The Effect of Methemoglobin Formation in Sickle Cell Disease
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Hemoglobinopathies: Clinical & Hematologic Features And
Hemoglobinopathies: Clinical & Hematologic Features and Molecular Basis Abdullah Kutlar, MD Professor of Medicine Director, Sickle Cell Center Georgia Health Sciences University Types of Normal Human Hemoglobins ADULT FETAL Hb A ( 2 2) 96-98% 15-20% Hb A2 ( 2 2) 2.5-3.5% undetectable Hb F ( 2 2) < 1.0% 80-85% Embryonic Hbs: Hb Gower-1 ( 2 2) Hb Gower-2 ( 2 2) Hb Portland-1( 2 2) Hemoglobinopathies . Qualitative – Hb Variants (missense mutations) Hb S, C, E, others . Quantitative – Thalassemias Decrease or absence of production of one or more globin chains Functional Properties of Hemoglobin Variants . Increased O2 affinity . Decreased O2 affinity . Unstable variants . Methemoglobinemia Clinical Outcomes of Substitutions at Particular Sites on the Hb Molecule . On the surface: Sickle Hb . Near the Heme Pocket: Hemolytic anemia (Heinz bodies) Methemoglobinemia (cyanosis) . Interchain contacts: 1 1 contact: unstable Hbs 1 2 contact: High O2 affinity: erythrocytosis Low O2 affinity: anemia Clinically Significant Hb Variants . Altered physical/chemical properties: Hb S (deoxyhemoglobin S polymerization): sickle syndromes Hb C (crystallization): hemolytic anemia; microcytosis . Unstable Hb Variants: Congenital Heinz body hemolytic anemia (N=141) . Variants with altered Oxygen affinity High affinity variants: erythrocytosis (N=93) Low affinity variants: anemia, cyanosis (N=65) . M-Hemoglobins Methemoglobinemia, cyanosis (N=9) . Variants causing a thalassemic phenotype (N=51) -thalassemia Hb Lepore ( ) fusion Aberrant RNA processing (Hb E, Hb Knossos, Hb Malay) Hyperunstable globins (Hb Geneva, Hb Westdale, etc.) -thalassemia Chain termination mutants (Hb Constant Spring) Hyperunstable variants (Hb Quong Sze) Modified and updated from Bunn & Forget: Hemoglobin: Molecular, Genetic, and Clinical Aspects. WB Saunders, 1986. -
18,8 Quaternary Structure of Proteins
570 CHAPTERt8 Amino Acids,Peptides, and Proteins 18,8Quaternary structure of proteins AIMS: Todefine the termssubunit dnd quaternarystructure. Io describethe quoternorystructure of hemoglobin.To distinguishomong oxyhemoglobin,deoxyhemoglobin, ond methemoglobin. Someproteins consist of more than one pollpeptide chain. Theseindiuid- ual chains are calledsubunits of the protein. Proteins composedof subunits In some proteins, polypeptide are said to haue quaternary structure. Many proteins have structures that chains aggregateto form contain subunits. Proteins consistingof dimers (two subunits), tetramers quaternary structures. (four subunits), and hexamers (six subunits) are fairly common. The pro- teins that comprise the individual subunits may be identical, or they may be different. Like the secondary and tertiary structures, the quaternary structure of a protein is determined by its primary structure. The pollpep- tide chains of subunits are held in place by the same forces that determine tertiary structure-hydrogen bonds, salt bridges, and sometimes disulfide bridges-except the forces are betweenthe polypeptide chains of the sub- units instead of within them. Hydrophobic aliphatic and aromatic side chains of subunits can aggregateto exclude water. Hemoglobin-the globular oxygen-transport protein of blood-is an example of a protein that has a quaternary structure. Max Perutz, also of the Medical ResearchCouncil laboratories,determined the structure of horse blood hemoglobin in 1959.Hemoglobin is a larger molecule than myoglo- bin. The hemoglobin molecule has a molar mass of 64,500.It contains about 5000 individual atoms, excluding hydrogens, in 574 amino acid residues. The quaternary structure of hemoglobin consistsof four peptide sub- units. TWo of the subunits are identical and are called the alpha subunits. -
The Role of Methemoglobin and Carboxyhemoglobin in COVID-19: a Review
