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Background: β-thalassemia (β-TH) is a hereditary hemolytic anemia that results in deficient hemoglobin (Hb) synthesis. It is characterized by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload. Exploration new potential biomarkers and drug candidates is important to facilitate the prevention and treatment of β-TH. Methods: We applied quasi-targeted metabolomics between wild type (Wt) and heterozygous β-TH mice (Th3/+), a model of non-transfusion-dependent β-TH intermedia, in plasma and peripheral blood (PB) cells. Futher data was deeply mined by Kyoto Encyclopedia of Genomes (KEGG) and machine algorithms methods. Results: Using KEGG enrichment analysis, we found that taurine and hypotaurine metabolism disorders in plasma and alanine, aspartate and glutamate metabolism disorders in PB cells. After systematically anatomize the metabolites by machine algorithms, we confirmed that alpha-muricholic acidUP and N-acetyl-DL-phenylalanineUP in plasma and Dl-3-hydroxynorvalineUP, O-acetyl-L-serineUP, H-abu-OHUP, S-(Methyl) glutathioneUP, sepiapterinDOWN, and imidazoleacetic acidDOWN in PB cells play key roles in predicting the occurrence of β-TH. Furthermore, Sepiapterin, Imidazoleacetic acid, Methyl alpha-Dglucopyranoside and alpha-ketoglutaric acid have a good binding capacity to hemoglobin E through molecular docking and are considered to be potential drug candidates for β-TH. Conclusion: Those results may help in identify useful molecular targets in the diagnosis and treatment of β-TH and lays a strong foundation for further research. [ABSTRACT FROM AUTHOR]

Bovine hemolytic anemia has a negative impact on animal welfare and productivity due to its associated clinical symptoms. Hemolysis is generally known to cause reticulocytosis, increased indirect bilirubin, decreased concentration of haptoglobin, and increased lactate dehydrogenase. Additionally, tissue hypoperfusion due to concomitant anemia increases blood lactate concentration. However, few studies have reported the correlation between these indicators and hemolytic anemia in cattle. We expected that alterations in hematological and biochemical parameters could identify cattle with hemolytic anemia. Therefore, in addition to reporting differences in indicators according to hemolytic anemia, this study aimed to derive indicators and set criteria for identification of bovine hemolytic anemia. In cattle with hemolytic anemia, reticulocytosis, increased indirect bilirubin, and increased L-lactate were observed, and the correlation of these indicators with hematocrit (HCT) was confirmed. And since HCT alone has limitations in identifying hemolytic anemia, we suggest additional criteria to identify hemolytic anemia in cattle. [ABSTRACT FROM AUTHOR]

Objectives: Anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is a representative of rapidly progressive interstitial pneumonia. However, its association with thrombotic microangiopathy (TMA), characterized by thrombocytopenia, haemolytic anaemia, and organ dysfunction, has not been defined. This study aimed to elucidate the characteristics of anti-MDA5 Ab-positive DM accompanied by TMA. Methods: We reviewed our hospital records from November 2009 to September 2022. We included patients in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria and the criteria of Bohan and Peter. TMA was diagnosed according to the criteria for transplantation-associated TMA proposed by the International Working Group. Results: This study enrolled a total of 26 anti-MDA5 Ab-positive DM patients, four of whom developed TMA. The patients with TMA had an increased urine protein/creatinine ratio. In addition, these four of them showed significantly elevated levels of ferritin and anti-MDA5 Ab titers and were considered to have high disease activity; yet, all of them survived. Conclusions: Our study indicated that anti-MDA5 Ab-positive DM patients with hyperferritinemia, a high anti-MDA5 Ab titer, and an increased urine protein/creatinine ratio should be carefully managed, bearing in mind a complication of TMA. [ABSTRACT FROM AUTHOR]

Purpose: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. Methods: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). Results: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. Conclusion: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12. [ABSTRACT FROM AUTHOR]

The article analyses data on the occurrence of hematological abnormalities in severe acute respiratory syndrome 2 infection. Among these hematological abnormalities, the majority of patients develop a hypercoagulable state associated with thromboembolic complications and poor prognosis. Approximately one-third of patients with severe acute respiratory syndrome 2 infection are diagnosed with mild to severe thrombocytopenia. Another hematological autoimmune disease observed in patients with coronavirus disease 2019 is autoimmune hemolytic anemia. A clinical case with the development of autoimmune hemolytic anemia in the setting of coronavirus infection was described. The diagnosis was based on the presence of anemia, reticulocytosis, a significant decrease in haptoglobin levels, and a positive antiglobulin test (Coombs test). Given the comorbidity, the risks of adverse effects of severe coronavirus disease were high, despite this, it was possible to achieve clinical and hematological remission of autoimmune hemolytic anemia by prescribing pathogenetic therapy with anti-CD-20 monoclonal antibody (rituximab), recombinant erythropoietin and glucocorticoid hormones. This clinical case demonstrates the possibility of successful treatment of patients with severe hemolytic anemia. Special attention should be paid to the discrepancy between the severity of the condition and objective data. This case demonstrates the need for a more in-depth approach to each patient with anemia associated with coronavirus disease infection, namely, in the presence of anemic syndrome, it is imperative to include a full range of laboratory tests. [ABSTRACT FROM AUTHOR]

