Pharmacogenetics in the thrombolytic treatment of myocardial infarction: role of the FXIII V34L polymorphism

Abstract number: OC168

Roldán^* V., Corral† J., Marín‡ F., Rivera§ J., González-Conejero† R., Pineda‡ J., Miñano§ A., Acuña§ M. C., López‡ F., Vicente† V.

§Centro Regional de Hemodonación, Murcia, Spain ‡Hospital General, Alicante, Spain; ^*Hospital San Vicente, Alicante, Spain; †University of Murcia, Spain;

The FXIII V34L polymorphism is one of the most relevant functional polymorphism in the hemostatic system. The change of V34, a residue located 3 amino acids upstream the thrombin-activation site of FXIII-A chain, results in a significant faster and higher FXIII-activation by thrombin. Consequently, the L34 variant associates with higher FXIII-specific transglutaminase activity. Moreover, the fibrin clot is structurally different according to the polymorphism, being the L34 variant more resistant to physical rupture by thromboelastography and plasmin-degradation. Pharmacogenetic has emerged as a new field in medicine that tries to identify gene variants able to explain the response of patients to a drug. Thrombolytic treatment is a very useful therapy in acute myocardial infarction (MI). Unfortunately, up to 40% of treated patients do not achieve optimal tissue perfusion. The aim of this study was to evaluate the pharmacogenetic role of the FXIII V34L polymorphism in the efficiency of thrombolytic therapy.

Methods  

Degradation of fibrin clots containing radioactive fibrinogen from V/V (n = 8) and L/L (n = 6) blood donors was evaluated in vitro using r-tPA (100 ng mL^-1). The FXIII genotype was determined in 72 consecutive young MI patients (<45 years) treated with standard doses of thrombolytic drugs (streptokinase n = 4; APSAC n = 9; and r-tPA n = 59). Non-invasive assessment of the efficacy of coronary thrombolysis was evaluated by serial electrocardiograms and creatine kinase time-activity curves. Declination of ST segment elevation >50% in 90 min and an early peak of CK (<12 h) were considered as reperfusion criteria.

Results  

In vitro studies show that fibrin clot degradation by r-tPA is less efficient in L/L than V/V individuals (P = 0.02). Moreover, thrombolysis of patients with V/V genotype was significantly more efficient than that achieved among patients carrying the L34 variant (P = 0.006). Thus, 44 out of 50 V/V patients (88%) but only 13 out of 22 patients with L/V or L/L genotype (59.1%) responded efficiently to the thrombolytic treatment. We did not observed differences according to the type of thrombolytic drug. In contrast, primary angioplasty performed in 11 young MI patients was efficient in all cases independently of the FXIII genotype.

Conclusion  

We show the first in vitro and clinical evidence suggesting that the L34 variant, associated with increased FXIII-transglutaminase activity, could reduce the efficiency of thrombolytic therapy in MI.