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![ Additional test results that are consistent with a specific cause of
hemolytic anemia (e.g., schistocytes or spherocytes on peripheral
blood smear; free hemoglobin or pink serum; newly positive direct
antiglobulin [Coombs] test [DAT]; hemoglobin analysis
demonstrating an abnormal hemoglobin)
These are highly supportive and in some cases diagnostic if
present, but their absence does not exclude the possibility of
hemolysis.](https://image.slidesharecdn.com/hemolyticanemia-anuja-250127044112-303dac42/75/HEMOLYTIC-ANEMIA-including-autoimmine-hemolytic-anemia-pptx-20-2048.jpg)
![2.Infection
F. malaria: intravascular hemolysis: severe called ‘Blackwater fever’
Cl. perfringens septicemia
This is a peripheral blood smear from a patient with severe intravascular hemolysis due to
sepsis with Clostridium perfringens. Neutrophils show toxic changes, including toxic
granulation and vacuoles. There is an increased number of spherocytes (blue arrows) and
polychromatophilic red cells (ie, reticulocytes [red arrow]). The major finding on this slide is
the large number of red blood cell ghosts (black arrows), due to the intravascular lysis of red
cells from the phospholipase and other lytic enzymes elaborated by the clostridial organisms.](https://image.slidesharecdn.com/hemolyticanemia-anuja-250127044112-303dac42/75/HEMOLYTIC-ANEMIA-including-autoimmine-hemolytic-anemia-pptx-57-2048.jpg)
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HEMOLYTIC ANEMIA -including autoimmine hemolytic anemia.pptx
- 1. APPROACH TO HEMOLYTICANEMIA
- 2. NORMAL SCENESCENCE OFRBC As RBCs age clustering of Band 3 protein (+) opsonization phagocytosis by macrophages in spleen and liver (+) Either RBC membrane damage or failure of cation pump IF RBC PRODUCTION = RBC DESTRUCTION COMPENSATED HAEMOLYSIS IF RBC PRODUCTION < RBC DESTRUCTION MANIFEST HAEMOLYTIC ANEMIA
- 3.
- 4. Hemolytic anemiais defined as anemia due to a shortened survival of circulating red blood cells (RBCs) due to their premature destruction. CLASSIFICATION History : Acute / Chronic Cause : Inherited / Acquired Site of destruction : Intravascular / Extravascular Defect : Intra – corpuscular / Extra – corpuscular .
- 5. CAUSES OF HEMOLYTICANEMIAS INTRACORPUSCULAR DEFECTS EXTRACORPUSCULAR FACTORS HEREDITARY HEMOGLOBINOPAGTHIES ENZYMOPATHIES MEMBRANE CYTOSKELETAL DEFECTS Familial HUS ACQUIRED PAROXYSMAL NOCTURNAL HEMOGLOBINURIA MECHANICAL DESTRUCTION (MICROANGIOPATHIC) TOXIC AGENTS DRUGS INFECTIOUS AUTO – IMMUNE
- 6. Extravascular hemolysis Redcell destruction occurs in the reticuloendothelial cell(liver or spleen) Free hemoglobin is not released in the plasma Intravascular hemolysis Free hemoglobin is released in plasma which binds to haptoglobin, an alpha 2 globulin produced by liver, resulting in fall in its levels Once haptoglobin are saturated, free hemoglobin is oxidised to form methemoglobin,which binds to albumin to form methemalbumin If all protective mechanisms are saturated, free hemoglobin may appear in urine(hemoglobinuria)
- 7.
- 9. Compensatory mechanisms to hemolysis: Bone marrow erythroid hyperplasia Reticulocytosis 5-10%- haemoglobinopathies 10-60%-Immune Hemolytic Anemia,Spherocytosis,G 6PD deficiency
- 11. History and physicalexamination A systematic approach, starting with a thorough history and physical examination is the cornerstone of the evaluation. Helpful clues from the history and physical examination include the following, if present: Rapid onset of symptoms of anemia in the absence of bleeding is consistent with brisk hemolysis. Jaundice is consistent with brisk hemolysis that overwhelms the capacity of the reticuloendothelial system to convert heme to storage iron. Dark urine is consistent with intravascular hemolysis.
