Explore the vast range of titles available.

No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sβ0thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. 67 (96%) of 70 enrolled patients—33 no preoperative transfusion and 34 preoperative transfusion—were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0·023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3·8 (95% CI 1·2–12·2, p=0·027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. NHS Blood and Transplant.

Pacing during exercise performance is well-established; however, little is known about the neural responses associated with changes in power output and the effect of exercise end-point knowledge. Therefore, the aim of this study was to examine the effect of deception of cycling distance on pacing, cerebral oxy- (O2Hb) and deoxy-haemoglobin concentrations, and alpha (α) wave activity. Ten well-trained male cyclists (23.7 ± 6.6 years) completed three cycling time trials (TT) on a stationary air-braked cycle ergometer and were informed the study was to examine the reliability of 3 × 30-km TT. Participants unknowingly completed three distances (24, 30, and 36 km) in a randomised order. Performance (power output; PO), physiological (heart rate; HR), perceptual (rating of perceived exertion; RPE), and neurological (O2Hb, HHb, and α activity) measures were recorded throughout each TT. Data were converted to a percentage relative to the total distance covered. At 100% completion, HR and PO were lower during the 36 km compared to the 30 km trial (P ≤ 0.01). Compared to the 24 km trial, α waves were reduced at 100% (effect size; ES = 1.01), while O2Hb was greater at 70% of completion in the 36 km trial (ES = 1.39). RPE was also higher for 36 km compared to 30-km trial at 80% and the 24-km trial at 10% and 40–100% of completion (P ≤ 0.02). We conclude that the increase in O2Hb and RPE during the 36-km trial, while a reduction in HR and PO is present, may indicate that the pre-frontal cortex may influence the regulation of exercise performance when deceived of the duration end-point by increasing perception of effort to reduce premature onset of physiological strain.

In a trial evaluating two daily-dose levels of voxelotor, which binds to sickle hemoglobin and prevents polymerization under hypoxic conditions, hemoglobin levels increased by more than 1 g per deciliter in approximately half the patients who received the drug, and markers of hemolysis decreased. Toxic effects were mainly low grade and not different from those with placebo.

The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.

The hitherto unknown thiol-disulfide redox potential (E0′) of the β93Cys residue in the HbS (β6Glu→Val) variant of human hemoglobin was calculated by MALDI-ToF mass spectrometry, which analyzes blood from a heterozygous carrier. To calculate the (E0′) value, a redox equilibrium model was adopted, and the previously calculated value for wild-type β-Hb chain (E0′ −121 mV) was used. An E0′ value of −130.5 ± 1.7 mV for the β93Cys residue of HbS was obtained, thus a more reducing value than E0′ in the wild-type isoform. Glutathionylation from this residue in the HbS tetramer lowers the extent of protein aggregation in fibrils and the clinical consequences, such as painful capillary occlusion and hemolysis. This finding confirmed the peculiar property of HbS as a more reactive scavenger of glutathione sulphinic acid (E0′ = −264 mV), which forms in the cytoplasm of red blood cells and reacts with structural and regulatory proteins, including hemoglobin. The ability to assess the erythrocyte oxidative status in sickle cell carriers can be developed into an additional functional test to rationally assess the effect of drug treatment and antioxidant dietary interventions on improving disease control.

Adenine base editing can convert sickle hemoglobin (HbS, βΕ6V) to G-Makassar hemoglobin (HbG, βE6A), a naturally occurring variant that is clinically asymptomatic. However, the quality and functionality of purified HbG and of mature HbGG and HbGS red blood cells (RBC) has not been assessed. Here, we develop a mouse model to characterize HbG. Purified HbG appears normal and does not polymerize under hypoxia. The topology of the hemoglobin fold with the βΕ6Α mutation is similar to HbA in the oxy and deoxy states. However, RBC containing HbGS are dehydrated, showing altered function and increased sickling under hypoxia. Blood counts and mitochondrial retention measures place HbGS RBCs as intermediate in severity between HbAS and HbSS, while organ function is comparable to HbAS. HbGG resembles HbAA for most metrics. Our results highlight the importance of functionally assessing the mature red cell environment when evaluating novel gene editing strategies for hematologic disorders. Authors show that base editing can convert sickle hemoglobin (HbS) to the rare but naturally occurring variant G-Makassar (HbG). Purified HbG appears normal, but in a mouse model, HbGS red cells sickle under hypoxia, highlighting the importance of assessing red cell quality when evaluating novel gene editing strategies for hematologic disorders.

