apolipoprotein B-100 (ApoB-100) that is covalently bound to apolipoprotein(a) [apo(a)] via a disulfide bond.[5] In addition to the atherogenic effects driven by the LDL component of Lp(a),[5] [6] [7] apo(a) confers unique inflammatory, prothrombotic, and antifibrinolytic properties to this complex particle.[5] [8] [9] [10] [11] Although a physiological function for Lp(a) remains elusive,[12] it may participate in wound healing through inhibition of fibrinolysis and cholesterol provision for tissue repair.[13] [14]

Elevated levels of Lp(a) are broadly recognized in research settings as levels ≥75 nmol/L (30 mg/dL), although thresholds of ≥125 nmol/L (≥50 mg/dL) are more commonly used in clinical practice.[15] Elevated Lp(a) is considered an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis,[1] as supported by a large body of preclinical[16] [17] and epidemiological studies.[18] [19] [20] [21] [22] [23] The prevalence of elevated Lp(a) levels in patients without ASCVD was not comprehensively investigated, although it was previously shown to be 12%.[19] For Lp(a) ≥125 nmol/L (50 mg/dL) in patients with ASCVD, the prevalence has been shown to be up to 25%.[19] [24] [25] Considering the strong genetic influence on the Lp(a) levels, Mendelian randomization (MR) studies point to a causal relationship between Lp(a) and both ASCVD and calcific aortic stenosis.[26] [27] [28] [29] [30] [31] [32] [33] Accordingly, the 2019 guidelines from the European Society of Cardiology and European Atherosclerosis Society recommended Lp(a) testing at least once in every adult to identify those with very high Lp(a) levels (>180 mg/dL), who may carry a lifetime risk of ASCVD equivalent to the risk associated with heterozygous familial hypercholesterolemia.[34] At the same time, evidence that Lp(a) lowering decreases ASCVD risk is plausible but not proven yet, pending the results of ongoing clinical trials.

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cardiovascular condition characterized by thrombus formation in the venous system. DVT typically occurs in the lower extremities, while PE results from thrombus migration to the pulmonary arteries, obstructing blood flow. Its pathophysiology involves a complex interplay of proinflammatory responses, impaired fibrinolysis, and prothrombotic states that promote clot formation and persistence.[35] Given that Lp(a) is also linked to proinflammatory, antifibrinolytic, and prothrombotic mechanisms, a relationship between elevated Lp(a) levels and increased VTE risk is plausible and warrants further consideration, particularly in light of forthcoming clinical trial results of Lp(a) reduction agents. Although in vitro experiments suggest fibrinolysis inhibition with high Lp(a) concentrations,[11] [36] [37] cohort, case-control, MR, and genome-wide association studies have failed to replicate those results consistently.[13] [32] [38] [39] [40] This review will summarize the current evidence on the role of Lp(a) in VTE, and critically evaluate the available data from experimental, epidemiological, and genetic studies investigating this potential association.

 

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Methods

We conducted a narrative review providing an overview of the structure, physiological role, and pathophysiological properties of Lp(a), and conducted a systematic search in PubMed to identify studies investigating the association between Lp(a) and incident VTE, as well as VTE outcomes in patients with existing VTE ([Supplementary Table S1] and [Supplementary Fig. S1], available in the online version). We prioritized prospective cohort studies and MR studies. We also considered retrospective cohort studies, case-control studies, and cross-sectional studies in the case of insufficient data from prospective studies. Ultimately, we reviewed randomized controlled trials of medications designed to specifically lower Lp(a) (muvalaplin, olpasiran, lepodisiran, zerlasiran, pelacarsen) or other lipid-lowering agents that can result in a reduction of Lp(a) levels (i.e., proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) and their association with VTE outcomes.

Lp(a) Structure

Lp(a) is a complex lipoprotein consisting of an LDL-like particle containing ApoB-100,[1] encircling a lipid core of cholesteryl ester and triglyceride.[41] The unique functional and metabolic features of Lp(a) are mainly attributed to the presence of apo(a),[42] as well as the large amount of oxidized phospholipids (OxPLs) carried by the particle[43] ([Fig. 1]).

Fig. 1 Lipoprotein(a) [Lp(a)] structure and properties. (A) Lp(a) size and weight consist of a combination of LDL-like core and apo(a) protein, which vary depending on the number of kringle type IV repeats. (B) Lp(a) is composed of a low-density lipoprotein (LDL) cholesterol-like particle containing ApoB-100, covalently bound to a protein called apo(a), which carries oxidized phospholipids. The role of Lp(a) in venous thrombosis is not well understood, while its impact in the arterial system is better recognized. Each component of the Lp(a) structure contributes to its distinct properties: (a) apo(a)'s structural similarity with plasminogen imparts antifibrinolytic properties; (b) oxidized phospholipids contribute to proinflammatory effects, inducing endothelial dysfunction, monocyte trafficking, and cytokine release; and (c) the LDL-like particle contributes to pro-atherosclerotic activity by infiltrating the intima and forming atherosclerotic plaque.

Apo(a) is a hydrophilic, highly glycosylated protein, bound to ApoB-100.[5] Its structure includes repetitive protein domains known as kringles, with a variable number of repeats of kringle IV (KIV), kringle V (KV), and an inactive protease domain.[44] The size of apo(a) can be variable and is influenced by the number of KIV-2 domains, which are determined by the LPA gene variations.[5] [45] Kringle domains contain lysine binding sites, which enable apo(a) to interact with various proteins, such as plasminogen, and endothelial cells,[5] [7] [46] and also facilitate the attachment of OxPLs to the KIV-10 domain.[7] Although the LDL-like core, apo-B100, and the overall size and weight of Lp(a) resemble those of LDL, the primary distinction lies in the variable size of apo(a)[47] ([Fig. 1A]).

