Blood, 1 May 2002, Vol. 99, No. 9, pp. 3476-3478
CORRESPONDENCE
To the editor:
Elevated lipoprotein(a) concentration is an independent risk
factor of venous thromboembolism
We have read with great interest the letter "Increased
lipoprotein(a) levels are not a steady prothrombotic defect" by Korte et al, recently published in Blood.1 The
authors report on a small case series of 7 pediatric patients treated
with asparaginase either because of acute lymphoblastic leukemia
(acute lymphoblastic leukemia
[ALL]-Berlin-Frankfurt-Münster [BFM] 95 trial) or because of
non-Hodgkin lymphoma (non-Hodgkin lymphoma [NHL]-BFM trial). In the longitudinally followed-up patients, mean lipoprotein (Lp)(a) concentrations decreased by approximately 75% during the course of
polychemotherapy, comparing values on day 8 with concentrations on day
22 (P = .049; paired t test). The results
obtained were discussed as mainly asparaginase-induced. Therefore,
Korte et al conclude that elevated Lp(a) concentrations could not be
assumed to be a stable risk marker of venous thromboembolism (VTE)
during chemotherapy. Moreover, they suggest that increased Lp(a) levels should not be looked upon as a "prothombotic defect" since a
clearly defined pathophysiological model on how increased Lp(a)
concentrations can convey an increased prothrombotic risk is still
missing.1
In their letter, Korte et al referred to 2 of our previously published
manuscripts.2,3 Because these 2 articles are not correctly
cited by the authors, we would like to comment on their findings.
The first of our studies not correctly cited by Korte et al
enrolled patients with venous thrombosis. The rate of recurrence with
respect to isolated or combined prothrombotic risk factors was
investigated. Lp(a) was included as a potential risk factor of
recurrent venous thrombosis because high levels of Lp(a) have already
been shown to be a risk factor for first manifestation of
cardiovascular disease4 and venous thromboembolism in
white children and adults.5-7 In this study, no
patient was suffering from acute leukemia or being treated with
asparaginase. Moreover, we could definitely not identify an elevated
level of Lp(a) as an isolated risk factor of recurrent venous
thrombosis: the relative risk of suffering a recurrent venous
thrombosis in patients with elevated levels of Lp(a) was 2.6 (95%
confidence interval 0.5-33.3) (both incorrectly stated by Korte et
al).2
In the second study mentioned by the authors, we prospectively
performed thrombophilia screening in children with acute lymphoblastic leukemia treated according to the BFM 90/95 trials (but not patients with non-Hodgkin lymphoma, as was incorrectly stated by Korte et al)
with respect to symptomatic venous thromboembolism as the study end
point.3 We found the rate of prothrombotic risk factors in
the total patient group to be within the range of the healthy population. However, 46% of the children with at least one
thrombophilic genetic risk (n = 58; factor V G1691A and factor II
G20210A mutation; protein C, protein S, or antithrombin deficiency;
homozygous MTHFR T677T genotype; high level of Lp(a)) suffered
symptomatic venous thrombosis during the study period. The children
affected with symptomatic vascular accidents and suffering from
elevated Lp(a) either alone (n = 2) or in combination with further of
the mentioned risk factors (n = 6) received Escherichia
coli asparaginase. Therefore, in the "Discussion"
section we clearly pointed out that, besides the genetic risk factors
of thrombophilia, additional factors such as endothelial cell injury or
further acquired coagulation imbalance commonly described during
combined steroid asparaginase administration may function as trigger
mechanisms for early thrombotic manifestation during childhood ALL
(BFM-adapted protocols).3 This has been ignored or
overlooked by Korte et al.1
In addition to the aspects mentioned above, we would like to
comment on some other points raised in the letter by Korte et al1: Lp(a), first identified by Berg in 1993,8
is strongly genetically determined, and its apo(a) phenotypes account
for more than 90% of the variation in Lp(a) plasma
concentrations.9-11 Different properties of antibodies and
calibrators used to determine Lp(a) have led to a wide range of values
that are not comparable between different methods and
laboratories.12 Therefore, the cutoff value indicating an
increased prothrombotic risk is not transferable between different
populations and studies. The letter published by this group
provides no information on which Lp(a) method is used in their setting.
Therefore, comparison between our values and the concentrations of the
7 cases is meaningless.12 Their findings are, however, in
accordance with previously published data on the influence of
asparaginase during the course of leukemia induction therapy in
BFM-adapted treatment protocols. The decrease is similar to that shown
for plasminogen and further coagulation proteins containing asparagine
or glutamine as amino acid, for example, the targets of
asparaginase.13 The percentage decrease is, however,
clearly dose- and source-dependent.13-15 Unfortunately, Korte et al provide no information on the source and dosage of asparaginase administered to the children, the asparaginase
activity, or the percentage of asparagine depletion concomitant with
Lp(a) value.
