Subject(s)
Leukemia, Large Granular Lymphocytic , Humans , Leukemia, Large Granular Lymphocytic/complications , Leukemia, Large Granular Lymphocytic/pathology , Male , Anemia, Hemolytic/etiology , Anemia, Hemolytic/pathology , Anemia, Hemolytic/complications , Aged , Female , Middle Aged , Anemia/etiology , Anemia/complicationsABSTRACT
Infantile pyknocytosis (IP) is a rare, probably misestimated, cause of non-immune neonatal hemolytic anemia evolving in two phases: an initial phase with severe jaundice, followed by a second phase with hemolytic anemia, which may require neonatal intensive care. The diagnosis of IP is based on the transient presence on blood smear of hyperdense, contracted, and/or spiculated red blood cells (pyknocytes), associated with the spontaneous resolution of clinico-biological features and the exclusion of other causes. If the etiology remains undetermined, some contributing factors, such as oxidative stress, have been proposed. We report the description of 16 patients with IP aiming at clarifying the circumstances associated with the development of this acquired disorder. In the acute phase, the mean hemoglobin nadir and pyknocyte count were 7.8 g/dL and 11%, respectively, and strikingly, Heinz bodies were evident in 50% of the newborns, but in 100% after prolonged incubation (4 hours). A high proportion of Mediterranean or African ancestry was noted in newborns, as well as a significant number of peripartum events, such as respiratory distress. If the etiology of IP is certainly multifactorial, our series reinforces the role of oxidative stress, which may, at least in part, find origin in desaturation episodes in newborns.
Subject(s)
Heinz Bodies , Humans , Infant, Newborn , Female , Male , Cohort Studies , Anemia, Hemolytic/pathology , Anemia, Hemolytic/blood , Infant , Anemia, Neonatal/blood , Anemia, Neonatal/pathologyABSTRACT
We studied the effect of biogenic ferrihydrite nanoparticles synthesized as a result of the culturing of Klebsiella oxytoca on Wistar rats with experimental toxic hemolytic anemia. The pathology was simulated by single intraperitoneal injection of phenylhydrazine hydrochloride. On day 4, the functional parameters of erythrocytes in rats corresponded to the state of toxic hemolytic anemia. It is shown that ferrihydrite nanoparticles suspension has chronic toxicity and causes morphological changes in organs (mainly in the spleen), which are characterized by accumulation of nanoparticles. Administration of phenylhydrazine induced systemic vascular damage and the formation of extramedullary hematopoietic foci, which indicated a compensatory activation in hematopoiesis in the liver and spleen. Injection of nanoparticles reduced discirculatory and necrotic changes in the kidneys.
Subject(s)
Anemia, Hemolytic , Nanoparticles , Rats , Animals , Rats, Wistar , Anemia, Hemolytic/chemically induced , Anemia, Hemolytic/pathology , Models, TheoreticalABSTRACT
Hemolysis is a ubiquitous pathology defined as premature red blood cell destruction within the circulation or local tissues. One of the most archetypal functions of macrophages is phagocytosis of damaged or extravasated red blood cells, preventing the extracellular release of toxic hemoglobin and heme. Upon erythrophagocytosis, spiking intracellular heme concentrations drive macrophage transformation into erythrophagocytes, leveraging antioxidative and iron recycling capacities to defend against hemolytic stress. This unique phenotype transformation is coordinated by a regulatory network comprising the transcription factors BACH1, SPI-C, NRF2, and ATF1. Erythrophagocytes negatively regulate inflammation and immunity and may modulate disease-specific outcomes in hemolytic anemia, wound healing, atherosclerosis, and cancer. In this opinion article, we outline the known and presumed functions of erythrophagocytes and their implications for therapeutic innovation and research.
