Life Span Of Erythrocytes Research Articles

ISPAD Clinical Practice Consensus Guidelines 2022: Glycemic targets and glucose monitoring for children, adolescents, and young people with diabetes.

ISPAD Clinical Practice Consensus Guidelines 2022: Glycemic targets and glucose monitoring for children, adolescents, and young people with diabetes.

The use of carbon monoxide breath test to detect the effect of iron overload on erythrocyte lifespan in MDS.

To investigate the effect of iron overload (IO) on red blood cell (RBC) lifespan in MDS patients with the use of carbon monoxide breath test. The red blood cell lifespan of 93 patients with myelodysplastic syndrome (MDS) and 22 healthy volunteers in the control group were measured by alveolar gas carbon monoxide (CO) assay, with the detection of liver iron concentration, iron metabolism index, erythropoietin (EPO) concentration, peripheral blood inflammatory cytokines, etc. The MDS patients were divided into the severe IO group, mild IO group and non IO group according to liver iron concentration. The effect of IO on RBC lifespan was analyzed in MDS patients. The RBC lifespan of MDS patients in the severe IO group was significantly lower than that in the mild IO group (p<0.05), while the RBC life span in the mild IO group was significantly lower than that in the non IO group (p<0.05). The expression of inflammatory cytokines in the severe IO group was significantly higher than that of the mild and non IO groups. After receiving iron removal treatment(ICT), the expression of inflammatory cytokines was decreased significantly, and the RBC lifespan was significantly prolonged (p<0.05).Besides, liver iron concentration was significantly positively correlated with EPO concentration, while EPO concentration was significantly negatively correlated with RBC lifespan, especially in the MDS-RS subgroup. The RBC lifespan in the EPO>1000 group was significantly lower than that in the EPO<1000 group. IO can shorten RBC lifespan in MDS patients, which may be result from the increase of endogenous EPO and the over-expression of inflammatory cytokines. After ICT, the ineffective hematopoiesis caused by increased EPO may reduced and the decrease of inflammatory cytokine may significantly prolong the RBC lifespan in MDS patients.

The Impact of Carbamylation and Anemia on HbA1c's Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease.

Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c's reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD. In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA1c and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia. The mean eGFR was 38.1 mL/min/1.73 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02-1.13]). However, using stratified analyses, HbA1c was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA1c and CKD progression (P-interaction = 0.025). In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia.

Canakinumab Effects on Erythropoiesis, Cardiovascular Risk, and Clonal Hematopoiesis: Proteogenomic Analysis of the Cantos Randomized Clinical Trial