- 12. Recent bloodtransfusion suggests possible acute hemolytic transfusion reaction; transfusion in the previous four weeks also raises the possibility of a delayed hemolytic transfusion reaction. • Initiation of a new medication with potential for causing hemolysis suggests possible drug-induced etiology(Cephalosporins (a class of antibiotics,Dapsone,Levodopa,Levofloxacin,Methyldopa) History of hemolytic anemia or unexplained anemia in family members suggests an inherited disorder; this is more likely if multiple first degree family members are affected. History of pigmented gallstones or presence of gallstones implies chronic hemolysis that overwhelms the reticuloendothelial system. Splenomegaly suggests expansion of the reticuloendothelial capacity.
- 13. However, theabsence of these features does not eliminate the possibility of hemolytic anemia. Patients with chronic compensated hemolytic anemia may have minimal to no symptoms of anemia, a negative family history, no new drugs, and no evidence of jaundice or splenomegaly.
- 14. Age at onset Whetherpallor developed At birth: hemolytic disease of newborn In 1st few months: thalassemia In childhood: thalassemia intermedia, sickle cell trait In adults: acquired cause of hemolysis Development of pallor Sudden: acute hemolysis(G6PD deficiency) Gradual: chronic hemolysis: Thalassemia
- 15. Jaundice Persistent: mildjaundice in thalassemia/sickle cell anemia Intermittent: hereditary spherocytosis Severe: hepatocellular and obstructive jaundice should be ruled out Duration of disease Acute or chronic Few days- acute hemolytic anemia Few months to years- chronic hemolytic anemia-hemoglobinopathies,AIHA Exposure to chemicals/drugs Exclude history of exposure to Chemicals like naphthalene,oxidising chemicals Drugs like primaquine,chloroquine,nitrofurantoin, which may induce hemolysis in G6PD deficient individual
- 16. Infection, fever Clostridiumwelchii infection P.falciparum infection Colour of urine Red coloured urine or cola coloured urine in morning hours-s/o PNH High coloured urine- s/o hemolytic process (increased urinary urobilinogen) Dark coloured urine – falciparum malaria (backwater fever) Colour of stool High coloured stool – increased stercobilinogen in hemolytic anemia Clay coloured stool – obstructive jaundice
- 17. Family history History of similar disease in family members should be excluded H.spherocytosis-AD Thalassemia-AR Sickle cell disorder-AR Other hemoglobinopathies-AR G6PD deficiency- sex linked, sufferers are males.
- 18. Triad of hemolyticanemia Norm macrocytic anemia Reticulocytosis Hyperbilirubinemia
- 19. Laboratory confirmation ofhemolysis There is no single specific diagnostic test for hemolytic anemia. However, most experts consider the diagnosis to be accepted if there are a majority of the following findings: Anemia that is not due to another obvious cause. Increased reticulocyte count that is not explained by accelerated RBC production due to recent bleeding; repletion of iron, vitamin B12, folate, or copper; or administration of erythropoietin. Signs of RBC destruction such as increased lactate dehydrogenase (LDH), low haptoglobin, increased unconjugated bilirubin.
- 20. Additional testresults that are consistent with a specific cause of hemolytic anemia (e.g., schistocytes or spherocytes on peripheral blood smear; free hemoglobin or pink serum; newly positive direct antiglobulin [Coombs] test [DAT]; hemoglobin analysis demonstrating an abnormal hemoglobin) These are highly supportive and in some cases diagnostic if present, but their absence does not exclude the possibility of hemolysis.