Subject(s)
Anemia, Hemolytic , Neoplasms , Humans , Anemia, Hemolytic/pathology , Phagocytosis , Heme , Hemolysis , Erythrocytes , Neoplasms/pathology , Wound HealingABSTRACT
At least 16 genetically determined conditions qualify as red blood cell enzymopathies. They range in frequency from ultrarare to rare, with the exception of glucose-6-phosphate dehydrogenase deficiency, which is very common. Nearly all these enzymopathies manifest as chronic hemolytic anemias, with an onset often in the neonatal period. The diagnosis can be quite easy, such as when a child presents with dark urine after eating fava beans, or it can be quite difficult, such as when an adult presents with mild anemia and gallstones. In general, 4 steps are recommended: (1) recognizing chronic hemolytic anemia; (2) excluding acquired causes; (3) excluding hemoglobinopathies and membranopathies; (4) pinpointing which red blood cell enzyme is deficient. Step 4 requires 1 or many enzyme assays; alternatively, DNA testing against an appropriate gene panel can combine steps 3 and 4. Most patients with a red blood cell enzymopathy can be managed by good supportive care, including blood transfusion, iron chelation when necessary, and splenectomy in selected cases; however, some patients have serious extraerythrocytic manifestations that are difficult to manage. In the absence of these, red blood cell enzymopathies are in principle amenable to hematopoietic stem cell transplantation and gene therapy/gene editing.
Subject(s)
Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/enzymology , Erythrocytes/enzymology , 5'-Nucleotidase/deficiency , Anemia, Hemolytic/pathology , Anemia, Hemolytic/therapy , Blood Transfusion , Child , Child, Preschool , Chronic Disease , Disease Management , Erythrocytes/pathology , Female , Glucosephosphate Dehydrogenase Deficiency/diagnosis , Glucosephosphate Dehydrogenase Deficiency/enzymology , Glucosephosphate Dehydrogenase Deficiency/pathology , Glucosephosphate Dehydrogenase Deficiency/therapy , Humans , Infant , MaleSubject(s)
Anemia, Hemolytic , Erythrocytes , Hemolysis , Acute Disease , Anemia, Hemolytic/chemically induced , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/pathology , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Clostridium Infections/drug therapy , Erythrocytes/drug effects , Erythrocytes/pathology , Female , Humans , Middle Aged , Sepsis/drug therapyABSTRACT
Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.
Subject(s)
Acute Kidney Injury/prevention & control , Anemia, Hemolytic/prevention & control , Bacillus anthracis/chemistry , Cell Wall/chemistry , Complement C5/antagonists & inhibitors , Peptidoglycan/toxicity , Sepsis/complications , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Anemia, Hemolytic/etiology , Anemia, Hemolytic/pathology , Animals , Anthrax/microbiology , Anthrax/pathology , Female , Hemolysis , Male , Papio , Sepsis/chemically inducedABSTRACT
Mutations in the KLF1 gene, which encodes a transcription factor playing a role in erythropoiesis, have recently been demonstrated to be a rare cause of hereditary haemolytic anaemia. We described the genotypic and phenotypic spectra of four unrelated families with compound heterozygous class 2/class 3 KLF1 mutations. All patients had p.G176RfsX179 on one allele and either p.A298P, p.R301H or p.G335R on the other allele. All presented on the first day of life with severe haemolytic anaemia with abnormal red blood cell morphology, markedly increased nucleated red blood cells and hyperbilirubinaemia. Three patients later became transfusion-dependent. All parents with heterozygous KLF1 mutation without co-inherited thalassaemia had normal to borderline mean corpuscular volume (MCV) and normal to slightly elevated Hb F. Fifteen previously reported cases of biallelic KLF1 mutations were identified from a literature review. All except one presented with severe haemolytic anaemia in the neonatal period. Our finding substantiates that compound heterozygous KLF1 mutations are associated with severe neonatal haemolytic anaemia and expands the haematologic phenotypic spectrum. In carriers, the previously suggested findings of low MCV, high Hb A2 and high Hb F are inconsistent; thus this necessitates molecular studies for the identification of carriers.
