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The structural similarity with plasminogen as well as thrombogenic and atherogenic in vitro functions raise the question if lipoprotein(a) (Lp(a)) is a risk factor for venous thromboembolism (VTE) and ischemic stroke. Numerous case–control and prospective studies using different cut-off values to deﬁne high Lp(a) generated conﬂicting evidence for both VTE and ischemic stroke. Several meta-analyses demonstrated independent associations of elevated Lp(a) with a history of VTE or ischemic stroke. However, the evidence of prospective studies for associations of Lp(a) with incident stroke or recurrent VTE remains inconclusive. For ischemic stroke, data suggest that Lp(a) increases the risk of large-artery atherosclerosis stroke, but not cardioembolic or lacunar stroke. Lp(a) may increase the risk of VTE in the presence of additional thrombophilic risk factors. Larger cohort studies are needed to elaborate the importance of higher Lp(a) cut-offs and interactions with other risk factors and subgroups of stroke or VTE. The value of Lp(a) to estimate residual vascular risk after the ﬁrst thromboembolic event remains to be adequately explored. Keywords Lipoprotein a · Atherosclerosis · Low-density lipoproteins · Ischemic stroke · Venous thrombosis Lipoprotein(a) [Lp(a)] resembles to low-density lipoprotein the presence of kringle IV and kringle V domains as well (LDL) by the presence of one molecule apolipoprotein B as a protease domain, which however is catalytically in- (apoB) and its relatively high content of cholesteryl esters active. A variable number of repeat polymorphism of the in the core. These features lend several in vitro athero- kringle IV domain encodes for 40 apo(a) isoforms which genic properties to Lp(a) which are also exerted by LDL, differ by size and whose number is inversely correlated for example proteoglycan binding and induction of foam with Lp(a) plasma concentrations . The similarity to plas- cell formation . Lp(a) differs from LDL by the pres- minogen as well as the presence of oxidized phospholipids ence of an additional apolipoprotein, termed apolipopro- have been made responsible for the thrombogenic proper- tein(a) (apo(a)), which is covalently bound to apoB by one ties of Lp(a) which include the inhibition of ﬁbrinolysis, the disulﬁde bond. Apo(a) is homologous to plasminogen by induction of plasminogen activator inhibitor type 1 (PAI-1) expression in endothelial cells, as well as the increasing of activity of tissue factor pathway inhibitor and platelet This article is part of the special issue “Lp(a) – Update 2018” responsiveness . Alexander Heinrich Nave These properties have led to the hypothesis that elevated email@example.com plasma levels of Lp(a) increase the risk of ischemic stroke Arnold von Eckardstein and venous thromboembolism (VTE). firstname.lastname@example.org Klinik und Hochschulambulanz für Stroke Neurologie, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Stroke is an acute and potentially life-threatening disease Center for Stroke Research Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany caused by the loss of cerebral blood supply leading to focal cerebral ischemia and ultimately to cell death of the cen- Berlin Institute of Health (BIH), Berlin, Germany tral nervous system . Worldwide, stroke is considered German Center for Cardiovascular Research (DZHK), partner the second most common cause of death and one of the site Berlin, Berlin, Germany leading causes of disability in adult life . Opposed to Institute of Clinical Chemistry, University and University hemorrhagic stroke (i. e. intracerebral hemorrhage), more Hospital of Zurich, Raemistraße 100, 8091 Zurich, Switzerland than 80% of all stroke cases are ischemic stroke events and K Is lipoprotein(a) a risk factor for ischemic stroke and venous thromboembolism? 