Hemolytic anemia - Approach and Management
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The document discusses hemolytic anemias, classifying them based on their causes into hereditary and acquired types, and outlining the diagnostic approach which includes patient history, peripheral blood smear, and laboratory tests. It emphasizes the importance of recognizing symptoms, triggers, and treatment strategies, including transfusion therapies and iron chelation, as well as the management of complications from hemolytic conditions like thalassemia and sickle cell anemia. Additionally, it highlights genetic factors influencing hemolytic anemias and the potential for future gene therapies in treatment.
Hemolytic anemia - Approach and Management
- 1. HEMOLYTIC ANEMIAS CHAIRPERSON – Dr.Sachin Hoskatti STUDENT – Dr. Manjunath
- 3. CLASSIFICATION OF ANEMIA (1) Decreasedproductionof red cells, (2) Increaseddestructionof red cells, and (3) Acuteblood loss.
- 6. Patients who are anemicasa resultof either • increaseddestructionof redcellsor • acutebloodloss Bothhaveoneimportant element in common: The anemia resultsfrom overconsumption of red cellsfrom the peripheral blood, whereas the supplyof cellsfrom the bonemarrow is normal (indeed, it isusually increased). Thesetwo groupsdiffer in • physicallossof red cellsfrom the bloodstreamor from the bodyitself, asinacute hemorrhage, • destructionof red cellswithin the body,asin hemolyticanemias.
- 7. Approachto HemolyticAnemia PlanofAction: 1. History andclinicalexamination 2. Peripheralblood smear 3. Confirm hemolysis 4. Whether hemolysisisintra orextravascular 5. Determine the etiology
- 8. PatientHistory • Acuteor chronic • Medication/Drugprecipitants – G6PD – AIHA • Familyhistory • Concomitant medicalillnesses • Clinicalpresentation
- 9. FEATURES
- 10. PeripheralBloodSmear • Determines the etiology ofhemolysis. • Intravascular hemolysis may reveal red cell fragmentation (i.e. schistocytes, helmet cells), whereas spherocytes indicate extravascular hemolysis. • Polychromasia and nucleated RBCs are indicators of increased erythropoiesis.
- 11. Peripheral smear
- 12. STEP BY STEP APPROACH 1. Calculate for Corrected Reticulocyte Count Retic count: 10% Pt’s Hct 29 Control Hct 40 Corrected Retic Count = % Retic x Pt’s Hct Control Hct = 10% x 29/ 40 = 7.73 % > 2% if no blood loss Indicates hemolysis
- 13. 2. Confirm (+) hemolysis: a) Corrected retic count > 2% b) Inc indirect bilirubins c) Inc LDH d) Low/absent haptoglobin 3. Look for cause of hemolysis - occult blood in urine, urine hemosiderin - peripheral blood smear - direct antiglobulin test, Hgb electrophoresis, RBC enzyme analysis
- 14. EVALUATION OF ANEMIA Low Hgb/Hct Corr. Retic Ct >2% Corr. Retic Ct <2% Acute Blood Loss MCV>100 MCV 80- 100 MCV<80 EVALUATE & TREAT APPRO- PRIATELY Evaluate for Hemolytic Anemias Evaluate for microcytic anemias Evaluate for macrocytic anemias Evaluate for normocytic anemias
- 18. HEREDITARY •Causescorrelate with intracorpuscular defects, becausethesedefectsare due to inherited mutations. ACQUIRED • Causescorrelate with extracorpuscular factors, becausemostlythesefactorsare exogenous.
- 19. Triad of hemolytic anemia • Normomacrocytic anemia • Reticulocytosis • Hyperbilirubinemia
- 20. Compensated vs decompensated hemolysis Redcelldestructionisapotentstimulusforerythropoiesis, whichismediatedbyerythropoietin(EPO) producedbythe kidney. Thismechanismis soeffectivethat inmany casesthe increased outputofredcellsfromthe bone marrow can fullybalance an increaseddestructionofredcells.Insuchcases,we saythat hemolysisiscompensated.
