PAI-1 gene: pharmacogenetic association of 4G/4G genotype with bleeding after cardiac surgery--pilot study

Abstract

Background and objective: To investigate whether the 4G/4G genotype of the PAI-1 gene is associated with bleeding after cardiac surgery and whether it may influence the use of antifibrinolytic drugs.

Methods: After a case-control association study to compare the distribution of genotypes of the 4G/5G polymorphism of the PAI-1 gene (4G/4G, 4G/5G and 5G/5G) between cardiac surgery patients (n = 260) and nonhospitalized age-matched controls (n = 111), we have evaluated the possible association of genotype homozygous 4G/4G (considered procoagulant) in two cohorts of cardiac surgery patients (treated with aprotinin or tranexamic acid) with postoperative bleeding and transfusion requirements. Chest tube output was measured at 6 h and 24 h and then total blood output. Genotypes were typed using restriction fragment length polymorphism analysis.

Results: The PAI-1 4G/4G genotype was not associated with bleeding except in the subgroup of patients treated with aprotinin in whom blood loss was significantly lower than in nonhomozygous 4G/4G patients at 6 h and 24 h [mean 135.9 ml (SD 101.8 ml) vs. mean 227.6 ml (SD 218.2 ml), P < 0.05; mean 314.5 ml (SD 180.3) vs. mean 482.7 ml (SD 349.8), P < 0.05, respectively]. Moreover, in homozygous 4G/4G patients, aprotinin was independently associated with lower total blood loss and also tended to require less transfusion (26.3 vs. 47.2%; 95% confidence interval, 0.3-2.7; P = 0.2). Only the European system of cardiac-operative risk evaluation score of at least 6 and therapy with platelet antiaggregants were associated with bleeding in the general patient population.

Conclusion: The 4G/4G genotype of the PAI-1 gene was associated with less bleeding after cardiac surgery only in the subgroup of patients treated with aprotinin.