Editorial

Mechanisms of Lipoprotein(a) Pathogenicity

Prothrombotic, Proatherosclerotic, or Both?
J. David Spence, Marlys Koschinsky

igh quality, large prospective population-based studies

are like well-tended orchards: they take many years to
bear fruit, but when they do, they yield a bounty. In this issue
of Arteriosclerosis, Thrombosis, and Vascular Biology, fruit
is on offer from 2 important Danish population-based studies, the Copenhagen City Heart Study and the Copenhagen
General Population Study, which previously provided key evidence that genetically based levels of C-reactive protein were
not related to vascular disease,1 and from 3 case-control studies conducted in Copenhagen. In the present study,2 Kamstrup
et al3 use a Mendelian randomization study similar to that
described in 2009 to probe the relationship between plasmaderived and genetically determined levels of lipoprotein(a)
(Lp[a]), and the development of venous thromboembolism
(VTE; thrombotic events), vascular stenosis (atherosclerotic
events), and myocardial infarction (which they called combined atherosclerotic and thrombotic events).

See accompanying article on page 1732

The ultimate goal of the study was to further our understanding of the mechanism of Lp(a) action in vascular disease, which has been controversial. Results over the years
from both in vitro and in vivo studies have reflected the duality of Lp(a) structure: in this regard, both proatherosclerotic
(low-density lipoproteinlike) and prothrombotic (plasminogen-like) functions have been reported (Figure).4 By comparing the contribution of genetically elevated Lp(a) to arterial
stenosis, thrombotic events secondary to atherosclerosis,
and pure thrombotic events in the veins, the authors hoped
to gain insight into the relative contribution of the 2 facets
of Lp(a) action to atherothrombotic events. Interestingly, the
authors report no association of Lp(a) levels and kringle IV
type 2 genotypes with VTE in large numbers of participants.
However, they do report positive relationships (albeit using
considerably smaller sample sizes) between Lp(a) and kringle
IV type 2 genotype atherosclerotic stenosis in the coronary,
carotid, and femoral arteries. Coronary stenosis was assessed

From the Stroke Prevention & Atherosclerosis Research Centre,

Robarts Research Institute, Western University, London (J.D.S.); and
Department of Chemistry and Biochemistry, University of Windsor,
Windsor, ON, Canada (M.K.).
Correspondence to J. David Spence, MD, FRCPC, FAHA, Stroke
Prevention & Atherosclerosis Research Centre, Robarts Research
Institute, Western University, 1400 Western Rd, London, ON, Canada
N6G 2V2. E-mail dspence@robarts.ca
(Arterioscler Thromb Vasc Biol. 2012;32:15501551.)
2012 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
DOI: 10.1161/ATVBAHA.112.251306

