Extracorpuscular hemolytic anemia

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  • 1. APPROACH TO A CASE OFEXTRACORPUSCULAR HEMOLYTICANEMIADr. Adrija Pathak

2. A.IMMUNE HEMOLYTIC ANEMIA1.AUTOIMMUNE HEMOLYTIC ANEMIAWarm antibodiesCold anti bodies2.ALLOIMMMUNE HEMOLYTICANEMIAHemolytic disease of newbornIncompatible blood transfusion3. DRUG INDUCEDB.NONIMMUNE HEMOLYTIC ANEMIAMicroangiopathic hemolytic anemias(DIC,TTP,HUS)Trauma:prosthetic cardiac valve, thermal,exerciseInfection: malaria, babesiaChemical and drugsAnimal venomsMalignant hypertensionPlasma lipid abnormalitiesHypersplenismEXTRA CORPUSCULAR DEFECT 3. HOW IS HEMOLYTIC ANEMIA DIAGNOSED?Two main principles One is to confirm that it is hemolysis Identify general diagnostic findings ofhemolytic anemia Two is to determine the etiologya. Hereditary anemias ( defects within RBC )b. Acquired anemias ( external causes ) 4. CLINICAL MANIFESTATIONS Compensated or Symptomatic anemia Weakness, dizziness Fever, weight loss, fatigue Pallor Jaundice Dark urine Gall stone Splenomegaly Thinning of cortical bone Extramedullary hematopoetic masses 5. Increased Bone Marrow Productionof ErythrocytesIncreased Erythrocyte destructionCOMMON LABORATORY FINDINGS IN HEMOLYTIC ANAEMIAReticulocytosis (RPI >2) anemiaIncreased IRF Presence of spherocytes , schistocytesand/or other poililocytesNucleated erythrocytes in peripheralbloodhaptoglobulin & hemopexin &glycosalated HbPolychromaisa of erythrocytes onromanowsky stained blood smearsbilirubin ( unconjugated)fecal & urine urobilinogenLeucocytosis Hemoglbinemia, Hemoglobinuria,Hemosiderinuria, MethhemoglobinemiaNormoblastic erythroid hyperplasia inbone marrowserum LD & expired COpositive DAT 6. EVALUATION OF ANEMIALow Hgb/HctCorr. ReticCt >2%Corr. ReticCt 100MCV 80-100MCV 2% if no blood loss Indicates hemolysis) 8. Reticulocyte production index(RPI) =corrected reticulocytecount/reticulocyte maturation time(days)Hct Maturation time (days).35 1.5.25 2.15 2.5>2RPI appropriate bone marrow responseEg -Retic count: 10%Pts Hct 29Corrected retic 7.73 Immature reticulocyte fraction(IRF)- some automated instrumentassess the maturity of reticulocyte by intensity of staining 9. ROLE OF PBSHemolytic Anemia (CRC>2% + no blood loss)1 SickledcellsBitecellsSchisto-cytesAcantho-cytesSphero-cytesTargetcellsparasiteinclusionsDAT(+)DAT(-)Hgb electro-phoresisG6PDlevelPT/PTTCreaplateletsAuto-ImmuneHemo-lyticAnemiaHeredi-tarySphero-cytosisSickleCellDsG6PDDeficientVsUnstableHgbsThalas-semiasHemo-globino-pathyLiver DsLiverDsMalariaBabe-siosisBarto-nellaTTP-HUSDICProsthe-ticValveMalignantHTN 10. Finding on pbs Type of aquired hemolytic anemia suggestedSchistocytes Fragmentation syndromes including microangiopathichaemolytic anaemiaSpherocytes Autoimmune, alloimmune or drug-induced immunehaemolytic anaemia, paroxysmal cold haemoglobinuria,burns, Clostridium perfringens sepsisa and mechanicalhaemolytic anaemiaMicrospherocytes Burns, fragmentation syndromesIrregularly contractedcellsOxidant damage, Zieves syndromeGhost cells, suspicionof Heinz bodiesAcute oxidant damageMarked red cellagglutinationCold-antibody-induced haemolytic anaemiaErythrophagocytosis Paroxysmal cold haemoglobinuria 11. Hypochromia,microcytosis andbasophilic stipplingLead poisoningAtypical lymphocytes Cold-antibody-induced haemolytic anaemiaassociated with infectious mononucleosis or, lessoften, other infectionsThrombocytopenia Autoimmune haemolytic anaemia (Evans syndrome),thrombotic thrombocytopenic purpura,microangiopathic haemolytic anaemia associated withdisseminated intravascular coagulation, paroxysmalnocturnal haemoglobinuriaNeutropenia Paroxysmal cold haemoglobinuria 12. Intravascular HemolysisRBC LYSISHBG in plasmaHAPTOGLOBINREMOVED BY LIVERHEMOGLOBINEMIAHEMOGLOBINURIAHBG TAKEN UP BY RENALTUBULAR CELLSHEMOSIDERINCELLS SLOUGHED INURINE 1 WEEK LATER 13. Features specific to intravascularhaemolysis: Absent haptoglobin and haemopexin Haemoglobinaemia Haemoglobinuria. Methaemoglobinaemia. Methemalbumin which is not excretedin urine but circulates in blood detectedby Schumms test Haemosiderinuria. LDH 14. Extravascular HemolysisDestruction of red cells byreticuloendothelial cells in theliver, spleen, and bonemarrowSignificant lab finding:Inc in expired carbonmonoxideCarboxyhemoglobinUnconjugated bilirubinUrine and fecal urobilinogenDec haptoglobin in severehemolysis 15. Intravascular hemolysis Extravascular hemolysis Activation ofcomplement- PNH,PCH, transfusion rxn MAHA Physical/ mechanicaltrauma Toxicmicroenvironment Hemoglobinopathies Enzymopathies Membrane defects Megaloblastic anemia AIHA Drug induced 16. WHAT IS THE PRECISE DIAGNOSIS?1.If a hereditary haemolytic anaemia is suspected: Osmotic-fragility glucose-6-phosphate dehydrogenase (G6PD)assay electrophoresis or high-performance liquidchromatography for abnormal Hb; tests for sickling; Examination of the proteins of the red cellmembrane and cytoskeleton (e.g. spectrin) by gelelectrophoresis and by specific radioimmunoassay. 