Genetic variation influences the risk of bleeding after cardiac surgery: novel associations and validation of previous findings.

Abstract

Severe post-operative bleeding in cardiac surgery is associated with increased morbidity and mortality. We hypothesized that variation in genetic susceptibility contributes to post-operative bleeding in addition to clinical factors. We included 1036 adults undergoing cardiac surgery with cardiopulmonary bypass. Two different endpoints for excessive post-operative bleeding were used, either defined as blood loss exceeding 2 ml/kg/h the first 4 h post-operatively or a composite including bleeding, transfusions, and reoperations. Twenty-two single nucleotide polymorphisms (SNPs) central in the coagulation and fibrinolysis systems or in platelet membrane receptors were genotyped, focusing on replication of earlier non-replicated findings and exploration of potential novel associations. Using logistic regression, significant SNPs were added to a model with only clinical variables to evaluate whether the genetic variables provided additional information. Univariate tests identified rs1799809 (located in the promoter region of the PROC gene), rs27646 and rs1062535 (in the ITGA2 gene), rs630014 (in the ABO gene), and rs6048 (in the F9 gene) as significantly associated with excessive post-operative bleeding (P < 0.05, P-values confirmed by permutation). The SNPs were significant also after adjustment with clinical variables, showing almost unchanged odds ratios except for rs1799809 (P = 0.06). Addition of the genetic covariates to a logistic regression model with clinical variables significantly improved the model (P < 0.01). We identified five SNPs associated with post-operative bleeding after cardiac surgery, of which two validated previously published associations. Addition of genetic information to models with only clinical variables improved the models. Our results indicate that common genetic variations significantly influence post-operative bleeding after cardiac surgery.