Abstract 11051: A Common Variant Near the Fibrinogen Gamma Chain Gene is an Independent Risk Factor for Thrombosis After Congenital Heart Surgery

Abstract

Introduction: Postoperative thrombosis is a common complication after congenital heart disease (CHD) surgery in children, and is associated with increased mortality and morbidity. Identification of risk factors may allow preventive therapy and improved outcomes. Hypothesis: We tested the hypothesis that genetic variants are associated with postoperative thrombosis after CHD surgery in children. Methods: Children with CHD were prospectively enrolled in an observational cohort study at the time of initial surgical repair/palliation. Clinically detected thrombosis within 30 days of surgery while in hospital was the primary outcome. Patients were genotyped on the Axiom Precision Medicine Research Array. Clinical and genetic (8 common variants in candidate genes) factors were assessed for association with the primary outcome with univariate and multivariate analysis. A two-tailed P-value of < 0.05 was considered statistically significant. Results: A total of 2,398 unique patients (median age 6 months, median weight 6.7 kg) had complete clinical and genetic data for analysis. Postoperative thrombosis occurred in 242 (10.1%). Patients with thrombosis were younger (P<0.001), with longer bypass time (P<0.001) and higher initial postoperative lactate (P<0.001). Thrombosis was also associated with longer hospital stay (50 ± 59 days vs 16 ± 31days, P<0.001) and mortality (15.3% vs 2.9%, P<0.001). One common variant near fibrinogen gamma ( FGG , rs7659024, NC_000004.12:g.154599778G>A) was associated with postoperative thrombosis, with a gene-dose effect (thrombosis observed in 8.9% GG, n=1370, 11% AG, n=869, 15.1% AA, n=159, P=0.025). In multivariate analysis age (per year older OR 0.7, 95% CI 0.61-0.79), bypass time (per hour OR 1.24, 95% CI 1.09-1.39), lactate (per mmol/L OR 1.15, 95% CI 1.19-1.32) and FGG genotype (GG reference, AG OR 1.51, 95% CI 1.09-2.08; AA OR 2.35, 95% CI 1.39-3.97) were each independently associated with postoperative thrombosis. Conclusions: A common variant near FGG previously associated with fibrinogen γ′ levels is an independent risk factor for postoperative thrombosis after CHD surgery. Preoperative genotyping with thromboprophylaxis for patients at sufficient risk may be considered.