Subject(s)
Anemia, Hemolytic/genetics , Kruppel-Like Transcription Factors/genetics , Point Mutation , Adolescent , Adult , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/pathology , Child , Child, Preschool , Female , Heterozygote , Humans , Infant , Infant, Newborn , Male , Mutation , Pedigree , Young AdultABSTRACT
Microparticles or microvesicles (MPs/MVs) are sub-cellular vesicles with a growing number of known biological functions. Microvesicles from a variety of parent cells within the vascular system increase in numerous pathological states. Red blood cell-derived MVs (RMVs) are relatively less studied than other types of circulating MVs despite red blood cells (RBCs) being the most abundant intravascular cell. This may be in part due the echoes of past misconceptions that RBCs were merely floating anucleate bags of hemoglobin rather than dynamic and responsive cells. The initial aim of this study was to maximize the concentration of RMVs derived from various blood or blood products by focusing on the optimal isolation conditions without creating more MVs from artificial manipulation. We found that allowing RBCs to sediment overnight resulted in a continuum in size of RBC membrane-containing fragments or vesicles extending beyond the 1 µm size limit suggested by many as the maximal size of an MV. Additionally, dilution and centrifugation factors were studied that altered the resultant MV population concentration. The heterogeneous size of RMVs was confirmed in mice models of hemolytic anemia. This methodological finding establishes a new paradigm in that it blurs the line between RBC, fragment, and RMV as well as suggests that the concentration of circulating RMVs may be widely underestimated given that centrifugation removes the majority of such RBC-derived membrane-containing particles.
Subject(s)
Anemia, Hemolytic/blood , Cell-Derived Microparticles/genetics , Centrifugation , Erythrocytes/cytology , Anemia, Hemolytic/genetics , Anemia, Hemolytic/pathology , Animals , Cell Lineage/genetics , Erythrocyte Count , Hemoglobins/genetics , Humans , MiceABSTRACT
INTRODUCTION: Over the past decade, Miracle Mineral Solution (sodium chlorite) has been promoted as a cure-all for many conditions. CASE REPORT: A 9-year-old boy presented with his brother after they accidentally ingested a small amount of undiluted 22.4% sodium chlorite. Symptoms included nausea, vomiting, diarrhea, and dyspnea. Oxygen saturation remained 71% despite supplemental oxygen (15L/min). The patient was noted to have dark chocolate-appearing blood, minimal urine output, diffuse pallor and cyanosis. He developed methemoglobinemia, renal failure requiring renal replacement therapy and hemolysis requiring blood transfusion. DISCUSSION: These are the 7th and 8th reported cases of sodium chlorite toxicity by ingestion and the second and third in children. Takeaway for Physicians: Miracle Mineral Solution is a commonly purchased potentially lethal compound that can cause methemoglobinemia with respiratory failure, hemolytic anemia requiring transfusion and renal failure requiring dialysis.
Subject(s)
Anemia, Hemolytic/chemically induced , Chlorides/toxicity , Methemoglobinemia/chemically induced , Renal Insufficiency/chemically induced , Anemia, Hemolytic/pathology , Anemia, Hemolytic/therapy , Blood Transfusion , Child , Hemolysis/drug effects , Humans , Male , Methemoglobinemia/pathology , Methemoglobinemia/therapy , Renal Dialysis , Renal Insufficiency/pathology , Renal Insufficiency/therapy , Siblings , Treatment OutcomeABSTRACT
Hereditary pyropoikilocytosis is a subtype of hereditary elliptocytosis because of biallelic mutations of SPTA1, SPTB, and EPB41. The authors present a proband with neonatal jaundice and hemolytic anemia, with poikilocytosis in the blood film. Targeted next-generation sequencing identified Q267del trans to the αLELY allele in SPTA1. In addition, the proband presented coexisting Gilbert syndrome as determined by homozygous mutation of UGT1A1. Investigation of 13 relatives and his sibling revealed that only his sibling showed the same phenotype and genotype as the proband. This is the first report of molecular confirmation of coexisting hereditary pyropoikilocytosis and Gilbert syndrome and a novel mutation in SPTA1.
