Anemias - JUdoctors
Anemias
Definition Reduction of total RBC MASS below averagelevels Reduction of oxygen carrying capacity of theblood Leads to tissue hypoxia Practically, measure by Hemoglobinconcentration, and Hematocrit (ratio of packedRBCs to total blood volume). They correlate wellwith anemia when the plasma volume is normal
Classification of anemiaaccording to cause Blood loss: acute, chronic Diminished RBC production Increased destruction (hemolytic anemia) Extrinsic factors (infection, antibody, mechanical) Intrinsic RBC abnormalities:1) Hereditary (membrane, enzyme, Hgabnormalities)2) Acquired (Paroxysmal nocturnal hematuria)
Classification of anemia According to morphology:Size: normo, micro, macrocyticColor: normo, hypochromicShape: anisopoikelocytosis (spherocytes, sickle,schistiocytes) Hypochromic microcytic anemia usually reflectsimpaired Hg synthesis Macrocytic anemia reflects stem cell disease andmaturation
RBC indices Hg concentration, Men: 13.8-18.0 g/dL, Women: 12-15 Hematocrit: volume % of RBCs in blood, 45% men, 40% women Mean Cell Volume (MCV): average size in femtoliter, 10 15 (normal:80-99 fL) Mean Cell Hg (MCH): average mass of Hg inside the RBC inpicograms, 10 12, normal (27-31) Mean Cell Hg Concentration (MCHC): the average concentration ofHg in a given volume of packed red cells, expressed in grams perdeciliter RBC count: number of cells/L Male: 4.7-6.1 million/ microliterFemale: 4.2-5.4 Reticulocyte index (0.5-1.5%) Red cell distribution width (RDW): the coefficient of variation in redcell volume
Clinical features of anemia iaDyspneaSpecial types: jaundice, bone and joint pain,growth retardation
Anemia of acute blood loss Symptoms are related to decreased intravascular volume, mightcause cardiovascular shock and death Body responds by shifting fluid from interstitial to intravascularspace, causing dilutional anemia and hypoxia Erythropoietin secretion is stimulated, activating BM erythropoiesis Mature RBCs as well as Reticulocytes appear in blood after 5 days In internal hemorrhage, iron is restored from extravasated RBCs andused again in erythropoiesis In external and GIT hemorrhage, iron is lost, which complicatedanemia The anemia is normochromic normocytic, with reticulocytosis Leukocytosis (secondary to stress) Thrombocytosis (secondary to high erythropoietin)
Anemia of chronic blood loss Occurs when the rate of RBC loss exceedsregeneration Mostly associated with iron deficiency anemia
Hemolytic Anemia Normally, RBCs age is around 120 days, aged RBCsare engulfed by phagocytic cells in spleen, liver andBM In Hemolytic anemia; premature destruction ofRBCs Accumulation of Hg degradation products Secondary increased erythropoiesis Extravascular hemolysis: increased phagocyticactivity Intravascular hemolysis: occurs inside blood vessels
Extravascular Hemolysis Generally caused when the RBC is less deformable orhaving abnormal shape Abnormal RBC shape prevents its normal movement insplenic sinusoids Prolonged time of RBCs passage attracts histiocytes toengulf them Free Hg from destructed RBCs binds Haptoglobin inserum Hg within phagocytes is converted to bilirubin The triad of extravascular HA is: Anemia, splenomegalyand jaundice
Intravascular Hemolysis Less common Caused by mechanical damage, complementfixation, microorganism, exogenous toxins Due to large amount of free Hg, haptoglobin iscleared from the serum free Hg in serum is oxidized to Methemoglobin(metHg), Excess free Hg and met Hg are excreted in urine(hemoglobinuria) causing dark urine Renal hemosiderosis may occur
Hereditary Spherocytosis This inherited disorder is caused by intrinsic defects inthe red cell membrane skeleton that render red cellsspheroid, less deformable, and vulnerable to splenicsequestration and destruction The prevalence of HS is highest in northern Europe AD inheritance pattern, in 75% of cases The remaining patients have a more severe form of thedisease that is usually caused by the inheritance of twodifferent defects (a state known as compoundheterozygosity)
Pathophysiology Normal RBC is durable and elastic Spectrin is the major internal membrane protein,consists of two helical polypeptides; α, β The tail of Spectrin binds Actin Spectrin-Actin complex, is connected by Ankyrinand band 4.2 to band 3, a transmembraneprotein Protein 4.1 binds the tail of spectrin toGlycophorin A, a transmembrane protein