Canakinumab is a monoclonal antibody that directly neutralizes interleukin (IL)-1β. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) - a randomized, double-blind, placebo-controlled trial that enrolled 10,061 patients with previous myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L - canakinumab prevented recurrent cardiovascular (CV) events (Ridker et al. NEJM 2017). Anemia of inflammation (AI) presents with mild to moderate anemia in the setting of systemic inflammatory conditions. The pathogenesis of AI involves deregulation of iron homeostasis via hepcidin and inflammatory cytokines such as IL-1β, IL-6, and TNF-α, resulting in skewed myeloid differentiation and decreased erythrocyte lifespan via enhanced erythrophagocytosis (Ganz et al. NEJM 2019). A CANTOS exploratory study revealed that canakinumab reduces the incidence of anemia and improves hemoglobin levels (Vallurupalli et al. Ann Intern Med. 2020). Among mutations associated with clonal hematopoiesis (CH), patients with TET2 variants had fewer major adverse CV events than those without CH mutations (Svensson et al. JAMA Cardiol. 2022). CH mutations in TET2 were associated with higher IL-1β levels (Bick et al. Nature 2020), generating the hypothesis that inhibition of IL-1β may provide preferential benefits to patients with CH mutations. To determine the association between CH mutations and clinical response to canakinumab and evaluate the underlying molecular mechanisms of anemia response, a proteogenomic study was performed in 13080 plasma samples from 4595 CANTOS participants, including highly multiplexed proteomics (4785 proteins) and targeted deep sequencing of CH mutations with variant allele fraction≥ 2% (Figure A). Longitudinal and cross-sectional analyses were performed in pre- and post-treatment samples from patients with at least one pre-treatment sample (baseline). CH mutations were associated with older age, anemia at baseline, and higher baseline IL-6 and TNF-α levels (all OR's >1.4 and p<0.003). Among patients without baseline anemia, canakinumab treatment prevented incidental anemia, compared to those treated with a placebo (without CH mutation: HR=0.72; 95% CI=0.61-0.84; P < 0.001, with CH mutations: HR=0.77; 95% CI=0.49-1.19; P =0.24). In individuals treated with canakinumab, however, those with CH mutations were more likely to develop incidental anemia compared to patients without CH mutations (HR=1.56; 95% CI=1.18-2.07; P=0.002). Conversely, among patients with baseline anemia, canakinumab treatment significantly improved hemoglobin levels in patients with CH mutations compared to a placebo (P< 0.001), whereas a significant difference was not found in hemoglobin levels of patients without CH mutations (Figure B). Enhanced hemoglobin response over time to canakinumab was observed in patients with concurrent baseline anemia and CH mutations, particularly in DNMT3A and TET2, compared to no CH mutations (all CH mutations, DNMT3A and TET2,P = 0.022, 0.004, 0.078 respectively). We observed that canakinumab treatment reversed multiple nodes of abnormal erythropoiesis associated with AI. Canakinumab treatment was associated with lower hepcidin and inflammatory cytokines (IL-6 and TNF-α) and down-regulation of pathways for complement activation and phagocytosis, which may prolong RBC lifespan and promote erythropoiesis. Higher odds of having both an increase in hemoglobin and a decrease in hepcidin (OR=1.88; 95% CI=1.62 - 2.17; P<0.001 ) and both an increase in hemoglobin and a decrease in IL-6 (OR=3.46; 95%CI=3.00 - 4.00; P<0.001) were observed with canakinumab treatment compared to placebo. The characterization of proteomic profiles in patients with CH mutations revealed novel biological links in dysregulation of RBC homeostasis, cardiovascular risk biomarkers, inhibitory immune molecules, and bone morphogenetic protein antagonists, which were reversed by canakinumab treatment more significantly in patients with TET2 mutations. Collectively this data provides direct clinical evidence that patients with concurrent anemia and CH mutations can benefit from canakinumab treatment by suppressing CH-mediated activation of the IL-1β/IL-6 axis and reversing ineffective erythropoiesis via multiple mechanisms, and the type of CH mutations may be associated with distinct clinical and biological response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Спадкова мікросфероцитарна гемолітична анемія в дітей: діагностичний алгоритм типового та атипового перебігу

Anemic syndrome in a child in the practice of a primary care doctor is a frequent problem that requires a balanced differential diagnosis. Features of the course and difficulties in the diagnosis of hemolytic anemia require attention to key points. Hemolytic anemia is characterized by a reduction in the life span of erythrocytes, which is clinically manifested by jaundice due to indirect hyperbilirubinemia, splenomegaly, and skeletal deformities during a long course. Considering the seriousness of the prognosis for hemolytic anemia, it was considered appropriate to demonstrate specific practical nuances of managing such patients in specific clinical cases. Clinical cases clearly demonstrate the need for careful collection of family anamnesis and additional examination of brothers/sisters, parents when hereditary microspherocytosis is suspected. Diagnostic criteria of hereditary hemolytic anemia are: jaundice (due to indirect hyperbilirubinemia), splenomegaly, anemia, reticulocytosis, similar cases in the family. It is presented a case when hemolytic crises in a child were accompanied by a transient increase in liver transaminases, in the absence of changes in ultrasound examination and negative markers of viral hepatitis. Conclusions. An anemic syndrome established in a child in combination with reticulocytosis requires a targeted examination for hemolytic genesis of anemia. At the same time, it should be remembered that in the case of an atypical course of hereditary microspherocytosis, the patient needs a comprehensive examination and dynamic monitoring of the course of hemolytic anemia in order to prevent serious complications. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the author.