- 21. • There isnoanemia. • Patientwitha hemolyticcondition,evenaninheritedone,maypresent withoutanemia;and • Compensatedhemolysis maybecome“decompensated,” ○ i.e., anemiamaysuddenlyappear, incertaincircumstances,for instancein □ pregnancy, □ folate deficiency,or □ renalfailureinterferingwithadequateEPOproduction. □ acute infection,depresseserythropoiesis ExampleisinfectionbyparvovirusB19, • Whichmaycausearatherprecipitousfallinhemoglobin • Anoccurrencesometimesreferred toasaplastic crisis. Compensated hemolysis
- 22. INHERITED HEMOLYTIC ANEMIAS Thereare three essentialcomponentsin the red cell: • Intracorpuscular (1)hemoglobin, (2)the membrane-cytoskeletoncomplex,and (3)the metabolicmachinerynecessaryto keephemoglobinandthe membrane-cytoskeletoncomplexin working order. • Extracorpuscular: Familial(atypical)hemolyticuremic syndrome
- 24. THALASSEMIAS/ THALASSEMIA SYNDROME Epidemiology : – Most Common genetic disorderin Pediatric ward. – 7% of the world population is carriers of hemoglobin disorder. – 1.5% of world population is carriers of ß Thalassemia gene (20 millions in India alone). – 8 to 10 thousand children born in India with homozygous state for the Thalassemia in every year. – There are around 65 to 67 thousand Thalassemia patients in our country. – In India, Prevalence of defective ß gene varies from 1 to 17%.
- 27. α THALASSEMIA SYNDROMES :
- 28. CLASSIFICATION, CLINICAL & HEMATOLOGICAL FEATURES OF ß THALASSEMIA
- 30. Leptocytes (Target cells) - liver disease (obstructive jaundice) - post splenectomy - hemoglobinopathies (hypochromic anemias) thalassemia Hgb C disease Hgb H diseasebeta thalassemia relative increase of cell membrane --> ―target‖ formation
- 31. PRINCIPLES OF MANAGEMENT Confirmation of the Diagnosis By HPLC Diagnose of Complication Correction of Anemia –Packed Red Blood Cell (PRBC) transfusion Management of Complications –Iron Overload and Chelation Therapy –Anemia/ Hypoxia –Arrest of Growth –Infections –Hypersplenism Pharmacological Methods –Increase gamma chain Synthesis (HbF) Curative Treatment –Stem cell transplantation Future Treatment –Gene Replacement therapy Prevention of Disease
- 32. DIAGNOSIS OF COMPLICATION: It is not sufficient to diagnose the case as Thalassemia ONLY. For complete management of the case, it is necessary to think about its genetic classification, clinical and patho-physiological stage in which it now belongs to. THALASSEMIA Spenomegaly SkeletalDeformity & Arrest of Growth Iron Overload & Chelation Therapy Anaemia Recurrent Blood BormeInfection DEATH
- 33. Why need a Transfusion? Correct Anemia &prevention ofhypoxia Reduce Hepatosplenomegaly &Hypersplenism Reducing ineffective erythropoesis& GI absorption Reduce hemolytic facies& skeletal deformities. Improve growth BT is Mandatory For All children with Thalassemia Major Thalassemia Intermedia , Hb < 7 gm% Evidence of growth retardation Types of Transfusion Palliative(8.5g%) Hyper Transfusion(10g%) Super Transfusion(>12g%) Moderate Transfusion(9-10.5g%) TRANSFUSION THERAPY IN THALASSEMIA
- 34. Frequency of Transfusion – Every 3-4 weeks – Shorter interval of 2-3 weeks is more physiological – avg. time taken 3-4 hrs(@5mi/kg/hr). Amount of Transfusion – 180 ml / kg. / yr in non spenctomised, non-sensitised pt. – 130 ml / kg /yr in spenctomised, sensitised pt. ( 30 % less) Efficacy of Transfusion – Rate of fall of Hb should not exceed 1 gm / dl /week with spleen – Rate of fall of Hb should not exceed 1.5 gm / dl /week without spleen Allo immunisation of RBC Hyperspenism Drag induced hemolysis Infection
- 35. Adequacy of Transfusion – First decade : normal growth – No. of Normoblast < 5 / 100 WBC Complication of Transfusion •Non hemolytic febrile Transfusion reaction NHFTR Allo Immunisation •Plasma Borne Infection •Steps to prevent those infections •Allergic reaction INDICATION OF SPLENECTOMY Annual PRBCc>200-250ml/kg >1.5times basal requirement Massive spleenomegaly hypersplenism
