Ashikhmina Swan, Elena

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Background: The objective of this study was to describe thrombin generation in children undergoing cardiac surgery with cardiopulmonary bypass. Change in the endogenous thrombin potential (ETP) across three measurements before and after cardiopulmonary bypass (after protamine and at chest closure) was the primary outcome. Secondary analyses explored an association between thrombin generation and transfusion requirements and predictors of the thrombin generation decline. Methods: Blood samples of children (median age, 6.3 months; 68.5% weighed less than 10 kg) were collected intraoperatively three times: before administration of heparin (baseline), shortly after protamine, and at sternal closure. Platelet-poor plasma obtained after centrifugation of these samples was frozen at −80ºC. Thrombin generation and anti-Xa assays were performed in series on batches of thawed samples to evaluate thrombin generation parameters and functional activity of unfractionated heparin, which could have affected thrombin generation assay results. Results: Between August 2022 and May 2024, 162 plasma samples from 54 patients were collected and analyzed. Compared with baseline, mean ETP decreased by 1,911 nM (95% CI, 1,655 to 2,168) after administration of protamine and by 1,865 nM (95% CI, 1,609 to 2,122) at sternal closure (P < 0.001). Similar changes were observed in secondary thrombin generation parameters. Median unfractionated heparin activity was less than 0.1 U/ml at all three time points. Secondary analyses showed a strong negative correlation between ETP after protamine and volume of transfusion after bypass (ρ = −0.52, P < 0.001). Among five examined factors, only total heparin dose was independently associated with ETP decline, with a higher dose being predictive of greater ETP decline (P = 0.002). Conclusions: In children undergoing cardiac surgery, thrombin generation assay revealed significant and persistent decline in endogenous thrombin potential after cardiopulmonary bypass, despite hemostatic interventions. This reduced thrombin potential correlated with a higher volume of transfusions. Additionally, greater intraoperative heparin requirements could be linked to a more pronounced decline in thrombin generation.

Background Pediatric cardiac surgery is associated with abnormal coagulation, bleeding, and nearly ubiquitous transfusions. With the popularization of patient blood management, attempts are being made to decrease liberal transfusions by administering prothrombin complex concentrates (PCCs). The safety and efficacy of PCCs in adult cardiac surgery has been studied extensively, but only few reports address this in children. We performed an observational study focused on transfusion requirements after off-label use of activated PCC Factor Eight Inhibitor Bypassing Activity (FEIBA) as an adjunct to post-cardiopulmonary bypass (CPB) hemostatic protocol. Methods We reviewed the medical records of children ≤15 kg undergoing cardiac operations with CPB between May 2018 and March 2022. A propensity score (PS) analysis was performed to identify matched pairs of patients who did and did not receive FEIBA. Results Out of 210 patients who met the inclusion criteria, 44 patients received FEIBA. Propensity score-based analysis identified 40 matched pairs of patients with similar baseline characteristics. There was no statistically significant difference in the primary outcome—the volume of transfusion after CPB, which included all allogeneic blood products and salvaged washed red cells administered after protamine. Specifically, FEIBA patients were transfused 28 (22-34) mL/kg and controls were transfused 22 (11-49) mL/kg, P = .989. Upon arrival to ICU, the FEIBA group averaged an 8% lower international normalized ratio, compared with the controls ( P = .009) and a 1.08 g/dL higher hemoglobin ( P = .050). Neither difference remained significant on POD 1. Conclusions In this exploratory study, we found no change in transfusion requirements after CPB despite FEIBA administration.