Characteristics of Anemia in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory, chronic and systemic disease that primarily affects the synovial joints. Anemia is a common extra-articular manifestation in the absence of an effective treatment. The main mechanisms involved include shortening the lifespan of erythrocytes, inadequate bone marrow and abnormalities in iron metabolism. Eighty-eight patients over 18 years with definite diagnosis of rheumatoid were included in this study. The prevalence, respectively the characteristics of anemia were analyzed, together with demographic data, the type of symptoms, the type of comorbidities, the hematological indices and treatments. The mean age of the study population was 65.31 ± 12.57 years. Treat to target was achieved in one third of the patients (36.4%). The prevalence of anemia was 55% with higher prevalence in males (57%) than females (50%). Anemia was associated with higher disease activity (p=0.036). Out of the anemic patients, 7.14% had megaloblastic anemia, 40.48% had anemia of chronic disease and 21.43% suffered from iron deficiency anemia. Microcytic normochromic and normocytic hypochromic patterns can have mixed causes, belonging to both iron-pathophysiological processes and chronic inflammation. The prevalence of anemia at the 1-year check-up was 29.44% and the percentage of patients who achieved treat-to-target goals increased from 36.40% to 40.90%. The majority (48.80%) did not prove to have anemia neither at admission nor at follow-up. The results of the study suggest that anemic patients tend to have a higher level of RA activity, therefore screening for anemic syndrome should be part of the management of these patients, in an effort to establish the best therapeutic conduct.

CD47 as a promising therapeutic target in oncology.

CD47 is ubiquitously expressed on the surface of cells and plays a critical role in self-recognition. By interacting with SIRPα, TSP-1 and integrins, CD47 modulates cellular phagocytosis by macrophages, determines life span of individual erythrocytes, regulates activation of immune cells, and manipulates synaptic pruning during neuronal development. As such, CD47 has recently be regarded as one of novel innate checkpoint receptor targets for cancer immunotherapy. In this review, we will discuss increasing awareness about the diverse functions of CD47 and its role in immune system homeostasis. Then, we will discuss its potential therapeutic roles against cancer and outlines, the possible future research directions of CD47- based therapeutics against cancer.

Missense mutation in RPS7 causes Diamond-Blackfan anemia via alteration of erythrocyte metabolism, protein translation and induction of ribosomal stress

Diamond-Blackfan anemia (DBA) is predominantly underlined by mutations in genes encoding ribosomal proteins (RP); however, its etiology remains unexplained in approximately 25 % of patients.We previously reported a novel heterozygous RPS7 mutation hg38 chr2:g.3,580,153G > T p.V134F in one female patient and two asymptomatic family members, in whom mild anemia and increased erythrocyte adenosine deaminase (eADA) activity were detected. We observed that altered erythrocyte metabolism and oxidative stress which may negatively affect the lifespan of erythrocytes distinguishes the patient from her asymptomatic family members. Pathogenicity of the RPS7 p.V134F mutation was extensively validated including molecular defects in protein translational activity and ribosomal stress activation in the cellular model of this variant.

Indoxyl Sulfate Induces Oxidative Changes in Plasma and Hemolysate

The deteriorating function of the kidneys in chronic kidney disease (CKD) is associated, among other things, with the retention of many unnecessary metabolic products in the body. Indoxyl sulfate (IS) belongs to the group of uremic toxins with a high protein binding affinity. Moreover, this compound can generate oxidative stress. We hypothesized that a high concentration of IS might induce oxidative changes in erythrocytes and plasma components, and could therefore contribute to CKD progression. In this study, we evaluated the influence of IS on the oxidative stress parameters in plasma and hemolysate. Moreover, as a result of the action of IS, we observed a decrease in the total antioxidant capacity and a change in the activity of catalase and superoxide dismutase in hemolysate and plasma. The obtained results indicate that IS induces oxidative damage to hemolysate and plasma components. Greater changes in the parameters of oxidative stress were observed in hemolysate than in plasma treated with indoxyl sulfate. The obtained results suggest that the increased concentration of IS in patients with chronic kidney disease may lead to a decrease in the lifespan of erythrocytes in their bloodstream.