Journal of Clinical Medicine Review The Role of Methemoglobin and Carboxyhemoglobin in COVID-19: A Review Felix Scholkmann 1,2,*, Tanja Restin 2, Marco Ferrari 3 and Valentina Quaresima 3 1 Biomedical Optics Research Laboratory, Department of Neonatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland 2 Newborn Research Zurich, Department of Neonatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; [email protected] 3 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] (M.F.); [email protected] (V.Q.) * Correspondence: [email protected]; Tel.: +41-4-4255-9326 Abstract: Following the outbreak of a novel coronavirus (SARS-CoV-2) associated with pneumonia in China (Corona Virus Disease 2019, COVID-19) at the end of 2019, the world is currently facing a global pandemic of infections with SARS-CoV-2 and cases of COVID-19. Since severely ill patients often show elevated methemoglobin (MetHb) and carboxyhemoglobin (COHb) concentrations in their blood as a marker of disease severity, we aimed to summarize the currently available published study results (case reports and cross-sectional studies) on MetHb and COHb concentrations in the blood of COVID-19 patients. To this end, a systematic literature research was performed. For the case of MetHb, seven publications were identified (five case reports and two cross-sectional studies), and for the case of COHb, three studies were found (two cross-sectional studies and one case report). The findings reported in the publications show that an increase in MetHb and COHb can happen in COVID-19 patients, especially in critically ill ones, and that MetHb and COHb can increase to dangerously high levels during the course of the disease in some patients. -
224 Subpart H—Hematology Kits and Packages
§ 864.7040 21 CFR Ch. I (4–1–02 Edition) Subpart H—Hematology Kits and the treatment of venous thrombosis or Packages pulmonary embolism by measuring the coagulation time of whole blood. § 864.7040 Adenosine triphosphate re- (b) Classification. Class II (perform- lease assay. ance standards). (a) Identification. An adenosine [45 FR 60611, Sept. 12, 1980] triphosphate release assay is a device that measures the release of adenosine § 864.7250 Erythropoietin assay. triphosphate (ATP) from platelets fol- (a) Identification. A erythropoietin lowing aggregation. This measurement assay is a device that measures the is made on platelet-rich plasma using a concentration of erythropoietin (an en- photometer and a luminescent firefly zyme that regulates the production of extract. Simultaneous measurements red blood cells) in serum or urine. This of platelet aggregation and ATP re- assay provides diagnostic information lease are used to evaluate platelet for the evaluation of erythrocytosis function disorders. (increased total red cell mass) and ane- (b) Classification. Class I (general mia. controls). (b) Classification. Class II. The special [45 FR 60609, Sept. 12, 1980] control for this device is FDA’s ‘‘Docu- ment for Special Controls for Erythro- § 864.7060 Antithrombin III assay. poietin Assay Premarket Notification (a) Identification. An antithrombin III (510(k)s).’’ assay is a device that is used to deter- [45 FR 60612, Sept. 12, 1980, as amended at 52 mine the plasma level of antithrombin FR 17733, May 11, 1987; 65 FR 17144, Mar. 31, III (a substance which acts with the 2000] anticoagulant heparin to prevent co- agulation). This determination is used § 864.7275 Euglobulin lysis time tests. -
Congenital Methemoglobinemia-Induced Cyanosis in Assault Victim
