Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis

Emile L. E. de Bruijne; Sarwa Darwish Murad; Moniek P. M. de Maat; Michael W. T. Tanck; Elizabeth B. Haagsma; Bart van Hoek; Frits R. Rosendaal; Harry L. A. Janssen; Frank W. G. Leebeek; for the Liver and Thrombosis Study Group

doi:10.1160/TH06-07-0407

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(02): 181-185
DOI: 10.1160/TH06-07-0407

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis

Emile L. E. de Bruijne

¹Departments of Hematology, Erasmus University Medical Center, Rotterdam

,

Sarwa Darwish Murad

²Departments of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam

,

Moniek P. M. de Maat

¹Departments of Hematology, Erasmus University Medical Center, Rotterdam

,

Michael W. T. Tanck

³Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam

,

Elizabeth B. Haagsma

⁴Department of Hepatogastroenterology, University Hospital Groningen, Groningen

,

Bart van Hoek

⁵Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden

,

Frits R. Rosendaal

⁶Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden; The Netherlands

,

Harry L. A. Janssen

²Departments of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam

,

Frank W. G. Leebeek

¹Departments of Hematology, Erasmus University Medical Center, Rotterdam

,

for the Liver and Thrombosis Study Group

› Institutsangaben

Abstract

Summary

Splanchnic vein thrombosis (SVT) has been associated with a hypercoagulable state. Thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to a hypercoagulable state, and therefore we were interested in the role of TAFI in SVT. Since the disease is frequently associated with liver insufficiency, which affects plasma levels ofTAFI, we studied the role of variation in theTAFI gene in SVT. In a multicenter case-control study on 118 patients with SVT (39 Budd-Chiari syndrome and 85 portal vein thrombosis) and 118 population-based controls, the relationship of SVT with single nucleotide polymorphisms (SNPs) and haplotypes in the TAFI gene (- 438G/A, Ala147Thr, Thr325Ile and 1583A/T) was determined. The risk for SVT was decreased (OR 0.2,95% CI 0.1–0.7) in 147Thr/Thr homozygotes and slightly,but not significantly,increased in carriers of the 325Ile allele (OR 1.6, 95%CI 0.9–2.7). Haplotype analysis confirmed that the Ala147Thr SNP has the strongest association with risk of SVT. In conclusion, genetic variation in the TAFI gene is associated with risk of SVT, suggesting a role for TAFI in the pathogenetic mechanism of SVT.

Keywords

Thrombin-activatable fibrinolysis inhibitor - Budd-Chiari syndrome - portal vein thrombosis - single nucleotide polymorphism - splanchnic vein thrombosis - inflammation - fibrinolysis

Volltext

Referenzen

References
1 Janssen HL, Garcia-Pagan JC, Elias E. et al. Budd- Chiari syndrome: a review by an expert panel. J Hepatol 2003; 38: 364-371.
2 Valla DC, Condat B. Portal vein thrombosis in adults: pathophysiology, pathogenesis and management. J Hepatol 2000; 32: 865-871.
3 Janssen HL, Meinardi JR, Vleggaar FP. et al. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood 2000; 96: 2364-2368.
4 Mahmoud AE, Elias E, Beauchamp N. et al. Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis. Gut 1997; 40: 798-800.
5 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995; 270: 14477-14484.
6 Campbell W, Okada H. An arginine specific carboxypeptidase generated in blood during coagulation or inflammation which is unrelated to carboxypeptidase N or its subunits. Biochem Biophys Res Commun 1989; 162: 933-939.
7 Hendriks D, Wang W, Scharpe S. et al. Purification and characterization of a new arginine carboxypeptidase in human serum. Biochim Biophys Acta 1990; 1034: 86-92.
8 Eaton DL, Malloy BE, Tsai SP. et al. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem 1991; 266: 21833-21838.
9 Plow EF, Allampallam K, Redlitz A. The plasma carboxypeptidases and the regulation of the plasminogen system. Trends Cardiovasc Med 1997; 7: 71-75.
10 Wang W, Boffa MB, Bajzar L. et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-27181.
11 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-2859.
12 Libourel EJ, Bank I, Meinardi JR. et al. Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein( a) to the absolute risk of venous thromboembolism. Haematologica 2002; 87: 1068-1073.
13 Eichinger S, Schonauer V, Weltermann A. et al. Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 2004; 103: 3773-3776.
14 Martini CH, Brandts A, de Bruijne EL. et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006; 134: 92-94.
15 Frere C, Tregouet DA, Morange PE. et al. Fine mapping of quantitative trait nucleotides underlying thrombin activatable fibrinolysis inhibitor antigen levels by a trans-ethnic study. Blood 2006; 108: 1562-1568.
16 Brouwers GJ, Vos HL, Leebeek FW. et al. A novel, possibly functional, single nucleotide polymorphism in the coding region of the thrombin-activatable fibrinolysis inhibitor (TAFI) gene is also associated with TAFI levels. Blood 2001; 98: 1992-1993.
17 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.
18 Brouwers GJ, Leebeek FW, Tanck MW. et al. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris. Thromb Haemost 2003; 90: 92-100.
19 Epstein MP, Satten GA. Inference on haplotype effects in case-control studies using unphased genotype data. Am J Hum Genet 2003; 73: 1316-1329.
20 Lake SL, Lyon H, Tantisira K. et al. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered 2003; 55: 56-65.
21 Schaid DJ, Rowland CM, Tines DE. et al. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425-434.
22 Juhan-Vague I, Morange PE, Aubert H. et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002; 22: 867-873.
23 Leebeek FW, Goor MP, Guimaraes AH. et al. High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke. JThromb Haemost 2005; 3: 2211-2218.
24 Amitrano L, Guardascione MA, Ames PR. et al. Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine in myeloproliferative disorders: relationship with splanchnic vein thrombosis and arterial disease. Am J Hematol 2003; 72: 75-81.
25 De Stefano V, Teofili L, Leone G. Acquired and inherited risk factors for splanchnic venous thrombosis. Blood 2001; 97: 3314-3315.
26 Guimaraes AH, Bertina RM, Rijken DC. A new functional assay of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost 2005; 3: 1284-1292.
27 Schneider M, Boffa M, Stewart R. et al. Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem 2002; 277: 1021-1030.
28 Murad SD, Valla DC, de Groen PC. et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004; 39: 500-508.