angiographically, but carotid stenosis (50%) was assessed by

Doppler ultrasound, and peripheral vascular disease by anklebrachial index. Thus, the evidence for stenosis in the present
study was stronger for coronary disease than for carotid stenosis or peripheral vascular disease. It is worth noting that in the
present study, the kringle IV type 2 genotype accounted for
only 25% of the variance of levels of Lp(a). This contribution
of apolipoprotein(a) isoform size to Lp(a) levels is lower than
would be expected in a white population.5 This may reflect
noise introduced with the genotyping method, which reports
the total number of kringle IV encoding repeats on the 2 LPA
alleles. Because large or nonexpressing alleles will be detected
by this method, this, in turn, results in an underestimation of
the relationship between genetically determined Lp(a) levels
and the end points under consideration, and needs to be considered in the interpretation of studies using this methodology.
How can we reconcile the data of Kamstrup et al with the
literature describing the relationship between Lp(a) and VTE?
Some, but not all, case-control studies have shown increased
risk of VTE with elevated Lp(a) concentrations, and a metaanalysis of 6 case-control studies of adult patients by Sofi
et al6 as well yielded a positive result for Lp(a) levels >30
mg/dL (odds ratio 1.77; 95% CI 1.142.75; P=0.01). On the
other hand, cohort studies, including the 2 Danish populations
studied by Kamstrup et al2 as well as the large Longitudinal
Investigation of Thromboembolism Etiology reported by Tsai
et al,7 have uniformly reported no relationship between Lp(a)
concentration and incidence of VTE. Although the cohort
studies eliminate the possibility of selection bias, it should
be noted that the incidence rate in these studies was small,
particularly in the case of the Longitudinal Investigation of
Thromboembolism Etiology study, possibly masking any
dose-dependent effect of Lp(a) concentration. Notably, in the
present study, Kamstrup et al reported that extremely high
Lp(a) concentrations (>95th percentile) were in fact associated with VTE. Curiously, several studies in children have
identified elevated Lp(a) as a significant risk factor for VTE.8,9
It is possible that elevated Lp(a) is not a risk factor for VTE,
despite the documented antifibrinolytic properties of this lipoprotein,4 or that the effects of Lp(a) are only significant at the
very highest concentrations of this lipoprotein.
Can the data from the present study support a conclusion
that Lp(a) operates through a proatherosclerotic rather than
a prothrombotic mechanism? Although tempting, it is diffi
cult to draw mechanistic conclusions from epidemiologi
cal studies. Indeed, in the present study, the relationship of
Lp(a) to atherostenosis may reflect a contribution of Lp(a) to
prothrombotic/antithrombolytic effects of Lp(a) in this process.
Klein et al reported in Arteriosclerosis, Thrombosis, and
Vascular Biology in 2008, based on data from 876 participants,

Downloaded from http://atvb.ahajournals.org/

by guest on August 1, 2016
1550

Spence and Koschinsky Lipoprotein(a): Prothrombotic, Proatherosclerotic, or Both? 1551

Figure. Mechanisms linking lipoprotein(a) (Lp[a]) to thrombosis and atherosclerosis. The Venn diagram depicts a series of factors that
potentially contribute to venous thrombosis (left side) and atherothrombosis (right side). A subset of these factors that are influenced by
Lp(a) is contained in the filled circles; note that all the factors potentially contributing to venous thrombosis that are influenced by Lp(a)
are in common with atherothrombosis (center). Factors that contribute uniquely to venous thrombosis or atherosclerosis, and are not
influenced by Lp(a), are contained in the open circles. EC indicates endothelial cell; ECM, extracellular matrix; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI-1, plasminogen activator inhibitor type 1; PL, phospholipids; SMC, smooth muscle cell; TFPI, tissue factor pathway inhibitor activity.

that high levels of Lp(a) were significantly associated with

carotid stenosis and occlusion, but not with carotid total
plaque area.10 Their interpretation, based on the doctrine of
compensatory enlargement,11 was that carotid stenosis was the
result of plaque rupture and stenosis, rather than the result of
simple progression of plaque burden, and that Lp(a) may have
contributed to arterial thrombosis (and impaired thrombolysis).
An important issue worthy of consideration is the differences between arterial thrombosis and venous thrombosis. In
the setting of arterial flow velocities, and in particular with
the very high velocities associated with arterial stenosis, there
is not sufficient time for red thrombus (fibrin polymer with
entrapped red cells) to form; white thrombus (characterized
by platelet aggregates)12,13 is the kind of thrombosis associated
with arterial stenosis, with red thrombus formation occurring
only after arteries occlude. Association of Lp(a) with arterial
stenosis and occlusion, and events such as myocardial infarction may relate to increased likelihood of plaque rupture, to
arterial thrombosis relating to platelet function, to formation
of red thrombus after the occlusion occurs, and to impaired
thrombolysis. As such, it is difficult to conclude with certainty
based on the present study that the prothrombotic effects of
Lp(a) are not important contributors to the pathogenicity
associated with elevated Lp(a) levels. The study is important,
however, in drawing attention to this issue which should spark
further mechanistic investigations aimed at elucidating the
role of this enigmatic lipoprotein in vascular disease.