Since the FDA's approval of rasburicase use for treatment of tumor lysis syndrome (TLS), multiple cases of rasburicase-induced methemoglobinemia and hemolytic anemia have been reported among patients with G6PD deficiency. This study aims to provide a systematic review of cases reporting such adverse reactions to rasburicase. A literature review of published cases in PubMed, Embase, Cochrane, and Web of Science was conducted. Descriptive studies reporting cases of rasburicase-induced methemoglobinemia and/or hemolytic anemia in English were analyzed and summarized in this study. Forty-three cases, including a case from our institution, were included in this study. Most cases (60.5%) received rasburicase for TLS treatment. Almost all patients (93.8%) were tested for G6PD after rasburicase administration. The median time to symptom onset was 24 h. The median methemoglobin level was 10%, peaking after a median of 24 h. The median hemoglobin nadir was 6.1 g/dL, and most patients (n = 32) required blood transfusion. Out of 39 cases with reported outcomes, 35 patients (89.7%) recovered, while four patients (three females and one male) died. The median time to recovery was 4.5 days while the median time to death was 8 days. Screening for G6PD deficiency among high-risk patients is important but not practical in acutely severe settings. When prior screening for G6PD deficiency is not feasible, close monitoring for methemoglobinemia and hemolytic anemia is recommended. Exchange transfusion is increasingly reported as a potentially successful therapeutic modality. Ascorbic acid may provide limited benefits. Methylene blue should be avoided as it may exacerbate hemolysis among these patients. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and target organ damage. Pregnancy is associated with several forms of TMA, including preeclampsia (PE), HELLP syndrome, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When HUS is secondary to a deregulation of the alternative complement pathway, it is known as atypical HUS (aHUS). Differential diagnosis is challenging, as these forms share clinical characteristics. However, early diagnosis is crucial for a specific treatment to be established and improve prognosis. We present the case of a 43 year-old primiparous woman admitted to hospital for an urgent C-section at 33 gestational weeks due to a diagnosis of severe preeclampsia and fetal distress. In the immediate postpartum, the patient developed acute liver failure and anuric renal failure in the context of the HELLP syndrome, anemia, thrombocytopenia, arterial hypertension (HTN) and neurological deficit. TMA study and differential diagnosis confirmed pregnancy-associated aHUS. Treatment with eculizumab was initiated, with good response and progressive improvement of clinical and analytical parameters. aHUS is a rare multifactorial disease that used to be associated with high mortality rates before the advent of eculizumab. Due to challenging diagnosis, the clinical laboratory plays a major role in the differential diagnosis and management of the disease. [ABSTRACT FROM AUTHOR]

Purpose: Primaquine (PQ) is recommended for radical cure of Plasmodium vivax (Pv) malaria, but its utilization is still limited due to high risk of severe haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-d). The aim of the present study is to assess the different genotypic variants leading to G6PD-d in Delhi and Goa regions of India. Methods: A total of 46 samples (34 retrospective Pv-mono-infected samples and 12 Pv-uninfected samples) were included in the study. Various genetic variants leading to G6PD-d were analysed by PCR amplification and DNA sequencing of different targeted exons of G6PD gene. Results: Molecular analysis showed presence of four mutations in study population viz. 1311 C > T, 34.1% & IVSXI 93T > C, 45.5% and two novel mutations 1388G > T, 2.3% and 1398 C > T, 2.3% (silent mutation). The bioinformatics and computational analysis demonstrate that the slight conformational changes caused by R643L mutation in protein are deleterious in nature. Conclusion: The observed mutations do not clarify the role or association between G6PD-d and Pv-infected cases. Further investigation is required in order to fully comprehend and analyse the precise role of these mutations with context to malaria infections. [ABSTRACT FROM AUTHOR]

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis (IVH) due to diminished or absent inhibition of the complement system because of deficient expression of cell-anchored complement regulating surface proteins. IVH leads to heterogeneous symptoms such as anemia, abdominal pain, dyspnea, fatigue and increased rates of thrombophilia. Inhibitors of the terminal Complement cascade can reverse IVH leading to a significant reduction of disease burden such as thrombembolic events and also mortality. Summary: Therapeutic inhibitors of the terminal complement cascade such as eculizumab or ravulizumab significantly improve overall survival through IVH-inhibition. However, not all patients experience complete disease control with normalization of hemoglobin levels and absolute reticulocyte counts (ARC) under terminal complement inhibition as a significant part of patients develop extravascular hemolysis (EVH). EVH can be clinically relevant causing persistent anemia and fatigue. New proximal complement inhibitors (CI) mainly targeting complement component C3 or factors of the amplification pathway such as pegcetacoplan, danicopan, and iptacopan became available and are meanwhile approved for marketing. Additional complement-inhibiting strategies are under clinical development. A switch from terminal to proximal CI in patients with significant EVH can achieve hemoglobin and ARC normalization and significant improvement in quality of life (QoL). Additional approvals of proximal CI agents for the treatment of hemolytic PNH in the first line are available for pegcetacoplan and iptacopan. So far, no evidence-based algorithm is available for decision-making in first-line treatment of which type of drug should be used for individual patients. Key Messages: Terminal CIs in hemolytic PNH patients can block IVH and have led to a dramatically improved survival. Proximal CIs ameliorate anemia and improve QoL in patients with relevant EVH. However, more (real-world) data are needed to demonstrate long-term improvement in all patients with hemolytic PNH, especially those under first-line treatment with proximal CI. [ABSTRACT FROM AUTHOR]

Summary The alpha‐thalassaemia alleles are very frequent in the world's population. The main molecular mechanism is a large deletion with the loss of one or two alpha genes. Another type of rarer abnormality exists: the gain of alpha genes. The consequence of a gain is an overproduction of alpha‐globin chains, which aggravates a beta‐thalassaemia trait into an intermedia phenotype (non‐transfusion‐dependent thalassaemia, NTDT). Here, we report the case of a young girl referred for a beta‐NTDT with a combination never described in the literature: a heterozygous beta‐thalassaemia mutation associated with a copy number gain of the alpha‐globin locus and ‐alpha 3.7 deletion on the same allele. [ABSTRACT FROM AUTHOR]

Cancer-associated microangiopathic hemolytic anemia (CA-MAHA) is a rare paraneoplastic syndrome. The most effective approach to treating CA-MAHA is to address the underlying malignancy. Documented cases of CA-MAHA are limited to fewer than 50 patients in the literature. Herein, we present a 51-year-old female patient who developed CA-MAHA as a complication of gastric adenocarcinoma. Despite receiving neoadjuvant and adjuvant chemotherapy for gastric cancer, the patient experienced disease progression with metastatic lesions in the liver, pancreas, and other sites. This report highlights the challenges in diagnosing and distinguishing CA-MAHA from other similar conditions such as disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and rheumatological paraneoplastic syndromes. Additionally, it concludes that CA-MAHA is associated with a poor prognosis and limited clinical benefit from treatment, emphasizing the need for early diagnosis and effective management strategies. [ABSTRACT FROM AUTHOR]