29 are caused by occlusion of brain-supplying arteries. Despite The analyses revealed a strong heterogeneity between the current secondary prevention strategies, the risk of recur- studies. In fact, studies that chose categorical cut-off values rent stroke events remains high within the ﬁrst years after to deﬁne elevated Lp(a) levels (comparing very high vs. stroke . The heterogeneous etiology of ischemic stroke very low Lp(a) levels) reported greater relative risks for leads to the distinction of subgroups of ischemic stroke . ischemic stroke, compared to studies analyzing continuous According to the most commonly used Trial of ORG 10172 relationships (e. g. change in risk per 1 standard deviation in Acute Stroke Treatment (TOAST) classiﬁcation , is- increase in Lp(a) level). Furthermore, subgroup-speciﬁc chemic stroke can be caused by large-artery atherosclerosis, analyses revealed that greater relative risks in studies inves- cardioembolic events, small artery occlusion (i. e. lacunar tigating younger individuals. In line with this observation stroke), other causes (e. g. arterial dissection), or unknown are previously published studies assessing the risk of high (cryptogenic) or competing causes. Of note, in population- Lp(a) in pediatric stroke that report much higher risk ratios based studies large-artery atherosclerosis represent <20% . It may be argued that this fact is due to the low abso- of all stroke events, whereas cryptogenic strokes represent lute risk that is present in younger stroke patients overall. 30–40% . High blood pressure, presence of atrial ﬁb- The performed meta-regression in the latest meta-analy- rillation, and dyslipidemia (among others) are established ses attributed some of the observed heterogeneity among risk factors for ischemic stroke; however, the causal role of case–control studies to subtypes of ischemic stroke. Studies Lp(a) in ischemic stroke is controversial. that investigated patients with large artery atherosclerosis or cryptogenic stroke demonstrated greater odds ratios than studies involving stroke patients of other cause. Thus, it Ischemic stroke and lipoprotein(a) seems to be important to investigate the role of Lp(a) in speciﬁc subgroups of ischemic stroke. A signiﬁcant association between high Lp(a) levels and in- creased risk of ischemic stroke was expected for a long Ischemic stroke subgroups time and ﬁrst clinical reports date back to the mid-1980s [9, 10]. However, a nested case–control study using prospec- tively collected plasma samples from the Physicians Health Many previously published studies investigating the risk of Study published by Ridker and colleagues in 1995 found stroke of patients with elevated levels of Lp(a) fail to re- no association between Lp(a) and the risk of future stroke port the underlying cause of the stroke event. As stroke among healthy, middle-aged men . Despite the nega- etiologies vary substantially between cohorts, this fact may tive ﬁnding of this study, a great number of case–control explain some of the inconsistent results reported in the lit- and several prospective studies examining different cohorts erature. For example, the prospective Atherosclerosis Risk have reported varying results since [12, 13]. in Communities (ARIC) study examined 14,221 individu- So far, three meta-analyses [14–16] summarized the als free of cardiovascular disease and investigated the risk existing evidence regarding Lp(a) and stroke from both of ischemic stroke with high levels of Lp(a) deﬁned as case–control and prospective studies. All three meta-analy- the 80th percentile of the cohort . After an average ses demonstrated a signiﬁcant and independent association follow-up of 13.4 years 531 ischemic stroke events had of elevated Lp(a) with increased risk of ischemic stroke. occurred. Comparing different stroke subtypes, high Lp(a) The largest meta-analysis performed by the Emerging Risk increased the adjusted risk for non-lacunar stroke (RR 1.42, Factor Collaboration  analyzed individual patient data 95% CI 1.10 to 1.84), but not for lacunar stroke (RR 1.16, from 13 prospective studies comprising 1684 ﬁrst-ever 95% CI 0.75 to 1.80) or cardio-embolic stroke (RR 1.07, ischemic stroke patients. After adjustment for confounding 95% CI 0.65 to 1.74). Similarly, a more recent analysis of variables, an increase per 3.5-fold (1 standard deviation) the ARIC study found that Lp(a) levels >50 mg/dl increase higher usual Lp(a) level resulted