Pathophysiology Various mutations involving α-spectrin, β-spectrin, ankyrin, band4.2, or band 3 that weaken the interactions between these proteinscause red cells to lose membrane fragments Most mutations are frame-shift, resulting in absent protein To accommodate the resultant change in the ratio of surface area tovolume these cells adopt an irreversible spherical shape Spherocytic cells are less deformable than normal ones andtherefore become trapped in the splenic cords, where they arephagocytosed by macrophages Na influx in spherocytes is twice than normal, while K efflux is thesame, facilitating hemolysis in the microenvironment of the spleen RBC Life span is dropped to less than 20 days
Clinical features Congestion of RBCs in the spleen causessplenomegaly and anemia Jaundice, pigmented gall bladder stones Reticulocytosis, BM erythroid hyperplasia,hemosiderosis Family Hx of anemia or splenectomy Abnormal osmotic fragility test Increased MCHC in 50% of cases Treatment: splenectomy
Morphology Blood film: RBCs are round, small,hyperchromatic, no visible central pallor “Howell-Jolly” bodies are seen in postsplenectomy. A fragment of chromosomewhich is detached and left in the cytoplasmafter the extrusion of the nucleus, secondaryto accelerated erythropoiesis. Appears as 1 or2 eccentric dots
Spherocytes appear as small, round cells without the central pallor. HowellJolly bodies are noted
Glucose-6-Phosphate Dehydrogenase Deficiency G6PD reduces nicotinamide adenine dinucleotidephosphate (NADP) to NADPH while oxidizingglucose-6-phosphate NADPH then provides reducing equivalentsneeded which protects against oxidant injury bycatalyzing the breakdown of compounds such asH 2O 2 G6PD deficiency is a recessive X-linked trait,placing males at higher risk for symptomaticdisease.
Types of G6PD deficiency Several hundred G6PD genetic variants areknown, but most are harmless The normal enzyme is G6PD-B Only two variants, designated G6PD-A andG6PD Mediterranean, cause most of theclinically significant hemolytic anemias G6PD-A is present in about 10% of Americanblacks; G6PD Mediterranean is prevalent inthe Middle East
Pathophysiology The half-life of G6PD-A is moderately reduced,whereas that of G6PD Mediterranean isfunctionally abnormal Because mature red cells do not synthesizenew proteins, G6PD-A or G6PD Mediterraneanenzyme activities fall quickly to levelsinadequate to protect against oxidant stress asred cells age. Thus, older red cells are muchmore prone to hemolysis than younger ones
Pathophysiology Oxidants cause both intravascular and extravascular hemolysis inG6PD-deficient individuals Exposure of G6PD-deficient red cells to high levels of oxidantscauses the cross-linking of reactive sulfhydryl groups on globinchains, which become denatured and form membrane-boundprecipitates known as Heinz bodies These are seen as dark inclusions within red cells stained withcrystal violet. Heinz bodies can damage the membranesufficiently to cause intravascular hemolysis Splenic macrophages identify Heinz bodies and pluck them outresulting in indentation. The remaining RBC is known as “bitecells”
Causes of hemolytic crisis Hemolysis happens upon exposure to oxidant stress The most common triggers are infections, in which oxygen-derivedfree radicals are produced by activated leukocytes Many infections can trigger hemolysis; viral hepatitis, pneumonia,and typhoid fever The other important initiators are drugs and certain foods Most important drugs are the antimalarials (e.g., primaquine andchloroquine), sulfonamides, nitrofurantoins Some drugs cause hemolysis only in individuals with the moresevere Mediterranean variant. The most frequently cited food is the fava bean (Favism) Uncommonly, G6PD deficiency presents as neonatal jaundice or achronic low-grade hemolytic anemia in the absence of infection orknown environmental triggers
Clinical features Majority of patients are asymptomatic, anemia developswhen the enzyme level drops below 20% of normal activity Hemolytic crisis appear 2-3 days after exposure to oxidant Only old RBCs hemolize, HB level drops, RBCs appearnormochromic normocytic, patients have bone pain Chronic hemolysis (splenomegaly and GB stones) areabsent G6PD-A usually is self-limited G6PD-Mediterranian has more severe crisis, might needblood transfusion Recovery is associated with reticulocytosis Dx: enzyme assay (measure conversion to NAPDH)
