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From www.bloodjournal.org by guest on August 12, 2017. For personal use only. 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. 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