Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34[+] HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.

Piroplasmosis, caused by Theileria and Babesia species, is an emerging threat to the health and productivity of cattle in Bangladesh. This study investigated clinical incidence of bovine piroplasms in commercial cattle farms across the country. A total of 480 clinically diseased cattle were examined for epidemiology, hematology and genetic profiling of piroplasms. PCR confirmed the morbidity rates 83.6% for theileriosis and 79.5% for babesiosis, respectively. Theileriosis was mostly found in Chattogram (89.47%), whereas babesiosis was predominantly recorded in Rajshahi and Mymensingh (90.9%) divisions. Mortality rates were 8.9% (32/360) for theileriosis and 9.16% (11/120) for babesiosis, with the highest in Mymensingh division, highlighting regional vulnerability. Mixed infection with Theileria and Babesia spp. was 18.18% of the positive cases, indicating the possible synergistic effects and clinical complexities. The common clinical signs of piroplasmosis were persistent fever, anemia, jaundice, with lymphadenopathy characteristic of theileriosis and pathognomonic hemoglobinuria for babesiosis. Hematology revealed the reduction of hemoglobin, packed cell volume, erythrocytes and platelet count, along with leukopenia. Seasonal variations, age, gender, breed, and tick infestation were identified as significant risk factors for occurrence of piroplasmosis. Phylogenetic analysis revealed that Theileria 18S rRNA clustered with T. orientalis from China and Babesia 18S rRNA with B. naoakii from Sri Lanka and Bangladesh. The phylogeny of spherical body protein (SBP4) gene was clustered with B. bovis reported from Tanzania. Future investigations into transmission dynamics, mixed infections and genetic diversity of parasites are recommended to strengthen effective control strategies.

Paroxysmal nocturnal hemoglobinuria (PNH) originates from hematopoietic stem cells (HSCs) harboring somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene. Clonal expansion of PIGA-mutated cells occurs uniquely in the setting of bone marrow (BM) failure, but specific pathophysiologic mechanisms remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of BM cells from patients with large (> 50%) and small (10-50%) PNH cell fractions. In patients with large PNH cell fractions, phenotypically normal hematopoietic stem and progenitor cells (HSPCs) upregulated immune response and apoptosis pathways and downregulated cell-cycling pathways compared with PNH-type HSPCs. BM effector cells upregulated immune response pathways, and cell-cell communication between effector cells and normal HSPCs was greater than in controls. In contrast, in patients with small PNH cell fractions, transcriptional changes in normal HSPCs were reversed: downregulation of immune response pathways and upregulation of the cell-cycling pathways. Notably, transcriptional differences associated with PNH cell fractions were primarily in normal HSCs, whereas PNH-type HSCs showed similar transcriptional profiles between patients with large and small PNH cell fractions. These results implicate immunological negative selection against normal HSCs in PNH. Error-corrected DNA sequencing of patients' blood samples identified multiple PIGA mutations in each patient, consistent with strong selection for the resulting phenotype.

Pegloticase is an effective therapy for refractory gout but carries a risk of oxidative hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Reported cases of hemolytic complications remain limited, particularly those with delayed presentation, where traditional markers such as haptoglobin and bilirubin may have normalized, making diagnosis challenging. We describe a 61-year-old female with known G6PD deficiency who presented with near syncope, nausea, vomiting, and volume depletion four days after receiving her first dose of intravenous pegloticase and recently starting mycophenolate. Initial evaluation revealed severe anemia (hemoglobin 5.1 g/dL) and acute kidney injury (creatinine 9.23 mg/dL). Hemolysis markers were not overtly diagnostic, with normal haptoglobin and bilirubin; however, urinalysis revealed heme-positive urine with no red blood cells, a finding highly suggestive of hemoglobinuria from recent intravascular hemolysis rather than true hematuria. An extensive workup for anemia and acute kidney injury was otherwise unrevealing. Given the temporal association with pegloticase exposure and underlying G6PD deficiency, oxidative hemolysis with concomitant prerenal acute kidney injury was suspected. The patient improved with discontinuation of the offending agents, blood transfusion, and supportive care, with stabilization of hemoglobin and gradual recovery of renal function. This case highlights the importance of recognizing delayed or atypical presentations of drug-induced hemolysis, in which traditional markers may be normal at the time of evaluation. Clinicians should maintain a high index of suspicion for hemolysis after pegloticase administration in G6PD-deficient patients and ensure appropriate screening prior to therapy.

We report two cases of aplastic anaemia (AA) with small populations of paroxysmal nocturnal haemoglobinuria (PNH)-phenotype cells that developed during osimertinib (OSIM) therapy for epidermal growth factor receptor mutation-positive lung adenocarcinoma (EGFR-LUAD). The first case was a 76-year-old woman with EGFR-LUAD accompanied by pleural dissemination. She developed pancytopenia 9 months after starting OSIM therapy. We diagnosed the patient with moderately severe AA and observed hematopoietic recovery following treatment with anabolic steroids and eltrombopag. The second case involved a 63-year-old woman diagnosed with EGFR-LUAD who received adjuvant chemotherapy with OSIM. She developed pancytopenia 6 months later and was diagnosed with non-severe AA. Cyclosporine and romiplostim treatment were effective, allowing for outpatient management. In the two cases described herein, a small number of PNH-phenotype cells were confirmed. The clinical importance of the small PNH-phenotype populations and the mechanism underlying AA during OSIM therapy remain unclear and warrant further investigation.

Understanding of the complement system in glomerulopathies has advanced significantly, revealing that this system-beyond its role in innate immunity-is a key mediator of kidney injury across a wide spectrum of nephropathies, from those driven by immune complexes to those caused by primary dysregulation of the alternative pathway. The introduction of complement inhibitors, such as C5 blockade with eculizumab, marked a milestone: in aHUS it significantly improved renal function and patient survival, and in paroxysmal nocturnal hemoglobinuria it reduced thrombotic complications, achieving survival rates comparable to the general population. These advances have spurred the extension of this approach to other nephropathies and the development of new anti-complement agents. However, the heterogeneity of complement dysregulation among glomerulopathies-and even among patients with the same disease-limits the application of a uniform therapeutic strategy. This scenario calls for a more precise characterization of the underlying pathophysiological mechanisms and the identification of critical points of intervention in each clinical context. Currently, inhibitors targeting both proximal and terminal steps of the cascade are being investigated to achieve more individualized therapies, although challenges remain, such as the lack of reliable biomarkers, uncertainty regarding optimal treatment duration, scarcity of disease-specific trials, high costs, and the integration of these agents with immunosuppressive regimens. The aim of this review is to analyze the role of the complement system in glomerulopathies and to summarize current and future therapeutic advances, with particular emphasis on the challenges and opportunities on the path toward more personalized medicine.