Hereditary Spherocytosis

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Hereditary Spherocytosis o RBC band 3 protein testing is a very sensitive and Indications for Ordering specific test for the diagnosis of hereditary Use to confirm diagnosis of hereditary spherocytosis when spherocytosis hemolytic anemia and spherocytes are present Physiology • RBC band 3 protein is a major structural protein of RBCs Test Description o Reduction in the amount of band 3 fluorescence after Test Methodology binding with EMA correlates with spherocytosis • Red blood cell (RBC) surface protein band 3 staining with Genetics eosin-5-maleimide (EMA) analyzed by flow cytometry Clinical Validation Genes: ANK1, EPB42, SLC4A1, SPTA1, SPTB • Validated against the clinical diagnosis of hereditary Inheritance spherocytosis supported by osmotic fragility and/or • Autosomal dominant: 75% molecular testing • Autosomal recessive: 25% Tests to Consider Penetrance: variable Structure/Function Primary Test • Chromosomal location: 17q21.31 RBC Band 3 Protein Reduction in Hereditary Spherocytosis • Provides structure for the red cell cytoskeleton 2008460 • Use to confirm diagnosis of hereditary spherocytosis Test Interpretation when hemolytic anemia and spherocytes are present Sensitivity/Specificity Related Test • Clinical sensitivity: 93% Osmotic Fragility, Erythrocyte 2002257 • Analytical sensitivity/specificity: unknown • Functional testing of RBC sensitivity to osmotic stress Results Disease Overview • Normal o Normal staining of band 3 protein with EMA does not Prevalence: 1/2,000 in northern Europeans suggest hereditary spherocytosis Symptoms • Abnormal • Hemolytic anemia o Decreased staining of band 3 protein with EMA provides o Pallor evidence for hereditary spherocytosis o Fatigue o Three rare disorders may be associated with a positive o Jaundice result for this test o Splenomegaly ▪ Congenital dyserythropoietic anemia type 2 • Kernicterus ▪ Southeast Asian ovalocytosis • Pigmented gallstones ▪ Hereditary pyropoikilocytosis • Equivocal Diagnostic Issues o Unclear whether the level of band 3 protein staining is • Depending on severity of symptoms, diagnosis of normal hereditary spherocytosis can rule out other causes of o Insufficient evidence to support or negate a diagnosis of hemolytic anemia hereditary spherocytosis o Examination of a peripheral blood smear is a quick and easy initial screen Limitations o Osmotic fragility can confirm compromised integrity to Not typically used as a screening test, but has been proposed osmotic stress as a screening test by many authorities ARUP Laboratories is a nonprofit enterprise of the University of Utah and its Department of Pathology. 500 Chipeta Way, Salt Lake City, UT 84108 | (800) 522-2787 | (801) 583-2787 | www.aruplab.com | www.arupconsult.com © 2021 ARUP LABORATORIES | Last Update: April 2021 .

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Molecular Basis of Spectrin Deficiency in Beta Spectrin Durham. a Deletion
Molecular basis of spectrin deficiency in beta spectrin Durham. A deletion within beta spectrin adjacent to the ankyrin-binding site precludes spectrin attachment to the membrane in hereditary spherocytosis. H Hassoun, … , S S Chiou, J Palek J Clin Invest. 1995;96(6):2623-2629. https://doi.org/10.1172/JCI118327. Research Article We describe a spectrin variant characterized by a truncated beta chain and associated with hereditary spherocytosis. The clinical phenotype consists of a moderate hemolytic anemia with striking spherocytosis and mild spiculation of the red cells. We describe the biochemical characteristics of this truncated protein which constitutes only 10% of the total beta spectrin present on the membrane, resulting in spectrin deficiency. Analysis of reticulocyte cDNA revealed the deletion of exons 22 and 23. We show, using Southern blot analysis, that this truncation results from a 4.6-kb genomic deletion. To elucidate the basis for the decreased amount of the truncated protein on the membrane and the overall spectrin deficiency, we show that (a) the mutated gene is efficiently transcribed and its mRNA abundant in reticulocytes, (b) the mutant protein is normally synthesized in erythroid progenitor cells, (c) the stability of the mutant protein in the cytoplasm of erythroblasts parallels that of the normal beta spectrin, and (d) the abnormal protein is inefficiently incorporated into the membrane of erythroblasts. We conclude that the truncation within the beta spectrin leads to inefficient incorporation of the mutant protein into the skeleton despite its normal synthesis and stability. We postulate that this misincorporation results from conformational changes of the beta spectrin subunit affecting the binding of the abnormal heterodimer to ankyrin, and we provide evidence […] Find the latest version: https://jci.me/118327/pdf Molecular Basis of Spectrin Deficiency in p8 Spectrin Durham A Deletion within .3 Spectrin Adjacent to the Ankyrin-binding Site Precludes Spectrin Attachment to the Membrane in Hereditary Spherocytosis Hani Hassoun,* John N.