We also would like to refer to the current underlying
pathophysiological models on how elevated Lp(a) functions as a
prothrombotic risk factor. There is a striking similarity between the
apo(a) gene and plasminogen, which share a partially
identical amino acid sequence.16 It has been demonstrated
by Harpel et al17 that Lp(a) inhibits the binding of
plasminogen to plasmin-modified immobilized fibrinogen, thus indicating
that both molecules compete for similar lysine-binding sites, providing
a potential mechanism to explain the association between thrombosis,
coronary atherosclerosis, and elevated blood concentrations of
Lp(a).17
From the statistical point of view, we have to add that Lp(a)
concentrations usually follow a clearly biased but not-normal distribution. Thus, the appropriate statistical method to
compare Lp(a) levels of patients followed up longitudinally is the
Wilcoxon signed rank test/Friedman test instead of the paired
t test, which is to be used for normal distributed data
only.18
In conclusion, as shown in several studies, an elevated Lp(a)
concentration is an independent risk factor for cardiovascular disease
as well as venous thromboembolism in patients suffering from
spontaneous thrombosis or from vascular accidents additionally triggered by underlying diseases. The 7 cases presented by Korte et al
in the September 15 issue of Blood raise methodological as
well as statistical problems and should therefore not be compared with
previously published articles. Finally, it is not justified from 7 cases to draw any conclusion on whether or not elevated Lp(a) is a
prothrombotic risk factor.
Ulrike Nowak-Göttl, Rosemarie Schobess, Karin Kurnik, Dirk Schwabe, Gudrun Fleischhack, and Ralf Junker
Correspondence: Ulrike Nowak-Göttl, Pediatric
Hematology/Oncology, University of Münster, Albert-Schweitzer-Str
33, D-48149 Münster, Germany; e-mail: leagottl{at}uni-muenster.de
References
1.
Korte W, Greiner J, Feldges A, Riesen WF.
Increased lipoprotein(a) levels are not a steady prothrombotic defect.
Blood.
2001;98:1993-1994[Free Full Text].
2.
Nowak-Göttl U, Junker R, Kreuz W, et al.
Risk of recurrent thrombosis in children with combined prothrombotic risk factors.
Blood.
2001;97:858-862[Abstract/Free Full Text].
3.
Nowak-Göttl U, Wermes C, Junker R, et al.
Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors.
Blood.
1999;93:1595-1599[Abstract/Free Full Text].
4.
Scanu AM, Fless GM.
Lipoprotein (a): heterogeneity and biological relevance.
J Clin Invest.
1990;85:1709-1715.
5.
Nowak-Göttl U, Junker R, Hartmeier M, et al.
Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood.
Circulation.
1999;100:743-748[Abstract/Free Full Text].
6.
Von Depka Prondzinski M, Nowak-Göttl U, Eisert R, et al.
Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism.
Blood.
2000;96:3364-3368[Abstract/Free Full Text].
7.
Griffin JH, Fernandez JA, Deguchi H.
Plasma lipoproteins, hemostasis and thrombosis.
Thromb Haemost.
2001;86:386-394[Medline]
[Order article via Infotrieve].
8. Berg K. A new serum type system in man: the Lp system. Acta Pathol
Microbiol Scand. 193;59:369-382.
9.
Utermann G, Duba C, Menzel HJ.
Genetics of the quantitative Lp(a) lipoprotein trait.
Hum Genet.
1988;78:47-50[CrossRef][Medline]
[Order article via Infotrieve].
10.
Helmhold M, Bigge J, Muche R, et al.
Contribution of the apo(a) phenotype to plasma Lp(a) concentrations shows considerable ethnic variation.
J Lipid Res.
1991;32:1919-1928[Abstract].
11.
Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs H.
Apolipoprotein (a) gene accounts for greater than 90% of the variation in plasma lipoprotein (a) concentrations.
J Clin Invest.
1991;90:52-60.
12.
Tate JR, Rifai N, Berg K, et al.
International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a): Phase I, evaluation of the analytical performance of lipoprotein(a) assay systems and commercial calibrators.
Clin Chem.
1998;44:1629-1640[Abstract/Free Full Text].
13.
Nowak-Göttl U, Werber G, Ziemann D, Ahlke E, Boos J.
Influence of two different Escherichia coli asparaginase preparations on fibrinolytic proteins in childhood ALL.
Haematologica.
1996;81:127-131[Medline]
[Order article via Infotrieve].
14.
Boos J, Werber G, Ahlke E, et al.
Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations.
Eur J Cancer.
1996;32:1544-1550.
15.
Nowak-Göttl U, Ahlke E, Schulze-Westhoff P, Boos J.
Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E coli asparaginase preparation.
Br J Haematol.
1996;95:123-126[CrossRef][Medline]
[Order article via Infotrieve].
16.
MacLean JW, Tomlinson JE, Kuang WJ, et al.
cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.
Nature.
1987;300:132-137.
17.
Harpel PC, Gordon BR, Parker TS.
Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin.
Proc Natl Acad Sci U S A.
1989;86:3847-3851[Abstract/Free Full Text].
18.
Petrie A,Sabin C,
eds.
Medical statistics at a glance. Oxford United Kingdom: Blackwell Science; 2000.