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH. [ABSTRACT FROM AUTHOR]

Background: Testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important consideration regarding treatment for malaria. G6PD deficiency may lead to haemolytic anaemia during malaria treatment and, therefore, determining G6PD deficiency in malaria treatment strategies is extremely important. Methods: This report presents the results of a scoping review and evidence and gap map for consideration by the Guideline Development Group for G6PD near patient tests to support radical cure of Plasmodium vivax. This scoping review has investigated common diagnostic tests for G6PD deficiency and important contextual and additional factors for decision-making. These factors include six of the considerations recommended by the World Health Organization (WHO) handbook for guideline development as important to determining the direction and strength of a recommendation, and included 'acceptability', 'feasibility,' 'equity,' 'valuation of outcomes,' 'gender' and 'human rights'. The aim of this scoping review is to inform the direction of future systematic reviews and evidence syntheses, which can then better inform the development of WHO recommendations regarding the use of G6PD deficiency testing as part of malaria treatment strategies. Results: A comprehensive search was performed, including published, peer-reviewed literature for any article, of any study design and methodology that investigated G6PD diagnostic tests and the factors of 'acceptability', 'feasibility,' 'equity,' 'valuation of outcomes,' 'gender' and 'human rights'. There were 1152 studies identified from the search, of which 14 were determined to be eligible for inclusion into this review. The studies contained data from over 21 unique countries that had considered G6PD diagnostic testing as part of a malaria treatment strategy. The relationship between contextual and additional factors, diagnostic tests for G6PD deficiency and study methodology is presented in an overall evidence and gap, which showed that majority of the evidence was for the contextual factors for diagnostic tests, and the 'Standard G6PD (SD Biosensor)' test. Conclusions: This scoping review has produced a dynamic evidence and gap map that is reactive to emerging evidence within the field of G6PD diagnostic testing. The evidence and gap map has provided a comprehensive depiction of all the available literature that address the contextual and additional factors important for decision-making, regarding specific G6PD diagnostic tests. The majority of data available investigating the contextual factors of interest relates to quantitative G6PD diagnostic tests. While a formal qualitative synthesis of this data as part of a systematic review is possible, the data may be too heterogenous for this to be appropriate. These results can now be used to inform future direction of WHO Guideline Development Groups for G6PD near patient tests to support radical cure of P. vivax malaria. [ABSTRACT FROM AUTHOR]

Background: The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare. Case Presentation: We describe a 7-month-old male patient presenting with fatigue and edema. His initial laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria. Further examinations reveals hemolysis in peripheral blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported a diagnosis of nephrotic syndrome. The patient's condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement. Discussion/Conclusion: This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again. [ABSTRACT FROM AUTHOR]

Objective: To investigate the risk factors of lupus retinopathy (LR) in patients with systemic lupus erythematosus (SLE). Methods: This is a retrospective, cross‐sectional study. LR patients admitted at Peking Union Medical College Hospital from June 2013 to April 2023 were reviewed. Age‐ and gender‐matched SLE patients without retinopathy were selected as controls. Medical records including clinical manifestations, laboratory data and ophthalmic examination were collected. Univariate and multivariate logistic regression analyses were conducted. Results: One hundred and twelve LR patients (198 eyes) were included, with 12 cases (14 eyes) presenting with retinal macrovascular obstruction, and 100 cases (184 eyes) only exhibiting microvasculopathy. Multivariate analysis indicated the presence of haemolytic anaemia, decreased haemoglobin (HGB) and higher relative percentage of neutrophils were independent risk factors for LR (p < 0.05). The first two were also risk factors for retinal microvasculopathy, whereas secondary antiphospholipid syndrome (APS) was for macrovascular obstruction. In male group, LR had significant associations with decreased HGB, no matter which types of retinopathy (p < 0.05). In female group, LR was significantly associated with haemolytic anaemia, presence of antiphospholipid antibodies, decreased white blood cells and relative high percentage of neutrophils. Specifically, haemolytic anaemia (p = 0.002) was significantly associated with retinal microvasculopathy, and APS (p = 0.003) was significantly associated with macrovasculature obstruction. Conclusion: LR was related to haemolytic anaemia, decreased HGB levels and higher percentage of neutrophils. Retinal microvasculopathy accounted for most cases and macrovasculature obstructions were rare. Male and female patients have distinct risk factors. Early ophthalmic screening is recommended especially for those with risk factors of LR. [ABSTRACT FROM AUTHOR]

Summary: Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow‐up) was common (52.5%), even in never‐transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients. [ABSTRACT FROM AUTHOR]

Purpose: Ascorbic acid has been proposed as an alternative treatment for methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, its efficacy has never been compared to that of methylene blue given the inability of patients with G6PD deficiency to receive methylene blue. We present a case of methemoglobinemia treated with ascorbic acid in a patient without G6PD deficiency who had previously received methylene blue. Summary: A 66-year-old male was treated for methemoglobinemia deemed to be secondary to benzocaine throat spray. He received intravenous (IV) methylene blue but had a severe reaction: diaphoresis, lightheadedness, and hypotension. The infusion was stopped prior to completion. Approximately 6 days later he presented with methemoglobinemia following an additional overconsumption of benzocaine and was treated with ascorbic acid. In both instances his methemoglobin levels were >30% on arterial blood gas on admission and decreased to 6.5% and 7.8%, respectively, after administration of methylene blue and ascorbic acid. Conclusion: Ascorbic acid had a similar effect on decreasing the concentration of methemoglobin compared to methylene blue. Further research into use of ascorbic acid as a recommended agent for treatment of methemoglobinemia is warranted. [ABSTRACT FROM AUTHOR]

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2–13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP. [ABSTRACT FROM AUTHOR]