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Erythrocytes: Overview, Morphology, Quantity by AH Rebar Et
In: A Guide to Hematology in Dogs and Cats, Rebar A.H., MacWilliams P.S., Feldman B.F., Metzger F.L., Pollock R.V.H. and Roche J. (Eds.). Publisher: Teton NewMedia, Jackson WY (www.veterinarywire.com). Internet Publisher: International Veterinary Information Service, Ithaca NY (www.ivis.org), 8-Feb-2005; A3304.0205 Erythrocytes: Overview, Morphology, Quantity A.H. Rebar1, P.S. MacWilliams2, B.F. Feldman 3, F.L. Metzger 4, R.V.H. Pollock 5 and J. Roche 6 1Dept of Veterinary Pathobiology, School of Veterinary Medicine, Purdue University, IN,USA. 2Dept of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, WI, USA. 3Dept of Biomedical Sciences & Pathobiology, VA-MD - Regional College of Veterinary Medicine, Virginia Tech, VA, USA. 4Metzger Animal Hospital,State College,PA, USA. 5Fort Hill Company, Montchanin, DE, USA. 6 Hematology Systems, IDEXX Laboratories, Westbrook, ME, USA. Overview Production Red blood cells (RBC) are produced in the bone marrow. Numbers of circulating RBCs are affected by changes in plasma volume, rate of RBC destruction or loss, splenic contraction, erythropoietin (EPO) secretion, and the rate of bone marrow production. A normal PCV is maintained by an endocrine loop that involves generation and release of erythropoietin (EPO) from the kidney in response to renal hypoxia. Erythropoietin stimulates platelet production as well as red cell production. However, erythropoietin does not stimulate white blood cell (WBC) production. Erythropoiesis and RBC numbers are also affected by hormones from the adrenal cortex, thyroid, ovary, testis, and anterior pituitary. Destruction Red cells have a finite circulating lifespan. In dogs, the average normal red cell circulates approximately 100 days.
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Hereditary Spherocytosis: Clinical Features
Title Overview: Hereditary Hematological Disorders of red cell shape. Disorders Red cell Enzyme disorders Disorders of Hemoglobin Inherited bleeding disorders- platelet disorders, coagulation factor Anthea Greenway MBBS FRACP FRCPA Visiting Associate deficiencies Division of Pediatric Hematology-Oncology Duke University Health Service Inherited Thrombophilia Hereditary Disorders of red cell Disorders of red cell shape (cytoskeleton): cytoskeleton: • Mutations of 5 proteins connect cytoskeleton of red cell to red cell membrane • Hereditary Spherocytosis- sphere – Spectrin (composed of alpha, beta heterodimers) –Ankyrin • Hereditary Elliptocytosis-ellipse, elongated forms – Pallidin (band 4.2) – Band 4.1 (protein 4.1) • Hereditary Pyropoikilocytosis-bizarre red cell forms – Band 3 protein (the anion exchanger, AE1) – RhAG (the Rh-associated glycoprotein) Normal red blood cell- discoid, with membrane flexibility Hereditary Spherocytosis: Clinical features: • Most common hereditary hemolytic disorder (red cell • Neonatal jaundice- severe (phototherapy), +/- anaemia membrane) • Hemolytic anemia- moderate in 60-75% cases • Mutations of one of 5 genes (chromosome 8) for • Severe hemolytic anaemia in 5% (AR, parents ASx) cytoskeletal proteins, overall effect is spectrin • fatigue, jaundice, dark urine deficiency, severity dependant on spectrin deficiency • SplenomegalSplenomegaly • 200-300:million births, most common in Northern • Chronic complications- growth impairment, gallstones European countries • Often follows clinical course of affected
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MICHIGAN BIRTH DEFECTS REGISTRY Cytogenetics Laboratory Reporting Instructions 2002
MICHIGAN BIRTH DEFECTS REGISTRY Cytogenetics Laboratory Reporting Instructions 2002 Michigan Department of Community Health Community Public Health Agency and Center for Health Statistics 3423 N. Martin Luther King Jr. Blvd. P. O. Box 30691 Lansing, Michigan 48909 Michigan Department of Community Health James K. Haveman, Jr., Director B-274a (March, 2002) Authority: P.A. 236 of 1988 BIRTH DEFECTS REGISTRY MICHIGAN DEPARTMENT OF COMMUNITY HEALTH BIRTH DEFECTS REGISTRY STAFF The Michigan Birth Defects Registry staff prepared this manual to provide the information needed to submit reports. The manual contains copies of the legislation mandating the Registry, the Rules for reporting birth defects, information