 

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Metabolism and Determinants of Plasma Lp(a) Levels

Lp(a) is assembled in the liver, the site of apo(a) and ApoB-100 synthesis. Its formation occurs in two steps: initially, apo(a) binds non-covalently to ApoB-100 through interactions involving its KIV domains; subsequently, a covalent disulfide bond is formed between apo(a) and ApoB-100.[48] The liver likely serves as the primary site for Lp(a) catabolism and clearance. Liver cirrhosis and hepatitis lead to lower Lp(a) levels.[49] Kidneys are involved to a lesser extent in clearing Lp(a),[2] [50] [51] with chronic kidney disease being associated with elevated Lp(a).[49] [52] There is no consensus regarding the contribution of LDL receptors to Lp(a) plasma clearance,[2] especially given that LDL-C–lowering agents such as statins, known to increase the number of LDL receptors, have shown inconsistent effects on Lp(a) levels and even a potential increase.[53]

Lp(a) plasma levels are approximately 80% genetically determined and mainly regulated by the LPA gene.[1] Lp(a) levels are significantly influenced by apo(a) isoform size, defined primarily by the KIV-2 copy number variant,[6] [32] as well as single-nucleotide polymorphisms (SNPs) in the LPA locus.[54] Smaller apo(a) isoforms, composed of fewer kringle repeats, are thought to be more efficiently secreted, whereas larger isoforms, with a greater number of kringle repeats, tend to be retained longer in the endoplasmic reticulum. This results in an inverse relationship between apo(a) isoform size and plasma Lp(a) levels.[7] Race and ethnicity influence Lp(a), with Black individuals having the highest Lp(a) level of all racial groups.[55] [56] [57] Sex-related differences in Lp(a) levels have also been observed, with post-menopausal women tending to have higher concentrations than men.[22] [58] The relationship with diet[49] [55] [59] and other hormones, such as thyroid and sex hormones[49] [60] has shown mixed results. Furthermore, studies have identified intraindividual variability in serial Lp(a) measurements.[3] [4]

 

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Pathophysiology of Lp(a) in Thrombosis and Atherosclerosis

The LDL-like component, apo(a), and OxPLs are all thought to contribute to the pathophysiology of Lp(a)-associated vasculopathy[5] [11] ([Fig. 1B]). Lp(a) is the main lipoprotein carrier of phosphocholine-containing OxPLs in plasma, conferring a strong inflammatory profile to this particle.[9] [43] [61] Kringle domains contained within Lp(a) also resemble the structure of plasminogen, and this structural homology is thought to confer antifibrinolytic properties to Lp(a).[10] [11] [45]

Apo(a) may enhance Lp(a)'s retention within the arterial wall by attaching to lysine binding sites on the endothelium.[13] [44] [62] The pro-inflammatory properties deriving from OxPLs within Lp(a) may impair the endothelial barrier, enhance lipoprotein penetration, and contribute to plaque instability.[8] [43] [63] Current evidence indicates a dose–response association between elevated Lp(a) levels and both stable and unstable ASCVD risk.[1]

The structural homology between apo(a) and plasminogen allows apo(a) to compete for binding sites on fibrin and endothelial cells, blocking plasminogen activation by tissue plasminogen activator (tPA), resulting in an antifibrinolytic effect.[10] [11] [64] [65] Uncompetitive mechanisms, such as direct inhibition of tPA and non-tPA-mediated plasminogen activation on fibrin and cell surfaces,[66] [67] increased expression of plasminogen activator inhibitor-1 (PAI-1) in endothelial cells, and decreased fibrin clot permeability has also been proposed.[68] [69] Other prothrombotic mechanisms beyond the antifibrinolytic properties have been suggested[10] [70] including increased tissue factor (TF) expression,[71] inhibition of TF pathway inhibitor,[72] and promoting platelet activation and aggregation.[11] [73] [74] [75] Notably, all these properties are also key mechanisms in the pathogenesis of VTE. Nevertheless, the association between Lp(a) and VTE remains inadequately characterized.

 

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Preclinical Studies

In vitro and animal models have consistently shown antifibrinolytic properties of Lp(a). Plasma clot formation time, clot lysis time, and clot permeability are key parameters used in preclinical studies to evaluate clot structure and function. Clot formation time reflects the efficiency of thrombin generation and fibrin polymerization, lysis time measures the duration for clot breakdown by the fibrinolytic system, and permeability indicates the density of the fibrin network, with lower values suggesting resistance to lysis.[76] Early studies revealed that Lp(a) and its apo(a) component inhibit plasminogen binding to monocytes and endothelial cell surface receptors by up to 20%, thereby impairing fibrinolysis.[77] [78] Furthermore, Lp(a) or recombinant constructs of human apo(a) inhibited tPA-mediated clot lysis[36] [79] through inhibition of plasminogen conversion from the inactive Glu1 to the Lys77 form,[67] [80] a better substrate for tPA, and suppressed plasminogen activation by tPA and urokinase-type plasminogen activator.[79] Studies in rabbits[81] and transgenic mice expressing apo(a)[82] confirmed resistance to tPA-mediated clot lysis. Although Lp(a) concentrations varied across in vitro studies,[66] antifibrinolytic effects have been observed at levels as low as 5 to 10 mg/dL, with measurable displacement of plasminogen from fibrin.[79] Functionally significant suppression of fibrinolysis typically occurred at concentrations between 10 and 25 mg/dL.[79] A recent study in transgenic mice showed that small-molecule inhibitors targeting apo(a) kringle domains to block Lp(a) formation also bound to rat plasminogen, inhibiting plasmin activity, highlighting the close structural similarity between apo(a) and plasminogen.[83]