Intravascular hemolysis is a central feature of congenital and acquired hemolytic anemias, complement disorders, infectious diseases, and toxemias. Massive and/or chronic hemolysis is followed by the induction of inflammation, very often with severe damage of organs, which enhances the morbidity and mortality of hemolytic diseases. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that modulates the functions of many immune cells, thus affecting inflammatory processes. Gal-3 is also one of the main regulators of fibrosis. The role of Gal-3 in the development of different kidney and liver diseases and the potential of therapeutic Gal-3 inhibition have been demonstrated. Therefore, the objective of this review is to discuss the possible effects of Gal-3 on the process of kidney and liver damage induced by intravascular hemolysis, as well as to shed light on the potential therapeutic targeting of Gal-3 in intravascular hemolysis. [ABSTRACT FROM AUTHOR]

Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA. [ABSTRACT FROM AUTHOR]

Mitapivat is a novel, first‐in‐class orally active pyruvate kinase activator approved by the US Food and Drug Administration in 2022 for the treatment of hemolytic anemia. There is no literature available regarding the identification of degradation impurities of mitapivat. The present study deals with the degradation behavior of mitapivat under various stress conditions such as hydrolytic, photolytic, thermal, and oxidative stress. The multivariate analysis found that the independent variables, that is, molarity, temperature, and time, are interacting with each other to affect the degradation of mitapivat. A specific, accurate, and precise high‐performance liquid chromatographic (HPLC) method was developed to separate mitapivat from its degradation products. The separation was achieved on the C‐18 column (250 mm × 4.6 mm × 5 µm) using the combination of 0.1% formic acid buffer and acetonitrile in gradient elution profile. The method was validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Q2(R2) guideline. LC‐electrospray ionization‐Quadrupole‐time of flight was employed to identify degradation products. A total of seven novel degradation products of mitapivat were identified based on tandem mass spectrometry and accurate mass measurement. In‐silico toxicity of mitapivat and its degradation products was qualitatively evaluated by the DEREK toxicity prediction tool. [ABSTRACT FROM AUTHOR]

Summary: Patients with sickle cell disease (SCD) often experience painful vaso‐occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso‐occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility. [ABSTRACT FROM AUTHOR]

Summary: Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty‐nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695‐1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non‐spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling. [ABSTRACT FROM AUTHOR]

The osmotic fragility of erythrocytes is a parameter that reflects the ability of cells to endure variations in the osmotic environment. The impairment of this ability is often associated with a variety of pathologies, encompassing hemolytic anemias, malignant tumors, and cardiovascular dysfunctions. Osmotic fragility exhibits variability across different animal taxa and is closely related with ecosystems. We developed the method for assessing osmotic fragility using a laser particle size analyzer, which facilitates real-time kinetic monitoring of cell concentration changes under controlled temperature conditions. The species examined included Homo sapiens, Rattus norvegicus domestica, Coturnix japonica domestica, Rana ridibunda, Carassius carassius, and Lampetra fluviatilis. The methodology was presented in two variants: (1) manual water additions and (2) automated medium dilution. The key parameters characterizing osmotic fragility included H50 (the osmolality that lysed half of lysis-susceptible cells), H90 (90% cell lysis), and W (population heterogeneity by the degree of lysis resistance). In terms of H50 and W, the results obtained via this method did not differ significantly from those obtained by spectrophotometry and flow cytometry. No significant differences were also observed between the outcomes of automated and manual variants of the method. Erythrocytes of aquatic and semiaquatic animals exhibited significantly higher resistance to hypotonic lysis. Among all species examined, amphibian (Rana ridibunda) and lamprey (Lampetra fluviatilis) erythrocytes demonstrated the lowest osmotic fragility. The most pronounced variability in the degree of lysis resistance was detected among amphibians, with an almost twofold difference compared to other taxa examined. While mammalian (human and rat) erythrocytes exhibited similar fragility levels, they were more variable in their resistance profiles. Avian erythrocytes demonstrated a half-lysis occurrence at higher osmolality levels compared to mammalian erythrocytes, although in the domestic quail (Coturnix japonica domestica), erythrocytes lysed over a considerably wider osmotic range and contained a subset of cells resistant to hypotonic lysis. These findings indicate that erythrocytes of lower vertebrates share a lower osmotic fragility compared to those of higher vertebrates, a phenomenon most likely attributable to embryonic characteristics, ecto-/endothermy, and habitat considerations. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are small, endogenous non-coding RNA molecules that inhibit gene expression through either destabilization of the target mRNA or translational repression. MiRNAs recognize target sites, most commonly found in the 3′-untranslated regions of cognate mRNAs. This review aims to provide a state-of-the-art overview of the role of miRNAs in the regulation of major blood group antigens such as ABH as well as cancer-specific glycans. Summary: Besides their known roles in the control of developmental processes, proliferation, apoptosis, and carcinogenesis, miRNAs have recently been identified to play a regulatory role during erythropoiesis and blood group antigen expression. Since only little is known about the function of the red cell membrane proteins carrying blood group antigens, it is of great interest to shed light on the regulatory mechanisms of blood group gene expression. Some carrier proteins of blood group antigens are not restricted to red blood cells and are widely expressed in other bodily fluids and tissues and quite a few play a crucial role in tumor cells, as either tumor suppressors or promoters. Key Message: All available data point at a tremendous physiological as well as pathophysiological relevance of miRNAs in context of blood group regulation. Furthermore, miRNAs are involved in the regulation of pleiotropic genetic pathways such as hematopoiesis and tumorigenesis and thus have to be studied in future research on this subject. [ABSTRACT FROM AUTHOR]

Haemolytic anaemia represents a risk factor for the development of pulmonary hypertension (PH), currently classified as World Health Organization group 5 PH, and data regarding appropriate therapeutic strategy are limited. A total of 28 patients, 85.7% with thalassaemia and 14.3% with sickle cell disease, with a diagnosis of PH confirmed by right heart catheterization were included in the study. The patients were divided into three groups according to the PH haemodynamic definition and overall diagnostic approach: 42.9% had precapillary PH (pulmonary arterial hypertension—PAH group), 25% had post-capillary PH, and 32.1% had chronic thromboembolic PH (CTEPH) (29% of b-thalassemia and 50% of SCD patients). The therapeutic approach in each group and its impact on the outcome and haemodynamics were recorded. PAH-specific drug therapy received 82.1% of patients, and balloon pulmonary angioplasty (BPA) was performed in six patients with CTEPH. There were statistically significant differences in baseline mPAP and PVR values between the CTEPH-haemolytic anaemia group and other groups. PAH-specific drug therapy resulted in haemodynamic improvement for the PAH group. Patients who underwent BPA had improved pulmonary haemodynamics. The median survival time was 162 months, and the survival rate was 1 year—100%; 2, 3, 4, 5, and 6 years—96%; 9 years—90%; and 13 years—78%. In patients with haemolytic anaemia, the wide spectrum of induced PH highlighted the importance of a correct predominant diagnosis. BPA in CTEPH patients and specific-PAH drug therapy for PAH patients represent potential therapeutic strategies; however, the management should be offered in expert PH centres under individualized approaches for patients. [ABSTRACT FROM AUTHOR]