Open Access Case Report DOI: 10.7759/cureus.14079 Congenital Methemoglobinemia-Induced Cyanosis in Assault Victim Atheer T. Alotaibi 1 , Abdullah A. Alhowaish 1 , Abdullah Alshahrani 2 , Dunya Alfaraj 2 1. Medicine Department, Imam Abdulrahman Bin Faisal University, Dammam, SAU 2. Emergency Department, Imam Abdulrahman Bin Faisal University, Dammam, SAU Corresponding author: Atheer T. Alotaibi , [email protected] Abstract Methemoglobinemia is a blood disorder in which there is an elevated level of methemoglobin. In contrast to normal hemoglobin, methemoglobin does not bind to oxygen, which leads to functional anemia. The signs of methemoglobinemia often overlap with other cardiovascular and pulmonary diseases, with cyanosis being the key sign of methemoglobinemia. Emergency physicians may find it challenging to diagnose cyanosis as a result of methemoglobinemia. Our patient is a healthy 28-year-old male, a heavy smoker, who presented to the emergency department with multiple minimum bruises on his body, claiming he was assaulted at work. He appeared cyanotic with an O2 saturation of 82% (normal range is 95-100%) in room air. He also mentioned that his sister complained of a similar presentation of cyanosis but was asymptomatic. All these crucial points strengthened the idea that methemoglobinemia was congenital in this patient. The case was challenging to the emergency physician, and there was significant controversy over whether the patient's hypoxia was a result of the trauma or congenital methemoglobinemia. Categories: Emergency Medicine, Trauma, Hematology Keywords: methemoglobinemia, cyanosis, hypoxia, trauma Introduction Methemoglobinemia is an important cause of cyanosis; however, clinical cyanosis is challenging in regard to forming a concrete diagnosis as causes are multiple especially in the absence of cardiopulmonary causes [1]. -
Methemoglobinemia in Patient with G6PD Deficiency and SARS-Cov-2
RESEARCH LETTERS Methemoglobinemia in A 62-year-old Afro-Caribbean man with a medi- cal history of type 2 diabetes and hypertension came Patient with G6PD Deficiency to the hospital for a 5-day history of fever, dyspnea, and SARS-CoV-2 Infection vomiting, and diarrhea. Auscultation of his chest showed bilateral crackles. He was tachycardic, hypo- tensive, and dehydrated, with a prolonged capillary Kieran Palmer, Jonathan Dick, Winifred French, refill time and dry mucous membranes. Lajos Floro, Martin Ford Laboratory tests showed an acute kidney injury. Author affiliation: King’s College Hospital National Health Service Blood urea nitrogen was 140 mg/dL, creatinine 5.9 Foundation Trust, London, UK mg/dL (baseline 1.1 mg/dL), capillary blood glu- cose >31 mmol/L, and blood ketones 1.1 mmol/L. DOI: https://doi.org/10.3201/eid2609.202353 A chest radiograph showed bilateral infiltrates, and We report a case of intravascular hemolysis and methe- a result for a SARS-CoV-2 reverse transcription PCR moglobinemia, precipitated by severe acute respiratory specific for the RNA-dependent RNA polymerase syndrome coronavirus 2 infection, in a patient with un- gene was positive (validated by Public Health Eng- diagnosed glucose-6-phosphate dehydrogenase defi- land, London, UK). ciency. Clinicians should be aware of this complication of The patient was treated for SARS-CoV-2 pneu- coronavirus disease as a cause of error in pulse oximetry monitis and a hyperosmolar hyperglycemic state and a potential risk for drug-induced hemolysis. with crystalloid fluid, oxygen therapy, and an insulin infusion. His creatinine increased to 9.3 mg/dL, sus- oronavirus disease is a novel infectious disease pected secondary to hypovolemia and viremia, and Cthat primarily manifests as an acute respiratory acute hemodialysis was started. -
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 -
Methemoglobinemia and Ascorbate Deficiency in Hemoglobin E Β Thalassemia: Metabolic and Clinical Implications
From www.bloodjournal.org by guest on April 2, 2015. For personal use only. Plenary paper Methemoglobinemia and ascorbate deficiency in hemoglobin E  thalassemia: metabolic and clinical implications Angela Allen,1,2 Christopher Fisher,1 Anuja Premawardhena,3 Dayananda Bandara,4 Ashok Perera,4 Stephen Allen,2 Timothy St Pierre,5 Nancy Olivieri,6 and David Weatherall1 1MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; 2College of Medicine, Swansea University, Swansea, United Kingdom; 3University of Kelaniya, Colombo, Sri Lanka; 4National Thalassaemia Centre, District Hospital, Kurunegala, Sri Lanka; 5School of Physics, University of Western Australia, Crawley, Australia; and 