The effect of Lp(a) on platelet aggregation has been less consistent.[11] Some studies suggested that elevated Lp(a) levels enhance platelet activation, promoting thrombin receptor-mediated platelet aggregation, serotonin release, and thromboxane A2 formation.[74] [84] Additionally, OxPLs may promote platelet activation by binding to CD36 receptors and inducing TF expression.[11] [73] [85] Conversely, other studies contradicted these findings, suggesting that Lp(a) might inhibit platelet activation by reducing collagen and ADP-induced platelet aggregation and impairing fibrinogen binding to GPIIb/IIIa.[86] [87] The reasons for these discrepancies likely include differences in experimental conditions, such as the use of washed platelets, and confounding through the inclusion of individuals receiving baseline antiplatelet therapy.[11]

Preclinical studies indicate impaired fibrinolysis by Lp(a) via inhibiting plasminogen activation and clot lysis, although the effect on platelet aggregation remains unclear, with conflicting evidence suggesting both pro- and anti-aggregatory effects likely influenced by experimental conditions.

 

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Epidemiological Studies of the Association between Lp(a) and (First Episode of) VTE

Epidemiological studies assessing the association between Lp(a) and VTE have yielded mixed results ([Table 1]). Overall, case-control studies have shown that elevated levels of Lp(a) (>30 mg/dL) were more frequently found in patients with VTE compared with healthy controls,[88] [89] [90] as shown in a pooled analysis of 10 case-control studies involving 13,541 patients which showed a modest but significant association (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.36–1.79).[39] However, these findings should be interpreted with caution, given that the included studies were limited by their retrospective design and heterogeneity in inclusion criteria. In contrast, prospective studies did not find an association between Lp(a) and the risk of first episode of VTE,[91] [92] except for one study that observed an association when comparing Lp(a) levels above the 99th percentile (130.6 mg/dL) with those below the 99th percentile (adjusted hazard ratio [HR] 1.88, 95% CI 0.93–3.78).[40] A recent pooled analysis of five prospective cohort studies, comprising 66,583 participants, suggested that a 1 standard deviation increase in baseline logarithm Lp(a) was not linked to a higher risk of VTE (relative risk [RR] 1.00, 95% CI 0.94–1.07; p = 0.58), and further analysis comparing the top (36.8 mg/dL) versus bottom quartiles (1.61 mg/dL) of Lp(a) showed similar results (RR 1.00, 95% CI 0.84–1.19).[91]

Table 1 Prospective and case-control studies evaluating the association between Lp(a) and VTE

Study	Patient population	Follow-up	Findings	Comments
Prospective studies
Danik et al, 2013[40]	28,345 patients from Women's Health Study[a]	Median 14.4 years	• The highest quintile of Lp(a) (median 65.20 [43.60–229.40] mg/dL) was numerically associated with an increased risk of VTE compared to the lowest quintile (1.90 [0.10–3.40] mg/dL), although it did not reach statistical significance (HR 1.04, 95% CI 0.77–1.41) • Lp(a) levels ≥99th percentile (≥130.6 mg/dL) were associated with a higher risk of provoked VTE when compared with levels <99th percentile (adjusted HR 2.55; 95% CI 1.13–5.74)	• Events were confirmed by imaging and adjudicated in a blinded fashion by a committee of physicians
Kunutsor et al, 2019[91]	2,180 men from the Kuopio Ischemic Heart Disease cohort study[b]	Median follow-up: 24.9 years	• No significant association was found between levels of Lp(a) and VTE (HR 1.06; 95% CI: 0.87 to 1.30; p = 0.53) • In further analysis that compared Lp(a) concentrations >30 mg/dL versus ≤30 mg/dL, no association was observed	• VTE events were identified by National Hospital Discharge Registry data and review of available hospital records, wards of health centers, health practitioner questionnaires, death certificates, autopsy registers, and medicolegal reports. VTE events were validated by two physicians • Association between extremes of Lp(a) and VTE risk were not assessed
van Schouwenburg et al, 2012[92]	7,627 patients from PREVEND study[c]	Median 10.5 years	• No statistically significant association between Lp(a) levels (2nd and 3rd tertiles) and the risk of VTE when compared with the 1st tertile  o 2nd tertile versus 1st tertile: HR 1.00 (95% CI: 0.60–1.65)  o 3rd tertile versus 1st tertile: HR 1.08 (95% CI: 0.67–1.73)	VTE cases were identified via clinic, hospital, and death registries, then confirmed from medical records by a blinded assessor; events were classified as provoked or unprovoked.
Case-control studies
Grifoni et al, 2012[90]	443 patients with the first episode of VTE (224 with DVT, 144 with PE + DVT, 75 with PE) versus 304 healthy controls	–	• Prevalence of elevated Lp(a) (>30 mg/dL) was significantly higher in patients compared with controls (OR; 95%CI) (p < 0.001)  o DVT: OR 2.6; 1.7–4.0  o DVT + PE: OR 2.4; 1.5–3.9  o PE: OR 3.1; 1.7–5.4	Patients from a local thrombosis center with imaging-confirmed VTE were included; controls were blood donors or patients' friends/partners from the same area.
Marcucci et al, 2003[88]	603 patients with a history of VTE versus 430 healthy controls	–	• Lp(a) levels >30 mg/dL were significantly more frequent in patients (24%; n = 146) as compared with controls (13%; n = 58) (p = 0.005) • In adjusted multivariate analysis, there was an association between elevated (>30 mg/dL) Lp(a) levels and VTE (OR 2.1; 95% CI: 1.4–3.2; p = 0.002)	• Included patients with a history of VTE who were referred to a thrombosis center; patients were studied 6 months to 1 year after the acute event and had not had any severe inflammatory disease for at least 6 months
Von Depka et al, 2000[89]	685 patients with a history of VTE versus 266 healthy controls	–	• Elevated Lp(a) levels >30 mg/dL were found in 20% of all patients, as compared with 7% among healthy controls [OR 3.2 (95% CI 1.9–5.3) (p < 0.001)]	• The diagnosis of VTE was confirmed by an independent radiologist who was unaware of the laboratory test results • The criterion for the recruitment of control subjects was the lack of any history of thromboembolic events
Vormittag et al, 2007[131]	233 patients with a history of VTE (128 symptomatic DVT, 105 symptomatic PE ± DVT) versus 122 healthy controls	–	• Lp(a) levels were not significantly different among groups (median levels [IQR]):  o DVT:17 mg/dL (5.1–38.6)  o PE ± DVT: 14 mg/dL (<2.0–42.7)  o Controls: 12.6 mg/dL (5.4–33.1) • OR (95%CI) for VTE for a 10.0 mg/dL increase of Lp(a):  o DVT versus controls: 1.1 (0.98–1.2)  o PE ± DVT versus controls: 1.1 (0.95–1.2)	• Included patients with a history of VTE referred to the outpatient department for an assessment of thrombosis risk factors; medical history was obtained by a standardized questionnaire and from medical records on the day of study inclusion

