J. Silvain (1), A. Pena (1), J.-B. Vignalou (1), J.-S. Hulot (2), S. Galier (1), G. Cayla (1), A. Bellemain-Appaix (1), O. Barthélémy (1), F. Beygui (1), C. Bal-dit-Sollier (3), L. Drouet (3), J. W. Weisel (4), G. Montalescot (1), J.-P. Collet (1)
(1) Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France; (2) Pharmacogenomic unit, INSERM UMRS 621, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France; (3) Institut des Vaisseaux et du Sang, CHU – Lariboisière – Paris, France; (4) Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
The FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (<45 years old) who survived a myocardial infarction (MI) and 242 healthy controls matched for age and gender. We evaluated its effect on long-term clinical outcome defined as a composite of cardiovascular death, recurrent MI and urgent revascularisation. In addition, fibrin clot stiffness (elastic modulus or EM) and response to rt-PA-mediated fibrinolysis (fibrinolysis rate) were measured ex vivo using the Hemodyne analyser and confocal microscopy as surrogate endpoint. FXIII-A Leu34 genetic variant was not associated with premature CAD (adj. odds ratio 0.83 [0.49–1.4]) nor did it influence clinical outcome in patients, during a median follow-up of 6.3 (± 2.4) years. Patients produced stiffer fibrin clots (median [IQR] EM =20.3 [14.9–28.1] vs. 12.8 [9.6–17.1] kdynes/cm²; p<0.0001) and displayed reduced response to fibrinolysis with lower fibrinolysis rate (6.7 [3.4–11.0] vs. 9.0 [5.0–16.7] sec-¹x10⁻⁴; p<0.0001) than healthy controls. Carriage of factor XIII-A Leu34 led to a stepwise decrease in fibrinolysis rate with a significant gene–dose-effect in patients (7.7 [4.1–12.2] vs. 4.8 [3.0–8.5] vs. 4.3 [2.4–8.1] sec-¹x10⁻⁴, for wild-type, heterozygous and homozygous, p for trend =0.003) and a non-significant trend in controls (p=0.01). In conclusion, FXIII-A Leu34 is a polymorphism which provides a strong resistance to fibrinolysis with a gene-dose effect, but does not relate to premature CAD or to recurrent coronary events in this study.
coronary disease, thrombosis, fibrinolysis, fibrin structure, Factor XIII Val34Leu, pharmacogenetic
N. Bauer, A. Moritz
Tierärztliche Praxis Kleintiere 2008 36 4: 235-246
M. Urooj Zafar1, Michael E. Farkouh1, Julio Osende1, Daichi Shimbo1, Stella Palencia1, Julia Crook2, Robert Leadley3, Valentin Fuster1, James H. Chesebro2
Thromb Haemost 2007 97 3: 487-492
Yi-Xin Wang, Valdeci da Cunha, Jon Vincelette, Lei Zhao, Mariko Nagashima, Kohichi Kawai, Shendong Yuan, Kumar Emayan, Imadul Islam, Junko Hosoya, Mark E. Sullivan, William P. Dole, John Morser, Brad O. Buckman, Ronald Vergona
Thromb Haemost 2007 97 1: 54-61
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