about reportable and non reportable birth defects, and methods of reporting. Changes in the manual will be sent to each hospital contact to assist in complete and accurate reporting. We are interested in your comments about the manual and any suggestions about information you would like to receive. The Michigan Birth Defects Registry is located in the Office of the State Registrar and Division of Health Statistics. Registry staff can be reached at the following address: Michigan Birth Defects Registry 3423 N. Martin Luther King Jr. Blvd. P.O. Box 30691 Lansing MI 48909 Telephone number (517) 335-8678 FAX (517) 335-9513 FOR ASSISTANCE WITH SPECIFIC QUESTIONS PLEASE CONTACT Glenn E. Copeland (517) 335-8677 Cytogenetics Laboratory Reporting Instructions I. INTRODUCTION This manual provides detailed instructions on the proper reporting of diagnosed birth defects by cytogenetics laboratories. A report is required from cytogenetics laboratories whenever a reportable condition is diagnosed for patients under the age of two years.
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Genetic Disorder
Genetic disorder Single gene disorder Prevalence of some single gene disorders[citation needed] A single gene disorder is the result of a single mutated gene. Disorder Prevalence (approximate) There are estimated to be over 4000 human diseases caused Autosomal dominant by single gene defects. Single gene disorders can be passed Familial hypercholesterolemia 1 in 500 on to subsequent generations in several ways. Genomic Polycystic kidney disease 1 in 1250 imprinting and uniparental disomy, however, may affect Hereditary spherocytosis 1 in 5,000 inheritance patterns. The divisions between recessive [2] Marfan syndrome 1 in 4,000 and dominant types are not "hard and fast" although the [3] Huntington disease 1 in 15,000 divisions between autosomal and X-linked types are (since Autosomal recessive the latter types are distinguished purely based on 1 in 625 the chromosomal location of Sickle cell anemia the gene). For example, (African Americans) achondroplasia is typically 1 in 2,000 considered a dominant Cystic fibrosis disorder, but children with two (Caucasians) genes for achondroplasia have a severe skeletal disorder that 1 in 3,000 Tay-Sachs disease achondroplasics could be (American Jews) viewed as carriers of. Sickle- cell anemia is also considered a Phenylketonuria 1 in 12,000 recessive condition, but heterozygous carriers have Mucopolysaccharidoses 1 in 25,000 increased immunity to malaria in early childhood, which could Glycogen storage diseases 1 in 50,000 be described as a related [citation needed] dominant condition. Galactosemia
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Hereditary Spherocytosis (HS)
Hereditary Spherocytosis (HS) Hereditary spherocytosis (HS) is a medical term for a condition What are the symptoms of HS? which affects the red blood cells. Symptoms of HS are due to 2 processes: hemolysis and anemia. What are red blood cells? When red blood cells break down (hemolysis), they release biliruin Blood contains 3 types of cells: red blood cells (RBC), white blood into the bloodstream, which causes yellowing of the skin (jaundice) cells (WBC), and platelets. Red blood cells are the most common and eyes. Hemolysis causes different problems depending on the type of blood cell, and are responsible for delivering oxygen to all age: parts of the body. • Newborns – may need light therapy or further measures Red blood cells, like white cells and platelets, are continuously made • Children – increasing size of the spleen in the bone marrow. When released into the bloodstream, the average lifespan of a red cell is 120 days. • Teens/adults – gallstones that may require surgery Under the microscope, normal red cells are shaped like discs or If enough red cells are destroyed, the red cell count will be low donuts with the centers partially scooped out. This shape makes (anemia). Symptoms of anemia include looking pale, being tired or them very soft and flexible, so they can easily squeeze through even weak, headaches, poor concentration, and challenges with behavior very small blood vessels. and school. Sometimes there is a problem with the wall of the red cell, and they How is HS treated? change shape to look like spheres or balls. These cells are called ‘spherocytes’.