Pyrovate kinase deficiency AR inheritance PK is an enzyme in the anaerobic glycolysis pathway(main pathway in RBCs) PK deficiency causes decreased ATP level which isessential for cell membrane pumps Intracellular Na accumulates, causing swelling of RBCsand rigidity Spleen clears abnormal shaped RBCs 2,3 diphosphoglycerate (DPG) level increases insideRBCs, facilitating O2 release, ameliorating the anemia
Clinical Degree of anemia varies according to type ofmutation, ranging from neonatal jaundice toanemia presenting in adulthood withjaundice, GB stones and splenomegaly Anemia is exacerbated by stress Blood film shows NN anemia, variablereticulocytosis, anisopoikelocytosis Diagnosis: enzyme assay Treatment: splenectomy
Paroxysmal Nocturnal Hematuria Acquired disease Normally, proteins are anchored into the lipid bilayer in two ways.Most have a hydrophobic region that spans the cell membrane;these are called transmembrane proteins. The others are attachedto the cell membrane through a covalent linkage to a specializedphospholipid called glycosylphosphatidylinositol (GPI) In PNH, there is a mutation in the phosphatidylinositol glycancomplementation group A gene (PIGA), which synthesizes GPI Thus, GPI and their normally anchored proteins are absent Because the causative mutations occur in a hematopoietic stemcell, all of its clonal progeny (red cells, white cells, and platelets) aredeficient in GPI-linked proteins
Patholophysiology Normal individuals harbor small numbers of bonemarrow cells with PIGA mutations In PNH, autoimmune reaction occurs against normalclones resulting in predominance of GPI-deficient clone PNH blood cells are deficient in three GPI-linkedproteins that regulate complement activity: (1) decayaccelerating factor, or CD55; (2) membrane inhibitor ofreactive lysis, or CD59; and (3) C8 binding protein. Ofthese factors, the most important is CD59, a potentinhibitor of C3 convertase that prevents thespontaneous activation of the alternative complementpathway
Clinical features Red cells, platelets, and granulocytes deficient in these GPI-linked factorsare abnormally susceptible to lysis or injury by complement. In red cellsthis manifests as intravascular hemolysis, which is caused by the C5b-C9membrane attack complex The hemolysis is intravascular, paroxysmal and nocturnal in only 25% ofcases; chronic hemolysis without dramatic hemoglobinuria is more typical.The tendency for red cells to lyse at night is explained by a slight decreasein blood pH during sleep, which increases the activity of complement Thrombosis is the leading cause of death in PNH. About 40% of patientssuffer from venous thrombosis, often involving the hepatic, portal, orcerebral veins. Autolysis of some platelets causes aggregation of otherssecondary to released prothrombotic factors In severe cases, pancytopenia develops About 5% to 10% of patients eventually develop acute myeloid leukemiaor a myelodysplastic syndrome, possibly because hematopoietic stem cellshave suffered some type of genetic damage.
Autoimmune hemolytic anemia A group of anemias in which an abnormal immunoglobulinis attached to RBC membrane causing damage and lysis Direct Coombs antiglobulin test: the patient's RBCs aremixed with sera containing antibodies that are specific forhuman immunoglobulin. If either immunoglobulin ispresent on the surface of the red cells, the multivalentantibodies cause agglutination, which is easily appreciatedvisually as clumping Indirect Coombs antiglobulin test, the patient's serum istested for its ability to agglutinate commercially availablered cells bearing particular defined antigens
Warm Antibody Type 70% of immunohemolytic anemia. 50% are idiopathic (primary); the others are related to apredisposing condition or exposure to a drug. Most causative antibodies are of the IgG class; less commonly,IgA antibodies A common target is the Rh antigen on RBCs The red cell hemolysis is mostly extravascular. IgG-coated redcells bind to Fc receptors on phagocytes, which remove redcell membrane during "partial" phagocytosis. As in hereditaryspherocytosis, the loss of membrane converts the red cells tospherocytes, which are sequestered and removed in thespleen. Moderate splenomegaly due to hyperplasia of splenicphagocytes is usually seen