Response:
Elevated lipoprotein(a) concentration is an independent risk
factor of venous thromboembolism
We thank Nowak-Göttl et al for their response, and we
appreciate their discussion of this issue. The aim of our
report1 was to bring attention to the fact that
lipoprotein (Lp)(a) levels can be modulated through disease processes
as well as pharmacological interventions. If one accepts that an
increase in Lp(a) conveys a risk for thromboembolism, it seems logical
that diseases or interventions that decrease Lp(a) should
reduce this (ie, the Lp(a)-associated) risk. Given the numerous issues
that Nowak-Göttl et al bring up with their rebuttal letter, we
would like to focus on those that seem important to us.
First, the statement with regard to their 2001 paper2 is very confusing to us. Nowak-Göttl et al
state that they could not identify an elevated Lp(a)
level as an "isolated" risk factor, whereas the title of the
rebuttal letter suggests that increased Lp(a) concentrations are an
"independent" risk factor. Besides, Nowak-Göttl et al
incorrectly cite their paper with regard to the 95% CI for the
Lp(a)-associated relative risk.
Second, given their results with acute lymphoblastic leukemia
(ALL) patients3 and considering our own
experience,4 we agree with Nowak-Göttl et al's
rebuttal comment that genetic factors cannot be the only risk factors
for venous thromboembolism (VTE) during ALL therapy. However,
this comment is contradictory to the title of the rebuttal letter. An
independent risk factor, by definition, is sufficiently strong on its
own to induce the change under investigation. Also, given
Nowak-Göttl et al's above comment, subordination of increased
Lp(a) levels under the subtitle "Prevalence of single established
prothrombotic risk factors" seems incorrect since it has
not been proven to be a single established risk
factor in this setting (ALL therapy). Finally, and interestingly enough, the Kaplan-Meier plot in the 1999 paper3 (Fig 1)
shows that most thromboses occurred between treatment days 20 and 30
exactly the time frame in which we found the most pronounced decrease in Lp(a) during asparaginase therapy, suggesting that the
potential thrombogenic influence of Lp(a) was
decreased at this point.
Third, Nowak-Göttl et al criticize our sample size, but the
sample was large enough to prove significant intra-individual changes.
Also, the criticism seems doubtful, given that Nowak-Göttl et al
base their discussion regarding Lp(a) and thrombosis in ALL therapy on
a total of 8 patients3; moreover, only 2 of those had no
other prothrombotic risk factors identified.
Fourth, our samples were measured with a commonly used nephelometric
assay (Dade Behring, Hamburg, Germany), and we agree that
standardization is an important issue.5 However,
methodology is a different thing and not an issue with our
results, since all intra-individual changes were measured with the same method.
Fifth, Lp(a) (described and investigated by Berg much earlier than
1993, namely, in the 1960s and 1970s) resembles plasminogen and
competes with plasminogen for binding sites in vitro. If
Nowak-Göttl et al accept this model, it is not conceivable why
they would not accept that this competition will diminish if Lp(a)
levels decrease.
Sixth, Lp(a) often shows a skewed distribution, but this obviously
depends on the population investigated. Our sample was normally
distributed, as proven by Kolgomorov-Smirnov testing. However, a
significant difference was also obtained using the (nonparametric)
Wilcoxon signed rank test.
In conclusion, we cannot concur with Nowak-Göttl et al that our
results were biased by methodological or statistical problems. Given
the current knowledge, we can also not concur that an elevated Lp(a)
concentration is a stable risk factor for VTE at any time; data to support this are yet to be generated. Although our patient sample was small, it was large enough to demonstrate that Lp(a) concentrations can be modulated during asparaginase-containing therapy,
as also shown by others. Disease processes and pharmacological interventions can modify Lp(a) levels and, thus,
the risk for VTE related to Lp(a) levels. This needs to be taken into
account when risk stratification for VTE on the basis of Lp(a)
concentrations is performed.
Wolfgang Korte, Jeanette Greiner, Andreas Feldges, and Walter Riesen
Correspondence: Wolfgang Korte, Institute for Clinical Chemistry
and Haematology, Kantonsspital, 9007 St Gallen, Switzerland
References
1.
Korte W, Greiner J, Feldges A, Riesen WF.
Increased lipoprotein (a) levels are not a steady prothrombotic defect.
Blood.
2001;98:1993-1994.
2.
Nowak-Göttl U, Junker R, Kreuz W, et al.
Risk of recurrent thrombosis in children with combined prothrombotic risk factors.
Blood.
2001;97:858-862.
3.
Nowak-Göttl U, Wermes C, Junker R, et al.
Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors.
Blood.
1999;93:1595-1599.
4.
Korte W, Feldges A, Baumgartner C, et al.
Increased thrombin generation during fibrinogen and platelet recovery as an explanation for hypercoagulability in children with L-asparaginase therapy for ALL or NHL: a preliminary report.
Klin Padiatr.
1994;206:331-333[Medline]
[Order article via Infotrieve].
5.
Wieringa G.
Lipoprotein(a): what's in a measure?
Ann Clin Biochem.
2000;37:571-580