Sickle cell disease (SCD) is an inherited hemoglobin disorder that is widespread across the globe. It is characterized by a very complex pathogenesis, but at the basis of the disease is the mutation of the HBB gene, which determines the production of a mutated hemoglobin: sickle cell hemoglobin (HbS). The polymerization of HbS, which occurs when the protein is in a deoxygenated state, and the greater fragility of sickle cell red blood cells (sRBCs) determine the release of iron, free heme, and HbS in the blood, favoring oxidative stress and the production of reactive oxygen species (ROS). These features are common to the features of a new model of cell death known as ferroptosis, which is characterized by the increase of iron and ROS concentrations and by the inhibition of glutathione peroxidase 4 (GPx4) and the System Xc−. In this context, this review aims to discuss the potential molecular and biochemical pathways of ferroptosis involved in SCD, aiming to highlight possible tags involved in treating the disease and inhibiting ferroptosis.

Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S (HbS), which polymerizes under deoxygenation, and induces the sickling of red blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently become anemic and develop frequent and recurrent vaso-occlusive crises. However, it is now evident that SCD is not only a RBC rheological disease. Accumulating evidence shows that SCD is also characterized by the presence of chronic inflammation and oxidative stress, participating in the development of chronic vasculopathy and several chronic complications. The accumulation of hemoglobin and heme in the plasma, as a consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs), which may activate endothelial inflammation through TLR-4 signaling and promote the development of complications, such as acute chest syndrome. It is also suspected that heme may activate the innate immune complement system and stimulate neutrophils to release neutrophil extracellular traps. A large amount of microparticles (MPs) from various cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into the plasma of SCD patients and participate in the inflammation and oxidative stress in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters the RBC properties. Increased pro-inflammatory cytokine concentrations promote the activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane and further alters the deformability of the cells, modifying their aggregation properties. These RBC rheological alterations have been shown to be associated to specific SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover, RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive to various inflammatory molecules that promote RBC dehydration and increase RBC adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle between abnormal RBC rheology and inflammation, which modulates the clinical severity of patients.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

Polymerization and adhesion, dynamic processes that are hallmarks of sickle cell disease (SCD), have thus far been studied in vitro only separately. Here, we present quantitative results of the simultaneous and synergistic effects of adhesion and polymerization of deoxygenated sickle hemoglobin (HbS) in the human red blood cell (RBC) on the mechanisms underlying vasoocclusive pain crisis. For this purpose, we employ a specially developed hypoxic microfluidic platform, which is capable of inducing sickling and unsickling of RBCs in vitro, to test blood samples from eight patients with SCD. We supplemented these experimental results with detailed molecular-level computational simulations of cytoadherence and biorheology using dissipative particle dynamics. By recourse to image analysis techniques, we characterize sickle RBC maturation stages in the following order of the degree of adhesion susceptibility under hypoxia: sickle reticulocytes in circulation (SRs) → sickle mature erythrocytes (SMEs) → irreversibly sickled cells (ISCs). We show that (i) hypoxia significantly enhances sickle RBC adherence; (ii) HbS polymerization enhances sickle cell adherence in SRs and SMEs, but not in ISCs; (iii) SRs exhibit unique adhesion dynamics where HbS fiber projections growing outward from the cell surface create multiple sites of adhesion; and (iv) polymerization stimulates adhesion and vice versa, thereby establishing the bidirectional coupling between the two processes. These findings offer insights into possible mechanistic pathways leading to vasoocclusion crisis. They also elucidate the processes underlying the onset of occlusion that may involve circulating reticulocytes, which are more abundant in hemolytic anemias due to robust compensatory erythropoiesis.