6Hemoglobinopathy Research, University Health Network, Toronto, ON During investigations of the phenotypic man hypoxia induction factor pathway is There was, in addition, a highly signifi- diversity of hemoglobin (Hb) E  thalasse- not totally dependent on ascorbate lev- cant correlation between methemoglobin mia, a patient was encountered with per- els. A follow-up study of 45 patients with levels, splenectomy, and factors that sistently high levels of methemoglobin HbE  thalassemia showed that methemo- modify the degree of globin-chain imbal- associated with a left-shift in the oxygen globin levels were significantly increased ance. Because methemoglobin levels are dissociation curve, profound ascorbate and that there was also a significant re- modified by several mechanisms and may deficiency, and clinical features of scurvy; duction in plasma ascorbate levels. Hap- play a role in both adaptation to anemia these abnormalities were corrected by toglobin levels were significantly re- and vascular damage, there is a strong treatment with vitamin C. -
Concentration of NADH-Cytochrome B5 Reductase in Erythrocytes of Normal and Methemoglobinemic Individuals Measured with a Quantitative Radioimmunoblotting Assay
Concentration of NADH-cytochrome b5 reductase in erythrocytes of normal and methemoglobinemic individuals measured with a quantitative radioimmunoblotting assay. N Borgese, … , G Pietrini, S Gaetani J Clin Invest. 1987;80(5):1296-1302. https://doi.org/10.1172/JCI113205. Research Article The activity of NADH-cytochrome b5 reductase (NADH-methemoglobin reductase) is generally reduced in red cells of patients with recessive hereditary methemoglobinemia. To determine whether this lower activity is due to reduced concentration of an enzyme with normal catalytic properties or to reduced activity of an enzyme present at normal concentration, we measured erythrocyte reductase concentrations with a quantitative radioimmunoblotting method, using affinity-purified polyclonal antibodies against rat liver microsomal reductase as probe. In five patients with the "mild" form of recessive hereditary methemoglobinemia, in which the activity of erythrocyte reductase was 4-13% of controls, concentrations of the enzyme, measured as antigen, were also reduced to 7-20% of the control values. The concentration of membrane-bound reductase antigen, measured in the ghost fraction, was similarly reduced. Thus, in these patients, the reductase deficit is caused mainly by a reduction in NADH-cytochrome b5 reductase concentration, although altered catalytic properties of the enzyme may also contribute to the reduced enzyme activity. Find the latest version: https://jci.me/113205/pdf Concentration of NADH-Cytochrome b5 Reductase in Erythrocytes of Normal and Methemoglobinemic -
Sickle Cell: It's Your Choice
Sickle Cell: It’s Your Choice What Does “Sickle Cell” Mean? Sickle is a type of hemoglobin. Hemoglobin is the substance that carries oxygen in the blood and gives blood its red color. A person’s hemoglobin type is not the same thing as blood type. The type of hemoglobin we have is determined by genes that we inherit from our parents. The majority of individuals have only the “normal” type of hemoglobin (A). However, there are a variety of other hemoglobin types. Sickle hemoglobin (S) is one of these types. There Are Two Forms of Sickle Cell. Sickle cell occurs in two forms. Sickle cell trait is not a disease; Sickle cell anemia (or sickle cell disease) is a disease. Sickle Cell Trait (or Sickle Trait) Sickle cell trait is found primarily in African Americans, people from areas around the Mediterranean Sea, and from islands in the Caribbean. Sickle cell trait occurs when a person inherits one sickle cell gene from one parent and one normal hemoglobin gene from the other parent. A person with sickle cell trait is healthy and usually is not aware that he or she has the sickle cell gene. A person who has sickle trait can pass it on to their children. If one parent has sickle cell trait and the other parent has the normal type of hemoglobin, there is a 50% (1 in 2) chance with EACH pregnancy that the baby will be born with sickle cell trait. When ONE parent has sickle cell trait, the child may inherit: • 50% chance for two normal hemoglobin genes (normal hemoglobin- AA), OR • 50% chance for one normal hemoglobin gene and one sickle cell gene (sickle cell trait- AS). -