- 21. 1) Hereditary Spherocytosis Usuallyinherited as AD disorder Hematologic findings PS-Spherocytosis Reticulocytosis Decreased Hb Decreased MCV,high MCHC High S.bilirubin,urine urobilinogen Bone Marrow-Erythroid hyperplasia Red Cell Membrane Defects
- 22. Low S.haptoglobin Osmotic fragility test-shift to right Flow cytometry based on Epithelial membrane antigen,Eosin 5 maliemide is a sensitive test • Peripheral blood smear shows multiple spherocytes, which are small, dark, dense hyperchromic red cells without central pallor (arrows). • These findings are compatible with hereditary spherocytosis or autoimmune hemolytic anemia.
- 23. 2.Hereditary Elliptocytosis ● AD/ AR Peripheral blood smear from a patient with hereditary elliptocytosis shows multiple elliptocytes. RX-Transfusion,splenectomy
- 24. Red Cell Enzymopathies 1. Glucose-6-Phosphate Dehydrogenase ( G6PD ) Deficiency ● Protection against Malaria ● X-linked ● Ppted by:fava beans,drugs(antimalarials,sulfa drugs,niftrancotrimoxasole,analgesics,dapsone),infections ●Inv: ● e/o non-spherocytic intravascular hemolysis>extravascular ● P. Smear: Bite cells, blister cells, irregular small cells, Heinz bodies(oxidized denatured hb clumps), polychromasia ● G-6-PD level Quantitative G6PD assay DNA analysis by PCR
- 25. GLYCOLYSIS & HMPSHUNT PATHWAY IN RBC METABOLISM
- 26. GLYCOLYSIS PATHWAY MakesATP needed for cation transport and membrane maintenance Makes NADH which keeps Fe in reduced state HMP SHUNT PATHWAY Makes NADPH that provides reduced Glutathione which protects RBCs against oxidative stress
- 27. Examples of abite cell (thick arrow) and blister cells (arrows) in a patient with G6PD deficiency.
- 28. Treatment Avoid drugs Vit E,FOLATE If AKI-HD
- 29. 2. Pyruvate KinaseDeficiency ● AR ● Inv: P. Smear: Prickle cells Quantitative assay of Pyruvate Kinase enzyme Rx-supportive,folate,splenectomy-severe,gene transfer,BMT
- 30. Hemoglobinopathies… 1) Thalassemia AR Thalassemic syndromes are classified into 3 types: A.Beta thalassemia Reduced synthesis of beta chain of globin B.Alpha thalassemia Reduced synthesis of alpha chain C.Misc.thalassemic syndromes Multiple combination of beta, alpha gene with other structurally abnormal haemoglobin like HbD,HbS,HbE
- 31. Anaemia DecreasedMCV,MCHC,MCH PS- anisopoikilocytosis with microcytic hypochromic blood picture Bone Marrow- hypercellular bone marrow showing marked erythroid hyperplasia with reversal of Myeloid:Erythroid ratio HbF level is high High performance liquid chromatography RX-Transfusion,iron chelation,folate,hydroxyurea
- 32. Peripheral smear froma patient with beta thalassemia intermedia post splenectomy. This field shows target cells, hypochromic cells, microcytic cells, red cell fragments, red cells with bizarre shapes, and a single nucleated red cell (arrow).
- 33. 2)Sickle cell anaemia Characterised by presence of HbS sickle haemoglobin which imparts sickle shape to red cells in state of reduced oxygen tension PS – anisopoikilocytosis, target cells and sickle cells Bone Marrow- hypercellular with erythroid hyperplasia demonstrating normoblastic reaction Diagnosis is confirmed by presence of HbS Hb electrophoresis This smear shows multiple sickle cells (arrows). There are also findings consistent with functional asplenia, including a nucleated red blood cell (upper left), a red blood cell containing a Howell-Jolly body (arrowhead), and target cells (dashed arrow).