Anemia of critical illness: a narrative review

The prevalence of anemia in patients admitted to the intensive care unit (ICU) reaches 66%. Moreover, numerous patients develop anemia during ICU hospitalization. In fact, anemia is the most common hematologic disease in the ICU. The majority of patients hospitalized in the ICU present with acute systemic inflammation, so called systemic inflammatory response syndrome (SIRS). These patients may develop anemia of inflammation (AI). In crtitically ill patients AI may present acutely (acute systemic inflammation) or chronically (comorbidities associated with prolonged systemic inflammation), here we describe both presentations of AI as ‘anemia of critical illness’ (ACI). The second most frequent type of anemia in critically ill patients is iron-deficiency anemia (IDA). A mixed type of anemia (ACI + IDA) may also be present in these patients. The three major pathophysiological mechanisms leading to ACI are: iron restriction, decreased erythropoiesis, and decreased erythrocyte lifespan. Cytokines synthesized during SIRS induce the production of hepcidin that inhibits the only transmembrane iron exporter (ferroportin) present in the duodenum and macrophages. Etiological classification of anemia in critically ill patients poses a significant challenge to clinicians, as there is a multitudeof tests available, and there are various reference ranges for these tests reported in the literature in the patient population in question. Pure ACI or mixed ACI + IDA can be diagnosed using a single laboratory test — complete blood count with analysis of reticulocytes — which provides Hb concentration in erythrocyte and reticulocyte. The management of ACI incorporates discontinuation with erythropoiesis-stimulating agent causing anemia, reduction of iatrogenic blood loss, parenteral iron, and combined therapy of parenteral iron with erythropoiesis-stimulating agents in approved indications.

Morphological Types of Anemia Associated with Chronic Renal Diseases

Introduction: Anemia develops early in the course of renal disease and worsens as kidney function declines; a typical consequence of CKD is caused by a disruption in erythropoietin production as well as caused by iron and vitamin shortages, blood loss, shortened erythrocyte life span, chronic inflammation, and the uremic environment. Aim: Our study aimed to identify and classify different types of anemia that complicated patient with chronic kidney disease. Methods: 40 patient were included in this study, 32 males (80%) and 8 females (20%), the age range was 40-70 for male and 48-68 for female .Depending on clinical sign, symptoms and laboratory diagnostic test All those patient are diagnosed previously as a cases of chronic renal failure by clinicians in our city and develop anemia during the course of diseases, so clinicians referred patients to our laboratory to find the cause of anemia. Depending’s on hematological laboratory data, peripheral blood smear examination from these 40 patients, which showed different types of anemia. Results: the most common types of anemia was Normochromic anemia (62.5 %) which develop in 25 patients followed by hypochromic microcytic anemia (8 %) which develop in 8 patients, and followed by macrocytic anemia (12.5 %) which develop in 5 patients and the less common type of anemia was hemolytic anemia (5 %) which was founded in 2 patients.. Conclusion: All types of anaemia can be detected in-patient with different types of renal diseases and it’s important to used different type of laboratory test to diagnosed type of anemia to treat it.

Levitt’s CO breath test in the differential diagnosis of chronic isolated hyperbilirubinemia

A key component of the differential diagnosis of isolated hyperbilirubinemia (HB) is distinguishing between hemolytic and non-hemolytic types. Routine hemolysis screening markers have unsatisfactory sensitivity and specificity. Erythrocyte (RBC) lifespan shortening, the gold standard marker of hemolysis, is seldomly measured due to the cumbersome and protracted nature of standard methods. A new Levitt’s CO breath test method may enable simple, rapid RBC lifespan measurement. In this pilot prospective diagnostic study, Levitt’s CO breath test was evaluated to discriminate hemolytic from non-hemolytic HB in adults. One hundred and thirty eligible non-smoking adult patients who were aged 18 or older, referred for chronic (>6 months) isolated HB or had a known diagnosis of isolated HB of a rare cause, were recruited, including 77 with non-hemolytic HB and 53 with hemolytic HB. ROC curve analysis was applied to determine the optimal cutoff for discriminating between hemolytic and non-hemolytic HB, and the performance was calculated. Results showed that the mean RBC lifespan in non-hemolytic HB (93 ± 26 d) was reduced (p = 0.001 vs. normal reference value of 126 d), but longer than that in hemolytic HB (36 ± 17 d; p = 0.001). RBC lifespans did not differ significantly between 26 patients with simple hemolytic HB (32 ± 14 d) and 27 patients with a Gilbert syndrome comorbidity (40 ± 18 d). ROC curve analysis revealed an optimal lifespan cutoff for discriminating between hemolytic and non-hemolytic HB of 60 d (AUC = 0.982), with a diagnostic accuracy of 95.4%, 94.3% sensitivity and 96.1% specificity respectively. These results indicate that Levitt’s CO breath test seems to be very sensitive and specific for detecting hemolysis in adult patients with chronic isolated HB, and could enable simple, rapid, and reliable differential diagnosis of isolated HB. A large-scale validation study of the method is warranted.