Abbreviations: CI, confidence interval; CSVT, cerebral sinus venous thrombosis; CT, computed tomography; CTA, computed tomography angiography; DVT, deep vein thrombosis; HR, hazard ratio; ICD, International Classification of Diseases; IQR, interquartile range; Lp(a), lipoprotein(a); MRI, magnetic resonance imaging; OR, odds ratio; PE, pulmonary embolism; RR, relative risk; V/Q, ventilation-perfusion; VTE, venous thromboembolism.

^a Women's Health Study was a randomized, double-blind, placebo-controlled trial evaluating the balance of benefits and risks of low-dose aspirin and vitamin E in reducing risks of cardiovascular disease and cancer among 39,876 US female health professionals aged 45 and older, with no history of coronary heart disease, cerebrovascular disease, cancer, or other major chronic illness.

^b Kuopio Ischemic Heart Disease (KIHD) study is a population-based prospective cohort study investigating risk factors for cardiovascular diseases, particularly in men aged 46 to 61 years.

^c PREVEND study is a prospective cohort study that investigated the role of albuminuria in renal and cardiovascular disease in patients aged 28 to 75 years from Groningen, Netherlands.

To date, few studies have evaluated the association of Lp(a) with other sites of venous thrombosis. The role of Lp(a) in retinal vein occlusion has undergone investigation, and a pooled analysis of 10 observational studies (cross-sectional, retrospective, and prospective cohort studies), involving 16,966 patients, found that Lp(a) levels above the normal limit (>30 mg/dL in the majority of studies) were more prevalent in patients with incident or recurrent retinal vein occlusion compared with controls (OR 2.38, 95% CI 1.70–3.34).[93]

Epidemiological studies on Lp(a) and VTE show mixed results: case-control studies suggest a modest association with higher Lp(a), while most prospective studies find no clear link except at very high levels.

 

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Mendelian Randomization Studies on LP(a) and VTE

Determining causality using traditional observational epidemiological studies is difficult due to challenges such as confounding, reverse causation, and other biases. MR studies implement the random allocation of alleles during gamete formation, which mimics the randomization process in controlled trials, reducing confounding and other biases and thereby validating causal relationships.[94] [95] The causal inferences from MR studies guide the design of clinical trials and improve the reliability of their outcomes.

Overall, MR studies have not found a consistent association between Lp(a) concentrations and VTE ([Table 2]). Additionally, previous genome-wide association studies, including more than 20,000 patients with VTE and 13 million DNA sequence variants, have not identified any association between the LPA gene region and VTE.[96] [97] However, when comparing individuals with extremely low versus extremely high Lp(a) levels, a study involving 53,908 participants from the Copenhagen General Population Study and the Copenhagen City Heart Study found that Lp(a) levels above the 95th percentile (median 124 mg/dL) were associated with an increased risk of VTE compared with levels below the 22nd percentile (median 3 mg/dL) (HR 1.33, 95% CI 1.06–1.69).[13] Another study using data from the UK Biobank reported that a genetically predicted 50 nmol/L increase in Lp(a), adjusted for KIV-2 repeats, was associated with a slightly increased odds of VTE (OR 1.04, 95% CI 1.00–1.09).[98] Additionally, a genetic association study, which, unlike MR, investigated correlations between genetic variants and traits without directly inferring causality, including 516 VTE patients without known thrombophilia and 1,117 age- and sex-matched healthy controls. This study demonstrated an association between Lp(a) and VTE only when comparing higher (>23) with much lower (<7) number of kringle repeats (OR 3.81, 95% CI 2.38–6.10).[32]

Table 2 Mendelian randomization and genetic association studies evaluating the association between Lp(a) and VTE

