hemolytic anemia (cell membrane defect)

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hemolytic anemia (cell membrane defect)

  1. 1. Hemolytic AnemiaDr. Rafi Ahmed GhoriFCPSProfessor MedicineLiaquat University of Medical & Health Sciences,Jamshoro
  2. 2. Classification of HemolyticAnemias1. Abnormalities of RBC interior1. Enzyme defects.2. Hemoglobinopathies2. RBC membrane abnormalities1. Hereditary spherocytosis etc.2. Paroxysmal nocturnal hemoglobinuria.3. Spur cell anemia.3. Extrinsic factor1. Hypersplenism.2. Antibody: immune hemolysis.3. Microangiopathic hemolysis.4. Infections, toxins, etc.IntracorpuscularExtracorpuscularHereditaryAcquired{{}}
  3. 3. Red Cell Membrane DisordersUsually detected by morphologicabnormalities of RBC on blood film.Three types of inherited RBC membraneabnormalities– Hereditary sphercytosis.– Hereditary elliptocytosis (including hereditarypyropoikilocytosis).– Hereditary stomatocytosis.
  4. 4. Red cell membrane has a lipid bilayer to which a‘skeleton’ of filamentous proteins is attached viaspecial linkage proteins.
  5. 5. RED CELL CYTOSKELETON
  6. 6. HEREDITARYSPHEROCYTOSIS Defective or absent spectrin molecule Leads to loss of RBC membrane, leading tospherocytosis Decreased deformability of cell Increased osmotic fragility Extravascular hemolysis in spleen
  7. 7. SPLENIC ARCHITECTURE
  8. 8. HEREDITARYSPHEROCYTOSISOsmotic Fragility0204060801000.3 0.4 0.5 0.6NaCl (% of normal saline)%HemolysisNormal HS
  9. 9. Hereditary SpherocytosisUsually has an autosomal dominantinheritance pattern and incidence ofapproximately 1:1000 to 1:4500.In ~20% patients, the absence ofhematologic abnormalities in familymembers suggests either autosomalrecessive inheritance or spontaneousmutation.
  10. 10. Hereditary SpherocytosisSometimes clinically apparent in earlyinfancy but often escapes detection untiladult life.
  11. 11. Hereditary SpherocytosisClinical Manifestations– Anemia.– Splenomegaly.– Jaundice.
  12. 12. Hereditary SpherocytosisClinical Manifestations– Prominent jaundice accounts for disorder’sprior designation as “congenital hemolyticjaundice” and is due to an increasedconcentration of unconjugated (indirect-reacting) bilirubin in plasma.
  13. 13. Hereditary SpherocytosisClinical Manifestations– Jaundice may be intermittent and tends to be lesspronounced in early childhood.– Due to increased bile pigment production,pigmented gallstones are common, even inchildhood.– Clinical course may be complicated by crisisHemolytic crisis (infection).Megaloblastic crisis (folate deficiency, especially inpregnancy).Aplastic crisis (parvovirus infection).
  14. 14. Hereditary SpherocytosisDiagnosis– Must be distinguished primarily from thespherocytic hemolytic anemias associated withRBC antibodies.– If present, family history of anemia and/orsplenectomy.– Immune spherocytosis  positive directCoombs test.
  15. 15. Hereditary SpherocytosisDiagnosis– Splenomegaly can also be seenCirrhosis.Clostridial infections.G6PD deficiency.
  16. 16. Hereditary SpherocytosisTreatment– Splenectomy reliably corrects the anemia.– Splenectomy in children should be postponeduntil the age of 4-years.– Polyvalent pneumococcal vaccine should beadministered at least 2-weeks beforesplenectomy.– In patients with severe hemolysis  folic acid(5-mg/d) should be administeredprophylactically.
  17. 17. Hereditary SpherocytosisTreatment– Acute, severe hemolytic crises requirestransfusion.
  18. 18. Hereditary ElliptocytosisHeterogeneous disorders in elliptocytic redcells.Functional abnormality of anchor proteinsin red cell membrane (alpha spectrin orprotein 4.1).Autosomal dominant or recessive.Less common than hereditary spherocytosis(1/10,000).
  19. 19. Red cell membrane has a lipid bilayer to which a‘skeleton’ of filamentous proteins is attached viaspecial linkage proteins.
  20. 20. Hereditary ElliptocytosisClinical presentation depends upon degreeof membrane defect.Asymptomatic diagnosed on blood film.Chronic compensated hemolytic state.
