Abstract 18481: Genetic Polymorphisms Associated with Response to Intraoperative Heparin Anticoagulation and Thrombosis Risk in Pediatric Patients Undergoing Cardiac Surgery

Abstract

Introduction: Thrombosis is an important and widespread post-operative complication of pediatric cardiac surgery. Prophylaxis intraoperative anticoagulation in this context is obtained by using heparin which requires a bond with antithrombin to achieve anticoagulant effect. We sought to identify SNPs associated with blood antithrombin levels, response to heparin and post-operative thrombosis risk in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: A total of 625 cardiac operations with CPB in 383 patients were reviewed. Ninety-six SNPs on 53 genes in the coagulation/fibrinolysis pathways were assayed using the the Illumina GoldenGate custom SNP panel. Genotyping was successful for >99% of SNPs. Regression models adjusted for repeated measures and bootstrap resampling (1,000 samples) were used to offset multiple comparisons bias; SNPs with very low minor allele frequencies were excluded. Results: Average preoperative antithrombin activity was 89±18% (normal 100%, adjusted for age and oxygen saturation) and average response to heparin was 1.0±0.3U/ml/100U/kg (blood heparin concentration achieved per 100U/kg of heparin). Post-operative thrombosis was observed after 86 operations (14%) (within 30 days of surgery, risk-adjusted according to a previously published model of post-operative thrombosis risk). SNPs associated with higher antithrombin levels, lower heparin response and higher postoperative thrombosis are listed in the Table. Conclusions: Polymorphisms in genes in the coagulation and fibrinolytic systems activity were associated with antithrombin levels, response to heparin and risk of post-operative thrombosis. The association of individual SNPs at the laboratory and clinical levels suggest a mechanism for upstream alteration in the coagulation system that is correlated with undesirable clinical outcome and could be the target for genetically tailored clinical interventions.