Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion

ObjectiveThe risk for thrombosis is increased after the Fontan operation. It is unknown whether children with univentricular heart disease have an intrinsic coagulation anomaly or acquire a defect in coagulation during the course of the staged repair. This prospective, longitudinal study evaluated changes in coagulation profiles in a cohort of patients with hypoplastic left heart syndrome from stage I palliation through completion of the Fontan operation.MethodsThirty-seven patients with hypoplastic left heart syndrome were enrolled prospectively, and the concentration of factors II, V, VII, VIII, IX, X, proteins C and S, fibrinogen, antithrombin, serum albumin, and liver enzymes were measured before stage I palliation (mean age 4 ± 2 days), before bidirectional Glenn (mean age 5.9 ± 1.8 months), before the Fontan procedure (mean age 27.1 ± 6.6 months), and after the Fontan procedure (mean age 49 ± 17.6months). Healthy children were used as age-matched controls for coagulation factors. Demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities.ResultsSignificantly lower levels of both procoagulation and anticoagulation factors were demonstrated through to completion of the Fontan procedure. After the Fontan procedure, there was a significantly higher factor VIII level (P < .005) but no correlation with hemodynamic variables or liver function.ConclusionThis longitudinal study in patients with identical cardiac disease and staged surgical procedures confirms the increase in factor VIII level after the Fontan procedure. This is an acquired defect, and although the cause remains to be determined, monitoring factor VIII levels after the Fontan operation could indicate a subset of patients at risk for thrombosis

Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion

ObjectiveThe risk for thrombosis is increased after the Fontan operation. It is unknown whether children with univentricular heart disease have an intrinsic coagulation anomaly or acquire a defect in coagulation during the course of the staged repair. This prospective, longitudinal study evaluated changes in coagulation profiles in a cohort of patients with hypoplastic left heart syndrome from stage I palliation through completion of the Fontan operation.MethodsThirty-seven patients with hypoplastic left heart syndrome were enrolled prospectively, and the concentration of factors II, V, VII, VIII, IX, X, proteins C and S, fibrinogen, antithrombin, serum albumin, and liver enzymes were measured before stage I palliation (mean age 4 ± 2 days), before bidirectional Glenn (mean age 5.9 ± 1.8 months), before the Fontan procedure (mean age 27.1 ± 6.6 months), and after the Fontan procedure (mean age 49 ± 17.6months). Healthy children were used as age-matched controls for coagulation factors. Demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities.ResultsSignificantly lower levels of both procoagulation and anticoagulation factors were demonstrated through to completion of the Fontan procedure. After the Fontan procedure, there was a significantly higher factor VIII level (P < .005) but no correlation with hemodynamic variables or liver function.ConclusionThis longitudinal study in patients with identical cardiac disease and staged surgical procedures confirms the increase in factor VIII level after the Fontan procedure. This is an acquired defect, and although the cause remains to be determined, monitoring factor VIII levels after the Fontan operation could indicate a subset of patients at risk for thrombosis

Volatile anesthetics affect macrophage phagocytosis.

BackgroundPerioperative infections, particularly surgical site infections pose significant morbidity and mortality. Phagocytosis is a critical step for microbial eradication. We examined the effect of commonly used anesthetics on macrophage phagocytosis and its mechanism.MethodsThe effect of anesthetics (isoflurane, sevoflurane, propofol) on macrophage phagocytosis was tested using RAW264.7 mouse cells, mouse peritoneal macrophages, and THP-1 human cells. Either opsonized sheep erythrocytes or fluorescent labeled Escherichia coli were used as phagocytic objects. The activation of Rap1, a critical protein in phagocytosis was assessed using the active Rap1 pull-down and detection kit. To examine anesthetic binding site(s) on Rap1, photolabeling experiments were performed using azi-isoflurane and azi-sevoflurane. The alanine scanning mutagenesis of Rap1 was performed to assess the role of anesthetic binding site in Rap1 activation and phagocytosis.ResultsMacrophage phagocytosis was significantly attenuated by the exposure of isoflurane (50% reduction by 1% isoflurane) and sevoflurane (50% reduction by 1.5% sevoflurane), but not by propofol. Photolabeling experiments showed that sevoflurane directly bound to Rap1. Mutagenesis analysis demonstrated that the sevoflurane binding site affected Rap1 activation and macrophage phagocytosis.ConclusionsWe showed that isoflurane and sevoflurane attenuated macrophage phagocytosis, but propofol did not. Our study showed for the first time that sevoflurane served as a novel small GTPase Rap1 inhibitor. The finding will further enrich our understanding of yet-to-be determined mechanism of volatile anesthetics and their off-target effects. The sevoflurane binding site was located outside the known Rap1 functional sites, indicating the discovery of a new functional site on Rap1 and this site would serve as a pocket for the development of novel Rap1 inhibitors