  21. 21. Hereditary ElliptocytosisTreatment– Same as hereditary spherocytosis only inchronic hemolytic anemia.Differential diagnosis includes– Iron deficiency anemia– Thalassaemia.– Mylofibrosis.– Mylodysplasia.– Pyruvate kinase deficiency.
  22. 22. Paroxysmal NocturnalHemoglobinuria Clonal cell disorder Ongoing Intra- & Extravascular hemolysis; classicallyat night Testing– Acid hemolysis (Ham test)– Sucrose hemolysis– CD-59 negative (Product of PIG-A gene) Acquired deficit of GPI-Associated proteins(including Decay Activating Factor)
  23. 23. GPI BRIDGE
  24. 24. Paroxysmal NocturnalHemoglobinuriaGPI Proteins GPI links a series of proteins to outer leaf of cellmembrane via phosphatidyl inositol bridge, withmembrane anchor via diacylglycerol bridge PIG-A gene, on X-chromosome, codes for synthesisof this bridge; multiple defects known to cause lackof this bridge Absence of decay accelerating factor leads to failureto inactivate complement & thereby to increased celllysis
  25. 25. HEMOLYTIC ANEMIAMembrane abnormalities -Enzymopathies Deficiencies in Hexose MonophosphateShunt– Glucose 6-Phosphate Dehydrogenase Deficiency Deficiencies in the EM Pathway– Pyruvate Kinase Deficiency
  26. 26. G6PD DEFICIENCYFunction of G6PDG6PDGSSG 2 GSHNADPH NADP2 H2O H2O26-PG G6PHgbSulf-HgbHeinz bodiesHemolysisInfectionsDrugs
  27. 27. Glucose 6-PhosphateDehydrogenaseFunctions Regenerates NADPH, allowing regeneration ofglutathione Protects against oxidative stress Lack of G6PD leads to hemolysis during oxidativestress– Infection– Medications– Fava beans Oxidative stress leads to Heinz body formation, extravascular hemolysis
  28. 28. Glucose 6-PhosphateDehydrogenaseDifferent Isozymes00.20.40.60.810 20 40 60 80 100 120RBC Age (Days)G6PDActivity(%)Normal (GdB) Black Variant (GdA-)Mediterranean (Gd Med)Level needed for protection vs ordinary oxidative stress
  29. 29. HEMOLYTIC ANEMIACauses INTRACORPUSCULAR HEMOLYSIS– Membrane Abnormalities– Metabolic Abnormalities– Hemoglobinopathies EXTRACORPUSCULAR HEMOLYSIS– Nonimmune– Immune
  30. 30. EXTRACORPUSCULARHEMOLYSISNonimmune Mechanical Infectious Chemical Thermal Osmotic
  31. 31. Microangiopathic HemolyticAnemiaCauses Vascular abnormalities– Thrombotic thrombocytopenic purpura– Renal lesions Malignant hypertension Glomerulonephritis Preeclampsia Transplant rejection– Vasculitis Polyarteritis nodosa Rocky mountain spotted fever Wegener’s granulomatosis
  32. 32. Microangiopathic HemolyticAnemiaCauses - #2– Vascular abnormalities AV Fistula Cavernous hemangioma Intravascular coagulation predominant– Abruptio placentae– Disseminated intravascular coagulation
  33. 33. IMMUNE HEMOLYTIC ANEMIAGeneral Principles All require antigen-antibody reactions Types of reactions dependent on:– Class of Antibody– Number & Spacing of antigenic sites on cell– Availability of complement– Environmental Temperature– Functional status of reticuloendothelial system Manifestations– Intravascular hemolysis– Extravascular hemolysis
  34. 34. IMMUNE HEMOLYTIC ANEMIAGeneral Principles - 2 Antibodies combine with RBC, & either1. Activate complement cascade, &/or2. Opsonize RBC for immune system If 1, if all of complement cascade is fixed to red cell,intravascular cell lysis occurs If 2, &/or if complement is only partially fixed,macrophages recognize Fc receptor of Ig &/or C3bof complement & phagocytize RBC, causingextravascular RBC destruction
  35. 35. IMMUNE HEMOLYTICANEMIACoombs Test - Direct Looks for immunoglobulin &/or complement ofsurface of red blood cell (normally neither found onRBC surface) Coombs reagent - combination of anti-humanimmunoglobulin & anti-human complement Mixed with patient’s red cells; if immunoglobulin orcomplement are on surface, Coombs reagent will linkcells together and cause agglutination of RBCs
  36. 36. IMMUNE HEMOLYTICANEMIACoombs Test - Indirect Looks for anti-red blood cell antibodies in thepatient’s serum, using a panel of red cells withknown surface antigens Combine patient’s serum with cells from a panelof RBC’s with known antigens Add Coombs’ reagent to this mixture If anti-RBC antigens are in serum, agglutinationoccurs