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Hemolytic Anemia (Aiha) Clinical Hemolysis Indicators
October 15, 2013 GME Morning report Harmesh Naik, MD. AUTO IMMUNE HEMOLYTIC ANEMIA (AIHA) CLINICAL HEMOLYSIS INDICATORS Anemia High reticulocyte counts Elevated LDH level Unconjugated (indirect) hyper bilirubinemia Reduced haptoglobin level Hemoglobinuria COMPARISON Autoimmune hemolytic anemia Hereditary spherocytosis Hemolysis Hemolysis Spherocytes Spherocytes Splenomegaly Splenomegaly DAT positive DAT negative No Family history Family history TYPE OF ANTIBODY Auto antibody – generally seen in AIHA- detected generally by DAT Allo antibody – generally seen after transfusion of donor RBCs containing antigen – detected generally by IAT ANTI GLOBULIN TEST (COOMB’S TEST) Developed by Coombs in 1945 THE DIRECT ANTIGLOBULIN TEST (DAT) AND INDIRECT ANTIGLOBULIN TEST (IAT). Zarandona J M , and Yazer M H CMAJ 2006;174:305-307 DIRECT COOMB’S TEST (DAT) Detects IgG or complement coating on surface of circulating RBCs Detects In Vivo sensitization of RBCs Useful in differentiating immune mediated hemolysis Generally detects auto-antibodies in AIHA DIRECT COOMB’S TEST (DAT) Auto antibodies in AIHA are generally IgG antibodies with high affinity for human RBCs at 37*C 9body temperature) As a result most of antibody is bound to RBCs and very little is free in plasma So DAT can find RBC bound antibody effectively INDIRECT COOMB’S TEST (IAT OR ANTIBODY SCREENING) Detects antibodies in serum (IgG antibodies in serum) Detects in vitro sensitization of RBCs COLD AUTO ANTIBODY Spontaneous agglutination after incubation of patient serum
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Bibliography of Human Genetics*
BIBLIOGRAPHY OF HUMAN GENETICS* R. H. POST Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan Selections from the Current List of Medical Literature through February, 1959 and other sources 296. AGER, J. A., LEHMANN, H., & VELLA, F. 1958. Haemoglobin Norfolk: a new haemoglobin found in an English family with observations on the naming of new haemoglobin variants Brit. M. J. 5095: 539-541. 297. ALEXANDER, J. O., & GRANT, P. W. 1958. Monilethrix; report of three cases with family his- tory. Scot. M. J. 3(8): 356-360. 298. ALLAN, J. D., CUSWORTH, D. C., DENT, C. E., & WILSON, V. K. 1958. A disease, probably hereditary, characterized by severe mental deficiency and a constant gross abnormality of aminoacid metabolism. Lancet, Lond. 1(7013): 182-187. 299. ALLISON, A. C. 1958. The genetical and clinical significance of the haptoglobins. Proc. R. Soc. Ml., Lond. 51(8): 641-645. 300. ALLISON, A. C., & BLUMBERG, B. S. 1958. Familial osteoarthropathy of the fingers. J. Bonc Surg. Brit. VZol. 40-B(3): 538-545. 301. ALLORI, L., & VITAMIA, P. 1958. Osservazioni genetistiche su 44 casi di cardiopatie acquisite. [Genetic observations on 44 cases of acquired heart disease] Acta genet. med. gemellol., Roma 7(3): 397-410. 302. AMYOT, R. 1958. L'Audi-mutite; document clinique portant sur trios membres (lune meme fratrie. [Audimutitas; clinical observation on three members of the same family] Presse med. 66(56): 1289-1292. 303. ANASTASI, A. 1958. Heredity, environment, and the question how? Psychol. Rev. 65(4): 197-208. 304. ANDERSEN, J. 1958. Modifying influence of the secretor gene on the development of the ABH substance; a contribution to the conception of the Lewis group system.
