Download Increased Lipoprotein (a) levels are not a steady prothrombotic defect

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BLOOD, 15 SEPTEMBER 2001 䡠 VOLUME 98, NUMBER 6
CORRESPONDENCE
Table 1. Association between TAFI genotypes and plasma TAFI Ag levels
No.
Percentage
TAFI Ag (SD)
U/dL
TT (Ile/Ile)
17
11.2
0.874 (0.136)
CT (Thr/Ile)
76
50.0
0.960 (0.139)
CC (Thr/Thr)
59
38.8
1.006 (0.139)
Allele T
110
36.2
Allele C
194
63.8
P*
1040
1993
TAFI resulting in altered antifibrinolytic activity. The possibility
that the same TAFI haplotype will affect levels and antifibrinolytic
activity in opposite directions will hamper the interpretation of
genetic association studies using this SNP.
Geert-Jan Brouwers, Hans L. Vos, Frank W. G. Leebeek, Saskia Bulk,
Mark Schneider, Michael Boffa, Marlys Koschinsky, Nico H. van Tilburg,
Michael E. Nesheim, Rogier M. Bertina, and Encarnación B. Gómez Garcı́a
.002
Correspondence: Geert-Jan Brouwers, Department of Hematology, Erasmus
University Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE,
Rotterdam, The Netherlands
⫺438
AA
13
8.6
0.887 (0.137)
AG
72
47.4
0.947 (0.136)
GG
67
44.0
1.007 (0.140)
Allele A
98
32.2
References
Allele G
206
67.8
1.
GG (Ala/Ala)
75
49.3
0.934 (0.139)
Henry M, Aubert H, Morange PE, et al. Identification of polymorphisms in the
promoter and the 3⬘ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood. 2001;97:2053-2058.
AG (Ala/Thr)
69
45.4
1.000 (0.141)
2.
AA (Thr/Thr)
8
5.3
1.029 (0.138)
Allele A
85
28.0
Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb
Haemost. 1998;80:949-955.
Allele G
219
72.0
3.
Franco RF, Fagundes MG, Meijers JCM, et al. Identification of polymorphisms
in the TAFI gene promoter; relationship with plasma TAFI levels and risk of venous thrombosis [abstract]. Blood. 2000;96:565a.
4.
Crainich P, Tang Z, Macy EM, et al. A polymorphism at position -438 in the promoter region of thrombin-activatable fibrinolysis inhibitor (TAFI) is strongly associated with plasma antigen levels in healthy older men and women [abstract].
Circulation. 2000;102(suppl II):866.
5.
Schneider MS, Boffa MB, Rahman MN, et al. A variant of human TAFI exhibits
increased thermal stability and increased antifibrinolytic potential [abstract].
Thromb Haemost (CD-ROM). July 2001 (suppl). Abstract OC1756.
6.
van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis
inhibitor and the risk for deep vein thrombosis. Blood. 2000;95:2855-2859.
7.
Marx PF, Bouma BN, Meijers JCM. Plasmin mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor [abstract]. Blood. 2000;96:44a.
.002
505
.001
*Test for trend.
In conclusion, the 1040T/C SNP located in the coding region of
the TAFI gene and resulting in the Thr325Ile substitution is
associated with TAFI plasma levels, just like other SNPs in and
around this gene. Presently, it is not known which SNP is/are
responsible for this effect on TAFI levels. On the other hand,
studies using recombinant proteins have demonstrated a functional
effect of the Thr325Ile substitution on the stability of activated
To the editor:
Increased Lipoprotein(a) levels are not a steady prothrombotic defect
We have read the paper by Nowak-Göttl and coworkers1 on the meaning
of combined prothrombotic defects for recurrence of venous thrombosis
in childhood with great interest and congratulate the authors for their
work. However, we would like to comment on their findings with regard
to Lipoprotein(a) [Lp(a)]. In their paper, the authors describe Lp(a) as
the second most prevalent “prothrombotic defect” for recurrent and
nonrecurrent venous thromboembolism (VTE) in childhood, using a
cut-off of 300 mg/L (30 mg/dL).
We had the chance to examine Lp(a) concentrations in a small group
of pediatric patients (n ⫽ 7) treated for acute lymphoblastic leukemia
(ALL) or lymphoma on the ALL- or NHL-BFM (non-Hodgkin
lymphoma–Berlin-Frankfurt-Muenster) trial 95, respectively. These 2
trials were used by Nowak-Göttl et al2 to study the incidence of
increased Lp(a) and its possible relationship to the incidence of venous
thrombosis in this setting. We found that Lp(a) was significantly
decreased during therapy on the BFM trial 95 (Figure 1), with every
patient showing reduction of Lp(a) concentration. A patient with an
increased Lp(a) of 325 mg/L displayed a decrease to a nadir of 58 mg/L,
only to end the first block of therapy with a level of 111 mg/L. Mean
Lp(a) fell by 75% from 116.1 mg/L on day 8, to 28.9 mg/L on day 16
(P ⫽ .049, Figure 1). It is very likely that these changes in Lp(a)
concentrations were due to the use of L-asparaginase, as described by
other investigators in a different setting.3
Variation of Lp(a) levels with albumin concentrations has been
described4 as well as with the state of thyroid function.5,6 Also,
Lp(a) levels have repeatedly been linked to acute-phase responses.7-10 On the other hand, negative acute-phase characteristics
and decreases in catabolic states have also been shown to
occur.11,12 In vitro experiments show that Lp(a) messenger RNA
(mRNA) expression can be positively regulated by interleukin-6
(IL-6), whereas it can be suppressed by transforming growth
Figure 1. Lp(a) levels can be unsteady: the course of Lp(a) concentration
during L-asparaginase containing chemotherapy is displayed and a significant
decrease can be seen.