- 36. IRON OVERLOAD Causes of Iron Overload – Treatment with multiple transfusion One bottle blood increases iron store by 200 – 250 mg iron. – Ineffective erythropoesis – Excessive dietary absorption of Iron Consequence of Iron overload – Iron overload in Liver Hepatomegaly, Fibrosis & cirrhosis – Iron overload in Spleen Splenomegaly, Hypersplenisim – Cardiac complication Failure &Arrhythmia – Endocrinal Dysfunction Thyroid, Para-Thyroid, Pituitary, Pancreas, Gonads – Iron overload in Bones Osteoporosis, Osteopenia
- 37. IRON CHELATION THERAPY Iron Chelation Therapy – Goal Reduce the Iron store & sub sequently maintain it at low level ( < 1000 µg/ml ) – When to start Start after 15-20 transfusion or S.Ferritin > 1000 µg/ml (approx. 3 yrs of age) Needle Biopsy of Liver : 3.2Mg iron per gm of Liver tissue ( – Drugs presently used Inj. Deferrioxamine (SC/IV) : DFO/Desferal Oral Deferiprone Oral Deferasirox – Newer Iron Chelator Desferrithiocin ( DFT) Hydroxy Benzyl Ethilene Diamine Diacetic acid (HBED) Pyridoxal iso nicotinyl Hydrazone (PIH) GT 56-252 40 SD02 (CHF 1540)
- 39. CURATIVE TREATMENT Stem Cell Transplantation This is the only curative therapy available today. Though expensive, it is cost effective as compared to yearly cost of regular BT & chelation therapy Sources Bone Marrow Cord Blood Fetal Liver Peripheral Blood
- 40. FUTURE TREATMENT Gene Therapy Aim : Insertion of a normal copy of gene along with key regulatory sequences(LOCUS CONTROL REGION) in the stem cells of recipients. Two main approaches Somatic gene therapy in which non-germ line cells are involved. Transgenic approach in which transfuse gene can be expressed in subsequent generations Need high titre vectors for sustained expression Lentiviral vector from HIV is a hope.
- 41. SCREENING & PREVENTION Premarital screening programmes Alternative is to screen pregnant woman in early pregnancy. PRENATALDIAGNOSIS: BY CVS AT9-11WK Recently there has been attempt to isolate fetal cells from maternal blood. PARENTERAL COUNSELLING
- 42. SICKLE CELL ANEMIA Synthesis of an abnormal Hb, HbS (alpha 2, betas 2) Substitution of valine for glutamic acid at position 6 on the beta chain Hb forms insoluble crystals at low oxygen tens. Red cells sickle and block the microcirculation causing infarcts in various organs Homozygous disease-severe haemolytic anaemia punctuated by crises
- 48. Clinical features • *Painful crises- frequent, due to ischaemia. • Precipitated by infections, acidosis, dehydration. •Infarcts of bones, lungs, spleen(small spleen), brain • *Haemolytic crises- fall in Hb, rise in retic count
- 50. Clinical features • Aplastic crises- fall in Hb, fall in retic count (parvo virus or folate def) • Visceral sequestration- severe chest syndrome, commonest cause of death • Leg ulcers • Pigment gall stones
- 51. Drepanocytes (sickle cells) - sickle cell anemia
- 52. Treatment • Avoid precipitating factors • Hydration • Good nutrition & hygiene • Blood transfusions • Drugs to enhance HbF (hydroxyurea,Azactydine) • Bone marrow transplant
- 54. SCREENING
- 56. B. Membrane defects Themembrane-cytoskeletoncomplexissointegrated. • An abnormality of almostanyof its componentswill be disturbingor disruptive, causingstructural failure, which resultsultimately in hemolysis. • These abnormalities are almostinvariably inherited mutations; thus, diseasesof the membrane- cytoskeleton complexbelongto the categoryof inherited HAs.
- 59. HEREDITARY SPHEROCYTOSIS Incidence:1/5000 in NorthEuropean population Autosomal dominant Defect in RBC cytoskeleton(spectrin,ankyrin) Pathophysiology:Adeficiency in spectrin, ankyrin,protein 3, leads to weakening of the “vertical”interaction of the lipid bilayer & loss of membrane microvescicle . Lossof surface area,↑cation permeability, ATPuse,& glycolysis leading to premature destruction in spleen.
- 62. -The main clinical findings are: Pigment gallstonesSplenomegalyJaundic e
- 63. CLINICAL FEATURES Neonatal period: anemia+ jaundice, more severe. Infancy&childhood:variable severity. Mild: asymptomatic Moderate: intermittent jaundice,spleenomegaly,anemia. Severe:tranfusion dependeat,bone expansion,gall stone
- 64. LAB. DIAGNOSIS:Anemia(Hb:6-10g%), PBS :Spherocytes lacking central pallor ,reticulocytes,MCV-N • MCH↑,MCHC >35,RDW>14.5,DCT:Negative • Osmatic fragility& Incubated osmotic fragilitytest. • Differential diagnosis: autoimmune hemolytic anemia, G6PDdef ,Clostridial sepsis, wilsons disease.