Drug induced hemolytic anemia Antigenic drugs. In this setting hemolysis usually follows large, intravenousdoses of the offending drug and occurs 1 to 2 weeks after therapy isinitiated. These drugs, like penicillin and cephalosporins, bind to the redcell membrane and are recognized by anti-drug antibodies. Sometimes theantibodies bind only to the drug, as in penicillin-induced hemolysis. Inother cases, such as in quinidine-induced hemolysis, the antibodiesrecognize a complex of the drug and a membrane protein. The responsibleantibodies sometimes fix complement and cause intravascular hemolysis,but more often they act as opsonins that promote extravascular hemolysiswithin phagocytes Tolerance-breaking drugs. These drugs, of which the antihypertensiveagent α-methyldopa is the prototype, induce in some unknown mannerthe production of antibodies against red cell antigens, particularly the Rhblood group antigens. About 10% of patients taking α-methyldopa developautoantibodies, as assessed by the direct Coombs test, and roughly 1%develop clinically significant hemolysis
Cold Agglutinin Type This form of immunohemolytic anemia is caused by IgM antibodies that bind redcells avidly at low temperatures (0 -4 C). It is less common than warm antibodyimmunohemolytic anemia, accounting for 15% to 30% of casesCold agglutinin antibodies sometimes appear transiently following certaininfections, such as with Mycoplasma pneumoniae, Epstein-Barr virus,cytomegalovirus, influenza virus, and human immunodeficiency virus (HIV). Inthese settings the disorder is self-limited and the antibodies rarely induce clinicallyimportant hemolysis. Chronic cold agglutinin immunohemolytic anemia occurs inassociation with certain B-cell neoplasms or as an idiopathic condition.Clinical symptoms result from binding of IgM to red cells in vascular beds wherethe temperature may fall below 30 C, such as in exposed fingers, toes, and ears.IgM binding agglutinates red cells and fixes complement rapidly. As the bloodrecirculates and warms, IgM is released, usually before complement-mediatedhemolysis can occur. However, the transient interaction with IgM is sufficient todeposit sublytic quantities of C3b, an excellent opsonin, which leads to theremoval of affected red cells by phagocytes in the spleen, liver, and bone marrow.The hemolysis is of variable severity
RBC agglutination in autoimmune hemolytic anemia
Cold Hemolysin Type Cold hemolysins are autoantibodies responsible for anunusual entity known as paroxysmal cold hemoglobinuria This rare disorder causes substantial, sometimes fatal,intravascular hemolysis and hemoglobinuria The autoantibodies are IgGs that bind to the P blood groupantigen on the red cell surface in cool, peripheral regions ofthe body. Complement-mediated lysis occurs when thecells recirculate to warm central regions, since thecomplement cascade functions more efficiently at 37 C Most cases are seen in children following viral infections; inthis setting the disorder is transient, and most of thoseaffected recover within 1 month.
Hemolytic Anemia Resulting fromTrauma to Red Cells Physical damage to RBCs Cardiac valve prosthesis Microangiopathic disease (disseminatedintravascular coagulation DIC, thromboticthrombocytopenic purpura (TTP), hemolyticuremic syndrome (HUS), malignant hypertension,systemic lupus erythematosus, and disseminatedcancer): aggregates of fibrin and platelets causesdamage to RBCs RBCs appear as fragments (schistocytes)
Schistocytes
Hemoglobinopathies
Normal Hemoglobin Structure Two pairs of globin chains with a haem groupattached. 7 chains are synthesized in normal subjects: 4embryonic: Hg Gower 1,2 Hg Portland 1,2. Hg F(fetal), Hg A, Hg A2 The individual chains synthesized in postnatal lifeare designated α, β, γ, and δ Hg A has two α chains and two β chains (α2 β2) Hg A2 has two α chains and two δ chains (α2 δ2),1.5-3% Hg F has two α chains and two γ chains (α2 γ2),1%
Genes controling Hg synthesis* α Chain synthesis is directed by two α genes, α 1 and α 2,on chromosome 16* β and δ chain synthesis by single β and δ genes onchromosome 11* γ Chain synthesis is directed by two genes, Gγ and Aγ,also on chromosome 11
Thalassemia The thalassemia syndromes are a heterogeneous group ofdisorders caused by inherited mutations that decrease thesynthesis of adult hemoglobin, HgA (α2β2) Endemic in Middle East, tropical Africa, India, Asia β-Thalassemia is caused by deficient synthesis of β chains,whereas α-thalassemia is caused by deficient synthesis of αchains The hematologic consequences of diminished synthesis of oneglobin chain stem not only from hemoglobin deficiency butalso from a relative excess of the other globin chain,particularly in β-thalassemia