Study	Patient population/Data sources	Lp(a) levels and genetic evaluation	Results
Mendelian randomization studies
Emdin et al, 2016[132]	The majority of data from 112,338 participants from the UK Biobank[a]; the study also included data from the Myocardial Infarction Genetics (MIGen) Consortium and from 7 genome-wide association study (GWAS) consortia	LPA variants rs3798220, rs10455872, rs41272114, and rs143431368 (effect of these variants on plasma Lp(a) levels was estimated using the data from the ARIC study)	• Per 1 standard deviation genetically lowered Lp(a) level (0.332 μmol/L): VTE: OR 0.99 (95% CI 0.91–1.07) • Per 1 standard deviation LPA variants associated with lower Lp(a) levels: VTE: OR 0.99 (95% CI 0.91–1.07)
Gudbjartsson et al, 2019[98]	143,087 participants from a case-control study in Iceland[b]	Measured and genetically imputed Lp(a) molar concentration; KIV-2 repeats, and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration	Per genetically imputed 50 nM[c] increase in Lp(a) levels: VTE: OR 1.00 (95% CI 0.96–1.04) • KIV-2: VTE: OR 1.03 (95% CI 0.99–1.07) • Lp(a) adjusted for KIV-2: VTE: OR 0.98 (95% CI 0.93–1.02) • KIV-2 adjusted for Lp(a): VTE: OR 1.04 (95% CI 1.00–1.09)
Helgadottir et al, 2012[133]	Pooled results from eight case-control studies conducted in Iceland, Spain, France, and Canada with a total of 3,752 VTE cases and 29,535 controls	LPA variants rs10455872 and rs3798220 were combined and examined as LPA scores	• LPA score: VTE: OR 0.97 (95% CI 0.87–1.09) • LPA rs10455872: VTE: OR 0.99 (95% CI 0.88–1.12) • LPA rs3798220: VTE: OR 0.81 (95% CI 0.64–1.03)
Kronenberg et al, 2022[34]	440,368 participants from the UK Biobank[a]	Lp(a) levels and the number of LPA variants rs10455872 or rs3798220 inherited	• Per 100 nmol/L increase in Lp(a) level: VTE: OR 0.99 (95% CI 0.96–1.03) • Number of Lp(a) increasing variants of LPA (0 as the reference: corresponding to median Lp(a) 13.6 nmol/L)  o 1 (median Lp(a) 146.3 nmol/L): VTE: OR 0.99 (95% CI 0.96–1.04)  o 2 (median Lp(a) 261.9 nmol/L): VTE: OR 1.00 (95% CI 0.85–1.19)
Larsson et al, 2020[38]	367,586 participants from the UK Biobank[a]	43 SNPs at the LPA locus conditionally associated with Lp(a) levels[134]	• Per genetically predicted 50 mg/dL increase in Lp(a) levels:  o DVT: OR 1.00 (95% CI 0.96–1.04)  o PE: OR 1.01 (95% CI 0.95–1.07)
Nordestgaard and Langsted, 2016[13]	53,908 patients from the Copenhagen City Heart Study[d] and Copenhagen General Population Study combined[b] [e]	Lp(a) levels, LPA KIV-2 number of repeats, and LPA variant rs10455872	• LPA KIV-2: VTE: HR 1.01 (95% CI 0.96–1.06) • LPA rs10455872: VTE: HR 1.03 (95% CI 0.99–1.07) Elevated Lp(a) levels were significantly associated with VTE only when comparing extremely low (<22 percentile or 3 mg/dL) with extremely high Lp(a) levels (>95 percentile or 124 mg/dL): HR 1.33 (95% CI 1.06-1.69).
Olmastroni et al, 2025[135]	410,177 participants from UK Biobank[a]	LPA genetic variants of rs10455872 and rs3798220 and Lp(a) concentration (additionally, two genetic scores that influence coagulation through the thrombin and platelet pathway were calculated)	• Lp(a) 100 nmol/L increase: VTE: HR 1.02 (95% CI 1.00–1.04) • Number of Lp(a) increasing variants of LPA (0 as the reference(median Lp(a) of 13.6 nmol/L) Lp(a) 13.6 nmol/L)  o 1 (median Lp(a) 146.3 nmol/L): VTE: OR 0.98 (95% CI 0.94–1.03)  o 2 (median Lp(a) 261.8 nmol/L): VTE: OR 1.03 (95% CI 0.88–1.21)
Genetic association studies
Sticchi et al, 2016[32]	560 patients with VTE and 1,117 healthy controls[f]	• LPA gene KIV-2 size polymorphism • LPA SNPs rs1853021, rs1800769, rs3798220, rs10455872	• KIV-2 repeats[g] quartiles (Q4: ≥23 repeats as reference):  o Q3: 13–22 repeats: VTE: OR 1.45 (95% CI 0.91–2.31)  o Q2: 8–12 repeats: VTE: OR 1.64 (95% CI 1.03–2.61)  o Q1: ≤7 repeats: VTE: OR 3.81 (95% CI 2.38–6.10)

Abbreviations: CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; ICD, International Classification of Diseases; KIV-2, kringle IV type 2; Lp(a), lipoprotein(a); OR, odds ratio; PE, pulmonary embolism; SNP, single nucleotide polymorphism; VTE, venous thromboembolism.

Notes:

^a VTE events were defined based on ICD codes and Health Related Problems codes, and self-reported data were validated by an interview with a nurse. It is unclear whether diagnostic codes in principal or secondary positions were used.

^b VTE events were defined based on ICD-9 and ICD-10 discharge diagnosis codes. However, it is unclear whether diagnostic codes in principal or secondary positions were used.

^c Units of molarity (nM) reflects the number of Lp(a) particles per liter of blood, allowing for standardized measurement regardless of particle size.

^d This study presents combined data from Copenhagen City Heart Study and Copenhagen General Population Study (random sample of patients between 20-93 years old from Copenhagen).

^e The Copenhagen General Population Study (CGPS) includes over 100,000 adults randomly selected from the Copenhagen general population, aged 20 to 100 years.

^f VTE patients were from a thrombosis center in Milan, Italy. Control patients were partners or friends of the patients referred to the Thrombosis Center. All participants were tested for thrombophilia and excluded if they had a history of thrombosis, a family history of thrombosis, or tested positive for any thrombophilia.