Objectives: In congenital hemolytic anemias (CHA), it is not always possible to determine the specific diagnosis by evaluating clinical findings and conventional laboratory tests. The aim of this study is to evaluate the utility of next‐generation sequencing (NGS) and clinical‐exome‐based copy number variant (CNV) analysis in patients with CHA. Methods: One hundred and forty‐three CHA cases from 115 unrelated families referred for molecular analysis were enrolled in the study. Molecular analysis was performed using two different clinical exome panels in 130 patients, and whole‐exome sequencing in nine patients. Exome‐based CNV calling was incorporated into the traditional single‐nucleotide variant and small insertion/deletion analysis pipeline for NGS data in 92 cases. In four patients from the same family, the PK Gypsy variant was investigated using long‐range polymerase chain reaction. Results: Molecular diagnosis was established in 86% of the study group. The most frequently mutated genes were SPTB (31.7%) and PKLR (28.5%). CNV analysis of 92 cases revealed that three patients had different sizes of large deletions in the SPTB and six patients had a deletion in the PKLR. Conclusions: In this study, NGS provided a high molecular diagnostic rate in cases with rare CHA. Analysis of the CNVs contributed to the diagnostic success. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Animals Methods Results Conclusions and Clinical Importance Benefit of adding a second‐line immunosuppressive drug to glucocorticoids for the treatment of non‐associative immune‐mediated hemolytic anemia (naIMHA) in dogs has not been defined prospectively.Evaluate the effectiveness of different immunosuppressive protocols in naIMHA dogs.Forty‐three client‐owned dogs.Open label, randomized, clinical trial. Dogs were treated with methylprednisolone (M‐group), methylprednisolone plus cyclosporine (MC‐group) or methylprednisolone plus mycophenolate mofetil (MM‐group). Dogs were defined as responders by disappearance of signs of immune‐mediated destruction and hematocrit stabilization. Frequency of responders was compared between M‐group and combined protocols (MC and MM‐group evaluated together), and among the 3 different therapeutic groups at 14 (T14), 30 (T30), 60 (T60) days after admission. Frequency of complications, length of hospitalization and relapse were also compared. Death rate was evaluated at discharge, T60 and 365 (T365) days.Proportion of responders was not significantly different between M‐group and combined protocols (MC and MM‐groups), nor among the 3 therapeutic groups at T14, T30, and T60 (P > .17). Frequency of relapse, complications, and length of hospitalization were not significantly different between M‐group and dogs treated with combined protocols, nor among the 3 treatment groups (P > .22). Death was significantly more common only for MM‐group compared with MC‐group at T60 (+42.8%; 95% CI: 11.5–67.4; P = .009), and at T365 (+50%; 95% CI: 17.5–73.2; P = .003).Combined immunosuppressive therapy did not improve hematological response in naIMHA. [ABSTRACT FROM AUTHOR]

Background: The emergence of new SARS‐CoV‐2 variants and the global COVID‐19 pandemic spurred urgent vaccine development. While common vaccine side effects are well‐documented, rare adverse events necessitate post‐marketing surveillance. Recent research linked messenger RNA vaccines to thrombotic microangiopathy (TMA), a group of syndromes characterized by microvascular hemolytic anemia and thrombocytopenia. This report describes a new‐onset atypical hemolytic‐uremic syndrome (aHUS) occurring after COVID‐19 vaccination and complements recent literature. Case Presentation: A previously healthy 25‐year‐old woman developed malaise, nausea, edema, and renal dysfunction 60 days postvaccination. Laboratory findings confirmed TMA diagnosis. Genetic testing for complement system mutations was negative. Kidney biopsy supported the diagnosis, and the patient required hemodialysis. Conclusion: This case illustrates the rare occurrence of aHUS following COVID‐19 vaccination, with unique characteristics compared to previous reports. Despite the critical role of vaccination in pandemic control, emerging adverse events, such as vaccine‐related TMA, must be recognized and investigated. Additional clinical trials are imperative to comprehend the clinical features and pathophysiological mechanisms underlying TMA associated with COVID‐19 vaccination. [ABSTRACT FROM AUTHOR]

Background: In patients with symptomatic mitral PVL, successful transcatheter reduction of the PVL to less than mild is associated with significant improvement in short- and midterm survival. Objectives: In this study, we present our single-centre, same operators' experience on percutaneous paravalvular leak closure with techniques and outcomes. Methods: In this retrospective observational designed study, we retrieved hospital records of patients with a surgical history of mechanical or biological prosthetic valve replacement and who subsequently underwent transcatheter mitral paravalvular leak closure (TMPLC). All procedures were performed by the same operators. Results: A total of 45 patients with 58 PVDs underwent TMPLC using 60 devices. All patients had moderate or severe mitral paravalvular regurgitation associated with symptomatic HF (15.6%), clinically significant haemolytic anaemia (57.8%) or both (26.7%). The technical success rate was 91.4%, with 53 defects successfully occluded. The clinical success rate was 75.6%. Among the clinical success parameters, the preprocedural median ejection fraction increased from 45% (35–55) to 50% (40–55) (p =.04). Mitral gradients decreased from max/mean 18/8 mmHg to max/mean 16/7 mmHg; p =.02). Haemoglobin levels increased from 9.9 (8.5–11.1) to 11.1 (3–13); p =.003. LDH levels decreased from 875 (556–1125) to 435 (314–579); p: <.001. All-cause 30-day and in-hospital mortality rates were the same at 8.9%. Conclusion: This single-centre study with a limited number of patients confirmed that TMPLC is a safe and effective procedure to improve symptoms and severity of PVL. [ABSTRACT FROM AUTHOR]