Disclosures
None.

References
1. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H,
Nordestgaard BG. Genetically elevated C-reactive protein and ischemic
vascular disease. N Engl J Med. 2008;359:18971908.
2. Kamstrup PR, Tybjrg-Hansen A, Nordestgaard BG. Genetic evidence
that lipoprotein(a) associates with atherosclerotic stenosis rather than
venous thrombosis. Arterioscler Thromb Vasc Biol. 2012;32:17321741.

3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG.

Genetically elevated lipoprotein(a) and increased risk of myocardial
infarction. JAMA. 2009;301:23312339.
4. Koschinsky ML. Lipoprotein(a) and atherosclerosis: new perspectives on
the mechanism of action of an enigmatic lipoprotein. Curr Atheroscler
Rep. 2005;7:389395.
5. Ronald J, Rajagopalan R, Cerrato F, Nord AS, Hatsukami T, Kohler T,
Marcovina S, Heagerty P, Jarvik GP. Genetic variation in LPAL2, LPA,
and PLG predicts plasma lipoprotein(a) level and carotid artery disease
risk. Stroke. 2011;42:29.
6. Sofi F, Marcucci R, Abbate R, Gensini GF, Prisco D. Lipoprotein(a)
and venous thromboembolism in adults: a meta-analysis. Am J Med.
2007;120:728733.
7. Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom
AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch
Intern Med. 2002;162:11821189.
8. Nowak-Gttl U, Junker R, Hartmeier M, Koch HG, Mnchow N,
Assmann G, von Eckardstein A. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation.
1999;100:743748.
9. Kenet G, Ltkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L,
Chabrier S, Chan A, deVeber G, Fiedler B, Fullerton HJ, Goldenberg NA,
Grabowski E, Gnther G, Heller C, Holzhauer S, Iorio A, Journeycake J,
Junker R, Kirkham FJ, Kurnik K, Lynch JK, Male C, Manco-Johnson M,
Mesters R, Monagle P, van Ommen CH, Raffini L, Rostsy K, Simioni P,
Strter RD, Young G, Nowak-Gttl U. Impact of thrombophilia on risk
of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates
and children: a systematic review and meta-analysis of observational
studies. Circulation. 2010;121:18381847.
10. Klein JH, Hegele RA, Hackam DG, Koschinsky ML, Huff MW,
Spence JD. Lipoprotein(a) is associated differentially with carotid stenosis, occlusion, and total plaque area. Arterioscler Thromb Vasc Biol.
2008;28:18511856.
11. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ.
Compensatory enlargement of human atherosclerotic coronary arteries.
N Engl J Med. 1987;316:13711375.
12. Deykin D. Thrombogenesis. N Engl J Med. 1967;276:622628.
13. Caplan LR, Fisher M. The endothelium, platelets, and brain ischemia.
Rev Neurol Dis. 2007;4:113121.
KEY WORDS: atherosclerosis fibrinolysis lipoprotein(a) lipoproteins
venous thrombosis

Downloaded from http://atvb.ahajournals.org/ by guest on August 1, 2016

Mechanisms of Lipoprotein(a) Pathogenicity: Prothrombotic, Proatherosclerotic, or Both?

J. David Spence and Marlys Koschinsky
Arterioscler Thromb Vasc Biol. 2012;32:1550-1551
doi: 10.1161/ATVBAHA.112.251306
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
Greenville Avenue, Dallas, TX 75231
Copyright 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 1079-5642. Online ISSN: 1524-4636

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://atvb.ahajournals.org/content/32/7/1550

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the
Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for
which permission is being requested is located, click Request Permissions in the middle column of the Web
page under Services. Further information about this process is available in the Permissions and Rights
Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online
at:
http://atvb.ahajournals.org//subscriptions/

Downloaded from http://atvb.ahajournals.org/ by guest on August 1, 2016