^g A higher number of KIV-2 repeats is associated with lower Lp(a) levels, and vice versa.

MR studies generally do not support a causal link between Lp(a) levels and VTE, though some evidence suggests increased risk at extremely high concentrations, indicating a potential association under specific conditions.

 

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Lp(a) and Outcomes of Patients with VTE

The association between Lp(a) levels and clinical outcomes among patients with VTE has not been investigated comprehensively. In a prospective cohort study from Canada, serum Lp(a) measurements were obtained from 510 patients with the first unprovoked VTE.[99] During a median follow-up of 16.9 months, 64 patients (12.5%) experienced adjudicated recurrent VTE. There was no significant difference in median Lp(a) levels between patients with recurrent VTE and those without (9 mg/dL versus 6 mg/dL, p = 0.15). In a single-center retrospective study conducted in Austria, 811 patients with acute PE were included.[100] Median Lp(a) concentrations were 17 mg/dL in 323 low-risk patients with PE, 16 mg/dL in 343 intermediate-low-risk patients with PE, 15 mg/dL in 64 intermediate-high-risk patients with PE, and 13 mg/dL in 81 high-risk patients with PE. No associations were observed between Lp(a) levels and PE severity (p = 0.36). In another study conducted in the same medical center in Austria, thrombus burden was assessed via computed tomography pulmonary angiography in 90 patients with acute PE, and no significant correlation was noted between Lp(a) levels and thrombus extent (r = 0.02, p = 0.92).[101] When analyzing the risk of recurrent VTE across different sites of thrombosis, a prospective study demonstrated that median Lp(a) levels were higher among patients with recurrent cerebral venous sinus thrombosis (CVST) compared with patients with no recurrence (28.3 [18.9–35.6] mg/dL versus 14.15 [8.85–25.25]; p = 0.001) and levels above 30 mg/dL were associated with an increased risk of recurrence (HR 3.9, 95% CI 1.23–12.4).[102]

Current evidence does not support a significant association between Lp(a) levels and clinical outcomes in patients with VTE. In both prospective and retrospective studies, including patients with unprovoked VTE and acute PE, Lp(a) concentrations were not significantly associated with VTE recurrence, PE severity, or thrombus burden, although not detecting effect due to small study size cannot be excluded.

 

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Reconciling Preclinical and Clinical Data for the Association between Lp(a) and VTE

Although preclinical studies have previously shown antifibrinolytic and prothrombotic properties of Lp(a), clinical studies have not consistently demonstrated an association between moderately elevated Lp(a) levels and subsequent VTE risk. However, some clinical studies have shown an association between extremely elevated Lp(a) levels and VTE risk. Various explanations have been proposed to account for these discrepant findings. The Lp(a) particle is found exclusively in humans, Old World monkeys, apes, and hedgehogs. Human Lp(a) contains a strong, functional lysine binding site in apo(a) KIV-10, which differs from non-human primates.[9] Although transgenic animal models were developed to address these concerns, they may not fully replicate human Lp(a) function.[1] [2] [17] [103] Studies indicate that transgenic mice exhibit free circulating apo(a) unbound to lipoproteins[104] or ApoB-100,[105] and species lacking Lp(a) may also lack co-evolved structures such as specific receptors,[106] limiting the applicability of the findings.

Some in vitro studies have suggested a dose–response relationship between Lp(a) concentrations and antifibrinolytic activity, with higher levels leading to progressively greater inhibition of plasminogen activation and fibrinolysis.[66] [79] [107] However, the relative abundance of plasminogen compared with Lp(a) in human plasma may explain why clinical studies have not consistently replicated in vitro results,[11] [108] except in cases of extremely elevated Lp(a). Nevertheless, a recent study including patients with Lp(a) levels >125 nmol/L (>50 mg/dL) found no changes in plasma clot formation and lysis time following a 70 to 85% reduction in Lp(a) levels through antisense oligonucleotide therapy.[109] Notably, no studies have yet assessed platelet function after Lp(a) reduction in humans.

Additionally, a few general limitations exist in regard to MR and genetic association studies. The databases used in those studies, such as the UK Biobank, represent distinct populations with limited racial and ethnic diversity, which may restrict the generalizability of findings. Moreover, previous research has raised concerns about construct validity and the misclassification of VTE cases, as case identification in these studies from administrative databases relies on International Classification of Diseases (ICD) codes that do not specify the position of the diagnosis (primary or secondary) and on self-reported diagnoses.[110] [111] [112] Observational studies may have also underestimated VTE incidence, as VTE events are often not systematically identified. Without routine surveillance imaging, VTE is frequently underdiagnosed, leading to potential misclassification and underreporting in these studies. Moreover, differences in measurement methods of Lp(a) levels may have contributed, at least in part, to the inconsistent findings regarding its association with VTE.[1] [113]

Although some preclinical studies suggest that Lp(a) may have prothrombotic effects, it is generally accepted that Lp(a) primarily impairs fibrinolysis rather than directly promoting coagulation.[36] [68] In this context, one proposed mechanism linking Lp(a) to venous thrombosis postulates that elevated Lp(a) levels, only in conjunction with hypercoagulable conditions, may increase the risk of VTE. However, further investigations are needed to test this hypothesis.[114] This contrasts with ASCVD, for which Lp(a) is thought to play a causal role through multiple pathways.