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Hereditary Spherocytosis (HS)
CP Presentation Rania Abadeer, MD HPI • 20-year-old white college student, diagnosed with infectious mononucleosis 6 months ago • He recovered, but a follow-up CBC revealed a hemoglobin of 9.3 gm/dl and a reticulocytosis of 7.4% • A direct Coombs test (direct anti- globulin test) was negative, and liver function tests normal except for an indirect bilirubin at 2.5 mg/dl Physical Exam • He is a healthy young man who has minimal scleral icterus • Non-tender liver with a vertical span of 10 cm, and a soft spleen tip which descended 4 cm below the LCM with deep inspiration Labs • WBC 6400 • Platelets 195,000 • Red blood cell indicies – Hgb 10.8 – Hct 30 – RBC 3.2 – MCV 94 – MCH 34 – MCHC 36 – Retics 6.8% Labs- cont. • LFTs normal except for indirect bilirubin of 2.2mg/dl • LDH elevated to 290 • Direct anti-globulin (DAT) test is negative Peripheral Blood Smear Peripheral Blood Smear (cont’d) Peripheral Blood Smear (cont’d) Hereditary spherocytosis (HS) • Initially described in 1871 • Increased in persons of northern European descent • In the US: 1 in 5000 • Most cases inherited in an autosomal dominant fashion Structure • The RBC membrane is composed of a lipid bilayer with associated proteins • This is linked to a protein network “membrane cytoskeleton” • This specific structural configuration gives the red blood cell flexibility (to squeeze through capillaries) Membrane Protein Defects- resulting in spherocytes • Spectrin deficiency alone • Spectrin and ankyrin deficiency • Band 3 deficiency • Protein 4.2 defects Pathophysiology • Spherocytes
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Hereditary Spherocytosis (HS)
Hereditary Spherocytosis (HS) What is hereditary spherocytosis (HS)? HS is found in about 1/5,000 people. It is more common in people of Northern European ancestry, but is found in Hereditary spherocytosis (HS) is a medical term for a other ethnic groups. condition which affects the walls of the red blood cells. They get stuck in an organ called the spleen, which then destroys them. The process where red blood cells are How severe are the symptoms of HS? destroyed is called hemolysis. The symptoms of HS vary from person to person, and can be mild, moderate or severe. Mild HS (about 20% of What are red blood cells? cases) will have minimal symptoms and may not be diagnosed until adulthood. Severe HS (about 5% of Blood contains 3 types of cells: red blood cells (RBC), cases) is usually diagnosed in newborns and infants, white blood cells (WBC), and platelets. Red blood cells and requires very careful medical attention. Moderate are the most common type of blood cells, and are HS (about 75% of cases) is somewhere in between. responsible for delivering oxygen to all parts of the body. Red blood cells, like white cells and platelets, are What are the symptoms of HS? continuously made in the bone marrow. When released into the bloodstream, the average lifespan of a red cell is Symptoms of HS are due to 2 processes: hemolysis and 120 days. anemia. Under the microscope, normal red cells are shaped like When red blood cells break down (hemolysis), they discs or donuts with the center partially scooped out.
