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Blood Sep 2020Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis... (Review)
Review
Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
Topics: Adolescent; Adult; Anemia, Hemolytic, Congenital Nonspherocytic; Blood Transfusion; Chelation Therapy; Child; Child, Preschool; Cholelithiasis; Clinical Trials as Topic; Disease Management; Female; Fetal Diseases; Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Iron Chelating Agents; Iron Overload; Jaundice, Neonatal; Male; Mutation; Pregnancy; Prevalence; Pyruvate Kinase; Pyruvate Metabolism, Inborn Errors; Splenectomy; Splenomegaly
PubMed: 32702739
DOI: 10.1182/blood.2019000945 -
American Journal of Hematology Jul 2012The direct antiglobulin test (DAT) is a laboratory test that detects immunoglobulin and/or complement on the surface of red blood cells. The utility of the DAT is to... (Review)
Review
The direct antiglobulin test (DAT) is a laboratory test that detects immunoglobulin and/or complement on the surface of red blood cells. The utility of the DAT is to sort hemolysis into an immune or nonimmune etiology. As with all tests, DAT results must be viewed in light of clinical and other laboratory data. This review highlights the most common clinical situations where the DAT can help classify causes of hemolysis, including autoimmune hemolytic anemia, transfusion-related hemolysis, hemolytic disease of the fetus/newborn, drug-induced hemolytic anemia, passenger lymphocyte syndrome, and DAT-negative hemolytic anemia. In addition, the pitfalls and limitations of the test are addressed. False reactions may occur with improper technique, including improper washing, centrifugation, and specimen agitation at the time of result interpretation. Patient factors, such as spontaneous red blood cell agglutination, may also contribute to false results.
Topics: Adult; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Anemia, Hemolytic, Congenital; Blood Group Incompatibility; Coombs Test; Hemolysis; Humans; Infant, Newborn
PubMed: 22566278
DOI: 10.1002/ajh.23218 -
Chirurgia (Bucharest, Romania : 1990) 2017Hereditary spherocytosis (HS) is a disease affecting the red blood cells membrane and belongs to the congenital hemolytic anemias. The clinical spectrum ranges from... (Review)
Review
Hereditary spherocytosis (HS) is a disease affecting the red blood cells membrane and belongs to the congenital hemolytic anemias. The clinical spectrum ranges from asymptomatic patients to severe forms requiring transfusions in early childhood. The diagnosis can be based on the physical examination, complete red blood cell count, reticulocytes count, medical history and specific tests, preferentially the EMA test (eosin-5-maleimide binding) test and AGLT (Acidified Glycerol Lysis Time). Splenectomy is considered the standard surgical treatment in moderate and severe forms of hereditary spherocytosis. Total splenectomy exposes the patient to a life - long risk of potentially lethal infections and thus, its usage was reconsidered. Because of this reason, a feasible alternative is the partial splenectomy. The use of partial splenectomy aims to retain splenic immunologic function, while at the same time to decrease the rate of hemolysis. The long - term outcomes of patients with total or subtotal splenectomy for congenital hemolytic anemia, still remain unclear, but the majority of the studies showed a qualitative resolution of anemia and reduction of transfusion rate. Despite the well known advantages of conservative surgery, the optimal choice of treatment and outcomes should be confirmed with the patient.
Topics: Erythrocyte Count; Erythrocyte Membrane; Evidence-Based Medicine; Hematologic Tests; Hemolysis; Humans; Reticulocytes; Spherocytes; Spherocytosis, Hereditary; Splenectomy; Treatment Outcome
PubMed: 28463670
DOI: 10.21614/chirurgia.112.2.110 -
Haematologica Aug 2017Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital...
Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.
Topics: Anemia, Hemolytic, Congenital; Guidelines as Topic; Humans; Splenectomy; Thrombosis
PubMed: 28550188
DOI: 10.3324/haematol.2016.161166 -
Nefrologia 2023
Topics: Adolescent; Humans; Nephritis, Hereditary; Anemia, Hemolytic, Congenital
PubMed: 36997470
DOI: 10.1016/j.nefroe.2023.03.005 -
Trends in Molecular Medicine May 2023Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for... (Review)
Review
Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.
Topics: Adult; Humans; Pyruvate Kinase; Quality of Life; Anemia, Hemolytic, Congenital Nonspherocytic; Pyruvate Metabolism, Inborn Errors
PubMed: 36935283
DOI: 10.1016/j.molmed.2023.02.005 -
Blood Jan 2023Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of...
Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout, and expression studies in an erythroblast cell line. We report the molecular bases of 5 Er blood group antigens: the recognized Era, Erb, and Er3 antigens and 2 novel high-incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn. Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low-abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.
Topics: Infant, Newborn; Humans; Mutation, Missense; Anemia, Hemolytic, Congenital; Erythrocytes; Ion Channels; Blood Group Antigens; Mechanotransduction, Cellular
PubMed: 36122374
DOI: 10.1182/blood.2022016504 -
Haematologica Sep 2020Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an... (Review)
Review
Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.
Topics: Anemia, Hemolytic, Congenital; Anemia, Hemolytic, Congenital Nonspherocytic; Humans; Mutation; Pyruvate Kinase; Pyruvate Metabolism, Inborn Errors
PubMed: 33054047
DOI: 10.3324/haematol.2019.241141 -
Tidsskrift For Den Norske Laegeforening... Mar 2024Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose.
BACKGROUND
Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose.
CASE PRESENTATION
A toddler presented with severe anemia with normal red cell indices and a low reticulocyte count. The remaining hematological parameters were normal, bar a slight thrombocytosis. At this point a diagnosis of transient erythroblastopenia of childhood (TEC) was made. The child continued to have slight anemia with intermittent macrocytosis and reticulocytopenia throughout childhood. Growth and development was normal, and there were no signs of congenital abnormalities in the heart or kidneys nor any craniofacial or phalangeal defects. Repeated bone marrow examinations showed no significant abnormal findings. As a teenager the patient was diagnosed with Diamond-Blackfan anemia through an exome-based gene panel which revealed a mutation in the RPL11 gene.
INTERPRETATION
Congenital bone marrow failure syndromes do not always present in the classical way, leading to a delayed diagnosis. The increasing availability of different gene panels for patients with persistent abnormal hematological laboratory parameters offers the possibility of a more accurate diagnostic pathway, which is important for adequate follow-up and genetic counselling.
Topics: Adolescent; Humans; Anemia; Anemia, Diamond-Blackfan; Anemia, Hemolytic, Congenital; Mutation
PubMed: 38506013
DOI: 10.4045/tidsskr.23.0415 -
Birth Defects Research May 2022Hereditary hemolytic anemia (HHA) results from genetic mutations that cause red blood cell abnormalities. Little research exists on the relationship between HHA and...
OBJECTIVES
Hereditary hemolytic anemia (HHA) results from genetic mutations that cause red blood cell abnormalities. Little research exists on the relationship between HHA and birth defects. Using data from the National Birth Defects Prevention Study (NBDPS), we described characteristics of HHA-exposed women and estimated associations between HHA during pregnancy and specific birth defects.
METHODS
The NBDPS was a population-based, case-control study of major birth defects and included pregnancies with estimated delivery dates from October 1997 through December 2011. Participants were ascertained from hospital discharge lists or birth defect registries at 10 sites. Trained interviewers collected information about pregnancy exposures via telephone questionnaire. We described characteristics among HHA-exposed women and calculated crude odds ratios and exact 95% confidence intervals for defects with ≥3 exposed cases.
RESULTS
Among 31 HHA-exposed women (28 cases/3 controls), 13 (42%) reported sickle cell anemia, 17 (55%) reported thalassemia, and one (3%) reported hereditary spherocytosis. The average age at delivery for HHA-exposed case women was 27.3 years (range: 17-38). The majority (82%) of HHA-exposed case women reported additional conditions during pregnancy, including hypertension, genitourinary infections, and respiratory illnesses. Additionally, 93% of case women reported using medication during pregnancy. Among the 28 cases, 18 (64%) had isolated birth defects. The defects with ≥3 exposed cases were anencephaly, atrial septal defect, gastroschisis, and cleft palate. Except for anencephaly, the 95% confidence intervals for all estimates were close to or included the null.
CONCLUSION
This hypothesis-generating study adds to the sparse literature on the association between HHA and birth defects.
Topics: Anemia, Hemolytic, Congenital; Anencephaly; Case-Control Studies; Female; Gastroschisis; Humans; Odds Ratio; Pregnancy
PubMed: 35247031
DOI: 10.1002/bdr2.2000