Gilbert's syndrome is the most common inherited jaundice worldwide. It affects 5-10% of the population. It is caused by a mutation of the UGT1A1 gene, which results in impaired bilirubin metabolism. It is a benign disease and does not affect the life expectancy of patients. Patients with Gilbert's syndrome should be alert to factors that exacerbate the course of the disease, interactions with medications taken and possible comorbidities such as hemolytic anemia, cholelithiasis or schizophrenia. However, it is the responsibility of physicians with such patients under their care to properly educate patients. Gilbert's syndrome carries not only the consequences associated with the mutation, but also has many benefits that patients may not be fully aware of. Mildly elevated bilirubin levels have an antioxidant and anti-inflammatory effect, which prevents the development of lifestyle diseases and cancer. Ongoing clinical trials suggest that this could be a great step toward new treatments for diseases affecting the entire human population. PURPOSE OF THE WORK: This review paper aims to show Gilbert's syndrome as a multifaceted disease and to sensitize doctors' attention to patients with the described mutation. MATERIALS AND METHODS: An analysis of papers available in PubMed and Google Scholar was performed using the following key words: Gilbert's syndrome, bilirubin, UDPglucuronosyltransferase, Gilbert's syndrome harmful and protective aspects, iatrogenic Gilbert's syndrome. RESULTS: The result of the work is to present Gilbert's syndrome as a disease that carries medical problems directly related to the mutation, but also, in some cases, has a protective effect on affected individuals. The work highlights the complexity of the problem. [ABSTRACT FROM AUTHOR]

Hereditary spherocytosis (HS) is a membranopathy that impacts the vertical junctions between the cytoskeleton and the plasma membrane of erythrocytes. The gold standard method for diagnosing it is osmotic gradient ektacytometry (OGE). However, access to this technique is scarce. We have devised a straightforward approach utilizing flow cytometry to quantify variations in an osmotic gradient, relying on FSC-H/SSC-H patterns. We studied 14 patients (9 pediatric, 5 adults) and 54 healthy controls (16 pediatric, 38 adults). After assessing the behavior of the samples in several osmolar gradients we selected for the study the 176, 308, and 458 mOsm/kg levels as hypo-osmolar, iso-osmolar, and hyper-osmolar references. We then selected the iso-osmolar point for assessment to determine its efficacy in discriminating between patient and control groups using a receiver operating characteristic curve. In the pediatric group, the area under the curve (AUC) was 1.0, indicating 100% sensitivity and 93.3% specificity. Conversely, in the adult group, the AUC was 0.98, with 80% sensitivity and 90.9% specificity. We introduce a method that is easily replicable and demonstrates high sensitivity and specificity. This technique could prove valuable in the diagnosis of spherocytosis. [ABSTRACT FROM AUTHOR]

Lead (Pb) toxicity has garnered attention from environmental scientists because of its detrimental impact on plants, animals and humans. Lead toxicity ranks among the most perilous metal poisonings, with avenues of entry including lead-based paint, dust, water, soil, tableware, and folk remedies. Children are particularly susceptible to its effects. Lead instigates oxidative stress by impeding glutathione replenishment and can provoke hemolytic anemia through lipid peroxidationinduced disruption of cellular membranes. Furthermore, it perturbs neurotransmitter levels and induces severe health complications, some fatal, due to organ damage. The primary objective of this review is to synthesize information on lead toxicity detection, its sources, and its mechanisms, encompassing its various toxicological impacts on human health. Additionally, it underscores strategies for lead toxicity prevention and treatment. [ABSTRACT FROM AUTHOR]

Yun Lu,1,2,&ast; Dan Zhang,2– 4,&ast; Dongsheng Han,2– 4 Fei Yu,2– 4 Xingnong Ye,5 Shufa Zheng2– 4 1Department of Clinical Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, People’s Republic of China; 2Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China; 4Institute of Laboratory Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 5Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shufa Zheng, Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Hangzhou, 310003, People’s Republic of China, Email zsfzheng@zju.edu.cn Xingnong Ye, Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Hangzhou, 310003, People’s Republic of China, Email xingnong@zju.edu.cnAbstract: Babesiosis, as a vector-borne infectious disease, remains relatively rare and is prone to being overlooked and misdiagnosed. Therefore, understanding the epidemiological characteristics and clinical manifestations of babesiosis is crucial for the prompt detection and treatment of the disease. We reported a 63-year-old male patient presenting with spontaneous fever and chills. Laboratory investigations revealed erythrocytopenia, reduced hemoglobin levels, and increased reticulocytes and total bilirubin. Bone marrow examination indicated vigorous cell proliferation, a decreased granulocyte to red cell ratio, and predominant erythroid cell proliferation, with a higher prevalence of intermediate and late-stage juvenile granulocyte and erythroid cells. Initial treatment focused on hemophagocytic syndrome triggered by Epstein-Barr virus infection yielded unsatisfactory results, leading to secondary multiple pulmonary infections. Metagenomic next-generation sequencing (mNGS) of sputum samples pointed to hemolytic anemia induced by Babesia infection, which was subsequently confirmed through peripheral blood smear analysis. The patient responded well to prompt administration of atovaquone and azithromycin, with symptoms resolving and laboratory parameters normalizing. Hemolytic anemia resulting from babesiosis should be distinguished from hemophagocytic syndrome caused by Epstein-Barr virus and other hematologic conditions. mNGS represents an efficient technique for Babesia detection.Keywords: Babesia, Hemolytic anemia, mNGS, Pneumonia

Objective To analyze a case of hyperhemolytic syndrome(HHS) and explore the laboratory diagnostic method and clinical treatment strategy. Methods Serological tests such as blood typing, direct antiglobulin test(DAT), anti-screening and antibody identification were performed, The complete blood count(CBC), as well as hemolysis indicators such as lactate dehydrogenase(LDH) and bilirubin were tested, and the changes and progression of hemolysis were monitored.By using genotyping methods to test 32 common rare blood type antigens in clinical practice, the accuracy of antibody identification results was supported. Results The patient had anti-E antibodies and autoantibodies in her serum. After blood transfusion, LDH and bilirubin increased significantly, but hemoglobin dropped sharply, far lower than before transfusion, presenting with unique manifestations such as hemoglobinuria.The patient made a full recovery after treatment with high-dose intravenous immunoglobulin and corticosteroids. Conclusion HHS is a rare and potentially fatal diseases, which is mainly manifested by hemolysis and severe anemia, and the hemoglobin level after blood transfusion is often lower than that before blood transfusion. This patient had typical clinical manifestations of post-transfusion hyperhemolytic reaction. After timely and correct treatment, the patient recovered completely and was discharged, accumulating valuable clinical experience for the diagnosis and treatment of such disease.