- 65. -In most cases, the diagnosis can be made on the basis of red cell morphology and of a test for osmotic fragility, which is called the “pink test.” .
- 66. SPLENECTOMY
- 67. HS treatment Donot havea causaltreatment for HS Becauseof specialrole of the spleen:almostobligatorytherapeutic measurewas splenectomy. • In mild cases,avoid splenectomy. • Delaysplenectomyuntil pubertyin moderate casesor until 4–6 yearsof age in severe cases. • Alongwith splenectomy,cholecystectomyshouldnot be regarded as automatic; it shouldbe carriedout, usuallybythe laparoscopicapproach, when clinicallyindicated.
- 68. 2.HEREDITARY ELLIPTOCYTOSIS Equatorial Africa, SEAsia AD / AR Functional abnormality in one or more anchor proteins in RBC membrane- Alpha & beta spectrin& defective spectrin heterodimer self association , Protein 4.1& glycophorinC. Usually asymptomatic Mx: Similar to H. spherocytosis Variant: 3. SE-Asian ovalocytosis: Common in Malaysia , Indonesia… Asymptomatic-usually Cells oval , rigid ,resist invasion by malarial parasites SAO is associated with protein3 abnormality.
- 69. Elliptocytes - heredirary elliptocytosis - iron def. anemia - myelofibrosis with myeloid metaplasia - megaloblastic anemia - sickle cell anemia - normal (<10% of cells)
- 70. 3.ENZYMOPATHIES
- 71. 1. Glucose-6-Phosphate Dehydrogenase ( G6PD ) Deficiency Pivotal enzyme in HMP Shunt & produces NADPH to protect RBC again oxidative stress Most common enzymopathy -10% world’s population 1% of indian males have G6PD deficiency Protection against Malaria X-linked recessive G6PDdeficiencyisaprimeexampleof anHAdueto interactionbetween an intracorpuscularcause andanextracorpuscularcause,becauseinthe majority of cases hemolysisistriggeredbyan exogenousagent.
- 75. Clinical manifestations of G6PD deficiency Majority asymptomatic throughouttheirlifetime All of them haveanincreasedriskof 1. Developing Neonataljaundice 2. ariskof developingacuteHA(AHA)whenchallengedbya numberof oxidative agents.
- 76. Neonatal jaundice in G6PD deficiency • NNJrelated to G6PDdeficiencyisveryrarelypresentat birth • the peakincidenceof clinicalonsetisbetween day2 andday3, andin most cases,the anemiais not severe. • veryseverein associationwith • prematurity, • infection, and/or • environmentalfactors(suchasnaphthalene-camphorballs,whichare used in babies’ beddingand clothing) • Severityof NNJisalsoincreasedbythe coexistenceof a • monoallelicor biallelicmutation in the uridyltransferasegene (UGT1A1; • the samemutationsare associatedwith Gilbert’s syndrome). •
- 77. Acute hemolytic anemia in G6PD deficiency AHAcandevelopasaresultof threetypesof triggers: (1) favabeans (2) infections (3) drugs. Typically,a hemolytic attack startswith malaise, weakness,andabdominalor lumbar pain. After aninterval of severalhoursto 2–3 days,the patient developsjaundiceandoften dark urine. Theonsetcanbeextremely abrupt, especiallywith favismin children. Theanemia is • moderate to extremely severe, • usuallynormocyticandnormochromic • duepartly to intravascularhemolysis;
- 78. Investigation : Chronic non-spherocytic intravascular hemolyis P.Smear: Bite cells, blister cells, irregular small cells, Heinz bodies, polychromasia G-6-PD level Treatment: Stop the precipitating drug or treat the infection Acute transfusions if required
- 80. BLISTER CELLS
- 81. HEINZ BODIES
- 82. 2. Pyruvate Kinase Deficiency AR Deficient ATP production, Chronic hemolytic anemia Inv : P.Smear: Prickle cells Decreased enzyme activity Treatment: Transfusion may be required
- 83. PRICKLE CELL
- 84. Intracorpuscular Acquired Hemolytic Anemia Paroxysmal Nocturnal Haemaglobinuria AcquiredchronicHA characterizedby persistentintravascularhemolysissubjectto recurrent exacerbations. Samefrequencyinmenandwomen. TRIAD • Hemolysis • Pancytopenia • Tendencyto venousthrombosis.