 

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Lipid-modifying Agents: Associations with Lp(a) and VTE

Current lipid-lowering medications have shown mixed effects on Lp(a) levels and on VTE events ([Table 3]). PCSK9 inhibitors are reported to reduce Lp(a) levels by 23 to 27%,[14] [115] and are also associated with a decreased risk of VTE compared with placebo, as demonstrated in a pooled analysis of the FOURIER and ODYSSEY OUTCOMES trials (HR 0.69, 95% CI 0.53–0.90).[115] In contrast, statins have been found to increase Lp(a) levels by 8 to 19% in some studies[53] even while demonstrating VTE risk reduction in epidemiological studies[116] and RCTs.[117] A pooled analysis of the JUPITER and HOPE-3 trials demonstrated a lower risk of VTE among patients receiving rosuvastatin compared with placebo (HR 0.53, 95% CI 0.37–0.75).[117] The beneficial effects of statins on VTE appear to result from multiple mechanisms, such as the downstream inactivation of the inflammatory system,[73] reduced expression of TF,[118] [119] and PAI-1.[120] Niacin[121] and cholesteryl ester transfer protein (CETP) inhibitors[122] [123] reduce Lp(a) levels by nearly 23% and 33 to 56%, respectively, though their impact on VTE risk has not been comprehensively investigated. Other medications, such as ezetimibe, bempedoic acid, and fibrates, have shown mixed or minimal effects on Lp(a) levels. Pemafibrate was recently shown to entail an excess risk of VTE.[124] Taken together, the widely available lipid-lowering agents have shown mixed effects on Lp(a) levels, and their association with future risk of VTE may be independent of the modest impact on Lp(a) concentrations.

Table 3 Lipid-lowering therapies' effects on Lp(a) levels and association with VTE

Drug		Association with Lp(a) levels		Association with VTE
				Study	Number of patients	Main findings
Statins		Mean increase of 8.5 to 19.6%[53]	Primary prevention of VTE	Joseph et al, 2022 (analysis of JUPITER and HOPE-3 trials)[136]	30,507	Rosuvastatin was associated with a 47% proportional reduction in the risk of VTE (HR 0.53, 95% CI 0.37–0.75)
				Kunutsor et al, 2017 (meta-analysis of 23 RCTs)[137]	118,464	Statin therapy was associated with a 15% reduction in the risk of VTE when compared with placebo or no treatment (RR 0.85, 95% CI 0.73–0.99; p = 0.038)
				Farmakis et al, 2024 (network meta-analysis of 45 RCTs [90 arms] of lipid-lowering agents)[117] [a]	254,933 in the whole network of RCTs	VTE risk: - Low/moderate-intensity statin versus placebo: RR 0.89 (95% CI 0.79–1.00; p = 0.05) - High-intensity statin versus placebo: RR 0.84 (95% CI 0.7–1.02, p = 0.07)
			Secondary prevention of VTE	Delluc et al, 2022 (pilot SAVER trial)[138]	312	This pilot trial supported the feasibility of a large-scale trial on adjuvant statins for secondary prevention VTE (NCT04319627)
PCSK9 inhibitors	Overall PCSK9 inhibitors	23.5 to 26.9% reduction		Marston et al., 2020 (pooled analysis of FOURIER and ODYSSEY OUTCOMES trials)[115]	46,488	Lower risk of VTE with PCSK9 inhibitors versus placebo (HR 0.69, 95% CI 0.53–0.90)
	Evolocumab	Median reduction of 26.9%		Marston et al, 2020 (analysis of the FOURIER trial)[115]	27,564	46% decreased risk of VTE after 1 year (HR 0.54, 95% CI 0.33–0.88)
	Alirocumab	Median reduction of 23.5%		Schwartz et al, 2020 (analysis of the ODYSSEY OUTCOMES trial)[14]	18,924	Trends toward lower risk of VTE with alirocumab versus placebo (HR 0.67, 95% CI 0.44–1.01)[115] [139]
Fibrates		Minimal effect,[140] possible increase[141]		Pradhan et al, 2022[124] (PROMINENT trial)	10,497	71 patients in the pemafibrate versus 35 patients in the placebo group had VTE (HR 2.05; 95% CI 1.35 to 3.17)
				FIELD study, 2005[142]	9,795	Fenofibrate was associated with a slight increase in PE compared with placebo (0.7% vs. 1.1%, p = 0·022)
Ezetimibe		Neutral effect[143] or minimal reduction of 7%[144]		Farmakis et al, 2024 (network meta-analysis of 45 RCTs [90 arms] of lipid-lowering agents)[117] [b]	254,933 in the whole network of RCTs	VTE risk: - Ezetimibe plus low/moderate-intensity statin vs placebo: RR 0.92 (95% CI 0.74–1.15) - Ezetimibe plus high-intensity statin vs placebo: RR 0.88 (95% CI 0.67–1.15) - Ezetimibe monotherapy vs placebo: RR 1.04 (95% CI 0.83–1.30)
Inclisiran (small interfering RNA)		6.3 to 21.9% reduction[145] [146] [147]		–	–	The risk of VTE was not specifically evaluated
Bempedoic acid		Neutral effect[148] [149]		–	–	The risk of VTE was not specifically evaluated
Niacin		Mean reduction of 22.9%[121]		–	–	The risk of VTE was not specifically evaluated
CETP inhibitors	Obicetrapib	Median reduction of 33.8 to 56.5%, depending on the dose[122]		–	–	The risk of VTE was not specifically evaluated
	Anacetrapib	Reduction by 34.1%[123]

Abbreviations: ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CETP, cholesteryl ester transfer protein; CI, confidence interval; HR, hazard ratio; Lp(a), lipoprotein(a); RCT, randomized controlled trial; RR, relative risk; VTE, venous thromboembolism.

^a Low/moderate intensity statin (25/90 arms), high intensity statin (22/90 arms), Placebo (26/90 arms).

^b Ezetimibe+low/moderate intensity statin (4/90 arms), Ezetimibe+high intensity statin (1/90 arms), Placebo (26/90 arms).