  37. 37. HEMOLYTIC ANEMIA -IMMUNE Drug-Related Hemolysis Alloimmune Hemolysis– Hemolytic Transfusion Reaction– Hemolytic Disease of the Newborn Autoimmune Hemolysis– Warm autoimmune hemolysis– Cold autoimmune hemolysis
  38. 38. IMMUNE HEMOLYSISDrug-Related Immune Complex Mechanism– Quinidine, Quinine, Isoniazid “Haptenic” Immune Mechanism– Penicillins, Cephalosporins True Autoimmune Mechanism– Methyldopa, L-DOPA, Procaineamide, Ibuprofen
  39. 39. DRUG-INDUCEDHEMOLYSISImmune Complex Mechanism Drug & antibody bind in the plasma Immune complexes either– Activate complement in the plasma, or– Sit on red blood cell Antigen-antibody complex recognized by RE system Red cells lysed as “innocent bystander” of destructionof immune complex REQUIRES DRUG IN SYSTEM
  40. 40. DRUG-INDUCEDHEMOLYSISHaptenic Mechanism Drug binds to & reacts with red cell surfaceproteins Antibodies recognize altered protein, ± drug,as foreign Antibodies bind to altered protein & initiateprocess leading to hemolysis
  41. 41. DRUG-INDUCEDHEMOLYSISTrue Autoantibody Formation Certain drugs appear to cause antibodiesthat react with antigens normally found onRBC surface, and do so even in the absenceof the drug
  42. 42. ALLOIMUNE HEMOLYSISHemolytic Transfusion Reaction Caused by recognition of foreign antigens on transfusedblood cells Several types– Immediate Intravascular Hemolysis (Minutes) - Due to preformedantibodies; life-threatening– Slow extravascular hemolysis (Days) - Usually due to repeatexposure to a foreign antigen to which there was a previousexposure; usually only mild symptoms– Delayed sensitization - (Weeks) - Usually due to 1st exposure toforeign antigen; asymptomatic
  43. 43. INCOMPATIBLE RBCTRANSFUSIONRate of Hemolysis0204060801000 1 2 3 4 5 6 7Weeks Post-TransfusionSurvivingCells(%)Normal Immediate Intravascular HemolysisSlow Extravascular Hemolysis Delayed Extravascular Hemolysis
  44. 44. ALLOIMMUNE HEMOLYSISTesting Pre-transfusion ABO & Rh Type of both donor & recipient Antibody Screen of Donor & Recipient,including indirect Coombs Major cross-match by same procedure(recipient serum & donor red cells)
  45. 45. ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn Due to incompatibility between mother negative foran antigen & fetus/father positive for that antigen.Rh incompatibility, ABO incompatibility mostcommon causes Usually occurs with 2nd or later pregnancies Requires maternal IgG antibodies vs. RBC antigensin fetus
  46. 46. ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn -#2 Can cause severe anemia in fetus, witherythroblastosis and heart failure Hyperbilirubinemia can lead to severe brain damage(kernicterus) if not promptly treated HDN due to Rh incompatibility can be almost totallyprevented by administration of anti-Rh D to Rhnegative mothers after each pregnancy
  47. 47. AUTOIMMUNE HEMOLYSIS Due to formation of autoantibodies thatattack patient’s own RBC’s Type characterized by ability ofautoantibodies to fix complement & site ofRBC destruction Often associated with eitherlymphoproliferative disease or collagenvascular disease
  48. 48. AUTOIMMUNE HEMOLYSISWarm Type Usually IgG antibodies Fix complement only to level of C3,if at all Immunoglobulin binding occurs at all temps Fc receptors/C3b recognized by macrophages;  Hemolysis primarily extravascular 70% associated with other illnesses Responsive to steroids/splenectomy
  49. 49. AUTOIMMUNE HEMOLYSISCold Type Most commonly IgM mediated Antibodies bind best at 30º or lower Fix entire complement cascade Leads to formation of membrane attack complex,which leads to RBC lysis in vasculature Typically only complement found on cells 90% associated with other illnesses Poorly responsive to steroids, splenectomy;responsive to plasmapheresis
  50. 50. HEMOLYTIC ANEMIASummary Myriad causes of increased RBC destruction Marrow function usually normal Often requires extra folic acid to maintainhematopoiesis Anything that turns off the bone marrow canresult in acute, life-threatening anemia

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