The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia
Case Report Yonsei Med J 2020 Dec;61(12):1064-1067 https://doi.org/10.3349/ymj.2020.61.12.1064 pISSN: 0513-5796 · eISSN: 1976-2437 The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia Dae Sung Kim1, Hee Jo Baek1,2, Bo Ram Kim1, Bo Ae Yoon1,2, Jun Hyung Lee3, and Hoon Kook1,2 1Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun; 2Department of Pediatrics, Chonnam National University Medical School, Gwangju; 3Department of Laboratory Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea. Hemoglobin M (HbM) is a group of abnormal hemoglobin variants that form methemoglobin, which leads to cyanosis and he- molytic anemia. HbM-Milwaukee-2 is a rare variant caused by the point mutation CAC>TAC on codon 93 of the hemoglobin sub- unit beta (HBB) gene, resulting in the replacement of histidine by tyrosine. We here report the first Korean family with HbM-Mil- waukee-2, whose diagnosis was confirmed by gene sequencing. A high index of suspicion for this rare Hb variant is necessary in a patient presenting with cyanosis since childhood, along with methemoglobinemia and a family history of cyanosis. Key Words: Hemoglobin M-Milwaukee-2, methemoglobinemia, cyanosis, congenital hemolytic anemia INTRODUCTION tion pathway.6 Methemoglobinemia occurs when metHb lev- els exceed 1.5% in blood.7 Hereditary methemoglobinemia is Hemoglobinopathy refers to abnormalities in hemoglobin often caused by methemoglobin reductase enzyme deficiency, -
Evidence of the Existence of a High Spin Low Spin Equilibrium in Liver Microsomal Cytochrome P450, and Its Role in the Enzymatic Mechanism* H
CROATICA CHEMICA ACTA CCACAA 49 (2) 251-261 (1977) YU ISSN 0011-1643 CCA-996 577.15.087.8 :541.651 Conference Paper Evidence of the Existence of a High Spin Low Spin Equilibrium in Liver Microsomal Cytochrome P450, and its Role in the Enzymatic Mechanism* H. Rei:n, 0. Ristau, J. Friedrich, G.-R. Jiinig, and K. RuckpauL Department of Biocatalysis, C'entral Institute of Molecular Biology, Academy of Sciences of the GDR 1115 Berlin, GDR Received November 8, 1976 In rabbit liver microsomal cytochrome P450 a high spin (S = = 5/2) low spin (S = 1/2) equilibrium has been proved to exist by recording temperature difference spectra in the Soret and in the visible region of the absorption spectrum of solubilized cytochrome P450. In the presence of type II substrates the predominantly low spin state of cytochrome P450 is maintained, only a very small shift to lower spin is observed. Ligands of the heme iron, such as cyanide and imidazole, pr9duce a pure low spin state and therefore in the presence of these ligands no temperature difference spectra can be obtained. In the presence of type I substrate, however, the spin equilibrium is shifted to the high spin state. The extent of this shift (1) depends on specific properties of the substrate and (2) it is generally relatively small, up to about 80/o in the case of substrates investigated so far. INTRODUCTION The first step in the reaction cycle of cytochrome P450 is the binding of the substrate to the enzyme. The binding is connected with changes in the absorption spectrum especially in the Soret region from which the binding constant can be evaluated1• Moreover, in the case of the so far best known cytochrome P450 from Pseudomonas putida it has been established that at substrate binding the low spin state of the heme iron is changed into the high spin state2• In the presence of camphor, a specific substrate, bacterial cytochrome P450 exhibits in the EPR spectrum g values of 8, 4, and 1.8, typical of high spin ferric heme iron in a strong distorted rhombic field.