- 35. TREATMENT FOLATE HYDROXYUREA L-GLUTAMINE VOXELOTAR-INCREASE AFFINITY OF HB FOR O2 CRIZANLIZUMAB-P SELECTIN BLOCKING MAB CHROMOSOME 11 GAMMA-BETA SWITCH INHIBITORS HSCT-<16 YRS
- 36. Paroxysmal nocturnal haemoglobinuria Acquired clonal haematopoietic stem cell disorder PIGA gene mutation Intravascular hemolysis is the characteristic feature CLINICAL FEATURE Hemolysis-periodic dark urine Venous thrombosis Pancytopenia Diagnostic test Peripheral blood Flow cytometry-detection of GP1 anchored CD59 proteins on RBC & WBC f/o hemolytic (intravascular),PS-shistocytes,pancytopenia RX:Transfusion,steroids,eculizumab,HSCT
- 37. IMMUNE HEMOLYTIC ANEMIAS Acute / chronic , Acquired, extra corpuscular, extravascular destruction Mechanisms : 1. INNOCENT BYSTANDER EFFECT : RBCs are damaged as a bystanders in Ag – Ab reaction 2. Auto Ab directed against RBCs antigens (m/c)
- 38. AUTO – IMMUNEHEMOLYTIC ANEMIAS DEPENDING ON THE THERMAL AMPLITUDE OF AUTO – ANTIBODIES : 1. Warm AIHA (AIHA) 2. Cold AIHA (Cold agglutinin Disease,PCH)
- 40. WARM AIHA Incidence: 1 – 3 / 1 lakh /year Prevalence : 17 / 1 lakh EVEN WITH APPROPRIATE MANAGEMENT : 5 – 10 % MORTALITY Autoantibody reacts best at 37 C It is usually Rhesus specific antibody – C/c/D/E/e ( sometimes specifically Anti – e )
- 41.
- 42.
- 43. TREATMENT RBC TRANSFUSION: If anemia is life threatening ABO matched least incompatible blood Transfused RBCs will be destroyed , but not more than the patient’s own RBCs STEROIDS : 1 st line of treatment – for atleast 2 weeks till Hb >12 g/dL Starting dose - 1 – 1.5 mg / kg /day Then taper 20 mg every weekly till daily dose 20 mg / day Later on , slow taper over 8 weeks
- 44. Role of RITUXIMABin warm AIHA Preferred 2nd line of Rx RCT of (steroids alone) vs (steroids+Rituximab) 1 yr CR rates : 36% vs 75% 3 year relapse – free survival : 45% vs 70% Dose : 375 mg /sq mt / week X 4 weeks 100mg / weekly X 4 weeks
- 45. PAROXYSMAL COLD HEMOGLOBINURIA Rareform of AIHA seen in male children Triggered by viral infection Previously seen in adults : Tertiary syphilis Polyclonal IgG targets : “P” Ag Ab : DONATH LANDSTEINER ANTIBODY INTRAVASCULAR HEMOLYSIS PCH (vs CAD)does not involve IgM Ab & lacks PS findings like RBC agglutination Characteritic PS finding : ERYTHROPHAGOCYTOSIS
- 46.
