Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris

Summary

Decrease of fibrinolytic potential is considered to be a risk factor for arterial thrombosis. The recently described thrombinactivatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis by cleaving of the C-terminal lysine residues from fibrin, thereby inhibiting tPA mediated plasminogen activation. The role of plasma TAFI antigen (Ag) levels and gene polymorphisms in arterial thrombosis is still not elucidated. In this prospective study, the association between plasma TAFI Ag levels and the TAFI gene polymorphisms, Ala147Thr, Thr325Ile and -438A/G, with refractory unstable angina pectoris (UAP) was determined. The study population consisted of 209 patients with UAP of whom 76 were refractory and 133 non-refractory to medical treatment. In the same study population the contribution of these polymorphisms to plasma TAFI Ag levels was determined.

Plasma TAFI Ag levels were significantly higher in non-refractory patients compared to refractory patients (geometric mean 114.4 and 105.6 U/dl respectively, p=0.042). Plasma TAFI Ag levels in the lowest quartile resulted in a 2.6 fold (95% confidence interval 1.2-5.9) increased risk for refractory UAP compared to plasma TAFI Ag levels in the upper quartile. The three studied TAFI polymorphisms had an independent and additive effect on plasma TAFI Ag levels. However, no significant association between the individual TAFI polymorphisms and refractiveness was observed.

In conclusion, in this study population plasma TAFI Ag levels are significantly correlated with refractiveness in patients with UAP. Furthermore, all three polymorphisms contribute independently to plasma TAFI Ag levels, but not to refractiveness.

Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

Keywords

Thrombin-activatable fibrinolysis inhibitor (TAFI) - gene polymorphisms - amino acid substitutions - protein levels - unstable angina pectoris

• References

• 1 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombinactivable fibrinolysis inhibitor. J Biol Chem 1995; 270: 14477-84.
• 2 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: 21833-8.
• 3 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.
• 4 Plow EF, Allampallam K Redlitz A. The plasma carboxypeptidases and the regulation of the plasminogen system. Trends Cardiovasc Med 1997; 7: 71-5.
• 5 Wang W, Boffa PB, Bajzar L. et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-81.
• 6 Helle I. Fibrinolysis and coagulation. Effect of calcium and of coagulation on the lysis of fibrin clots. Scand J Haemat 1968; suppl 4: 1-46.
• 7 Minnema MC, Friederich PW, Levi M. et al. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI: in vivo evidence for a role of factor XI as an ant-fibrinolytic factor. J Clin Invest 1998; 101: 10-4.
• 8 Klement P, Liao P, Bajzar L. A novel approach to arterial thrombolysis. Blood 1999; 94: 2735-43.
• 9 Nagashima M, Werner M, Zhao L. et al. Inhibition of activated TAFI (thrombin activatable fibrinolysis inhibitor) enhances tissue plasminogen activator-induced thrombolysis in a rabbit jugular vin thrombolysis model. Thromb Res 2000; 98: 333-42.
• 10 Nagashima M, Yin ZF, Zhao L. et al. Throm-bin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life. J Clin Invest 2002; 109: 101-10.
• 11 Chetaille P, Alessi MC, Kouassi D. et al. Plasma TAFI antigen variations in healthy subjects. Thromb Haemost 2000; 83: 902-5.
• 12 Stromqvist M, Schatteman K, Leurs J. et al. Immunological assay for the determination of procarboxypeptidase U antigen levels in human plasma. Thromb Haemost 2001; 85: 12-7.
• 13 Juhan-Vague I, Renucci JF, Grimaux M. et al. Thrombin-activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2000; 20: 2156-61.
• 14 Zhao L, Morser J, Bajzar L. et al. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb Haemost 1998; 80: 949-55.
• 15 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: 2053-8.
• 16 Franco RF, Fagundes MG, Meijers JCM. et al. Identification of polymorphisms in the 5’-untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis. Haematologica 2001; 86: 510-7.
• 17 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: 1992-3.
• 18 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: 1021-30.
• 19 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-32.
• 20 Hamsten A, Wiman B, de Faire U. et al. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
• 21 Hamsten A, de Faire U, Walldius G. et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
• 22 Silveira A, Schatteman K, Goossens F. et al. Plasma procarboxypeptidase U in men with symptomatic coronary artery disease. Thromb Haemost 2000; 84: 364-8.
• 23 Schroeder V, Chatterjee T, Marti B. et al. Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography. [abstract] Thromb Haemost 2001. (Suppl July)
• 24 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: 867-73.
• 25 Morange PE, Henry M, Frere C. et al. Thr325Ile polymorphism of the TAFI gene does not influence the risk of myocardial infarction. Blood 2002; 99: 1878-9.
• 26 Verheggen PW, de Maat MP, Cats VM. et al. Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function. Eur Heart J 1999; 20: 567-4.
• 27 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215
• 28 Mosnier LO, von dem Borne PA, Meijers JC. et al. Plasma TAFI levels influence the clot ly-sis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemostas 1998; 80: 829-35.
• 29 Schattaman KA, Goossens FJ, Scharpe SS. et al. Assay of procarboxypeptidase U, a novel determinant of the fibrinolytic cascade in human plasma. Clin Chem 1999; 45: 807-13.
• 30 Slatkin M, Excoffier L. Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm. Heredity 1996; 76: 377-83.
• 31 Excoffier L, Slatkin M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921-7.
• 32 Schneider S, Roessli D, Excoffier L. Arlequin ver. 2. 000: A software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Switzer-land: 2000
• 33 Klerkx AHEM, Tanck MWT, Kastelein JJP. et al. Haplotype analysis of the CETP gene:not TaqIB, but the closely linked –629 A poly-morphism and a novel promoter variant are independently associated with CETP concentration. Hum Mol Genet 2003; 12: 111-23.
• 34 Gils A, Alessi MC, Brouwers E. et al. Development of a genotype 325specific proCPU/TAFI ELISA. Arterioscler Thromb Vasc Biol 2003; 23 in press.
• 35 Van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-9.
• 36 Cushman M, Folsom AR, Wang L. et al. A prospective study of thrombin activatable fibrinolysis inhibitor (TAFI) concentration and the TAFI-438 polymorphism in relation to venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). [abstract] Thromb Haemost 2001. (Suppl July)
• 37 Sato T, Miwa T, Akatsu H. et al. Pro-carboxy-peptidase R is an acute phase protein in the mouse, whereas carboxypeptidase N is not. J Immunol 2000; 15: 1053-8.
• 38 Boffa MB, Brown D, Nesheim ME. et al. Characterization of the response to the human TAFI promoter to acute phase mediators. [abstract] Thromb Haemost 2001. (Suppl July).
• 39 Tregouet DA, Aubert H, Henry M. et al. Combined segregation-linkage analysis of plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels with TAFI gene polymorphisms. Hum Genet 2001; 109: 191-7.