Abstract Background The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare. Case Presentation We describe a 7-month-old male patient presenting with fatigue and edema. His initial laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria. Further examinations reveals hemolysis in peripheral blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported a diagnosis of nephrotic syndrome. The patient’s condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement. Discussion/Conclusion This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

Autoimmune hemolytic anaemia (AIHA) is an uncommon cause of antibody-induced hemolytic anemia in children. It is divided into three categories: warm AIHA, cold antibody AIHA and paroxysmal cold hemoglobinuria. The diagnostic work-up typically begins with a peripheral smear and a direct antiglobulin test. Further diagnostic approaches and pathogenesis of all three entities are discussed. Clinical trials are lacking for AIHA in children. First-line therapy for warm AIHA is corticosteroids and for cold antibody AIHA is rituximab. Data on other therapeutic agents is reviewed. Supportive care is an important aspect, particularly in cold AIHA and paroxysmal cold hemoglobinuria. Issues related to blood transfusion due to antibodies including the least incompatible blood are discussed. Tables and figures provide an overview of pathology, diagnosis and diagnostic algorithm.

The clinical course of patients with chronic hemolytic anemia can be complicated by the development of splenomegaly and consequent hypersplenism. This may warrant management by medical or surgical methods. Furthermore, in some patients, splenic manipulation may be warranted in the absence of hypersplenism, spleen being the primary site of red cell destruction. Wherever possible, splenectomy is avoided or deferred in view of the life-long risks of infection and thrombosis associated with this procedure. Optimal management in hemolytic anemia, therefore, incorporates prevention of hypersplenism as one of the key treatment goals.

Objective This study aimed to determine if treatment with IVIG of neonates with ABO incompatibility (without Rh incompatibility) results in decreased number of packed red blood cell (pRBC) transfusions and phototherapy use. Study Design An Institutional Review Board (IRB)-approved, single-institution retrospective study was conducted. Neonates ≥38 weeks' gestational age born between January 1, 2007, and December 31, 2016, with ABO incompatibility were included. The comparison among groups was performed using chi-square and Fisher's exact tests for categorical variables; continuous variables were assessed by Kruskal–Wallis test. Results Six hundred and sixty-eight neonates with ABO incompatibility met inclusion criteria, 579 were included in the analyses. From these, 431 (74%) neonates had positive Direct Antiglobulin Test (DAT); 98 (17%) received IVIG and 352 (61%) received phototherapy. Thirty-six (6%) neonates received pRBC and 6 (1%) required exchange transfusions. Only 3 (0.5%) infants received pRBC transfusions postdischarge, by 3 months of age. Neonates requiring IVIG had lower initial hemoglobin (13.6 vs. 16.0 g/dL, p ≤ 0.0001) and higher bilirubin at start of phototherapy (9.1 vs. 8.1 mg/dL, p = 0.0064). From the 42 (7%) neonates who received simple and exchange transfusions, IVIG use was not associated with decreased use or number of transfusions (p = 0.5148 and 0.3333, respectively). Newborns with A+ and B+ blood types had comparable initial hemoglobin, DAT positivity, APGAR, and bilirubin. However, infants with B+ blood group were more likely (than A +) to require phototherapy (p < 0.001), receive IVIG (p = 0.003), and need phototherapy for a longer duration (p = 0.001). Conclusion The results of this large retrospective study reveal that giving IVIG to neonates with ABO incompatibility was associated with increased simple or exchange transfusions. Newborns with B+ blood type required more phototherapy and IVIG. Further studies are needed to better stratify neonates who would benefit from IVIG use in order to optimize treatment strategies and avoid unnecessary risks and adverse events. Key Points IVIG use not associated with decreased use of pRBC or exchanges. Phototherapy duration associated with increased IVIG and pRBC use. Newborns with B+ blood type had worse hemolytic anemia. [ABSTRACT FROM AUTHOR]

Inherited disorders affecting the red blood cell (RBC) membrane result from mutations in membrane or skeletal proteins. Such mutations can impede red cell deformability, leading to a shortened lifespan and early removal of erythrocytes from circulation. This, in turn, results in anemia and jaundice. Hereditary spherocytosis (HS), hereditary elliptocytosis, hereditary ovalocytosis, and hereditary stomatocytosis are examples of these disorders, with HS being the most prevalent form of inherited hemolytic anemia. Disorders of the RBC membrane may stem from structural or transport functional changes, but they inevitably lead to clinical symptoms of hemolytic anemia. Accurate diagnosis is crucial to avoid complications or inappropriate treatment as management varies depending on pathophysiology. In this review, we describe few cases of different types of RBC membrane disorders with variable age of presentation, emphasizing the significance of correct approach, limitations of certain investigations and the need for genetic test to reach a precise diagnosis.

