Understanding the roles of intrinsic disorder in subunits of hemoglobin and the disease process of sickle cell anemia

One of the common genetic disorders is sickle cell anemia, in which 2 recessive alleles must meet to allow for destruction and alteration in the morphology of red blood cells. This usually leads to loss of proper binding of oxygen to hemoglobin and curved, sickle-shaped erythrocytes. The mutation causing this disease occurs in the 6(th) codon of the HBB gene encoding the hemoglobin subunit β (β-globin), a protein, serving as an integral part of the adult hemoglobin A (HbA), which is a heterotetramer of 2 α chains and 2 β chains that is responsible for binding to the oxygen in the blood. This mutation changes a charged glutamic acid to a hydrophobic valine residue and disrupts the tertiary structure and stability of the hemoglobin molecule. Since in the field of protein intrinsic disorder, charged and polar residues are typically considered as disorder promoting, in opposite to the order-promoting non-polar hydrophobic residues, in this study we attempted to answer a question if intrinsic disorder might have a role in the pathogenesis of sickle cell anemia. To this end, several disorder predictors were utilized to evaluate the presence of intrinsically disordered regions in all subunits of human hemoglobin: α, β, δ, ε, ζ, γ1, and γ2. Then, structural analysis was completed by using the SWISS-MODEL Repository to visualize the outputs of the disorder predictors. Finally, Uniprot STRING and D(2)P(2) were used to determine biochemical interactome and protein partners for each hemoglobin subunit along with analyzing their posttranslational modifications. All these properties were used to determine any differences between the 6 different types of subunits of hemoglobin and to correlate the mutation leading to sickle cell anemia with intrinsic disorder propensity

Safety and effects of two red blood cell transfusion strategies in pediatric cardiac surgery patients: a randomized controlled trial

To investigate the safety and effects of a restrictive red blood cell (RBC) transfusion strategy in pediatric cardiac surgery patients. Randomized controlled trial. Pediatric ICU in an academic tertiary care center, Leiden University Medical Center, Leiden, The Netherlands. One hundred seven patients with non-cyanotic congenital heart defects between 6 weeks and 6 years of age. One hundred three patients underwent corrective surgery on cardiopulmonary bypass. Prior to surgery patients were randomly assigned to one of two groups with specific RBC transfusion thresholds: Hb 10.8 g/dl (6.8 mmol/l) and Hb 8.0 g/dl (5.0 mmol/l). Length of stay in hospital (primary outcome), length of stay in PICU, duration of ventilation (secondary outcome), incidence of adverse events and complications related to randomization (intention to treat analysis). In the restrictive transfusion group, mean volume of transfused RBC was 186 (±70) ml per patient and in the liberal transfusion group 258 (±87) ml per patient, (95% CI 40.6-104.6), p < 0.001. Length of hospital stay was shorter in patients with a restrictive RBC transfusion strategy: median 8 (IQR 7-11) vs. 9 (IQR 7-14) days, p = 0.047. All other outcome measures and incidence of adverse effects were equal in both RBC transfusion groups. Cost of blood products for the liberal transfusion group was 438.35 (±203.39) vs. 316.27 (±189.96) euros (95% CI 46.61-197.51) per patient in the restrictive transfusion group, p = 0.002. For patients with a non-cyanotic congenital heart defect undergoing elective cardiac surgery, a restrictive RBC transfusion policy (threshold of Hb 8.0 g/dl) during the entire perioperative period is safe, leads to a shorter hospital stay and is less expensiv