Predicting the response to SGLT-2 inhibitors as add-on therapy to multiple day injection insulin with glycated albumin: a pilot study.

Achieving optimal glycemic targets is the main therapeutic goal in patients with type 2 diabetes (T2D) mellitus. HbA1c is the reference biomarker for monitoring glycemic control; however, in specific conditions affecting erythrocyte turnover or in patients on multiple daily injection (MDI) insulin regimens, the determination of glycated albumin (GA) may be preferable. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a novel class of antidiabetic drugs that lower plasma glucose concentrations quickly, with insulin-independent mechanisms. Herein, we explored the role of GA in predicting the short-term response to SGLT-2 inhibitors as add-on to MDI insulin. Sixteen patients with long-standing, poorly controlled T2D on MDI insulin starting an SGLT-2 inhibitor were subjected to plasma GA and HbA1c measurements at 30 days intervals for up to 3 months in order to examine the temporal changes of these glycemic biomarkers. At the end of the study, grossly coincident with the life span of erythrocytes, a significant decrease in median HbA1c was observed, (from 8.7 [range: 8.2-9.3%] at baseline to 7.2 [range: 7.0-7.9%]), with the advantage of less insulin dose requirements. However, significant, and incremental reductions in median GA determinations could be already evident after 30 days (-3.5 [range: -7.5, -2.5%]) and 60 days (-6.4 [range: -10.5, -4.7%]) from the start of SGLT-2 inhibitor treatment and persisted for up to 3 months (-8.6 [range: -12.1, 6.1%]). The decrements of HbA1c observed at the 3-month visit were highly correlated with the concurrent absolute reductions of plasma GA (ρ=0.550, P=0.027), whereas a borderline significance could be demonstrated with reference to reductions in plasma GA at 30 and 60 days. Although limited by the small number of participants, these preliminary findings suggest that GA, rather than HbA1c, could represent a useful and reliable biomarker in T2D to monitor the early glucose-lowering effects of antidiabetic drugs with rapid onset of action, such as SGLT-2 inhibitors and MDI insulin.

Angiotensin II-Induced Erythrocyte Senescence Contributes to Oxidative Stress.

Oxidative stress may be an important cause of erythrocyte senescence. Angiotensin II (Ang II) has recently been shown to promote vascular cell senescence. However, its effects on erythrocytes remain unclear. This study aims at investigating the role of Ang II in regulating erythrocyte lifespan through oxidative stress. Experiments were performed in C57/BL6J mice infused with Ang II (1500 ng/kg per minute) or saline for 7 days. After Ang II infusion, we found that Ang II increased erythrocyte number, hemoglobin, and red blood cell distribution width. These differences were accompanied by a decrease in glutathione (GSH) and an increase in malondialdehyde (MDA) concentration. In vitro, after 24 hours of Ang II treatment, erythrocytes showed reduced surface expression of CD47 and increased phosphatidylserine exposure. In parallel, Ang II reduced the levels of antioxidant enzymes, including Cu/ZnSOD, catalase, and peroxidase 2 (PRDX2). These effects were reversed by the addition of the antioxidant N-acetyl-L-cysteine or the Ang II type 1 (AT1) receptor blocker losartan. In addition, Ang II treatment increased pro-inflammatory oxylipin, including hydroxyeicosatetraenoic acids (HETEs) and dihydroxyoctadecenoic acids (DiHOMEs), in the erythrocyte membranes. Collectively, Ang II induced erythrocyte senescence and susceptibility to eryptosis, partially due to enhanced oxidative stress.

Labile glycated hemoglobin: an underestimated laboratory marker of short term glycemia.