Subject(s)
Anemia, Hemolytic/pathology , Elliptocytosis, Hereditary/complications , Gilbert Disease/complications , Jaundice, Neonatal/pathology , Mutation , Spectrin/genetics , Anemia, Hemolytic/etiology , Child, Preschool , Female , High-Throughput Nucleotide Sequencing , Humans , Infant , Infant, Newborn , Jaundice, Neonatal/etiology , Male , Pedigree , Phenotype , PrognosisABSTRACT
BACKGROUND: Rheumatic diseases have many hematological manifestations. Blood dyscrasias and other hematological abnormalities are sometimes the first sign of rheumatic disease. In addition, novel antirheumatic biological agents may cause cytopenias. SUMMARY: The aim of this review was to discuss cytopenias caused by systemic lupus erythematosus and antirheumatic drugs, Felty's syndrome in rheumatoid arthritis, and autoimmune hemolytic anemia, thrombosis, and thrombotic microangiopathies related to rheumatological conditions such as catastrophic antiphospholipid syndrome and scleroderma renal crisis. Key Message: The differential diagnosis of various hematological disorders should include rheumatic autoimmune diseases among other causes of blood cell and hemostasis abnormalities. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner.
Subject(s)
Antirheumatic Agents/therapeutic use , Hematologic Diseases/pathology , Rheumatic Diseases/drug therapy , Anemia, Hemolytic/complications , Anemia, Hemolytic/drug therapy , Anemia, Hemolytic/pathology , Felty Syndrome/complications , Felty Syndrome/drug therapy , Felty Syndrome/pathology , Glucocorticoids/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematologic Diseases/complications , Hematologic Diseases/drug therapy , Leukopenia/complications , Leukopenia/drug therapy , Leukopenia/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/pathology , Protein Kinase Inhibitors/therapeutic use , Rheumatic Diseases/complications , Rheumatic Diseases/diagnosisABSTRACT
Patients with hereditary or acquired hemolytic anemias have a high risk of developing in situ thrombosis of the pulmonary vasculature. While pulmonary thrombosis is a major morbidity associated with hemolytic disorders, the etiological mechanism underlying hemolysis-induced pulmonary thrombosis remains largely unknown. Here, we use intravital lung microscopy in mice to assess the pathogenesis of pulmonary thrombosis following deionized water-induced acute intravascular hemolysis. Acute hemolysis triggered the development of αIIbß3-dependent platelet-rich thrombi in precapillary pulmonary arterioles, which led to the transient impairment of pulmonary blood flow. The hemolysis-induced pulmonary thrombosis was phenocopied with intravascular ADP- but not thrombin-triggered pulmonary thrombosis. Consistent with a mechanism involving ADP release from hemolyzing erythrocytes, the inhibition of platelet P2Y12 purinergic receptor signaling attenuated pulmonary thrombosis and rescued blood flow in the pulmonary arterioles of mice following intravascular hemolysis. These findings are the first in vivo studies to our knowledge to suggest that acute intravascular hemolysis promotes ADP-dependent platelet activation, leading to thrombosis in the precapillary pulmonary arterioles, and that thrombin generation most likely does not play a significant role in the pathogenesis of acute hemolysis-triggered pulmonary thrombosis.
Subject(s)
Anemia, Hemolytic/genetics , Hemolysis/genetics , Pulmonary Artery/metabolism , Receptors, Purinergic P2Y12/genetics , Thrombosis/genetics , Adenosine Diphosphate/metabolism , Anemia, Hemolytic/metabolism , Anemia, Hemolytic/pathology , Animals , Arterioles/metabolism , Arterioles/pathology , Blood Coagulation/genetics , Blood Platelets/metabolism , Humans , Lung/metabolism , Lung/pathology , Mice , Pulmonary Artery/pathology , Thrombin/genetics , Thrombin/metabolism , Thrombosis/metabolism , Thrombosis/pathologySubject(s)
Anemia, Hemolytic , Erythrocytes, Abnormal , Erythropoiesis , Myelodysplastic Syndromes , Purpura, Thrombotic Thrombocytopenic , Aged , Anemia, Hemolytic/blood , Anemia, Hemolytic/pathology , Erythrocytes, Abnormal/metabolism , Erythrocytes, Abnormal/pathology , Humans , Male , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/pathology , Purpura, Thrombotic Thrombocytopenic/blood , Purpura, Thrombotic Thrombocytopenic/pathologySubject(s)