β-Thalassemias caused by mutations that diminish thesynthesis of β-globin chains β0 mutations, associated with absent β-globinsynthesis β mutations, characterized by reduced (butdetectable) β-globin synthesis 100 different causative mutations, mostlyconsisting of point mutations
Types of mutations Splicing mutations: most common cause of β -thalassemia. Most of thesemutations lie within introns, while a few are located within exons. Some ofthese mutations destroy the normal RNA splice junctions and completelyprevent the production of normal β-globin mRNA, resulting in β0thalassemia Promoter region mutations. These mutations reduce transcription by 75%to 80%. Some normal β-globin is synthesized; thus, these mutations areassociated with β -thalassemia. Chain terminator mutations. These are the most common cause of β0thalassemia. Two subtypes of mutations fall into this category. The mostcommon type creates a new stop codon within an exon; the secondintroduces small insertions or deletions that shift the mRNA readingframes, Both block translation and prevent the synthesis of any functionalβ-globin
Pathophysiology The deficit in HgA synthesis produces "underhemoglobinized"hypochromic, microcytic red cells with subnormal oxygentransport capacity Diminished survival of red cells and their precursors, whichresults from the imbalance in α- and β-globin synthesis.Unpaired α chains precipitate within red cell precursors, forminginsoluble inclusions, which damage cell membrane and results incell death in RBC precursors (Ineffective erythropoiesis) Those red cells that are released from the marrow also bearinclusions and membrane damage and are prone to splenicsequestration and extravascular hemolysis
Pathophysiology In severe β-tha
Uncommonly, G6PD deficiency presents as neonatal jaundice or a chronic low-grade hemolytic anemia in the absence of infection or known environmental triggers. Clinical features Majority of patients are asymptomatic, anemia develops when the enzyme level drops below 20% of normal activity
3/1/2021 1 Diagnosing Anemias Like a Pro! Amelie Hollier, DNP, FNP‐BC, FAANP President,
Cooley's Anemia) - Blackfan-Diamond Anemia - Pure Red Cell Aplasia - Sickle Cell Disease Other Disorders of Blood Cell Proliferation Anemias Anemias are deficiencies or malformations of red cells. - severe Aplastic Anemia - Congenital Dyserythropoietic Anemia - Fanconi Anemia (Note: the first cord blood transplant in 1988 was for this disease)
., part ill. nutrition facts what is a vitamin? 171 recommended dietary allowances for vitamins 174 in defense of the cholesterol report 177 water soluble vitamins: diagnosing deficiencies 179 summary of "nutritional anemias" 188 nutritional anemias 189 ama concepts of nutrition and heal th 199 food, nutrition and a defamatory attack on
Page 4 Saudi Fellowship Final Written Examination; Paediatric Haematology and Oncology Blueprint Outlines: No. Sections Percentage (%) 1 Anemias 15% 2 Hemostasis and Platelets 18% 3 Bone Marrow Failure Disorders 5% 4 Immunologic abnormalities and Leukocytes disorders 3% 5 Pediatric Transfusion Medicine 4% 6 Leukemias and Lymphomas 15% 7 Solid Tumors, Neurooncology and Histiocytic Disorders 18%
Barrett’s Esophagus Chronic Kidney Disease Polycystic Kidney Disease Kidney Injury & Failure Vesicoureteral Reflux Urinary Incontinence Urinary Tract Infections Benign Prostatic Hyperplasia Chronic Prostatitis Painful Bladder Syndrome Anemias & Iron Overload Sickle Cell Disease Division o
Jul 13, 2011 · G6PD deficiency & Enzymopathies Statistical . Macrocytic DBA Fanconi Anemia . Prevention of eating iron-rich foods – Lead Poisoning – Vegan/Poor Meat Intake Blood Loss – Menorrhagia . Avoid oxidant stress, tx infections,
para proteger la salud y promover el adecuado crecimiento físico y el desarrollo intelectual. A corto plazo una dieta saludable ayudará a los niños/as y a los/as jóvenes a mejorar su concentración y rendimiento escolar. También reduce algunos riesgos para la salud, como la deficiencia de vitamina A, anemias y otras deficiencias de .
OF ARCHAEOLOGICAL ILLUSTRATORS & SURVEYORS LSS OCCASIONAL PAPER No. 3 AAI&S TECHNICAL PAPER No. 9 1988. THE ILLUSTRATION OF LITHIC ARTEFACTS: A GUIDE TO DRAWING STONE TOOLS FOR SPECIALIST REPORTS by Hazel Martingell and Alan Saville ASSOCIATION OF ARCHAEOLOGICAL ILLUSTRATORS & SURVEYORS THE LITHIC STUDIES SOCIETY NORTHAMPTON 1988 ISBN 0 9513246 0 8 ISSN 0950-9208. 1 Introduction This booklet .