Several trials are now evaluating the efficacy of specific antisense oligonucleotides (pelacarsen), small interfering RNAs (i.e., olpasiran, lepodisiran, and zerlasiran), and oral small molecule inhibitors (muvalaplin) in lowering Lp(a) and decreasing cardiovascular events, with Lp(a) reduction capacities consistently exceeding 80% ([Fig. 2]). VTE has not been included in the prespecified outcomes of these phase 2 trials due to the limited number of anticipated VTE events, although phase 3 trials may have more power to explore such results, providing valuable information on the effect of Lp(a) modification on VTE risk, particularly in the subset with substantially high Lp(a) levels.

Fig. 2 Randomized controlled trials (RCTs) of specific lipoprotein(a) [Lp(a)] lowering therapies and association with venous thromboembolism (VTE). RCTs of agents specifically designed to lower Lp(a), including those that work through antisense or siRNA and plasma apheresis (currently the only approved Lp(a) lowering therapy), have been included in this figure. The studies included patients with Lp(a) levels within the top 90th to 95th percentile of the population distribution. Included are those with available results regarding their effect on Lp(a) levels. All agents demonstrated significant reductions in Lp(a) levels. The impact on cardiovascular disease and VTE is still under investigation. CAD, coronary artery disease; FH, familial hypercholesterolemia. ^†The reduction of 101% reflects the placebo-adjusted mean percentage change, as the placebo group experienced a slight increase in Lp(a) levels. ^‡Conversion of Lp(a) values between mg/dL and nmol/L may lead to imprecise measurements due to variability in apolipoprotein(a) isoform sizes. Therefore, we did not perform conversions for studies that did not report them originally. References: Pelacarsen,[125] muvalaplin,[126] olpasiran,[127] zerlasiran,[128] lepodisiran,[129] and plasma apheresis.[130]

Among the existing lipid-modifying therapies, a clear correlation between their impact on Lp(a) and risk of VTE has not been identified. The direct effect of Lp(a) lowering on incident VTE will be better understood upon completion of the large clinical trials of Lp(a) lowering therapies.

 

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Knowledge Gaps and Future Perspectives

The role of Lp(a) in modulating thrombotic risk in individuals with an underlying prothrombotic state remains poorly understood. Key areas requiring further investigation include the association between extreme levels of Lp(a) and VTE outcomes, as well as potential interactions between Lp(a) and mechanisms that are more specific to VTE. Additionally, the impact of Lp(a) on platelet function and the specific contribution of Lp(a)-associated OxPL to thrombogenesis remain to be explored. A major challenge in advancing this research is the lack of an appropriate animal model for studying Lp(a)-mediated thrombosis, highlighting the need for transgenic models incorporating both apo(a) and human ApoB.[83] Ultimately, it is important that analyses of the ongoing RCTs include ancillary studies considering VTE outcomes, which may offer insights into the impact of Lp(a) reduction on the risk of incident or recurrent VTE.

 

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Conclusion

Although in vitro studies have suggested a potential prothrombotic role for Lp(a), results from epidemiological studies are mixed and MR studies have not consistently confirmed the association between elevated levels of Lp(a) and VTE, except for those with extremes of increased levels. Current evidence does not support Lp(a) as an independent driver of venous thrombosis; however, the possibility that elevated Lp(a) exacerbates an existing prothrombotic state or that extremes of Lp(a) elevation confer an excess risk for incident VTE or worse outcomes in those with new VTE remains to be explored. Reporting of results for VTE outcomes in the ongoing clinical trials of Lp(a) reduction will not only shed light on the mechanistic association but also can assess an additional therapeutic potential for these drugs.

 

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Conflict of Interest

Outside the submitted work, Dr. Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814). Dr. Bikdeli was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital. Dr. Bikdeli reports that he was a consulting expert on behalf of the plaintiff for a litigation related to two specific brand models of IVC filters. Dr. Bikdeli has not been involved in the litigation in 2022–2025, nor has he received any compensation in 2022–2025. Dr. Bikdeli reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum and serves on the Data Safety and Monitoring Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute and Translational Sciences. Dr. Bikdeli is a collaborating consultant with the International Consulting Associates and the US Food and Drug Administration in a study to generate knowledge about the utilization, predictors, retrieval, and safety of IVC filters. Dr. Bikdeli receives compensation as an Associate Editor for the New England Journal of Medicine Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for JACC, and is a Section Editor for Thrombosis and Haemostasis (no compensation). Dr. O'Donoghue receives grants via Brigham and Women's Hospital from Amgen, Novartis, and AstraZeneca; and consulting and/or DSMB fees from Amgen, Novartis, AstraZeneca, Janssen, NovoNordisk, Verve, and New Amsterdam. Dr. Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos (no fees are received personally). Dr. Gregory Piazza reports research grants paid to his institution from BMS/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Regeneron, and NIH 1R01HL164717–01 and consulting fees from BSC, Amgen, NAMSA, BMS/Pfizer, and Janssen. Dr. Nissen reports that the Cleveland Clinic Center for Clinical Research (C5Research) has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Kardigan, CRISPR Therapeutics, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. Dr. Nissen is involved in conducting these clinical trials but receives no personal remuneration for his participation. Dr. Nissen consults for these pharmaceutical companies, but does not accept compensation. Dr. Nicholls received grant/research support from AstraZeneca, NewAmsterdam Pharma, Amgen, Anthera, Cyclarity, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and was a consultant for Abcentra, AstraZeneca, Amarin, Akcea, CRISPR Therapeutics, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Daiichi Sankyo, Scribe, Silence Therapeutics, CSL Seqirus, and Vaxxinity. Other authors report no disclosures.

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Publication History

Received: 24 May 2024

Accepted: 01 August 2025

Article published online:
22 August 2025