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Successful Autologous Peripheral Blood Stem Cell Harvest and Transplantation After Splenectomy in a Patient with Multiple Myeloma with Hereditary Spherocytosis
International Journal of Myeloma 8(3): 11–15, 2018 CASE REPORT ©Japanese Society of Myeloma Successful autologous peripheral blood stem cell harvest and transplantation after splenectomy in a patient with multiple myeloma with hereditary spherocytosis Daisuke FURUYA1,4, Rikio SUZUKI1,4, Jun AMAKI1, Daisuke OGIYA1, Hiromichi MURAYAMA1,2, Hidetsugu KAWAI1, Akifumi ICHIKI1,3, Sawako SHIRAIWA1, Shohei KAWAKAMI1, Kaito HARADA1, Yoshiaki OGAWA1, Hiroshi KAWADA1 and Kiyoshi ANDO1 Hereditary spherocytosis (HS) is the most common inherited red cell membrane disorder worldwide. We herein report a 58-year-old male HS patient with mild splenomegaly who developed symptomatic multiple myeloma (MM). Autologous stem cell transplantation (ASCT) was considered to be adopted against MM, although there was a possibility of splenic rupture following stem cell mobilization. Therefore, splenectomy was performed prior to stem cell harvest, and he was able to safely mobilize sufficient CD34+ cells with G-CSF and plerixafor and undergo ASCT. This case suggests that stem cell mobilization after splenectomy is safe and effective in HS patients complicated with malignancies. Key words: multiple myeloma, hereditary spherocytosis, splenectomy, autologous peripheral blood stem cell harvest Introduction Consolidation with melphalan-based HDT followed by ASCT is still the standard treatment option for transplant-eligible Multiple myeloma (MM) is characterized by clonal prolifera- patients with MM, leading to higher complete response rates tion of abnormal plasma cells in the bone marrow (BM) micro- and increased progression-free survival and overall survival environment, monoclonal protein in the blood and/or urine, compared with conventional chemotherapy regimens [2]. bone lesions, and immunodeficiency [1]. In recent years, the Importantly, the emergence of novel agent-based therapy introduction of high-dose chemotherapy (HDT) and autol- combined with ASCT has revolutionized MM therapy [2].
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Congenital Heinz-Body Haemolytic Anaemia Due to Haemoglobin Hammersmith
Postgrad Med J: first published as 10.1136/pgmj.45.527.629 on 1 September 1969. Downloaded from Case reports 629 TABLE 1 After transfusion Before transfusion 24 hr 72 hr 6 days Haemoglobin (g) ND 7-5 7-6 7-6 PCV 20 29 23 29 Plasma free Hb (mg/100 ml) 241 141 5 6 Bleeding time 14 6 4 1 Clotting time No clot 8 5-5 2 Haemolysins 3±+ - - Serum bilirubin (mg/100 ml) 4-0 4-8 1-3 0-6 Urine volume/24 hr (ml) 970 1750 1500 1300 Haemoglobinuria 4+ 1 + - - Urobilin 2+ 3+ 3 + 1+ Blood urea (mg/100 ml) 30 148 75 32 Serum Na (mEq/l) 128 132 136 140 Serum K (mEq/l) 3-8 4-2 4-6 4-6 Serum HCO3 (mEq/l) 21-2 27-6 28-4 30 0 SGOT Frankel Units ND 110 84 36 SGPT Frankel Units 94 96 68 Acknowledgment Reference We are greatly indebted to Dr P. E. Gunawardena, REID, H.A. (1968) Snake bite in the tropics. Brit. med. J. 3, Superintendent of the National Blood Transfusion Service 359. for his help in this case. Protected by copyright. Congenital Heinz-body haemolytic anaemia due to Haemoglobin Hammersmith N. K. SHINTON D. C. THURSBY-PELHAM M.D., M.R.C.P., M.C.Path. M.D., M.R.C.P., D.C.H. H. PARRY WILLIAMS M.R.C.S., F.R.C.P. Coventry and Warwickshire Hospital and City General Hospital, Stoke-on-Trent http://pmj.bmj.com/ THE ASSOCIATION of haemolytic anaemia with red shown by Zinkham & Lenhard (1959) to be associ- cell inclusion bodies was well recognized at the end ated with an hereditary deficiency of the red cell ofthe Nineteenth Century in workers exposed to coal enzyme glucose-6-phosphate dehydrogenase.
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