- 86. Thenatural historyof PNHcanextendover decades. • Without treatment, the median survivalisestimated to be about 8–10 years; • Mostcommoncauseof death hasbeen § venousthrombosis, § followed by infection secondaryto severeneutropenia & hemorrhage becozof severe thrombocytopenia. • Rarely(estimated 1–2%of all cases),PNHmayterminate in acute myeloidleukemia. • Onthe other hand, full spontaneousrecoveryfrom PNHhasbeen documented,albeit rarely.
- 88. Diagnosis of PNH • Definitive diagnosisof PNH patient’sredcellshaveanincreasedsusceptibility to complement (C), dueto the deficiencyontheir surfaceof proteins (particularly CD59andCD55). • The sucrosehemolysistest isunreliable. • The acidifiedserum(Ham) test is highlyreliable but iscarriedout onlyin a few labs. • Thegoldstandardtodayisflow cytometry,whichcanbecarriedout on granulocytes aswell asonred cells. • Abimodaldistributionof cells,with adiscretepopulationthat isCD59 andCD55negative,isdiagnosticof PNH.
- 90. Management • Mostpatients receive supportivetreatment only. Transfusion Folicacid supplements Iron supplements Regular anticoagulant prophylaxis for those who had venous thrombosis • Long-termglucocorticoidsare not indicated. • Humanizedmonoclonal antibody,eculizumab,whichbindsto the complementcomponentC5. • Definitive curefor PNHisthroughallogeneic BMT.
- 95. MECHANICAL DESTRUCTION ACUTE • Self-inflicted • Prolongedbarefoot ritual dancingor intenseplayingof bongo drums. CHRONIC • Iatrogenic • Prostheticheart valves, especiallywhen paraprosthetic regurgitation ispresent. • Usuallymicroangiopathic hemolytic anemia.
- 99. AUTOIMMUNE HEMOLYTIC ANEMIAS Thesecanarisethroughat leasttwo distinct mechanisms. (1) Thereisa true autoantibody directedagainsta redcell antigen,i.e., a moleculepresentonthe surfaceof redcells. (2) When anantibody directedagainsta certain molecule(e.g., a drug) reactswith that molecule, red cellsmaygetcaughtin the reaction, wherebythey are damagedor destroyed.
- 100. Becausethe antibodiesinvolveddiffer in optimum reactivity temperatures, • They are classifiedin the time-honored categoriesof • “cold”and“warm”. Autoantibody-mediated HAsmaybeseenin • Isolation(when they are calledidiopathic)or • Aspart of a systemicautoimmunedisordersuchassystemiclupus erythematosus.
- 104. • AIHAisa serious condition; without appropriatetreatment, it may havea mortality ofapproximately. • Theonsetisoften abrupt andcanbe dramatic. • Thehemoglobin level candrop, within days,to aslow as4g/dL; • the massivered cellremoval will producejaundice;and • sometimesthe spleenis enlarged. • When thistriad ispresent,the suspicionofAIHAmustbe high.
- 111. PAROXYSMAL COLD HEMOGLOBINURIA • PCHisarather rareformofAIHAoccurring • Mostlyin children, • Usuallytriggeredbyaviral infection, • Self-limited,and • Characterizedbythe involvementof the so-calledDonath-Landsteinerantibody. • Clinicallythe differential diagnosismustincludeother causesof hemoglobinuria, • But the presenceof the Donath-Landsteinerantibodywill provePCH. • Activesupportivetreatment, • Includingbloodtransfusion,isneededto controlthe anemia • subsequently,recoveryisthe rule.
- 112. CAD; Cold Agglutinin Disease Aform of chronicAIHAthat usuallyaffectsthe elderly . First,the term cold refersto the fact that the autoantibodyinvolved reactsstronglyat lower temperatures Theantibody isusually IgM Second,the antibody isproducedbyanexpandedcloneof Blymphocytes, and isa monoclonalgammopathy. Third,becausethe antibody isIgM, CADisrelated to Waldenström’s macroglobulinemia(WM)
- 113. Treatment of CAD • In mild formsof CAD,avoidanceof exposureto cold. • In more severeforms, the managementof CADisnot easy. o Bloodtransfusionisnotveryeffective o Immunosuppressive/cytotoxictreatment with azathioprineorcyclophosphamidecan reduce the antibodytiter, but clinicalefficacyislimited o prednisoneandsplenectomyareineffective. o Plasmaexchangewill removeantibodybut it is laboriousandmustbecarriedout at frequent intervalsif it isto bebeneficial. o Upto 60%of patientsrespond,andremissionsmaybemoredurablewith a rituximab-fludarabine combination.
- 116. References • Harrisons Principle Of Internal Medicine 20th Edition • Williams Hematology 9th edition • Robbins Basic Pathology 10th Edition
- 117. • THANK YOU