Anemia, Hemolytic/pathology , Erythrocytes/pathology , Glucosephosphate Dehydrogenase Deficiency/pathology , Glucosephosphate Dehydrogenase/genetics , Protein Isoforms/genetics , Anemia, Hemolytic/genetics , Chronic Disease , Erythrocytes/metabolism , Glucosephosphate Dehydrogenase Deficiency/genetics , Humans , Infant , MaleSubject(s)
Anemia, Hemolytic/diagnosis , Hemangioma/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Aged, 80 and over , Anemia, Hemolytic/blood , Anemia, Hemolytic/etiology , Anemia, Hemolytic/pathology , Atrial Fibrillation/complications , Coronary Artery Disease/complications , Heart Failure/complications , Hemangioma/blood , Hemangioma/complications , Humans , Hypertension, Pulmonary/complications , Liver Neoplasms/blood , Liver Neoplasms/complications , Magnetic Resonance Imaging , Male , Pulmonary Disease, Chronic Obstructive/complications , UltrasonographyABSTRACT
Two domestic shorthair cats were presented with anorexia and dehydration following ingestion of caramelized onions. Shared key findings from a CBC (ADVIA 2120), serum biochemistry, and urinalysis included a spurious, marked leukocytosis with discordant basophil (BASO) channel and peroxidase channel WBC counts, normal manual leukocyte counts, mild, non-regenerative anemia with discrepancies between automated and manual reticulocyte counts, an abundance of large Heinz bodies (HBs), and highly irregular scattergrams. Case 1 also demonstrated a markedly elevated mean corpuscular hemoglobin concentration (MCHC) and discrepancies between RBC hemoglobin indices. Spurious leukocyte results were confirmed through re-analysis of samples (including the acquisition of a new sample, use of an alternate analyzer (Sysmex XT-2000iV; Case 1 only), and evaluation of scattergrams and blood films (Cases 1 and 2). Repeatedly discrepant reticulocyte counts were also identified. In both cases, the erroneous BASO WBC counts, discrepancies in reticulocyte counts and RBC indices, and atypical scattergrams were interpreted to result from various effects of the HBs. These cases emphasize the importance of reviewing blood films, interpreting scattergrams, and the usefulness of duplicate methods for determining various measurands on hematology analyzers.
Subject(s)
Anemia, Hemolytic/veterinary , Cat Diseases/diagnosis , Leukocytosis/veterinary , Anemia, Hemolytic/blood , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/pathology , Animals , Basophils/pathology , Cat Diseases/blood , Cat Diseases/pathology , Cats , Female , Heinz Bodies/pathology , Hematology/instrumentation , Hemolysis , Leukocyte Count/veterinary , Leukocytosis/blood , Leukocytosis/diagnosis , Leukocytosis/pathology , Male , Oxidative Stress , Reticulocyte Count/veterinary , Urinalysis/veterinaryABSTRACT
Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress erythropoiesis responses to acute hemolytic anemia were normal. TGF-ß potently inhibits stromal CXCL12 expression in vitro; however, G-CSF induced decreases in bone marrow CXCL12 expression and subsequent hematopoietic stem/progenitor cell mobilization were normal in Osx-Cre, Tgfbr2fl/fl mice, in which all TGF-ß signaling in mesenchymal stromal is lost. Finally, although a prior study showed that TGF-ß enhances recovery from myeloablative therapy, hematopoietic recovery following single or multiple doses of 5-flurauracil were normal in Osx-Cre, Tgfbr2fl/fl mice. Collectively, these data suggest that TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions.
Subject(s)
Anemia, Hemolytic/metabolism , Erythropoiesis , Hematopoietic Stem Cells , Mesenchymal Stem Cells , Transforming Growth Factor beta/physiology , Transforming Growth Factors/physiology , Acute Disease , Anemia, Hemolytic/pathology , Animals , Bone Marrow/metabolism , Bone Marrow/pathology , Cells, Cultured , Chemokine CXCL12/metabolism , Female , Granulocyte Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/pathology , Male , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/pathology , Mice , Mice, Inbred C57BL , Stem Cell NicheABSTRACT
The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.