in an adjusted risk ra- the relative risk of stroke by 42% among individuals with- tio of 1.11 (95% conﬁdence interval [95% CI] 1.02 to out atrial ﬁbrillation, but not among patients with present 1.20) indicating Lp(a) to be a modest, continuous, and atrial ﬁbrillation reinforcing a pathological role of Lp(a) independent risk factor for ischemic stroke. No analyses primarily in atherothrombotic (atherosclerotic) stroke . were performed on speciﬁc ischemic stroke subgroups. This assumption is supported by a previous Korean study The most recent meta-analysis assessed generic data of where higher Lp(a) levels were found in patients with large- both prospective and observational studies and aimed to artery atherosclerotic stroke compared to patients with other explore subgroup-speciﬁc risk differences . The meta- stroke subtypes . The authors also demonstrated a sig- analysis of nine prospective studies demonstrated an ad- niﬁcant correlation of Lp(a) levels with the degree of in- justed relative risk (RR) of 1.29 (95% CI 1.06 to 1.58) for tracranial and extracranial carotid stenosis. Further evidence ischemic stroke when comparing high vs. low Lp(a) levels. is provided by a previous genetic study that investigated K 30 A. H. Nave, A. von Eckardstein the association of ischemic stroke risk with two variants pants of the Copenhagen City Heart Study, of whom 735 (rs10455872 and rs3798220) of the apolipoprotein (a) gene experienced a VTE event during 15 to 18 years of follow- (LPA). Among 9396 stroke patients that were analyzed, the up, Kamstrup et al. did not ﬁnd any signiﬁcant association odds ratio per variant allele was 1.27 (95% CI 1.11 to 1.46) of Lp(a) levels with the incidence of VTE. Adjusted haz- for large-artery atherosclerotic stroke, 1.03 (95% CI 0.88 to ard ratios for second (median, IQR: 17, 12–27 mg/dl) and 1.22) for cardioembolic stroke, and 1.06 (95% CI 0.90 to third tertiles (median, IQR: 59, 40–94 mg/dl) vs. ﬁrst ter- 1.24) for lacunar stroke. tile of Lp(a) (median, IQR: 3,1–5 mg/dl) were 1.1 (95% CI 0.8–1.4) and 0.8 (95% CI 0.6–1.1), respectively . Like- wise, in a 12-center study of 510 patients with ﬁrst unpro- Risk of recurrent ischemic events voked VTE treated for 5–7 months with anticoagulants and followed up for 16.9 ± 11.2 months, Rodgers et al. did not So far, only few studies have investigated the residual risk ﬁnd any signiﬁcant association of Lp(a) levels >300 mg/L of ﬁrst-ever ischemic stroke patients with high levels of with risk of recurrent VTE events (relative risk 1.4, 95% Lp(a). One study comprising 250 ﬁrst-ever, acute stroke CI 0.7–2.6) . Conversely, in a study of 467 patients patients found an increased risk for the composite endpoint with ﬁrst VTE followed up for one year, Marcucci et al. of recurrent stroke, transient ischemic attack, myocardial found a 5-fold increased risk of recurrent VTE for Lp(a) infarction, revascularization procedures, or cardiovascular >30 mg/dL (OR 5.1, 95% CI 3.1–8.4) which was similar to death after one year with high Lp(a) deﬁned at a cut-off that for hyperhomocysteinemia and even higher than that level of 30 mg/dl (adjusted odds ratio [OR] 2.60, 95% CI for factor V Leiden or the factor II 20210GA polymorphism 1.19 to 5.47) . Interestingly, most of the recurrent vas- . cular events occurred during the ﬁrst months after the index Mendelian randomization studies also made controver- stroke. Using the same cut-off level of 30 mg/dl, a recent sial ﬁndings on the association of LPA polymorphisms with Chinese study demonstrated an increased risk of recurrent risk of VTE. Kamstrup and colleagues  excluded any ischemic stroke events at follow-up three months after the contribution of the kringle IV repeat polymorphism to VTE index stroke (adjusted OR 2.58, 95% CI 1.11 to 6.01) . in the Copenhagen City Heart Study (N = 9190, 443 events) Future studies with larger cohorts are needed to investigate, and the Copenhagen General Population study (N = 28,538; if high Lp(a) levels increase the risk of recurrent vascular 926 with history of VTE). Of note, in the same study, the events, especially within the ﬁrst months after the index authors found genetically