Polymorphisms on PAI-1 and ACE genes in association with fibrinolytic bleeding after on-pump cardiac surgery

Abstract

Background: Carriers of plasminogen activator inhibitor -1 (PAI-1) -675 genotype 5G/5G may be associated with lower preoperative PAI-1 plasma levels and higher blood loss after heart surgery using cardiopulmonary bypass (CPB). We speculate if polymorphisms of PAI-1 -844 A/G and angiotensin converting enzyme (ACE) intron 16 I/D also might promote fibrinolysis and increase postoperative bleeding.

Methods: We assessed PAI-1 -844 A/G, and ACE intron 16 I/D polymorphisms by polymerase chain reaction technique and direct sequencing of genomic DNA from 83 open heart surgery patients that we have presented earlier. As primary outcome, accumulated chest tube drainage (CTD) at 4 and 24 h were analyzed for association with genetic polymorphisms. As secondary outcome, differences in plasma levels of PAI-1, t-PA/PAI-1 complex and D-dimer were determined for each polymorphism. SPSS® was used for statistical evaluation.

Results: The lowest preoperative PAI-1 plasma levels were associated with PAI-1 -844 genotype G/G, and higher CTD, as compared with genotype A/A at 4 and 24 h after surgery. Correspondingly, 4 h after the surgery CTD was higher in carriers of ACE intron 16 genotype I/I, as compared with genotype D/D. PAI-1 plasma levels and t-PA/PAI-1 complex reached nadir in carriers of ACE intron 16 genotype I/I, in whom we also noticed the highest D-dimer levels immediately after surgery. Notably, carriers of PAI-1 -844 genotype G/G displayed higher D-dimer levels at 24 h after surgery as compared with those of genotype A/G.

Conclusions: Increased postoperative blood loss secondary to enhanced fibrinolysis was associated with carriers of PAI-1 -844 G/G and ACE Intron 16 I/I, suggesting that these genotypes might predict increased postoperative blood loss after cardiac surgery using CPB.

Fig. 1

PAI-1-844 A/G polymorphism and blood loss after open heart surgery. Relationship between PAI-1 -844 A/G polymorphism and accumulated postoperative blood loss after cardiac surgery with cardiopulmonary bypass. Data presented as the mean ± standard error of the mean. PAI-1, Plasminogen activator inhibitor type −1; A, adenosine; G, guanine; mL, milliliters; h, hours. *P < 0.05 4 h blood loss between PAI-1 -844 of genotypes G/G and A/A; † P < 0.05 between 24 h blood loss associated with genotypes G/G and A/A of PAI-1 -844; & P < 0.05 between 24 h blood loss associated with PAI-1 -844 of genotypes A/G and A/A

Fig. 2

ACE Intron 16 I/D polymorphism and blood loss after open heart surgery. Relationship between ACE Intron 16 I/D polymorphism and accumulated postoperative blood loss after cardiac surgery with cardiopulmonary bypass. Data presented as the mean ± standard error of the mean. ACE, Angiotensin Converting Enzyme; I, insertion; D, deletion; mL, milliliters; h, hours. # P < 0.05 between 4 h blood loss associated with ACE Intron 16 of genotypes I/I and D/D; ‡ P < 0.05 between 4 h blood loss associated with ACE Intron 16 of genotypes I/I and I/D