Background: Transplacental-derived anti-D IgG in RhD-negative pregnant women can trigger an immune response to Rh D-positive red cells in fetuses and newborns. We assessed the effect of anti-D titers in RhD-negative pregnant women on fetuses and newborns. Methods: The clinical data of 142 singleton RhD-sensitized pregnancies were retrospectively collected. The pregnant women received routine prenatal care and the newborns had standard care. Based on the tertile categories of the pregnancies, the maximum titers of anti-D IgG in the pregnant women were divided into three groups ranging from low to high as follows: low-titer group (anti-D titer: 1:4–1:128, n = 57); medium-titer group (anti-D titer: 1:256–1:512, n = 50); and high-titer group (anti-D titer: 1:1024–1:4096, n = 35). Results: The frequencies of major neonatal complications did not significantly differ among the three groups. The high-titer group had the highest frequency of pregnancies requiring intrauterine transfusion (IUT) and number of IUTs among the three groups. The high-titer group had a significantly higher frequency of newborns treated with top-up transfusion, number of top-up transfusions, frequency of newborns treated with exchange transfusion (ET), and number of ETs when compared to the low-titer group. Conclusion: Higher anti-D titers in RhD-negative pregnant women predict more severe fetal and neonatal hemolytic anemia. Increasing maternal anti-D titers results in an increased need for IUTs, and neonatal top-up transfusions and ETs. Methods for reducing titers of anti-D IgG in RhD-sensitized pregnant women warrants further investigation.

Abstract Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (MTRR). Patients usually exhibit early‐onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.

Background: Sickle hepatopathy is the hepatobiliary dysfunction associated with sickle cell disease. It has a varied spectrum ranging from asymptomatic transaminasemia to gallstones or fulminant liver failure. Hepatobiliary manifestations may be the initial presentation in children with undiagnosed sickle cell disease as seen in our three index cases. This may mimic a primary liver disease, delaying definite diagnosis and management. Case presentation: We describe three cases. The first case was a 9-year-old girl child with cholecystitis with choledocholithiasis, the second case was a 15-year-old boy with acute hepatitis of unidentified aetiology, and the third case was a 3-month-old infant with neonatal cholestasis in absence of common structural or metabolic cause. All three cases had underlying haemolytic anaemia with splenomegaly and belonged to the sickle belt of the region. The final diagnosis in all three index cases was sickle cell disease with hepatopathy. Conclusion: The clinical syndrome of hepatitis or cholestasis with or without cholangitis in the background of splenomegaly and haemolytic anaemia should prompt screening for sickle cell disease. [ABSTRACT FROM AUTHOR]

Introduction: Hemolytic uremic syndrome (HUS) is characterized by progressive kidney injury accompanied by thrombotic microangiopathy, which is clinically defined as microangiopathic hemolytic anemia with thrombocytopenia and organ injury. Shiga toxin-producing Escherichia coli (STEC)-HUS is caused by infection with pathogenic E. coli strains, typically O157, O26, and O111. However, the prevalence of other types of pathogenic E. coli has been increasing, and these pathogens sometimes cause atypical clinical manifestations of STEC-HUS. Case Presentation: We report the case of a 3-year-old girl diagnosed with STEC-HUS associated with a rare O80:H2 stx2 serotype, characterized by an atypical clinical course. She presented with severe hemolytic anemia and mild renal dysfunction but did not have enterohemorrhagic diarrhea. The first culture test of her stool sample collected using a swab upon admission yielded no signs of STEC, leading to an initial diagnosis of atypical HUS; thus, eculizumab was administered adding to red blood cell transfusion and recombinant thrombomodulin alfa and haptoglobin. However, a subsequent culture test of her second stool sample revealed the presence of O80:H2 stx2, confirming the diagnosis of STEC-HUS. Subsequently, the patient’s condition improved, and her serum creatinine level gradually normalized over the course of 3 months. Conclusion: Diligently diagnosis is crucial in cases lacking typical STEC-HUS symptoms. We advocate for repeated stool culture testing to ensure accurate identification and timely management of such cases. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) arises from beta‐globin gene mutations, with global estimates indicating around 500 000 affected neonates in 2021. In the United States, it is considered rare, impacting fewer than 200 000 individuals. The key pathogenic flaw lies in mutant haemoglobin S, prone to polymerization under low oxygen conditions, causing erythrocytes to adopt a sickled shape. This leads to complications like vascular occlusion, haemolytic anaemia, inflammation and organ damage. Beyond erythrocyte abnormalities however, there is a body of literature highlighting the hypercoagulable state that is likely a contributor to many of the complications we see in SCD. The persistent activation of the coagulation cascade results in thromboembolic events, notably venous thromboembolism (VTE) which is independently associated with increased mortality in both adults and children with SCD. While the increased risk of VTE in the SCD population seems well established, there is a lack of guidelines for thromboprophylaxis in this population. This Wider Perspective will describe the hypercoagulable state and increased thrombosis risk in the SCD population, as well as advocate for the development of evidence‐based guidelines to aid in the prevention of VTE in SCD. [ABSTRACT FROM AUTHOR]

Background: Hemotropic Mycoplasma species (hemoplasmas) cause hemolytic anemia in cats worldwide and are recognized as emerging zoonotic pathogens. There is no comprehensive study on the prevalence and species diversity of hemoplasmas in domestic cat populations in different regions in Iran. Thus, the aims of the present study were to provide data on the prevalence and molecular characterization of hemotropic Mycoplasma species in apparently healthy cats from six Iranian provinces with different climates. In addition, potential risk factors associated with hemoplasmosis in cats were assessed. Results: Mycoplasma spp. DNA was detected in the blood of 56 / 361 cats (15.5%) using genus-specific PCR. Further examinations with species-specific PCR and Sanger sequencing showed that 38 cats (10.5%) tested positive for Candidatus Mycoplasma haemominutum (CMhm), 8 cats (2.2%) tested positive for Mycoplasma haemofelis (Mhf), and 2 cats (0.6%) tested positive for Candidatus Mycoplasma turicensis (CMt). Co-infection with CMhm, and Mhf was observed in 7 cats (1.9%). One cat (0.3%) showed mixed infection with CMhm, Mhf, and CMt. There were statistically significant relationships between Mycoplasma positivity and being female, living in shelter (cattery), and being over 3 years old (P < 0.05). No significant association was observed for the cat breed and sampling localities. Conclusions: Current study findings revealed that hemoplasma infections are common among Iran cat populations. Considering the impact of such emerging zoonotic pathogens on the One Health, routine screenings, increasing public awareness, effective control, and prophylactic strategies for minimizing infection in cats and subsequently in human are strongly recommended. [ABSTRACT FROM AUTHOR]