Diabetes mellitus is a major public health problem. Hemoglobin A1c (HbA1c) is a key laboratory parameter in the management of diabetes patients. However, in diabetes monitoring, interpretation of HbA1c results is hampered by the important interindividual variation in red blood cell (RBC) life span. Furthermore, HbA1c only slowly responds to changes in glucose metabolism. Besides HbA1c, there exists a labile HbA1c fraction (l-HbA1c), exhibiting much faster kinetics. As both HbA1c and l-HbA1c are measured by modern standard chromatography, we explored the possibilities of using the l-HbA1c fraction for monitoring glycemia. l-HbA1c and HbA1c fractions were simultaneously assayed on a Tosoh G8 analyzer and expressed as %. l-HbA1c results were compared with serum glucose and HbA1c. Concomitantly, RBC distribution width (RDW) was determined on a Sysmex SN analyzer as a marker for erythrocyte life span. l-HbA1c could be measured with between-run coefficient of variations (CVs) between 2.2 and 2.3%. l-HbA1c correlated with both glycemia (r=0.80) and HbA1c results (r=0.73). In a multiple regression model (r2=0.752), glycemia and HbA1c were the most determining factors. To a lesser extent, RDW correlated with l-HbA1c (r=0.158). Furthermore, the l-HbA1c/HbA1c ratio weakly positively correlated with RDW (r=0.247). L-HBA1c represents an additional marker for monitoring the rapid occurrence of glycemic disorders that escape detection when using only HbA1c and blood glucose. RDW can be used as an indicator of atypical RBCs life span, in which the l-HbA1c fraction may be helpful.

Quantitative Systems Pharmacology Model of Sickle Cell Disease and Response to Gene Editing Therapy to Support Clinical Development of SAR445136 (BIVV003)

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene that produces abnormal hemoglobin (HbS), leading to clinical manifestations such as painful vaso-occlusive crises, anemia, and shortened lifespan due to organ damage. SAR445136 (BIVV003) is a zinc finger nuclease ex vivo gene editing therapy in Ph1/2 clinical development for treatment of SCD (PRECIZN-1; NCT03653247). SAR445136 targets the erythroid specific enhancer (ESE) region of the transcription factor BCL11A, which controls the switch from fetal hemoglobin (HbF) to adult forms (HbA in healthy subjects and HbS in SCD subjects). By expressing increased levels of HbF, SAR445136-edited cell progeny exhibit reduced HbS polymerization which is expected to ameliorate RBC sickling and the SCD phenotype.To better understand the dynamics and variability of clinical response to SAR445136, we developed a Quantitative Systems Pharmacology (QSP) model of SCD to describe both key elements of disease biology and the mechanism of action of SAR445136. The QSP approach provides a cohesive representation of the key disease processes in SCD by leveraging additional data sources (e.g. published and internal, clinical and preclinical) to complement data from ongoing clinical trials. The QSP model is applied to help assess mechanism-related questions, such as the observed inter-patient variability with respect to SAR445136 cellular dose, indels, and induced HbF and F cells.To explore the clinical factors that could influence the response to SAR445136, we centered the structure of the QSP model on a realistic representation of erythropoiesis that can describe hematopoietic stem and progenitor cells and erythroid progenitors in the bone marrow and the periphery, including regulation by cytokines EPO, IL-3, and stem cell factor (SCF) (Figure 1A). We first confirmed that the model recapitulates published bone marrow aspirate and blood cell sorting data from healthy individuals (Figure 1B). Next, we modified the model to describe stress erythropoiesis in SCD by incorporating published data on clinical, natural history, and in vitro assessments of SCD progenitor cells, and the resulting reticulocyte and erythrocyte levels (Figure 1B). The updated model describes key features of the SCD disease state, including reduced lifespan of HbS erythrocytes, elevated plasma reticulocytes (Steinberg MH, et al. Blood. 1997;89: 1078-1088), and altered levels of erythroid progenitors (Hoss SE, et al. Haematologica. 2020 Aug 27. doi: 10.3324/haematol.2020.265462) and cytokines, as well as the protective effects of endogenous HbF.Finally, we applied the SCD erythropoiesis model to describe the mechanism of action of SAR445136 by representing ablation followed by the introduction of CD34+ cells containing indels with enhanced HbF expression. The model captures the SAR445136 clinical data and simulates the therapeutic effects of increased total Hb and increased proportion of HbF due to the progeny of SAR445136 cells (Figure 1C). The model provides a quantitative framework for evaluating the effects of treatment parameters including cellular dose, mobilization and engraftment variability, indel quality (i.e., variable editing and HbF expression in erythroid progeny [Lessard S, et al. Blood. 2019;134(Supplement_1):97]) and assessing the pan-cellularity of the response. Due to its mechanistic structure, the model also enables exploration of inter-patient variability in terms of cytokine effects on erythropoiesis.In summary, the QSP model is a computational tool to provide mechanistic insight into emerging SAR445136 clinical data in the context of current understanding of SCD disease biology. The model is intended to provide both qualitative and quantitative support for the clinical development and competitive differentiation of SAR445136. For future development, the model can be expanded to include additional data representing the SCD bone marrow microenvironment to further explore patient heterogeneity. [Display omitted] DisclosuresKaddi: Sanofi: Current Employment. Holz: Sanofi: Current Employment. Tao: Sanofi: Current Employment. Galeon: Sanofi: Current Employment. Reiner: Sanofi: Current Employment. Rendo: Sanofi: Current Employment, Other: May hold shares and/or stock options . Zaph: Sanofi: Current Employment.

Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Hemoglobin A1c and Fructosamine Evaluated in Patients with Type 2 Diabetes Receiving Peritoneal Dialysis Using Long-Term Continuous Glucose Monitoring

Introduction: Shortened erythrocyte life span and erythropoietin-stimulating agents may affect hemoglobin A_1c (HbA_1c) levels in patients receiving peritoneal dialysis (PD). We compared HbA_1c with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with type 2 diabetes receiving PD. Methods: Fourteen days of CGM (Ipro2, Medtronic) were performed in 23 patients with type 2 diabetes receiving PD and in 23 controls with type 2 diabetes and an estimated glomerular filtration rate over 60 mL/min/1.73 m². Patients were matched on gender and age (±5 years). HbA_1c (mmol/mol), its derived estimate of mean plasma glucose (eMPG_A1c) (mmol/L), and fructosamine (µmol/L) were measured at the end of the CGM period and compared with the mean sensor glucose (mmol/L) from CGM. Results: In the PD group, mean sensor glucose was 0.98 (95% con­fidence interval (CI): 0.43–1.54) mmol/L higher than the eMPG_A1c compared with the control group (p = 0.002) where glucose levels were nearly identical (−0.05 (95% CI: −0.35–0.25) mmol/L). A significant association was found between fructosamine and mean sensor glucose using linear regression with no difference between slopes (p = 0.89) or y-intercepts (p = 0.28). Discussion/Conclusion: HbA_1c underestimates mean plasma glucose levels in patients with type 2 diabetes receiving PD. However, the clinical significance of this finding is undetermined. Fructosamine seems to more accurately reflect glycemic status. CGM or fructosamine could complement HbA_1c to increase the accuracy of glycemic monitoring in the PD population.

High-volume endurance exercise training stimulates hematopoiesis by increasing ACE NH2-terminal activity.

One of the health benefits of endurance exercise training (ET) is the stimulation of hematopoiesis. However, the mechanisms underlying ET-induced hematopoietic adaptations are understudied. N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) inhibits proliferation of early hematopoietic progenitor cells. The angiotensin I-converting enzyme (ACE) NH2-terminal promotes hematopoiesis by inhibiting the anti-hematopoietic effect of Ac-SDKP. Here we demonstrate for the first time the role of ACE NH2-terminal in ET-induced hematopoietic adaptations. Wistar rats were subjected to 10 weeks of moderate-(T1) and high-(T2) volume swimming-training. Although both protocols induced classical ET-associated adaptations, only T2 increased plasma ACE NH2-domain activity (by 40%, P=0.0003) and reduced Ac-SDKP levels (by 50%, P<0.0001). T2 increased the number of hematopoietic stem cells (HSCs; ∼200%, P=0.0008), early erythroid progenitor colonies (∼300%, P<0.0001) and reticulocytes (∼500%, P=0.0007), and reduced erythrocyte lifespan (∼50%, P=0.022). Following, Wistar rats were subjected to T2 or T2 combined with ACE NH2-terminal inhibition (captopril (Cap) treatment: 10 mg.kg-1.day-1). T2 combined with ACE NH2-terminal inhibition prevented Ac-SDKP decrease and attenuated ET-induced hematopoietic adaptations. Altogether, our findings show that ET-induced hematopoiesis was at least partially associated with increased ACE NH2-terminal activity and reduction in the hematopoietic inhibitor Ac-SDKP.

Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa

BackgroundSingle low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting.MethodsA nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status.ResultsThe predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2–8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11–13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7–8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin.ConclusionsThis study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.Graphical abstract