causal associations of Lp(a) levels event. and kringle IV repeats with coronary, carotid and femoral atherosclerosis as well as of factor V Leiden with VTE . A more recent but smaller study of 516 patients with Venous thromboembolism in adults a history of VTE and 1117 controls found signiﬁcant in- verse and dose-dependent associations of kringle IV repeat The majority of studies which investigated the association numbers with venous thrombosis . of Lp(a) with VTE were cross-sectional rather than prospec- tive. The most recent meta-analysis analyzed the data of Venous thromboembolism in children and ten studies encompassing 13,541 subjects of whom 5660 had a history of deep vein thrombosis and/or pulmonary adolescents embolism . As the cut-off deﬁning elevated Lp(a), the authors used the upper limit of the manufacturer’s product With an annual incidence of less than 1 in 100,000, VTE reference range (usually 30 mg/dL) in nine studies and the is a rare condition in childhood and adolescence. Never- 75th percentile of Lp(a) value in the control group in one theless, several studies have investigated the associations of study. With these deﬁnitions, elevated Lp(a) was associated Lp(a) and other thrombophilic risk factors with the presence with the presence of VTE at an odds ratio of 1.56 (95% CI and recurrent incidence of VTE in this young population. 1.36 to 1.79). Much stronger risk associations were found A meta-analysis of eight studies encompassing 589 pa- in patients who have a very high risk of VTE, for example tients with VTE and 1441 controls, Lp(a) levels >300 mg/L patients immobilized due to paraplegia. In a case–control was associated with a 4.5-fold higher risk of ﬁrst VTE (95% study of 279 Chinese patients with spinal cord injury of CI 3.19 to 6.35) . One of the studies included also in- whom 55 had a VTE, an Lp(a) level >30 mg/dL was as- vestigated the association of the kringle IV repeat poly- sociated with a more than 10-fold increased risk of VTE morphism with VTE. In 186 patients with VTE and 186 (multivariate OR 10.35, 95% CI 2.37 to 45.15) . matched controls the highest quartile of Lp(a) levels and In contrast to case–control studies, the data of prospec- the lowest quartile of kringle IV repeats were associated tive studies are more controversial. Among 8960 partici- with similar risks of VTE (7.68 vs. 8.14) . Also the K Is lipoprotein(a) a risk factor for ischemic stroke and venous thromboembolism? 31 history of cerebral venous thrombosis in childhood was as- and/or thrombophilic basal conditions (e. g. long-term im- sociated with elevated Lp(a) signiﬁcantly (multivariate OR mobilization). 4.1; 95% CI 1.9–8.6) and even more strongly than with Larger cohort studies are necessary to test whether higher factor V Leiden or the 20210GA polymorphism . cut-off values than conventional 30 mg/dl or 50 mg/dl, in- A meta-analysis of six studies with 135 recurrent VTEs teractions with other risk factors, or etiological disease dif- among 1155 children and adolescents followed up for a me- ferentiation are needed to ﬁrmly establish or rule-out any dian time of 48 months (minimum, 12 months; maximum, role of Lp(a) as a risk factor of ischemic stroke or VTE. 96 months) after the ﬁrst VTE did not ﬁnd any signiﬁcant Conﬂict of interest A.H. Nave and A. von Eckardstein declare that association of high Lp(a) levels with the risk of recurrent they have no competing interests. VTE events (OR 0.84; 95% CI 0.5 to 1.4). However, in this Open Access This article is distributed under the terms of the meta-analysis neither factor V Leiden nor the prothrombin Creative Commons Attribution 4.0 International License (http:// polymorphism were signiﬁcantly associated with the risk creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give of recurrent VTE. Only the combination of at least two appropriate credit to the original author(s) and the source, provide a thrombophilic risk factors including elevated Lp(a) evolved link to the Creative Commons license, and indicate if changes were as a prognostic risk factor for recurrent VTE (OR 4.91; made. 95% CI 3.12 to 7.74) . 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