From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
1994
CORRESPONDENCE
factor ␤1 (TGF-␤1) and tumor necrosis factor-␣ (TNF-␣),
suggesting that in vivo Lp(a) levels may be dependent on the
balance between stimulatory and inhibitory cytokines,13 which
could help to explain the variation of Lp(a) levels with regard to
different clinical settings.
In a case control study with patients and controls matched for
age and sex, the authors also considered acute-phase responses to
control for “falsely” increased Lp(a) concentrations14; in this study,
no increased risk for VTE with increased Lp(a) concentrations
could be demonstrated.
Epidemiologically, there seems to be a relationship between
increased Lp(a) concentrations and VTE. However, given the fact
that a clearly defined pathophysiologic model on how increased
Lp(a) concentrations can convey an increased prothrombotic risk is
still missing, we suggest that increased Lp(a) levels should not be
looked at as a “prothrombotic defect” but rather a “surrogate risk
marker.” This view is important in light of the above data, showing
that Lp(a) levels are (although largely genetically determined) not
“fixed” to a certain concentration.
Therefore, disregarding circumstances (such as comorbidity or
treatment effects) that might cause variation of Lp(a) levels could
lead to false estimation of numbers of patients at risk for VTE in a
given population. In addition, an increased Lp(a) concentration
cannot be assumed to be a stable risk marker of VTE during
chemotherapy with asparaginase-containg regimens, since asparaginase greatly reduces Lp(a) levels.
Wolfgang Korte, Jeanette Greiner, Andreas Feldges, and Walter F. Riesen
BLOOD, 15 SEPTEMBER 2001 䡠 VOLUME 98, NUMBER 6
References
1. Nowak-Göttl U, Junker R, Kreuz W, et al. Risk of recurrent venous thrombosis
in children with combined prothrombotic risk factors. Blood. 2001;97:858-862.
2. Nowak-Göttl U, Wermes C, Junker R, et al. Prospective evaluation of the
thrombotic risk in children with acute lymphoblastic leukemia carrying the
MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood. 1999;93:1595-1599.
3. Halton JM, Nazir DJ, McQueen MJ, Barr RD. Blood lipid profiles in children with
acute lymphoblastic leukemia. Cancer. 1998;83:379-384.
4. Yang WS, Min WK, Park JS, Kim SB. Effect of increasing serum albumin on
serum lipoprotein(a) concentration in patients receiving CAPD. Am J Kidney
Dis. 1997;30:507-513.
5. de Bruin TW, van Barlingen H, van Linde-Sibenius Trip M, van Vuurst de Vries
AR, Akveld MJ, Erkelens DW. Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid, euthyroid, and hyperthyroid subjects. J Clin Endocrinol Metab. 1993;76:121-126.
6. Engler H, Riesen WF. Effect of thyroid function on concentrations of lipoprotein(a). Clin Chem. 1993;39:2466-2469.
7. Lee YH, Choi SJ, Ji JD, Seo HS, Song GG. Lipoprotein(a) and lipids in relation
to inflammation in rheumatoid arthritis. Clin Rheumatol. 2000;19:324-325.
8. Kario K, Matsuo T, Kobayashi H, Matsuo M, Asada R, Koide M. High lipoprotein
(a) levels in chronic hemodialysis patients are closely related to the acute
phase reaction. Thromb Haemost. 1995;74:1020-1024.
9. Gurbuz O, Ozdemir Y, Cosar CB, Kural G. Lipoprotein (a) in Behcet’s disease
as an indicator of disease activity and in thrombotic complications. Eur J Ophthalmol. 2001;11:62-65.
10. Noma A, Abe A, Maeda S, Seishima M, Makino K, Yano Y, Shimokawa K.
Lp(a): an acute-phase reactant? Chem Phys Lipids. 1994;67-68:411-417.
11. Andreassen AK, Berg K, Torsvik H. Changes in Lp(a) lipoprotein and other
plasma proteins during acute myocardial infarction. Clin Genet. 1994;46:410416.
12. Mooser V, Berger MM, Tappy L, Cayeux C, Marcovina SM, Darioli R, Nicod P,
Chiolero R. Major reduction in plasma Lp(a) levels during sepsis and burns.
Arterioscler Thromb Vasc Biol. 2000;20:1137-1142.
Correspondence: Wolfgang Korte, Institute for Clinical Chemistry and
Haematology, Kantonsspital, 9007 St Gallen, Switzerland; e-mail:
[email protected]
13. Ramharack R, Barkalow D, Spahr MA. Dominant negative effect of TGF-beta1
and TNF-alpha on basal and IL-6-induced lipoprotein(a) and apolipoprotein(a)
mRNA expression in primary monkey hepatocyte cultures. Arterioscler Thromb
Vasc Biol. 1998;18:984-990.
Data on Lp(a) during the BFM 95 trials was reported in poster form at the Annual
Meeting of the Gesellschaft für Thrombose-und Hämostaseforschung, in
Freiburg, Germany, February 16-19, 2000.
14. Lippi G, Bassi A, Brocco G, Manzato F, Marini M, Guidi G. Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control
study. Haematologica. 1999;84:726-729.
From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
2001 98: 1993-1994
doi:10.1182/blood.V98.6.1993
Increased Lipoprotein(a) levels are not a steady prothrombotic defect
Wolfgang Korte, Jeanette Greiner, Andreas Feldges and Walter F. Riesen
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