- 47. Ig GAb against : Anti P antibody Binds to RBC only at a low temperatures (optimally at 4 C) RBC lysis occurs when the temperature is shifted to 37 C RBC lysis occurs in the presence of complement activation In – vivo hemolysis leading to hemoglobinuria TREATMENT : Supportive care with blood transfusion (Recovery is the rule)
- 48. COLD AGGLUTININ DISEASE 1.Chronic and Indolent 2. Auto – Ab reacts strongly with RBCs at lower temperatures 3. Ab is produced by a clone of auto-reactive B – Lymphocytes IgM Ab ƙ , hence CAD is a form of IgM monoclonal gammopathy Not MYD88 mutation(Waldenström macroglobulinemia), but KMT2D mutation in CAD intravascular + extravascular hemolysis) 4. Unlike in AIHA , no predominance of spleen in RBC lysis Liver (max. complement is present in liver) 5. DCT : IgM Typically positive for C3
- 49. Causes of CAD PRIMARY / IDIOPATHIC CAD (m/c) Secondary Monoclonal CAD : B – cell neoplasms : WM, CLL, MM Non – hematologic neoplasms Secondary Polyclonal CAD : Mycoplasma infection : M.pneumoniae Viral : EBV/CMV, mumps, varicella, rubella, adeno, HIV, HCV, Influenza Bacterial : Legionella, syphilis, Listeria Parasitic : Malaria, Trypanosomiasis
- 50. CLINICAL FEATURES OFCAD Acrocyanosis (painful & purple toes/ fingers) Chronic fatigue (Anemia) Hemoglobinuria (prolonged exposure to cold) LNP / Fever (secondary CAD) Respiratory symptoms (secondary CAD) Livedo Reticularis Blood will be agglutinated while collecting the sample itself
- 51. Work Up forCAD CBC : URE , LDH, Bilirubin , Haptoglobin DAT : at 35 – 37 C with polyspecific and monospecific sera) Imaging : CXR / CT SPEP, SIFE, SFLC Cold agglutinin titers (>1 :64) is abnormal Infectious disease testing Collagen vascular disease testing BM study : if malignancy is suspected
- 52. TREATMENT AVOIDANCE OFCOLD : adequate clothing, avoid icy drinks, cold showers etc… HOSPITALIZED : application of body warming blankets, pre – warming of IV fluids & blood products CLONAL B LYMPHOCYTOSIS : 1. Rituximab : 50% ORR, 5%CRs, median DOR : 7 – 11 months 2. Bendamustine + Rituximab : 70 – 80 % RR or 40 – 50 % CRs, median DOR : NR after 88 months 3. Fludarabine + Rituximab : 70 % ORR, 20 % CRs , but toxicity 4. BTK inhibitors : Ibrutinib 5. Proteasome Inhibitor : Bortezomib Complement mediated hemolysis : ECULIZUMAB (Anti – C5 Antibody), Sutimlimab (Anti - C1s antibody)
- 53. Algorithm of CADmanagement
- 54. Non-Immune Acquired HemolyticAnemia Mechanical Trauma A) Mechanical heart valves, Arterial grafts: cause shear stress damage B) March hemoglobinuria: Red cell damage in capillaries of feet C) Thermal injury: burns D) Microangiopathic hemolytic anemia (MAHA): by passage of RBC through fibrin strands deposited in small vessels disruption of RBC eg: DIC,PIH, Malignant HTN,TTP,HUS
- 55. Microangiopathic haemolytic anaemia Characterisedby Hemolytic anemia due to red cell fragmentation Small vessel disease with thrombotic lesions Causes Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Metastatic mucin producing adenocarcinoma Pre-eclampsia Haemolysis with elevated liver function test and low platelet DIC
- 56. Schistocytes arehallmark of diagnosis in this group of haemolytic anaemia
- 57. 2.Infection F. malaria:intravascular hemolysis: severe called ‘Blackwater fever’ Cl. perfringens septicemia This is a peripheral blood smear from a patient with severe intravascular hemolysis due to sepsis with Clostridium perfringens. Neutrophils show toxic changes, including toxic granulation and vacuoles. There is an increased number of spherocytes (blue arrows) and polychromatophilic red cells (ie, reticulocytes [red arrow]). The major finding on this slide is the large number of red blood cell ghosts (black arrows), due to the intravascular lysis of red cells from the phospholipase and other lytic enzymes elaborated by the clostridial organisms.
- 58. 3.Chemical/Drugs: Oxidant denaturation ofhemoglobin Eg: Dapsone, sulphasalazine, Arsenic gas, Cu, Nitrates & Nitrobenzene
- 60.