17. 2.If acquired haemolytic anaemia is suspected: Direct antiglobulin test tests for autoantibodies in the patients serum titration of cold agglutinins DonathLandsteiner test demonstration of thermal range of autoantibodies tests for agglutination and/or lysis of enzyme-treatedcells by autoantibodies history of autoimmune disease, recent blood transfusion, recentinfection, exposure to drugs or toxins the presence of a cardiac prosthesis and risk of malaria. Previous clinical history and laboratory results will help to establishthat the disorder is acquired. 18. 3.If the haemolytic anaemia is suspected of being drug induced:Screening test for red cell G6PD; glutathione stability test;staining for Heinz bodies; identification of methaemoglobin (Hi)and sulphaemoglobin (SHb); tests for drug-dependentantibodies.4.If mechanical stress is suspected: Red cell morphology; platelet count; renal function tests;coagulation screen; fibrinogen assay; test for fibrinogen/fibrindegradation products5.In obscure cases: Investigations for paroxysmal nocturnal haemoglobinuria (PNH)(e.g. acidified serum test [Hams test], sucrose lysis test, flowcytometric immunophenotyping for erythrocyte and neutrophilantigens) Measurement of lifespan of patients red cells If splenectomy is contemplated, determination of sites ofhaemolysis by radionuclide imaging 19. IMMUNE HEMOLYTIC ANEMIA Immune Hemolysis is mediated by the antibodiesand/or complement that bind to the RBC surfaceand initiate destruction RBC destruction may be intravascular orextravascular Classified as autoimmune, alloimmune, druginduced 20. SCHEME FOR SEROLOGICAL INVESTIGATION OF HAEMOLYTICANAEMIA SUSPECTED TO BE OF IMMUNOLOGICAL ORIGIN Are the patients red cells coated by immunoglobulins orcomplement (indicating an antigenantibody reaction)?Perform a DAT using a polyspecific broad-spectrum reagent,which contains both anti-IgG and anti-C. (If the DAT is negative, itis unlikely, although not impossible, that the diagnosis is AIHA.) If the DAT is positive, are immunoglobulins or complementadsorbed to the red cells?Repeat the DAT using monospecific sera (i.e. anti-IgG and anti-C3d). If immunoglobulins are present on the red cells, is thereantibody specificity?Prepare eluates from the patients red cells. Test these later 21. What is the patients blood group?Determine the patients ABO and RhD and Kell type.The Rh phenotype is particularly important in warm-typeAIHA; other antigens must be determined ifalloantibodies are to be differentiated fromautoantibodies Is there free antibody in the serum? Is there anyunderlying alloantibody present?Screen the serum with two or three red cellsuspensions suitable for routine pretransfusionantibody screening looking for agglutination and lysis at37C by the IAT. If positive, identify the antibody usingan antibody identification panel. If an alloantibody is identified, blood lacking thecorresponding antigen must be selected for transfusion. 22. If the autoantibody is pan-reacting antibody adsorptiontests are needed to remove the autoantibody so as toidentify any underlying alloantibody. If there is a warm/cold autoantibody, what is thespecificity of the autoantibody? Test the serum also at 20C against antibody-screeningcells to show whether cold or warm antibodies or a mixtureof the two, are present in the serum. Test the eluate against the antibody identification panel ofred cells by IAT. Titration of autoantibody may be useful in the presence ofa strong alloantibody. 23. If there is a cold antibody:a. Has the antibody any specificityb. What is the titre/thermal range of the antibody? Test the serum/plasma against a panel of O cells, O cordcells and patients own cells at 20C. If an autoantibody is found, titrate at 4C with ABO-compatibleadult (I) cells, cord blood (i) cells and thepatients cells Determine the highest temperature at whichautoagglutination of the patients whole blood takes place If PCH is suspected, carry out the direct and two-stageindirect DonathLandsteiner tests 24. Is a drug suspected as the cause of the haemolyticanaemia? If haemolysis induced by drugs is suspected, add the drugin solution to a mixture of the patients serum, normal cellsand fresh normal serum. Look for agglutination of normaland enzyme-treated cells and use the IAT. Are there any other serological abnormalities?Consider carrying out the following tests: serum proteinelectrophoresis and quantitative estimation ofimmunoglobulins, estimation of complement, tests forantinuclear factor, a screening test for heterophileantibodies (infectious mononucleosis screening test) and atest for mycoplasma antibodies. 25. AIHA CLASSIFICATIONWarm autoimmune hemolytic anemia Idiopathic, Secondary (Lymphoproliferative disorders, autoimmune diseases-SLE,RA,viral, neoplastic) Cold autoimmune hemolytic anemia Cold agglutinin syndrome (Idiopathic, Secondary- mycoplasma, infectious mono, LPD) Paroxysmal cold hemoglobinuria (Idiopathic, Se